Sie sind auf Seite 1von 324
Med Clin N Am 88 (2004) xv–xvi
Med Clin N Am 88 (2004) xv–xvi

Preface

Type 2 Diabetes Mellitus

N Am 88 (2004) xv–xvi Preface Type 2 Diabetes Mellitus Alan J. Garber, MD, PhD Guest

Alan J. Garber, MD, PhD Guest Editor

Diabetes has become a plague upon modern America. It is the most ex- pensive chronic illness in the country and has become a scourge of multiple inpatient medical and surgical services. Indeed, diabetes is the fourth most common comorbid condition in hospitals and accounts for prolonged lengths of stay and excess costs for virtually one quarter of all hospital admissions in the United States. More importantly, however, is the bur- geoning number of diabetic patients. Each year, approximately 1 million new cases of type 2 diabetes are diagnosed, and even type 1 diabetes appears to be increasing in incidence in the United States. Because of our ability to reduce or prevent the costly chronic complications of diabetes, as shown by the results of recent clinical trials, newer, more aggressive standards of care for both glucose control—as well as blood pressure, lipids, and other risk factors for these chronic complications—have been promulgated recently by a variety of organizations, chiefly the American Association of Clinical Endocrinologists, The National Cholesterol Education Program, and the American Diabetes Association. As new classes of compounds and new agents within each class develop, thereby expanding our therapeutic options for patients with diabetes, the potential for drug interactions and drug dif- ficulties seems to mount geometrically. In this issue of the Medical Clinics of North America, we have endeavored to bring to practicing clinicians the most modern strategies by which to

0025-7125/04/$ - see front matter 2004 Elsevier Inc. All rights reserved.

doi:10.1016/j.mcna.2004.05.003

xvi

A.J. Garber / Med Clin N Am 88 (2004) xv–xvi

manage patients with diabetes by meeting these goals and guidelines. We hope to improve the risk of complications and to better the lives of those patients who have diabetes, both type 1 and type 2.

Alan J. Garber, MD, PhD Departments of Medicine, Biochemistry and Molecular Biology and Molecular and Cellular Biology Baylor College of Medicine Chief of Endocrinology Diabetes, and Metabolism The Methodist Hospital 6550 Fannin Street, Suite 1045 Houston, TX 77030, USA

E-mail address: agarber@bcm.tmc.edu

Med Clin N Am 88 (2004) 787–835
Med Clin N Am 88 (2004) 787–835

Pathogenesis of type 2 diabetes mellitus

Ralph A. DeFronzo, MD

Diabetes Division, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA

Normal glucose homeostasis

A discussion of the pathogenesis of type 2 diabetes mellitus must start with a review of mechanisms involved in the maintenance of normal glucose homeostasis in the basal or postabsorptive state (10–12 h overnight fast) and following ingestion of a typical mixed meal [1–9]. In the postabsorptive state the majority of total body glucose disposal takes place in insulin- independent tissues. Thus, approximately 50% of all glucose use occurs in the brain, which is insulin-independent and becomes saturated at a plasma glucose concentration of approximately 40 mg/dL [10]. Another 25% of glucose disposal occurs in the splanchnic area (liver plus gastrointestinal tissues), which is also insulin-independent. The remaining 25% of glucose use in the postabsorptive state takes place in insulin-dependent tissues, primarily muscle, and to a lesser extent adipose tissue. Basal glucose use, approximately 2.0 mg/kg/min, is precisely matched by the rate of endog- enous glucose production (Fig. 1). Approximately 85% of endogenous glucose production is derived from the liver, and the remaining 15% is produced by the kidney. Glycogenolysis and gluconeogenesis contribute equally to the basal rate of hepatic glucose production. Following glucose ingestion, the increase in plasma glucose concentration stimulates insulin release, and the combination of hyperinsulinemia and hyperglycemia (1) stimulates glucose uptake by splanchnic (liver and gut) and peripheral (primarily muscle) tissues and (2) suppresses endogenous (primarily hepatic) glucose production (Box 1) [1–9]. The majority ( 80%–85%) of glucose uptake by peripheral tissues occur in muscle, with a small amount ( 4%–5%) metabolized by adipocytes. Although fat tissue is responsible for only a small amount of total body glucose disposal, it plays a very important role in the maintenance of total body glucose homeostasis by regulating the release of free fatty acids (FFA) from stored triglycerides (see discussion below) and through the production of adipocytokines that influence insulin sensitivity in muscle and liver

0025-7125/04/$ - see front matter 2004 Elsevier Inc. All rights reserved.

doi:10.1016/j.mcna.2004.04.013

788 R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

788 R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835 Fig. 1. Postabsorptive state. Glucose

Fig. 1. Postabsorptive state. Glucose production and glucose use in the normal human in the postabsorptive state. (From DeFronzo RA. Pathogenesis of type 2 diabetes mellitus: metabolic and molecular implications for identifying diabetes genes. Diabetes 1997;5:117–9; with permission.)

[11–14]. Insulin is a potent antilipolytic hormone, and even small increments in the plasma insulin concentration markedly inhibit lipolysis, leading to a decline in the plasma level of free fatty acid [12]. The decline in plasma FFA concentration augments muscle glucose uptake and contributes to the inhibition of hepatic glucose production. Thus, changes in the plasma FFA concentration in response to increased plasma levels of insulin and glucose play an important role in the maintenance of normal glucose homeostasis

[11–14].

Glucagon also plays a central role in the regulation of glucose homeostasis [9,15]. Under postabsorptive conditions, approximately half of total hepatic glucose output is dependent on the maintenance of normal basal glucagon levels, and inhibition of basal glucagon secretion with somatostatin causes a reduction in hepatic glucose production and plasma

Box 1. Factors responsible for the maintenance of normal glucose tolerance in healthy subjects

A. Insulin secretion

B. Tissue glucose uptake

1. Peripheral (primarily muscle)

2. Splanchnic (liver plus gut)

C. Suppression of HGP

1. Decreased FFA

2. Decreased glucagons

D. Route of glucose administration

R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

789

glucose concentration. After a glucose-containing meal, glucagon secretion is inhibited by hyperinsulinemia, and the resultant hypoglucagonemia contributes to the suppression of hepatic glucose production and mainte- nance of normal postprandial glucose tolerance. The route of glucose entry into the body also plays an important role in the distribution of administered glucose and overall glucose homeostasis [9,16,17]. Intravenous insulin exerts only a small stimulatory effect on splanchnic (liver plus gut) glucose uptake, whereas intravenous glucose augments splanchnic glucose uptake in direct proportion to the increase in plasma glucose concentration. In contrast, oral glucose administration markedly enhances splanchnic glucose uptake. The portal signal that stimulates hepatic glucose uptake after glucose ingestion is directly pro- portional to the negative hepatic artery–portal vein glucose concentration gradient [9]. As this gradient widens, the splanchnic nerves are stimulated, and this activates a neural reflex in which vagal activity is enhanced, and sympathetic nerves innervating the liver are inhibited. These neural changes augment liver glucose uptake and stimulate hepatic glycogen synthase, while simultaneously inhibiting glycogen phosphorylase. In contrast to intravenous glucose/insulin administration, in which muscle accounts for the majority ( 80%–85%) of glucose disposal, the splanchnic tissues are responsible for the removal of approximately 30%–40% of an ingested glucose load. Glucose administration through the gastrointestinal tract also has a potentiating effect on insulin secretion. Thus, the plasma insulin response following oral glucose is approximately twice as great as that following intravenous glucose, despite equivalent increases in the plasma glucose concentration. This increase in effect is related to the release of glucagon-like peptide (GLP)-1 and glucose- dependent insulinotropic polypeptide (GIP) (previously called gastric in- hibitory polypeptide) from the intestinal tissues cells [18,19].

Glucose homeostasis in type 2 diabetes mellitus

Type 2 diabetic subjects manifest multiple disturbances in glucose homeostasis, including: (1) impaired insulin secretion; (2) insulin resistance in muscle, liver, and adipocytes; and (3) abnormalities in splanchnic glucose uptake [1,2,20,21].

Insulin secretion in type 2 diabetes mellitus

Impaired insulin secretion is found uniformly in type 2 diabetic patients in all ethnic populations [1,2,20–29]. Early in the natural history of type 2 diabetes, insulin resistance is well established but glucose tolerance remains normal because of a compensatory increase in insulin secretion. This dynamic interaction between insulin secretion and insulin resistance has been well documented. Within the normal glucose tolerant population, approximately

790 R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

20%–25% of individuals are severely resistant to the stimulatory effect of insulin on glucose uptake (Fig. 2) (measured with the euglycemic insulin clamp), and subjects in the lowest quartile of insulin sensitivity are as insulin resistant as type 2 diabetics (see Fig. 2). Insulin secretion (measured with the hyperglycemic clamp technique) in these insulin-resistant, nondiabetic individuals, however, is increased in proportion to the severity of the insulin resistance, and glucose tolerance remains normal. Thus, the beta cells are able to ‘‘read’’ the severity of insulin resistance and adjust their secretion of insulin to maintain normal glucose tolerance. In type 2 diabetics, the fasting plasma insulin concentration is normal or increased and basal insulin secretion (measured from C-peptide kinetics) is elevated. The relationship between the fasting plasma glucose (FPG) and

relationship between the fasting plasma glucose (FPG) and Fig. 2. ( A ) Whole-body rate of
relationship between the fasting plasma glucose (FPG) and Fig. 2. ( A ) Whole-body rate of

Fig. 2. (A) Whole-body rate of glucose disposal during euglycemic insulin clamps in 32 women divided according to quartiles of insulin sensitivity. * P 0.001 for each quartile versus the adjacent quartile. (B) Time course of plasma insulin response during the hyperglycemic clamp in the same 32 women divided into quartiles of insulin sensitivity. Insulin secretion rose progressively from the highest to the lowest quartile of insulin sensitivity (P 0.01). , Quartile 1; 6, quartile 2; , quartile 3; C, quartile 4. (From Diamond MP, Thornton K, Connolly- Diamond M, Sherwin RS, DeFronzo RA. Reciprocal variations in insulin-stimulated glucose uptake and pancreatic insulin secretion in women with normal glucose tolerance. J Soc Gynecol Invest 1995;2:708–15.)

R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

791

insulin concentrations resembles an inverted U shape or horseshoe [1,2]. Because this curve resembles Starling’s curve of the heart, it has been referred to as Starling’s curve of the pancreas. As the fasting glucose rises from 80 to 140 mg/dL, the fasting plasma insulin concentration increases progressively, reaching a peak value 2.0–2.5-fold greater than in normal weight, nondiabetic, age-matched controls. The progressive rise in fasting plasma insulin level can be viewed as an adaptive response of the pancreas to offset the progressive deterioration in glucose homeostasis. When the FPG exceeds 140 mg/dL, the beta cell is unable to maintain its elevated rate of insulin secretion, and the fasting insulin concentration declines pre- cipitously. This decrease in fasting insulin level has important physiologic implications, because it is at this point that hepatic glucose production (the primary determinant of the FPG concentration) begins to rise. The relationship between the mean plasma insulin response during an OGTT and the FPG concentration also resembles an inverted U-shaped curve (Fig. 3) [1,2]. The curve, however, is shifted to the left compared with the basal insulin secretory rate, and the glucose-stimulated insulin response begins to decline at a fasting glucose concentration of approximately 120 mg/dL. A typical type 2 diabetic subject with a FPG level of 150–160 mg/dL secretes an amount of insulin similar to that in a healthy nondiabetic individual; however, a ‘‘normal’’ insulin response in the presence of hyperglycemia and underlying insulin resistance is markedly abnormal. At FPG levels in excess of 150–160 mg/dL, the plasma insulin response, when viewed in absolute terms, becomes

insulin response, when viewed in absolute terms, becomes Fig. 3. Starling’s curve of the pancreas for

Fig. 3. Starling’s curve of the pancreas for insulin secretion. In normal-weight patients with IGT and mild diabetes, the plasma insulin response to OGTT increases progressively until the fasting glucose reaches 120 mg/dL. Thereafter, further increases in the fasting glucose concentration are associated with a progressive decline in insulin secretion. (From DeFronzo RA. Lilly lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes 1988;37(6):667–87; with permission.)

792 R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

insulinopenic. Finally, when the fasting glucose exceeds 200–220 mg/dL, the plasma insulin response to a glucose challenge is markedly blunted. Nonethe- less, the fasting hyperinsulinemia persists despite FPG concentrations as high as 250–300 mg/dL, and 24-hour integrated plasma insulin and C-peptide profiles in lean type 2 diabetic patients remain normal. These normal day-long values result from the combination of elevated fasting and decreased postprandial insulin and C-peptide secretory rates [30,31]. It should be emphasized that, even though the plasma insulin response is increased in absolute terms early in the development of type 2 diabetes (FPG 140 mg), this does not mean that beta-cell function is normal. The beta cell responds to an increment in plasma insulin ( DI) by an increment in plasma glucose (D G) and this response is modulated by the severity of insulin resistance, that is, the more severe the insulin resistance, the greater the insulin response. When this index of beta-cell function is plotted against the 2-hour plasma glucose concentration during the OGTT, the loss of 60%–70% of beta-cell function can be appreciated in individuals with impaired glucose tolerance. In fact, normal glucose tolerant individuals in the upper tertile of glucose tolerance (2-h plasma glucose, 120–140 mg/dL) already have lost 50% of their beta-cell function [32]. The natural history of type 2 diabetes, starting with normal glucose tolerance, insulin resistance, and compensatory hyperinsulinemia, with pro- gression to impaired glucose tolerance (IGT) and overt diabetes mellitus, has been observed in a variety of populations including whites, Native Americans, Mexican Americans, and Pacific Islanders, and in the rhesus monkey, an animal model that closely resembles type 2 diabetes in humans [1, 2,20–28,33– 35]. These population studies have demonstrated a strong association between obesity and type 2 diabetes, leading to the new-world syndrome of ‘‘diabesity.’’ In high-risk populations, the progression from normal to IGT is associated with marked increases in both fasting and glucose-stimulated plasma insulin levels and a decrease in tissue sensitivity to insulin (Fig. 4). The progression from IGT to type 2 diabetes with mild fasting hyperglycemia (120–140 mg/dL, 6.7–7.8 mmol/L) is heralded by an inability of the beta cell to maintain its previously high rate of insulin secretion in response to a glucose challenge without further or only minimal deterioration in tissue sensitivity to insulin. Increased basal insulin secretion and fasting hyperinsulinemia, however, are maintained until the FPG exceeds 140 mg/dL. A similar pattern of insulin secretion has been observed during the development of diabetes in the rhesus monkey [33]. The aging monkey becomes obese, and a high percentage of monkeys develop typical type 2 diabetes. The earliest detectable abnormality (preceding the onset of diabetes mellitus) is a decrease in tissue sensitivity to insulin, with a compensatory increase in fasting and glucose- stimulated plasma insulin concentrations. With time, the high rate of insulin secretion cannot be maintained, the beta cell starts on downward slope of Starling’s curve (see Fig. 3), and fasting hyperglycemia and glucose in- tolerance ensue. In summary, these studies are consistent in demonstrating

R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

793

R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835 793 Fig. 4. Summary of the

Fig. 4. Summary of the plasma insulin (top, ) and plasma glucose (bottom, C) responses during a 100-g OGTT and tissue sensitivity to insulin (top, C) in control (CON), obese nondiabetic (OB), obese glucose intolerant (OB-GLU INTOL), obese hyperinsulinemic diabetic (OB-DIAB Hi INS), and obese hypoinsulinemic diabetic subjects (OB-DIAB Lo INS). See text for a detailed discussion. (From DeFronzo RA. Lilly lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes 1988;37(6):667–87; with permission.)

that hyperinsulinemia precedes the development of type 2 diabetes, and hyperinsulinemia is a strong predictor of the development of IGT and type 2 diabetes. It should be emphasized, however, that overt diabetes (fasting glucose 126 mg/dL) does not develop in the absence of a significant defect in beta-cell function. The nature of this beta-cell defect is considered in subsequent sections.

Type 2 diabetes with hypoinsulinemia A large body of clinical and experimental evidence documents that hyperinsulinemia and insulin resistance precede the onset of type 2 diabetes. Nonetheless, a number of studies have shown that absolute insulin deficiency, with or without impaired tissue insulin sensitivity, can lead to the development

794 R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

of type 2 diabetes. This scenario is best exemplified by patients with maturity onset diabetes of youth (MODY) [36–38]. This familial subtype of type 2 diabetes is characterized by early age of onset, autosomal dominant in- heritance with high penetrance, mild to moderate fasting hyperglycemia, and impaired insulin secretion. MODY originally was described by Fajans and coworkers [39], and subsequently it was demonstrated that MODY1 resulted from a nonsense mutation in exon 7 of the hepatic nuclear factor (HNF)4 a gene. It later was demonstrated that the occurrence of MODY in French families resulted from mutations in the glucokinase gene on chromosome 7p (MODY2) [40]. Six specific mutations in different genes have been implicated in the MODY profile, including glucokinase and five transcription factors [36–40]:

MODY1, HNF4 a ; MODY2, glucokinase; MODY3, HNF1 a ; MODY4, insulin promoter factor 1; MODY5, HNF1 b ; and MODY6, neurogenic differentiation 1/beta-cell E-box transactivator 2. The hallmark defect in MODY individuals is impaired insulin secretion in response to glucose and other secretagogues; however, peripheral tissue resistance to insulin and abnormalities in hepatic glucose metabolism also have been shown to play some role in the development of impaired glucose homeostasis [41,42]. Although glucokinase mutations are characteristic of MODY2, genetic studies in typical older-onset type 2 diabetic individuals have shown that glucokinase mutations account for less than 1% of the common form of type 2 diabetes [43]. Cerasi [21] and Luft [44] and Hales [45] and coworkers proposed that insulin deficiency represents the primary defect responsible for glucose intolerance in typical type 2 diabetics who do not have glucokinase or other MODY mutations. According to these investigators, impaired early insulin secretion leads to an excessive rise in plasma glucose concentration, and the resultant hyperglycemia is responsible for late hyperinsulinemia. Hales and colleagues [45] have demonstrated that many lean whites with mild fasting hyperglycemia ( 140 mg/dL, 7.8 mmol/L) are characterized by insulin deficiency at all time points during an OGTT. An impaired early insulin response also has been a characteristic finding in Japanese Americans who progress to type 2 diabetes [46]. Unfortunately, none of these studies provide information about insulin sensitivity. In whites, several investigating groups [47,48] have demonstrated normal insulin sensitivity in a minority of type 2 diabetic individuals, and it has been suggested that up to 50% of African- American type 2 diabetic patients who reside in New York City are characterized by severely impaired insulin secretion and normal insulin sensitivity [49]. A similar defect in insulin secretion has been described in black African type 2 diabetics living in Cameroon [50]. In summary, it is clear that impaired insulin secretion, in the absence of insulin resistance, can lead to the development of full-blown type 2 diabetes, but it remains to be clarified how frequently a pure beta-cell defect results in typical type 2 diabetes in the general population.

R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

795

First-phase insulin secretion In response to intravenous glucose, insulin is secreted in a biphasic pattern, with an early burst of insulin release within the first 10 minutes followed by a progressively increasing phase of insulin secretion that persists as long as the hyperglycemic stimulus is present [51]. This biphasic insulin response is not observed after taking oral glucose because of the more gradual rise in plasma glucose concentration. Loss of first-phase insulin secretion is a characteristic and early abnormality in patients destined to develop type 2 diabetes. In most type 2 diabetic subjects, a reduction in the early phase of insulin secretion during the OGTT (0–30 min) and during the intravenous glucose tolerance test (0–10 min) becomes evident when FPG concentration exceeds 110–120 mg/dL (6.1–6.7 mmol/L) [34,35,51–53]. During the OGTT, the defect in early insulin secretion is most obvious if the incremental plasma insulin response at 30 min is expressed relative to the incremental plasma glucose response at 30 min ( DI 30 DG 30 ). Although the first-phase insulin secretory response to intravenous glucose characteristi- cally is diminished or lost in type 2 diabetes, this defect is not consistently observed until the FPG concentration rises to approximately115–120 mg/dL (6.4–6.7 mmol/L). The defect in first-phase insulin response can be partially restored with tight metabolic control [54,55], indicating that at least part of the defect is acquired, most likely secondary to glucotoxicity or liptoxicity [11,56–59] (see subsequent discussion). Loss of the first phase of insulin secretion has important pathogenic consequences, because this early burst of insulin primes insulin target tissues, especially the liver, that are responsible for the maintenance of normal glucose homeostasis [60,61].

Causes of impaired insulin secretion in type 2 diabetes mellitus Progression from normal glucose tolerance to IGT to type 2 diabetes with mild fasting hyperglycemia ( 120–140 mg/dL, 6.7–7.8 mmol/L) is charac- terized by hyperinsulinemia (see Figs. 3 and 4) [1,2,32]. When the fasting glucose concentration exceeds approximately 120 mg/dL (6.7 mmol/L) and approximately140 mg/dL (7.8 mmol/L), respectively, the fasting and glucose-stimulated plasma insulin levels decline progressively. A number of pathogenic genetic and acquired factors have been implicated in the progressive impairment in insulin secretion. Pancreatic beta cells are in a constant state of dynamic change, with continued regeneration of islets from ductal endothelial cells of the exocrine pancreas and simultaneous apoptosis [62]. Multiple abnormalities have been shown to disturb the delicate balance between islet neogenesis and apoptosis (see subsequent discussion). Studies in first degree relatives of type 2 diabetic patients and in twins have provided strong evidence for the genetic basis of beta-cell dysfunction [63–66]. Impaired insulin secretion also has been shown to be an inherited trait in Finnish families with type 2 diabetes mellitus with evidence for a susceptibility locus on chromosome 12 [67].

796 R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

Both ‘‘glucotoxicity’’ [2,56] and ‘‘lipotoxicity’’ [11,57–59] are among the acquired defects that can lead to impaired insulin secretion (Fig. 5). The glucotoxicity hypothesis is supported by the observation that improved

glycemic control, however it is achieved (diet, insulin therapy, sulfonylureas, metformin), leads to enhanced insulin secretion [54,55]. More direct support

of the glucotoxicity hypothesis comes from animal studies in which diabetic

rats were treated with phlorizin, a potent renal tubular glucose transporter inhibitor that reduces the plasma glucose concentration without altering other circulating substrate levels [68]. When administered to partially pancreatectomized, chronically hyperglycemic diabetic rats, phlorizin re- stores normoglycemia and results in a dramatic improvement in both first- and second-phase insulin secretion. Conversely, when nondiabetic rats with

a reduced beta-cell mass are exposed in vivo to a chronic physiologic

increment in plasma glucose concentration of as little as 15 mg/dL, insulin secretion by the pancreas perfused in vitro is inhibited by 75% [69,70]. These provocative results suggest that a minimal elevation in mean plasma glucose concentration, in the presence of a reduced beta-cell mass, can lead to a major impairment in insulin secretion by the remaining pancreatic tissue. Prolonged beta cell exposure to high glucose concentrations in vitro also has been shown to impair insulin gene transcription, leading to decreased insulin synthesis and secretion [71]. Lipotoxicity [11,57–59,72] also has been implicated as an acquired cause of impaired beta-cell function, as individuals progress from IGT to overt type 2 diabetes mellitus. Short-term exposure of beta cells to physiologic increases in free fatty acids stimulates insulin secretion. Within the beta cell, long-chain fatty acids are converted to their fatty acyl-CoA derivatives, which lead to increased formation of phosphatidic acid and diacylglycerol. These lipid intermediates activate specific protein kinase C isoforms, which enhances the exocytosis of insulin. Long-chain fatty acyl-CoA also stimulate

of insulin. Long-chain fatty acyl-CoA also stimulate Fig. 5. Pathogenetic factors implicated in the progressive

Fig. 5. Pathogenetic factors implicated in the progressive impairment in insulin secretion in type 2 diabetes mellitus. TNF a, tumor necrosis factor-a.

R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

797

exocytosis, cause closure of the K þ -ATPase channel, stimulate Ca 2þ - ATPase and increase intracellular calcium, thus augmenting insulin secre- tion. In contrast to these acute effects, chronic beta cell exposure to elevated fatty acyl-CoA inhibits insulin secretion through operation of the Randle cycle. Increased fatty acyl-CoA levels within the beta cells also stimulate ceramide synthesis, which augments inducible nitric-oxide synthase. The resultant increase in nitric oxide increases the expression of inflammatory cytokines, including interleukin-1 and tumor necrosis factor a , which impair beta-cell function and promote beta cell apoptosis. Most recently, deficiency of or resistance to ‘‘incretins’’ have been implicated in the pathogenesis of beta-cell dysfunction in type 2 diabetic patients [18,19,73–78]. When glucose is administered through the gastroin- testinal route, a much greater stimulation of insulin secretion is observed compared with a similar level of hyperglycemia created with intravenous glucose [73]. This observation prompted a search for the responsible ‘‘incretins’’ or gut-derived hormones that enhance glucose-stimulated in- sulin secretion following the oral route of glucose administration. Two gastrointestinal hormones, GIP and GLP-1, have been shown to account for more than 90% of the incretin effect observed following glucose or mixed- meal ingestion [74–78]. Both GIP and GLP-1 are released from endocrine cells of the duodenum and jejunum in response to intraluminal carbohy- drate but not in response to circulating glucose. The stimulation of insulin secretion by both GIP and GLP-1 is dependent on the ambient glucose concentration, which is greater when plasma glucose concentration is high and absent when the plasma glucose concentration returns to basal levels. Antibodies that neutralize GIP and GLP-1 impair glucose tolerance in a variety of animal species, including primates. Although the amount of GLP-1 released is considerably less than that of GIP, GLP-1 is such a potent potentiator of insulin secretion that it is thought to be the major incretin. In type 2 diabetic humans, the GIP response to glucose ingestion is normal, indicating the presence of beta-cell resistance to the incretin-effect of GIP. In contrast, the GLP-1 response to oral glucose is reduced. Acute intravenous administration of GLP-1 in type 2 diabetic patients enhances the post- prandial insulin secretory response, and chronic continuous GLP-1 admin- istration restores near-normal glycemia in type 2 diabetic patients [74,79]. GLP-1 also has been shown to augment islet regeneration in rodents [80]. Amylin (islet amyloid polypeptide [IAPP]) has been implicated in progressive beta-cell failure in type 2 diabetes mellitus [81–83]. IAPP, which is packaged with insulin in secretory granules and co-secreted into the sinusoidal space, is the precursor for the amyloid deposits that are frequently observed in type 2 diabetic and occur spontaneously in diabetic monkeys. At very high doses, amylin has been shown to inhibit insulin secretion by the perfused rat pancreas in vitro. Elevated plasma islet amyloid polypeptide levels have been demonstrated in type 2 diabetic subjects, obese glucose-intolerant subjects, glucose-intolerant first-degree

798 R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

relatives of type 2 diabetic patients, and in animal models of diabetes [81– 83]. Following its secretion, amylin accumulates extracellularly in close proximity to the beta cell, and it has been suggested that amylin deposits

cause beta-cell dysfunction. Although it is attractive, this theory has been challenged by Bloom and coworkers [84], who failed to find any inhibitory effect of amylin on insulin secretion when the peptide was infused in pharmacologic doses in rats, rabbits, and humans. Studies in transgenic mice [85], which express the gene encoding either human or rat IAPP under control of an insulin promoter, also mitigate against an important role of IAPP in the development of beta-cell dysfunction. Thus, although pancre- atic and plasma amyloid polypeptide levels were significantly elevated in these transgenic mice, hyperglycemia and hyperinsulinemia did not develop.

A recent provocative review [86] even suggests that IAPP in the islets of

Langerhans may serve a protective role under conditions of increased

insulin secretion. In summary, definitive evidence that amylin contributes to beta-cell dysfunction in human type 2 diabetes remains elusive, although recent evidence [81] suggests that the combination of elevated plasma FFA levels and amylin hypersecretion may interact synergistically to impair insulin secretion and cause beta-cell injury. The number of beta cells within the pancreas is an important determinant

of the amount of insulin that is secreted. Most [87–90] but not all [91,92]

studies have demonstrated a modest reduction (20%–40%) in beta-cell mass

in patients with long-standing type 2 diabetes. Obesity, another insulin-

resistant state, is characterized by a significant increase in beta-cell mass [88], and the majority of type 2 diabetics are overweight. Thus, even a modest reduction (20%–40%) in beta-cell mass is most impressive. On routine histologic examination, the islets of Langerhans appear normal with the exception of beta-cell degranulation [87–90]. Insulitis is not observed. The factors responsible for the decrease in beta-cell mass in type 2 diabetics remain to be identified. Several studies suggest that new islet formation from

exocrine ducts is reduced in type 2 diabetic individuals [93]. In animal model

of diabetes, there is evidence that islet neogenesis is reduced and beta-cell

apoptosis is accelerated [94]. Although recent studies with well-matched controls (age, gender, and obesity) suggest that beta-cell mass is reduced, even during the early stages of the development of type 2 diabetes, it seems likely that factors in addition to beta-cell loss must be responsible for the impairment in insulin secretion. Low birth weight is associated with the development of IGT and type 2 diabetes in a number of populations [95]. Developmental studies in animals and humans have demonstrated that poor nutrition and impaired fetal growth (small babies at birth) are associated with impaired insulin secretion or reduced beta-cell mass. Fetal malnutrition also can lead to the de-

velopment of insulin resistance later in life [96]. One could hypothesize that

an environmental influence, for example, impaired fetal nutrition leading to an acquired defect in insulin secretion or reduced beta-cell mass, when

R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

799

superimposed on insulin resistance, could eventuate in type 2 diabetes later in life. Thus, during the normal aging process, with the onset of obesity or with a worsening of the genetic component of the insulin resistance, the beta cell would be called on to augment its secretion of insulin to offset the defect in insulin action. If beta-cell mass (or function) is reduced (or impaired) by an environmental insult during fetal life, this would lead to the development of IGT and eventually to overt type 2 diabetes. Although such a defect would limit the maximum amount of insulin that could be secreted, it would not explain the progressive decline in insulin secretion in response to physiological stimuli as individuals progress from IGT to type 2 diabetes (see Fig. 4).

Insulin resistance and type 2 diabetes

In cross-sectional studies and long-term, prospective longitudinal studies, hyperinsulinemia has been shown to precede the onset of type 2 diabetes in all ethnic populations with a high incidence of type 2 diabetes [1,2,20– 27,34,35,97–102]. Studies using the euglycemic insulin clamp, minimal model, and insulin suppression techniques have provided direct quantitative evidence that the progression from normal to impaired glucose tolerance is associated with the development of severe insulin resistance, whereas plasma insulin concentrations, both in the fasting state and in response to a glucose load (see Figs. 3 and 4) are increased when viewed in absolute terms (see above discussion of insulin secretion). It should be emphasized, however, that, even though the absolute insulin secretory rate is increased, beta-cell sensitivity to glucose is markedly reduced in individuals with IGT. Himsworth and Kerr [103], using a combined oral glucose and in- travenous insulin tolerance test, were the first to demonstrate that tissue sensitivity to insulin is diminished in type 2 diabetic patients. In 1975, Reaven and colleagues [104], using the insulin suppression test, provided further evidence that the ability of insulin to promote tissue glucose uptake in type 2 diabetes was severely reduced. A defect in insulin action in type 2 diabetes also has been demonstrated with the arterial infusion of insulin into the brachial artery (forearm muscle) and femoral artery (leg muscle) as well as with radioisotope turnover studies, the frequently sampled intravenous glucose tolerance test, and the minimal model technique [1,2,5,105–107]. DeFronzo et al [1,2,5,12,105,108,109], using the more physiologic eugly- cemic insulin clamp technique, have provided the most conclusive documen- tation that insulin resistance is a characteristic feature of lean, as well as obese, type 2 diabetic individuals. Because diabetic patients with severe fasting hyperglycemia ( 180–200 mg/dL, 10.0–11.1 mmol/L) are insulinopenic (see Fig. 3), and because insulin deficiency is associated with the emergence of a number of intracellular defects in insulin action, these initial studies focused on diabetics with mild to modest elevations in the FPG concentration (mean, 150 8 mg/dL, 8.3 0.4 mmol/L). Insulin-mediated whole-body glucose

800 R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

disposal in these lean diabetics was reduced by approximately 40%–50%, providing conclusive proof of the presence of moderate to severe insulin resistance. Three additional points are noteworthy: (1) lean type 2 diabetics with more severe fasting hyperglycemia (198 10 mg/dL) have a severity of insulin resistance that only is slightly greater (10%–20%) than diabetics with mild fasting hyperglycemia; (2) the defect in insulin action is observed at all plasma insulin concentrations, spanning the physiologic and pharmacologic range (Fig. 6); and in (3) diabetic patients with overt fasting hyperglycemia even maximally stimulating plasma insulin concentrations (under euglycemic conditions) cannot elicit a normal glucose metabolic response. With a few exceptions, the majority of investigators have demonstrated that lean type 2 diabetic subjects are resistant to the action of insulin [24–27,29,34,35,97, 101,107,110–112]. The ability of glucose (hyperglycemia) to stimulate its own uptake, that is, the mass action effect of hyperglycemia, also is impaired in type 2 diabetics [113].

Site of insulin resistance in type 2 diabetes

Maintenance of normal whole-body glucose homeostasis requires a nor- mal insulin secretory response and normal tissue sensitivity to the in- dependent effects of hyperinsulinemia and hyperglycemia to augment glucose uptake [1–7]. The combined effects of insulin and hyperglycemia to promote glucose disposal are dependent on three tightly coupled mechanisms (see Box 1): (1) suppression of endogenous (primarily hepatic) glucose production; (2) stimulation of glucose uptake by the splanchnic

(2) stimulation of glucose uptake by the splanchnic Fig. 6. Dose-response curve relating the plasma insulin

Fig. 6. Dose-response curve relating the plasma insulin concentration to the rate of insulin- mediated whole-body glucose uptake in control ( C ) and type 2 diabetic ( ) subjects. * P 0.01 versus control subjects. (From Groop LC, Bonadonna RC, DelPrato S, Ratheiser K, Zyck K, Ferrannini E, DeFronzo RA. Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance. J Clin Invest 1989;84(1):205– 13; with permission.)

R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

801

(hepatic plus gastrointestinal) tissues; and (3) stimulation of glucose uptake by peripheral tissues, primarily muscle. Muscle glucose uptake is regulated by flux through two major metabolic pathways: glycolysis (of which 90% represents glucose oxidation) and glycogen synthesis.

Hepatic glucose production

In the postabsorptive state, the liver of healthy subjects produces glucose at the rate of 2.0 mg/kg/min [1,2,12,114]. This glucose efflux is essential to meet the needs of the brain and other neural tissues, which use glucose at a constant rate of approximately 1.0 to 1.2 mg/kg/min [10,115]. Brain glucose uptake is insulin-independent and accounts for approximately 50% to 60% of glucose disposal under fasting conditions. Therefore, brain glucose uptake occurs at the same rate during absorptive and postabsorptive periods, and it is not altered in type 2 diabetes. During glucose ingestion, insulin is secreted into the portal vein where it is taken up by the liver and suppresses hepatic glucose output. If the liver does not perceive this insulin signal and continues to produce glucose, there will be two inputs of glucose into the body, one from the liver and a second from the gastrointestinal tract, and marked hyperglycemia will ensue. In type 2 diabetics with mild fasting hyperglycemia ( 140 mg/dL), the postabsorptive level of hyperinsulinemia is sufficient to offset the hepatic insulin resistance and maintain a normal basal rate of hepatic glucose output [114]. In diabetic subjects with mild to moderate fasting hyperglycemia (140– 200 mg/dL, 7.8–11.1 mmol/L), however, basal hepatic glucose production is increased by approximately 0.5 mg/kg/min (Fig. 7) [1,2,12,114]. Thus, during overnight sleeping hours (20:00 h to 08:00 h), the liver of an 80-kg diabetic individual with modest fasting hyperglycemia adds approximately 30 g of additional glucose to the systemic circulation. The increase in basal hepatic glucose production (HGP) is closely correlated with the severity of fasting hyperglycemia (see Fig. 7) [1,2,12,114], and this has been demonstrated in numerous studies [116–118]. In conclusion, in type 2 diabetics with overt fasting hyperglycemia ( 140 mg/dL, 7.8 mmol/L), an excessive rate of hepatic glucose output is the major abnormality responsible for the elevated FPG concentration. Under postabsorptive conditions, the fasting plasma insulin concentration in type 2 diabetics is 2- to 4-fold greater than in nondiabetic subjects [1,2]. Because hyperinsulinemia is a potent inhibitor of HGP, it is obvious that hepatic resistance to the action of insulin must be present to explain the excessive output of glucose by the liver. Because hyperglycemia per se exerts a powerful suppressive action on HGP, the liver also must be resistant to the inhibitory effect of hyperglycemia on hepatic glucose output, and this has been well documented. The dose response relationship between hepatic glucose production and the plasma insulin concentration has been examined with the euglycemic

802 R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

802 R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835 Fig. 7. Summary of hepatic

Fig. 7. Summary of hepatic glucose production (HGP) in 77 normal-weight type 2 diabetic subjects ( ) with fasting plasma glucose concentrations ranging from 105 to greater than 300 mg/ dL. Seventy-two control subjects matched for age and weight are shown by filled circles. In the 33 diabetic subjects with fasting plasma glucose levels less than 140 mg/dL (shaded area), the mean rate of hepatic glucose production was identical to that of control subjects. In diabetic subjects with fasting plasma glucose concentrations greater than 140 mg/dL, there was a progressive rise in hepatic glucose production that correlated closely (r, 0.847; P 0.001) with the fasting plasma glucose concentration. (From DeFronzo RA, Ferrannini E, Simonson DC. Fasting hyperglycemia in non-insulin-dependent diabetes mellitus: contributions of excessive hepatic glucose production and impaired tissue glucose uptake. Metabolism 1989;38(4):387–95; with permission.)

insulin clamp technique and radioisotopic glucose (Fig. 8) [12]. The following points deserve emphasis: (1) the dose-response curve relating inhibition of HGP to the plasma insulin level is very steep, with a half- maximal insulin concentration (ED 50 ) of approximately 30 to 40 l U/mL; (2)

(ED 5 0 ) of approximately 30 to 40 l U/mL; (2) Fig. 8. Dose-response curve

Fig. 8. Dose-response curve relating the plasma insulin concentration to the suppression of hepatic glucose production in control ( C) and type 2 diabetic ( ) subjects with moderately severe fasting hyperglycemia. * P 0.05; ** P 0.01 versus control subjects. (From Groop LC, Bonadonna RC, DelPrato S, Ratheiser K, Zyck K, Ferrannini E, DeFronzo RA. Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance. J Clin Invest. 1989;84(1):205–13; with permission.)

R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

803

in type 2 diabetics, the dose-response curve is shifted to the right, indicating resistance to the inhibitory effect of insulin on hepatic glucose production. Elevation of the plasma insulin concentration to the high physiologic range ( 100 l U/mL), however, can overcome the hepatic insulin resistance and cause a near normal suppression of HGP; and (3) the severity of the hepatic insulin resistance is related to the level of glycemic control. In type 2 diabetics with mild fasting hyperglycemia, an increment in plasma insulin concentration of 100 l U/mL causes a complete suppression of HPG; however, in diabetic subjects with more severe fasting hyperglycemia, the ability of the same plasma insulin concentration to suppress HGP is impaired. These observations indicate that there is an acquired component of hepatic insulin resistance, which becomes progressively worse as the diabetic state decompensates over time. Hepatic glucose production can be derived from either glycogenolysis or gluconeogenesis [9]. Using the hepatic vein catheter technique, the uptake by the liver of gluconeogenic precursors, especially lactate, has been shown to increased in type 2 diabetic subjects [119], and this has been confirmed with radioisotope turnover studies using radiolabeled lactate, alanine, glutamine, and glycerol [120,121]. More recent studies using 13 C-labeled magnetic resonance imaging [122] and D 2 O [123] have confirmed that approximately 90% of the increase in HGP above baseline can be accounted for by accelerated gluconeogenesis. A variety of mechanisms has been shown to contribute to the increase in hepatic gluconeogenesis, including hypergluca- gonemia, enhanced sensitivity to glucagon, increased circulating levels of gluconeogenic precursors (lactate, alanine, glycerol), increased FFA oxida- tion, and decreased sensitivity to insulin. Because of the inaccessibility of the liver in humans, it has been difficult to examine the role of key enzymes involved in the regulation of gluconeogenesis (pyruvate carboxylase, phosphoenol-pyruvate carboxykinase), glycogenoly- sis (glycogen phosphorylase), and net hepatic glucose output (glucokinase, glucose-6-phosphatase). Considerable evidence from animal models of type 2 diabetes and some evidence in humans, however, has implicated increased activity of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase in the accelerated rate of hepatic glucose production [123,124]. The kidney possesses all of the gluconeogenesis enzymes required to produce glucose, and estimates of the renal contribution to total endogenous glucose production have ranged from 5% to 20% [125,126]. These varying estimates of the contribution of renal gluconeogenesis to total glucose pro- duction are largely related to the methodology used to measure renal glucose production [127]. One unconfirmed study suggests that the rate of renal gluconeogenesis is increased in type 2 diabetics with fasting hyperglycemia [128], but studies using the hepatic vein catheter technique have shown that all of the increase in total body endogenous glucose production (measured with [3- 3 H]glucose) in type 2 diabetics can be accounted for by increased hepatic glucose output (measured by the hepatic vein catheter technique) [5].

804 R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

Peripheral (muscle) glucose uptake

Muscle is the major site of insulin-stimulated glucose disposal in humans [1–3,5,129,130]. Under euglycemic conditions, studies using the euglycemic insulin clamp in combination with femoral artery or vein catheterization have shown that approximately 80% of total body glucose uptake occurs in skeletal muscle. In response to a physiologic increase in plasma insulin concentration ( 80–100 lU/mL), leg muscle glucose uptake increases progressively in healthy subjects and reaches a plateau value of approxi- mately 10 mg/kg leg weight/min (Fig. 9) [5]. In contrast, in lean type 2 diabetic subjects, the onset of insulin action is delayed by approximately 40 min, and the amount of glucose taken up by the leg is markedly blunted, even though the insulin infusion is continued for an additional 60 min to allow insulin to more fully express its biologic effects. During the last hour of the insulin clamp study, the rate of glucose uptake was reduced by 50% in the type 2 diabetic group. These results provide conclusive evidence that muscle represents the primary site of insulin resistance during euglycemic insulin clamp studies performed in type 2 diabetic subjects. Using the forearm and leg catheterization techniques, a number of investigators have demonstrated a decrease in insulin-stimulated muscle glucose uptake. Studies using positron emission tomography have provided additional support for the presence of severe muscle insulin resistance in type 2 diabetic subjects.

muscle insulin resistance in type 2 diabetic subjects. Fig. 9. Time course of change in leg

Fig. 9. Time course of change in leg glucose uptake in type 2 diabetic ( ) and control (C) subjects. In the postabsorptive state, glucose uptake in the diabetic group was significantly greater than that in control subjects. The ability of insulin (euglycemic insulin clamp) to stimulate leg glucose uptake, however, was reduced by 50% in the diabetic subjects. * P \ 0.05; ** P \ 0.01. (From DeFronzo RA, Gunnarsson R, Bjorkman O, Olsson M, Wahren J. Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II) diabetes mellitus. J Clin Invest 1985;76(1):149–55; with permission.)

R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

805

Splanchnic (hepatic) glucose uptake

Because of the difficulty in catheterizing the portal vein in humans, glucose disposal by the liver has not been examined directly. Use of the hepatic vein catheterization technique in combination with the euglycemic insulin clamp, however, has allowed investigators to examine the contribution of the splanchnic (liver plus gastrointestinal) tissues to overall glucose homeostasis in lean type 2 diabetic subjects [3,5,129]. In the postabsorptive state, there is a net release of glucose from the splanchnic area (ie, negative balance) in both control and diabetic subjects, reflecting glucose production by the liver. When insulin is infused while maintaining euglycemia, splanchnic glucose output is promptly suppressed (reflecting inhibition of HGP) and, within 20 min, the net glucose balance across the splanchnic region decreases to zero (i.e., no net uptake or release). After 2 hours of sustained hyperinsulinemia, the splanchnic area manifests a small net uptake of glucose, approximately 0.5 mg/kg/min (i.e., positive balance), which is virtually identical to the rate of splanchnic glucose uptake during in the basal state. These results indicate that the splanchnic tissues, like the brain, are largely insensitive to insulin with respect to the stimulation of glucose uptake. There were no differences between diabetic and control subjects in the amount of glucose taken up by the splanchnic tissues at any time during the insulin clamp study.

In summary, under conditions of euglycemic hyperinsulinemia, very little

infused glucose is taken up by the splanchnic (and therefore hepatic) tissues. Because the difference in insulin-mediated total body glucose uptake between type 2 diabetic and control subjects during the euglycemic insulin clamp study was 2.5 mg/kg/min, it is obvious that a defect in splanchnic (hepatic) glucose removal cannot account for the impairment in total body glucose uptake following intravenous glucose/insulin administration; how- ever, following glucose ingestion, the gastrointestinal route of glucose entry and the resultant hyperglycemia conspire to enhance splanchnic (hepatic) glucose uptake [4,9,16,17,131] and, under these conditions, diminished hepatic glucose uptake has been shown to contribute to impaired glucose tolerance in type 2 diabetes (see discussion below).

Summary: whole-body glucose use

A summary of insulin-mediated whole-body glucose metabolism during

the euglycemic insulin clamp is depicted in (Fig. 10). The height of each bar

represents the total amount of glucose taken up by all tissues in the body during the insulin clamp in control and type 2 diabetic subjects. Net splanchnic glucose uptake (quantitated by hepatic vein catheterization) is similar in both groups and averaged 0.5 mg/kg/min. Adipose tissue glucose uptake accounts for no more than 5% of total glucose disposal. Brain glucose uptake, estimated to be 1.0–1.2 mg/kg/min in the postabsorptive state, is unaffected by hyperinsulinemia. Muscle glucose uptake (extrapo- lated from leg catheterization data) in control subjects accounts for

806 R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

806 R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835 Fig. 10. Summary of glucose

Fig. 10. Summary of glucose metabolism during euglycemic insulin (100 lU/mL) clamp studies performed in normal-weight type 2 diabetic and control subjects (see text for a more detailed discussion). NIDD, non-insulin-dependent diabetes. (From DeFronzo RA. Pathogenesis of type 2 diabetes mellitus: metabolic and molecular implications for identifying diabetes genes. Diabetes 1997;5:117–269; with permission.)

approximately 75%–80% of glucose uptake by the body. In type 2 diabetic subjects, the largest part of the impairment in insulin-mediated glucose uptake is explained by the defect in muscle glucose disposal. Numerous studies have demonstrated that adipocytes from type 2 diabetics are resistant to insulin, but because the total amount of glucose taken up by fat cells during the insulin clamp is small [130], even if adipose tissue of type 2 diabetic subjects took up no glucose, it could, at best, explain only a small fraction of the defect in whole-body glucose metabolism.

Glucose disposal during OGTT

During daily life, the normal route of glucose entry into the body is through the gastrointestinal tract. To assess tissue glucose disposal following glucose ingestion, Ferrannini, DeFronzo, and colleagues [131– 133] administered oral glucose combined with hepatic vein catheterization to healthy control subjects to examine splanchnic glucose metabolism. The oral glucose load and endogenous glucose pool were labeled with [1- 14 C]glucose and [3- 3 H]glucose, respectively, to quantitate total body glucose disposal (from tritiated glucose turnover) and endogenous HGP (difference between the total rate of glucose appearance, measured with tritiated glucose, and the rate of oral glucose appearance, measured with [1- 14 C]glucose). During the 3.5 hours after glucose (68 g) ingestion: (1) 28% (19 g) of the oral load was taken up by splanchnic tissues; (2) 72% (48 g) was removed by nonsplanchnic tissues; (3) of the 48 g taken up by peripheral tissues, the

R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

807

brain (an insulin-independent tissue) disposed of 22% (15 g or 1 mg/kg/min) of the total glucose load; and (4) basal HGP declined by 53% [131]. Similar percentages for splanchnic glucose uptake (24%–29%) and suppression of HGP (50%–60%) in normal subjects have been reported by other inves- tigators [8,134–136]. The contribution of skeletal muscle to the disposal of an oral glucose load has been reported to vary from a low of 26% [135] to a high of 56% [136], with a mean of 45% [8,131,134–136]. These results demonstrate a number of important differences between oral and in- travenous glucose administration. After glucose ingestion, HGP is less completely suppressed, most likely because of activation of local sympa- thetic nerves that innervate the liver, peripheral tissue (primarily muscle) glucose uptake is quantitatively less important [3], and splanchnic glucose uptake quantitatively is much more important. When an oral glucose is given to type 2 diabetic individuals, marked glucose intolerance is observed, and this results from decreased tissue (muscle) glucose uptake and impaired suppression of HGP. The uptake of glucose by the splanchnic tissues is similar in diabetic and control groups. Impaired suppression of HGP accounts for approximately one third of the defect in total-body glucose homeostasis, whereas reduced peripheral (muscle) glucose uptake accounts for the remaining two thirds. It should be noted that, even though the total amount of glucose taken up by the splanchnic region in type 2 diabetics is ‘‘normal,’’ splanchnic glucose metabolism is quite abnormal. Because hyperglycemia per se enhances splanchnic (hepatic) glucose uptake in proportion to the increase in plasma glucose concentration, and because the rise in plasma glucose concentration in diabetics is excessive, the splanchnic glucose clearance (splanchnic glucose uptake plasma glucose concentration) following glucose ingestion is markedly reduced in type 2 diabetic subjects. Using a combined insulin clamp/OGTT technique, an impairment in glucose uptake by the splanchnic tissues in type 2 diabetics has been demonstrated directly [137]. In summary, following glucose ingestion both impaired suppression of HGP and decreased muscle glucose uptake are responsible for the glucose intolerance of type 2 diabetes. The efficiency of the splanchnic (hepatic) tissues to take up glucose (as reflected by the splanchnic glucose clearance) also is impaired in type 2 diabetic individuals.

Summary: insulin resistance in type 2 diabetes

Insulin resistance in muscle and liver is a characteristic feature of type 2 diabetes mellitus. In the basal state, the hepatic insulin resistance is manifested by overproduction of glucose despite fasting hyperinsulinemia, and the increased rate of hepatic glucose output is the primary determinant of the elevated FPG concentration in type 2 diabetic individuals. Although muscle glucose uptake in the postabsorptive state is increased when viewed in absolute terms, the efficiency with which glucose is taken up (ie, the glucose

808 R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

clearance) by muscle is diminished. During insulin-stimulated conditions, both decreased muscle glucose uptake and impaired suppression of HGP contribute to the glucose intolerance.

Dynamic interaction between insulin sensitivity and insulin secretion in type 2 diabetes

Insulin resistance is present in approximately 25% of the adult population [138–140]. The majority of these individuals, however, have normal glucose tolerance because the pancreatic beta cells are able to read the severity of insulin resistance and appropriately augment their insulin secretory rate. This dynamic interaction between insulin sensitivity and insulin secretion is demonstrated by results obtained in healthy, lean, young normal-glucose- tolerant women who received a euglycemic insulin clamp (1 mU/kg/min) and were stratified into quartiles based on the rate of insulin-mediated glucose disposal (see Fig. 2A) [141]. Women in the lowest quartile were as insulin resistant as type 2 diabetic individuals. Insulin secretion was measured on a separate day with a þ125-mg/dL hyperglycemic clamp (see Fig. 2B). Women who were the most insulin resistant (quartile 1) had the highest fasting plasma insulin concentrations and highest early and late-phase plasma insulin res- ponses (see Fig. 2B). Conversely, women who were the most insulin sensitive (quartile 4) had the lowest plasma insulin response. A very strong positive correlation (r, 0.79, P 0.001) was observed between the severity of insulin resistance and the insulin secretory response. Similar results relating the plasma insulin response and the severity of insulin resistance have been reported in normal-glucose-tolerant subjects with the minimal model tech- nique and the insulin suppression/OGTT. The dynamic interaction between insulin secretion and insulin sen- sitivity in type 2 diabetic individuals has been the subject of intensive investigation. DeFronzo [2] studied lean (ideal body weight 120%) and obese (ideal body weight 125%) subjects with varying degrees of glucose tolerance: group I, obese subjects (n = 24) with normal glucose tolerance; group II, obese subjects (n = 23) with impaired glucose tolerance; group III, obese subjects (n = 35) with overt diabetes, who were subdivided into those with a hyperinsulinemic response and those with a hypoinsulinemic response during an OGTT; group IV, normal weight type 2 diabetics (n = 26); and group V, normal weight subjects (n = 25) with normal glucose tolerance (see Fig. 4). All subjects received a euglycemic insulin ( 100 l U/mL) clamp to quantitate whole-body insulin sensitivity and an OGTT to provide a measure of glucose tolerance and insulin secretion. The insulin clamp was performed with indirect calorimetry to quantitate rates of glucose oxidation and nonoxidative glucose disposal, which primarily reflects glycogen synthesis. In normal weight type 2 diabetic subjects, insulin-mediated whole-body glucose uptake was reduced by 40%–50%, and the impairment in insulin

R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

809

action resulted from defects in both glucose oxidation and glycogen synthesis. It is particularly noteworthy that obese, normal glucose tolerant individuals were as insulin resistant as the lean normal-weight diabetic subjects (see Fig. 4) and that the insulin resistance resulted from defects in both glucose oxidation and glycogen synthesis. Thus, from the metabolic standpoint, obesity and type 2 diabetes closely resemble each other. Similar results concerning reduced whole-body insulin sensitivity in obese and type 2 diabetic individuals have been reported by other investigators [142,143]. Despite nearly identical degrees of insulin resistance, the normal-weight diabetic subjects (see Fig. 4) had fasting hyperglycemia and marked glucose intolerance, whereas the obese nondiabetic individuals had normal oral glucose tolerance. This apparent paradox is explained by the plasma insulin response during the OGTT (see Fig. 4). Compared with control subjects, the obese group secreted more than twice as much insulin, and this hyper- insulinemic response was sufficient to offset the insulin resistance. In contrast, the pancreas of normal-weight diabetic subjects, when faced with the same challenge, was unable to augment its secretion of insulin sufficiently to compensate for the insulin resistance. This imbalance between insulin secretion and the severity of insulin resistance in liver and muscle resulted in a frankly diabetic state, with fasting hyperglycemia and marked glucose intolerance. The coexistence of obesity and diabetes in the same individual resulted in a severity of insulin resistance that was only slightly greater than that in either the normal-weight diabetic or nondiabetic obese groups (see Fig. 4). Although hyperinsulinemic and hypoinuslinemic obese diabetic subjects were equally insulin resistant, the glucose intolerance was much worse in the hypoinsulinemic group, and this was related entirely to the presence of severe insulin deficiency (see Fig. 4). The interaction between insulin secretion and insulin resistance in lean, obese, and diabetic groups can be summarized as follows. In the obese nondiabetic subjects, tissue sensitivity to insulin (Fig. 4, top) is markedly reduced, but glucose tolerance (bottom) remains normal because the pancreas is able to augment its secretion of insulin (top) to offset the defect in insulin action. The development of IGT, the mean plasma glucose concentration during the OGTT, increases only minimally because the pancreas is able to further augment its secretion of insulin to counteract the deterioration in insulin sensitivity. Progression from IGT to overt diabetes is signaled by a decrease in insulin secretion without any worsening of insulin resistance (see Fig. 4). The obese diabetic has tipped over the top of Starling’s curve of the pancreas and is now on the descending portion (see Figs. 3 and 4). Although, compared with nondiabetic control subjects, the plasma insulin response is increased, the hyperinsulinemia is insufficient to offset the severity of insulin resistance. In the normal-weight diabetic group, there is a further decline in glucose tolerance, which results from a greater impairment in insulin secretion without any additional deterioration in

810 R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

insulin sensitivity. Last, the obese diabetic group with a low insulin response manifests the greatest glucose intolerance owing to the presence of marked insulin deficiency without further worsening of insulin sensitivity (see Fig. 4). The natural history of type 2 diabetes described above (see Fig. 4) is consistent with that described by other investigators in humans and monkeys [1,2,20,22–27,29,33–35,97–99,102,144–146]. In lean subjects span- ning a wide range of glucose tolerance, Reaven et al [97] demonstrated that the progression from normal glucose tolerance to IGT was signaled by the development of severe insulin resistance, which was largely counterbalanced by increased insulin secretion. Progression from IGT to type 2 diabetes was associated with a marked decline in insulin secretion with no (or only slight) further deterioration in tissue sensitivity to insulin (Fig. 11). A similar sequence of events has been documented prospectively in Pima Indians, Pacific Islanders, and rhesus monkeys. In summary, insulin resistance is an early and characteristic feature of the natural history of type 2 diabetes in high-risk populations. Overt diabetes develops only when the beta cells are unable to appropriately augment their secretion of insulin to compensate for the defect in insulin action. It should be recognized, however, that there are well-described type 2 diabetic populations in whom insulin sensitivity is normal at the onset of diabetes, whereas insulin secretion is severely impaired. This insulinopenic variety of type 2 diabetes appears to be more common in African Americans, elderly subjects, and lean whites. In this latter group, it is important to exclude type 1 diabetes, because approximately 10% of white individuals with older onset diabetes are islet cell antibody, or glutamic acid decarboxylase, positive.

cell antibody, or glutamic acid decarboxylase, positive. Fig. 11. Insulin-mediated glucose clearance (measured with

Fig. 11. Insulin-mediated glucose clearance (measured with the insulin suppression test) and the plasma insulin response (measured with an OGTT) in controls (top), in subjects with IGT (bottom), and in type 2 diabetic individuals (top) with varying severity of glucose intolerance (see text for a more detailed discussion). (Data from Reaven GM, Hollenbeck CB, Chen YDI. Relationship between glucose tolerance, insulin secretion, and insulin action in non-obese individuals with varying degrees of glucose tolerance. Diabetologia 1989;32:52–5.)

R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

811

Role of the adipocyte in the pathogenesis of type 2 diabetes mellitus: the harmonious quartet

The majority ( 80%–90%) of type 2 diabetics in the United States are overweight or obese [147]. Both lean and especially obese type 2 diabetics are characterized by day-long elevation in plasma free fatty-acid concen- tration, which fails to suppress normally following ingestion of a mixed meal or oral glucose load [30]. FFA are stored as triglycerides in adipocytes and serve as an essential energy source during fasting conditions. Insulin is a potent antilipolytic hormone and restrains the release of FFA from the adipocyte by inhibiting the enzyme hormone-sensitive lipase [11,12]. The fat cells of type 2 diabetics (and nondiabetic obese individuals) are markedly resistant to the inhibitory effect of insulin on lipolysis. In the postabsorptive state, the rate of lipolysis (as reflected by impaired suppression of radioactive palmitate turnover) is increased despite plasma insulin levels that are 2- to 4-fold elevated. Moreover, the ability of exogenous insulin to inhibit the elevated basal rate of lipolysis and to reduce the plasma FFA concentration is markedly impaired. Many studies have shown that chronically elevated plasma FFA concentrations cause insulin resistance in muscle and liver and impair insulin secretion (Fig. 12) [1,2,11,14,58,148– 152]. Thus, increased plasma FFA levels can cause or aggravate the three major pathogenic disturbances that are responsible for impaired glucose homeostasis in type 2 diabetic individuals, and the time has arrived for the ‘‘triumvirate’’ (muscle, liver, beta cell) to be joined by the ‘‘fourth musketeer’’ [152] to form the ‘‘harmonious quartet’’ (Fig. 13) [11]. In addition to the FFA that circulate in plasma in increased amounts, type 2 diabetic and obese nondiabetic individuals have increased stores of triglycerides in muscle and liver, and the increased fat content correlates closely with the presence of insulin resistance in these tissues [153–156]. Triglycerides in liver and muscle are in a state of constant turnover, and the intracellular metabolites of triglycerides and FFA (ie, fatty acyl-CoA, ceramides, and diacylglycerol) have been shown to impair insulin action

and diacylglycerol) have been shown to impair insulin action Fig. 12. Etiology of type 2 diabetes

Fig. 12. Etiology of type 2 diabetes mellitus (T2DM). The deleterious effect of chronically elevated plasma FFA concentrations on basal or insulin-suppressed rate of hepatic glucose production, insulin-stimulated glucose uptake in muscle, and glucose-stimulated insulin secretion.

812 R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

812 R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835 Fig. 13. Harmonious quartet. Insulin

Fig. 13. Harmonious quartet. Insulin resistance in adipocytes, muscle, and liver in combination with impaired insulin secretion by the pancreatic beta cells, represent the four major organ system abnormalities that play a central role in the pathogenesis of type 2 diabetes mellitus.

in both liver and muscle [11,157–159]. Evidence also has accumulated to

implicate lipotoxicity as an important cause of beta-cell dysfunction (see earlier discussion) [11,58,150,151]. The sequence of events whereby elevated plasma FFA and increased lipid deposition in tissues cause insulin resistance and promote beta-cell failure has been referred to as ‘‘lipotoxicity,’’ and several recent in depth reviews of this subject have been published [11,58].

Cellular mechanisms of insulin resistance

The cellular events through which insulin initiates its stimulatory effect on glucose metabolism start with binding of the hormone to specific receptors that are present on the cell surface of all insulin target tissues [2,160–162]. After insulin has bound to and activated its receptor, ‘‘second messengers’’ are generated, and these second messengers activate a cascade of phosphorylation-dephosphorylation reactions that eventually result in the stimulation of intracellular glucose metabolism. The first step in glucose use involves activation of the glucose transport system, leading to glucose influx into insulin target tissues, primarily muscle. The free glucose, which has entered the cell, subsequently is metabolized by a series of enzymatic steps that are under the control of insulin. Of these, the most important are glucose phosphorylation (catalyzed by hexokinase), glycogen synthase (which controls glycogen synthesis), and phosphofructokinase (PFK) and pyruvate dehydrogenase (PDH) (which regulate glycolysis and glucose oxidation, respectively).

Insulin receptor/insulin receptor tyrosine kinase

The insulin receptor is a glycoprotein that consists of two a -subunits and two b -subunits linked by disulfide bonds (Fig. 14) [2,160–162]. The two a-

subunits of the insulin receptor are entirely extracellular and contain the insulin-binding domain. The b -subunits have an extracellular domain,

a transmembrane domain, and an intracellular domain that expresses

R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

813

R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835 813 Fig. 14. Insulin transduction system.

Fig. 14. Insulin transduction system. Insulin receptor and the cascade of intracellular signaling molecules that have been implicated in insulin action (see text for a more detailed discussion).

insulin-stimulated kinase activity directed toward its own tyrosine residues. Phosphorylation of the b -subunit, with subsequent activation of insulin receptor tyrosine kinase, represents the first step in the action of insulin on glucose metabolism. Mutagenesis of any of the three major phosphorylation sites (at residues 1158, 1163, and 1162) impairs insulin receptor kinase activity, leading to a decrease in the metabolic and growth-promoting effects of insulin [163,164].

Insulin receptor signal transduction

Following its activation, insulin receptor tyrosine kinase phosphorylates specific intracellular proteins, of which at least nine have been identified [160,165]. In muscle insulin-receptor substrate (IRS)-1 serves as the major docking protein that interacts with the insulin receptor tyrosine kinase and undergoes tyrosine phosphorylation in regions containing specific amino acid sequence motifs that, when phosphorylated, serve as recognition sites for proteins containing src-homology 2 (SH2) domains. Mutation of these specific tyrosines severely impairs the ability of insulin to stimulate muscle glycogen synthesis, glucose oxidation, and other acute metabolic- and growth-promoting effects of insulin [164]. In liver, IRS-2 serves as the primary docking protein that undergoes tyrosine phosphorylation and mediates the effect of insulin on hepatic glucose production, gluconeogen- esis, and glycogen formation [166]. In muscle, the phosphorylated tyrosine residues of IRS-1 mediate an association with the 85-kDa regulatory subunit of phosphatidylinositol 3-kinase (PI3K), leading to activation of the enzyme (see Fig. 14) [160– 162,165,167]. PI3K is composed of an 85-kDa regulatory subunit and a 110- kDa catalytic subunit. The latter catalyzes the 39 phosphorylation of PI 4-phosphate and PI 4,5-diphosphate, resulting in the stimulation of glucose

814 R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

transport. Activation of PI3K by phosphorylated IRS-1 also leads to activation of glycogen synthase through a process that involves activation of protein kinase B/Akt and subsequent inhibition of kinases, such as glycogen synthase kinase-3, and activation of protein phosphatase 1 (PP1) (also called glycogen synthase phosphatase, see later discussion). Inhibitors of PI3K impair glucose transport and block the activation of glycogen synthase and hexokinase (HK)-II expression [160–162,165,167–169]. The action of insulin to increase protein synthesis and inhibit protein degradation also is mediated by PI3K. Other proteins with SH2 domains, including the adapter protein Grb2 and Shc, also interact with IRS-1 and become phosphorylated following exposure to insulin [160–162,165]. Grb2 and Shc link IRS-1/IRS-2 to the mitogen-activated protein kinase (MAPK)-signaling pathway (see Fig. 14), which plays an important role in the generation of transcription factors and promotes cell growth, proliferation, and differentiation [160,165]. Inhibition of the MAPK kinase pathway prevents the stimulation of cell growth by insulin but has no effect on the metabolic actions of the hormone [170]. Under anabolic conditions, insulin augments glycogen synthesis by simultaneously activating glycogen synthase and inhibiting glycogen phos- phorylase [171,172]. The effect of insulin is mediated through the PI3K pathway, which inactivates kinases such as glycogen synthase kinase-3 and activates phosphatases, particularly PP1. PP1 is believed to be the primary regulator of glycogen metabolism. In skeletal muscle, PP1 associates with a specific glycogen-binding regulatory subunit, causing dephosphorylation (activation) of glycogen synthase. PP1 also phosphorylates (inactivates) glycogen phosphorylase. The precise steps that link insulin receptor tyrosine kinase/PI3K activation to stimulation of PP1 have yet to be defined. Studies [160,173] have demonstrated convincingly that inhibitors of PI3K inhibit glycogen synthase activity and abolish glycogen synthesis.

Insulin receptor signal transduction defects in type 2 diabetes

Insulin receptor number and affinity Both receptor and postreceptor defects have been shown to contribute to insulin resistance in individuals with type 2 diabetes mellitus. Some studies have demonstrated a modest 20%–30% reduction in insulin binding to monocytes and adipocytes from type 2 diabetic patients, but this has not been a consistent finding [1,174–177]. The decrease in insulin binding is caused by a reduction in the number of insulin receptors without change in insulin receptor affinity. Some caution, however, should be used in interpreting these studies because muscle and liver not adipocytes are the major tissues responsible for the regulation of glucose homeostasis in vivo, and insulin binding to solubilized receptors obtained from skeletal muscle and liver has been shown to be normal in obese and lean diabetic individuals [175,176,178]. Moreover, a decrease in insulin receptor number cannot be

R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

815

demonstrated in over half of type 2 diabetic subjects, and it has been difficult to demonstrate a correlation between reduced insulin binding and the severity of insulin resistance [179–181]. A variety of defects in insulin receptor internalization and processing have been described in syndromes of severe insulin resistance and diabetes. The insulin receptor gene, however, has been sequenced in a large number of type 2 diabetic patients from diverse ethnic populations and, with very rare exceptions, physiologically significant mutations in the insulin receptor gene have not been observed [182,183]. This excludes a structural gene abnormality in the insulin receptor as a cause of common type 2 diabetes mellitus.

Insulin receptor tyrosine kinase activity Insulin receptor tyrosine kinase activity has been examined in skeletal muscle, adipocytes, and hepatocytes from normal-weight and obese diabetic subjects. Most [1,175,176,179,184,185] but not all [178] investigators have found a reduction in tyrosine kinase activity (Fig. 15) that cannot be explained by alterations in insulin receptor number or insulin receptor binding affinity. Restoration of normoglycemia by weight loss, however, has been shown to correct the defect in insulin receptor tyrosine kinase activity [186], suggesting that the defect in tyrosine kinase is acquired secondary to some combination of hyperglycemia, distributed intracellular glucose metabolism, hyperinsuline- mia, and insulin resistance, all of which improved after weight loss. Exposure of cultured fibroblasts to high glucose concentration also has been shown to

to high glucose concentration also has been shown to Fig. 15. Insulin signaling cascade in T2DM.

Fig. 15. Insulin signaling cascade in T2DM. Effect of insulin on insulin receptor (top) and IRS- 1 tyrosine phosphorylation (bottom) and the association of IRS-1 with the p85 regulatory subunit of PI3K and PI3K activity in muscle from T2DM and control (CON) subjects. Data are expressed as percentages of the mean insulin-stimulated values in the control groups. Open bars, basal state; filled bars, insulin-stimulated state; * P 0.05, T2DM versus CON.

816 R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

inhibit insulin receptor tyrosine kinase activity [187]. Because insulin receptor tyrosine kinase activity assays are performed in vitro, the results of these assays could provide misleading information with regard to insulin receptor function in vivo. To circumvent this problem, investigators have used the euglycemic hyperinsulinemic clamp with muscle biopsies and anti-phospho- tyrosine immunoblot analysis to provide a ‘‘snap shot’’ of the insulin- stimulated tyrosine phosphorylation state of the receptor in vivo [185]. In insulin-resistant obese nondiabetic and type 2 diabetic subjects, a substantial decrease in insulin receptor tyrosine phosphorylation has been demonstrated; however, when insulin-stimulated insulin receptor tyrosine phosphorylation was examined in normal-glucose-tolerant insulin-resistant individuals (off- spring of two diabetic parents) at high risk for developing type 2 diabetes, a normal increase in tyrosine phosphorylation of the insulin receptor was observed [188]. These findings are consistent with the concept that impaired insulin receptor tyrosine kinase activity in type 2 diabetic patients is acquired secondary to hyperglycemia or some other metabolic disturbance.

Insulin-signaling (IRS-1 and PI3K) defects In insulin-resistant obese nondiabetic subjects, the ability of insulin to activate insulin receptor and IRS-1 tyrosine phosphorylation in muscle is modestly reduced, whereas in type 2 diabetics insulin-stimulated insulin receptor and IRS-1 tyrosine phosphorylation are severely impaired (see Fig. 15) [185]. Association of the p85 subunit of PI3K with IRS-1 and activation of PI3K also are greatly attenuated in obese nondiabetic and type 2 diabetic subjects compared with lean healthy controls (see Fig. 15) [185,189,190]. The decrease in insulin-stimulated association of the p85 regulatory subunit of PI3K with IRS-1 is closely correlated with the reduction in insulin-stimulated muscle glycogen synthase activity and in vivo insulin-stimulated glucose disposal [185]. Impaired regulation of PI3K gene expression by insulin also has been demonstrated in skeletal muscle and adipose tissue of type 2 diabetic subjects [191]. In animal models of diabetes, an 80%–90% decrease in insulin-stimulated IRS-1 phosphoryla- tion and PI3K activity has been reported [192]. In the insulin-resistant, normal glucose tolerant offspring of two type 2 diabetic parents, IRS-1 tyrosine phosphorylation and the association of p85 protein/PI3K activity with IRS-1 are markedly decreased despite normal tyrosine phosphorylation of the insulin receptor; these insulin signaling defects are correlated closely with the severity of insulin resistance measured with the euglycemic insulin clamp technique [188]. In summary, impaired association of PI3K with IRS-1 and its subsequent activation are charac- teristic abnormalities in type 2 diabetics, and these defects are correlated closely with in vivo muscle insulin resistance. A common mutation in the IRS-1 gene (Gly-972-Arg) has been associated with type 2 diabetes, insulin resistance, and obesity, but the physiologic significance of this mutation remains to be established [193].

R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

817

Insulin resistance of the PI3K signaling pathway contrasts with an intact stimulation of the MAPK pathway by insulin in insulin-resistant type 2 diabetic and obese nondiabetics individuals [185,189]. Physiologic hyperinsulinemia increases mitogen-activated protein kinase/extracellular signal-regulated kinase 1 activity (MEK-1) and extracellular signal-regulated kinase1/2 phosphorylation activity (ERK) similarly in lean healthy subjects, insulin-resistant obese nondiabetic, and type 2 diabetic patients. Intact stimulation of the MAPK pathway by insulin in the presence of insulin resistance in the PI3K pathway may play an important role in the develop- ment of atherosclerosis [185]. If the metabolic (PI3K) pathway is impaired, plasma glucose levels rise, resulting in increased insulin secretion and hyper- insulinemia. Because insulin receptor function is normal or only modestly impaired, especially early in the natural history of type 2 diabetes, this leads to excessive stimulation of the MAPK (mitogenic) pathway in vascular tissues, with resultant proliferation of vascular smooth muscle cells, increased collagen formation, and increased production of growth factors and inflammatory cytokines [194,195].

Glucose transport

Activation of the insulin signal transduction system in insulin target tissues stimulates glucose transport through a mechanism that involves translocation of a large intracellular pool of glucose transporters (associated with low-density microsomes) to the plasma membrane and their subsequent activation after insertion into the cell membrane [196,197]. There are five major, different facilitative glucose transporters (GLUT) with distinctive tissue distributions (Table 1) [198,199]. GLUT4, the insulin regulatable transporter, is found in insulin-sensitive tissues (muscle and adipocytes), has a K m of approximately 5 mmol/L, which is close to that of the plasma glucose concentration, and is associated with HK-II [198,199]. In adipocytes and muscle, GLUT4 concentration in the plasma membrane increases markedly after exposure to insulin, and this increase is associated with

Table 1 Classification of glucose transport and HK activity according to their tissue distribution and functional regulation

Organ

Glucose transporter

Hexokinase computer

Classification

Brain Erythrocyte Adipocyte Muscle Liver Glucokinase beta cell Gut Kidney

GLUT1

HK-I

Glucose dependent

GLUT1

HK-I

Glucose dependent

GLUT4

HK-II

Insulin dependent

GLUT4

HK-II

Insulin dependent

GLUT2

HK-IVL

Glucose sensor

GLUT2

HK-IVB (glucokinase)

Glucose sensor

GLUT3-symporter

Sodium dependent

GLUT3-symporter

Sodium dependent

Data from DeFronzo RA. Pathogenesis of type 2 diabetes mellitus: metablic and molecular implications for identifying diabetes genes. Diabetes 1997;5:177–269.

818 R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

a reciprocal decline in the intracellular GLUT4 pool. GLUT1 is the

predominant glucose transporter in the insulin-independent tissues (brain and erythrocytes) but also is found in muscle and adipocytes. GLUT1 is located primarily in the plasma membrane where its concentration is unchanged following exposure to insulin. It has a low K m ( 1 mmol/L)

and is well suited for its function, which is to mediate basal glucose uptake.

It is found in association with HK-I [200]. GLUT2 is the predominant

transporter in liver and pancreatic beta cells where it is found in association

with a specific hexokinase, HK-IV or glucokinase [201]. GLUT2 has a very high K m ( 15–20 mmol/L), which allows the glucose concentration in cells

expressing this transporter to increase in direct proportion to the increase in plasma glucose concentration. This unique characteristic allows these cells

to function as glucose sensors.

In adipocytes and muscle of type 2 diabetic patients, glucose transport activity is severely impaired [179,196,197,202–204]. In adipocytes from human and rodent models of type 2 diabetes, GLUT4 mRNA and protein content are markedly reduced, and the ability of insulin to elicit a normal translocation response and to activate the GLUT4 transporter after insertion into the cell membrane is decreased. In contrast to the adipocytes, muscle tissue from lean and obese type 2 diabetic subjects exhibits normal or

increased levels of GLUT4 mRNA expression and normal levels of GLUT4 protein, thus demonstrating that transcriptional and translational regulation

of GLUT4 is not impaired [205,206]. In contrast to the normal expression of

GLUT4 protein and mRNA in muscle of type 2 diabetic subjects, every study

that has examined adipose tissue has reported reduced basal and insulin- stimulated GLUT4 mRNA levels and decreased GLUT4 transporter number

in all subcellular fractions. These observations demonstrate that GLUT4

expression in humans is subject to tissue-specific regulation. Using a novel triple-tracer technique, the in vivo dose-response curve for the action of insulin on glucose transport in forearm skeletal muscle has been examined in type 2 diabetic subjects, and insulin-stimulated inward muscle glucose transport has been shown to be severely impaired [207,208]. Impaired in vivo muscle glucose transport in type 2 diabetics also has been demonstrated using magnetic resonance imaging [209] and positron emission tomography [210]. Because the number of GLUT4 transporters in the muscle of diabetic subjects is normal, impaired GLUT4 translocation and decreased intrinsic activity of the glucose transporter must be responsible for the defect in muscle glucose transport. Large populations of type 2 diabetics have been screened for mutations in the GLUT4 gene [211]. Such mutations are very uncommon and, when detected, have been of questionable physiologic significance.

Glucose phosphorylation

Glucose phosphorylation and glucose transport are tightly coupled phenomena [212]. Hexokinase isoenzymes (HK-I–IV) catalyze the first

R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

819

committed step of glucose metabolism, the intracellular conversion of free glucose to glucose-6-phosphate (Glu-6-P) (see Table 1) [198–200,213]. HK-I, HK-II, and HK-III are single-chain peptides that have a very high affinity for glucose and demonstrate product inhibition by Glu-6-P. HK-IV, also called glucokinase, has a lower affinity for glucose and is not inhibited by Glu-6-P. Glucokinase (HK-IVB) represents the glucose sensor in the beta cell, whereas HK-IVL plays a central role in the regulation of hepatic glucose metabolism. In human skeletal muscle, HK-II transcription is regulated by insulin, whereas HK-I mRNA and protein levels are not affected by insulin [214– 216]. In response to physiologic euglycemic hyperinsulinemia of 2 to 4 hours’ duration, HK-II cytosolic activity, protein content, and mRNA levels increase by 50% to 200% in healthy nondiabetic subjects, and this is associated with the translocation of hexokinase II from the cytosol to the mitochondria. In forearm muscle, insulin-stimulated glucose transport (measured with the triple-tracer technique) is markedly impaired in lean type 2 diabetics [207,208], but the rate of intracellular glucose phosphory- lation is impaired to an even greater extent, resulting in an increase in the free glucose concentration within the intracellular space that is accessible to glucose. These observations indicate that in type 2 diabetic individuals, although both glucose transport and glucose phosphorylation are severely resistant to the action of insulin, impaired glucose phosphorylation (HK-II) appears to be the rate-limiting step for insulin action. Studies using 31 P nuclear magnetic resonance in combination with [1- 14 C]glucose also have demonstrated that both insulin-stimulated muscle glucose transport and glucose phosphorylation are impaired in type 2 diabetic subjects, but the defect in transport exceeds the defect in phosphorylation [209]. Because of methodologic differences, the results of the triple-tracer technique [207,208] and magnetic resonance imaging [209] studies cannot be reconciled at present. Nonetheless, these studies are consistent in demonstrating that abnormalities in both muscle glucose phosphorylation and glucose transport are well established early in the natural history of type 2 diabetes and cannot be explained by glucose toxicity. In healthy nondiabetic subjects, a physiologic increase in the plasma insulin concentration for as little as 2 to 4 hours increases muscle HK-II activity, gene transcription, and translation [214]. In lean type 2 diabetics, the ability of insulin to augment HK-II activity and mRNA levels are markedly reduced compared with controls [215]. Decreased basal muscle HK-II activity and mRNA levels and impaired insulin-stimulated HK-II activity in type 2 diabetic subjects have been reported by other investigators [216,217]. A decrease in insulin-stimulated muscle HK-II activity also has been described in subjects with IGT [218]. Several groups have looked for point mutations in the HK-II gene in individuals with type 2 diabetes, and, although several nucleotide substitutions have been found, none are close to the glucose and ATP binding sites and none have been associated with insulin resistance

820 R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

[218–220]. Thus, an abnormality in the HK-II gene is unlikely to explain the inherited insulin resistance in common variety type 2 diabetes mellitus.

Glycogen synthesis

Following phosphorylation by hexokinase II, glucose either can be converted to glycogen or enter the glycolytic pathway. Of the glucose that enters the glycolytic pathway, approximately 90% is oxidized, and the remaining 10% is released as lactate. At low physiologic plasma insulin concentrations, glycogen synthesis and glucose oxidation contribute equally to glucose disposal; however, with increasing plasma insulin concentrations, glycogen synthesis predominates [1,2,221]. Impaired insulin-stimulated glycogen synthesis is a characteristic finding in all insulin-resistant states, including obesity, IGT, diabetes, and diabesity in all ethnic groups, and accounts for the majority of the defect in insulin-mediated whole-body glucose disposal [1,2,12,98,210,222–224]. Impaired glycogen synthesis also has been documented in the normal-glucose tolerant offspring of two diabetic parents, in the first-degree relatives of type 2 diabetic individuals, and in the normoglycemic twin of a monozygotic twin pair in which the other twin has type 2 diabetes [65,98,225]. Glycogen synthase is the key insulin-regulated enzyme that controls the rate of muscle glycogen synthesis [171,173,216, 226–228]. Insulin activates glycogen synthase by stimulating a cascade of phosphorylation-dephos- phorylation reactions (see above discussion of insulin receptor signal transduction), which ultimately lead to the activation of PP1 (also called glycogen synthase phosphatase). The regulatory subunit of PP1 has two serine phosphorylation sites, called site 1 and site 2. Phosphorylation of site 2 by cAMP-dependent protein kinase inactivates PP1, whereas phosphor- ylation of site 1 by insulin activates PP1, leading to the stimulation of glycogen synthase. Phosphorylation of site 1 of PP1 by insulin in muscle is catalyzed by insulin-stimulated protein kinase (ISPK)-1. Because of their central role in muscle glycogen formation, the three enzymes, glycogen synthase, PP1, and ISPK-1, have been extensively studied in individuals with type 2 diabetes. Glycogen synthase exists in an active (dephosphorylated) and an inactive (phosphorylated) form [171–173]. Under basal conditions, total glycogen synthase activity in type 2 diabetic subjects is reduced, and the ability of insulin to activate glycogen synthase is severely impaired [185,229–231]. The ability of insulin to stimulate glycogen synthase also is diminished in the normal glucose-tolerant, insulin-resistant relatives of type 2 diabetic individuals [232]. In insulin-resistant nondiabetic and diabetic Pima Indians, activation of muscle PP1 (glycogen synthase phosphatase) by insulin is severely reduced [233]. Because PP1 dephosphorylates glycogen synthase, leading to its activation, a defect in PP1 appears to play an important role in the muscle insulin resistance of type 2 diabetes mellitus.

R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

821

The effect of insulin on glycogen synthase gene transcription and trans- lation in vivo has been studied extensively. Most studies have demonstrated that insulin does not increase glycogen synthase mRNA or protein expression in human muscle [214,234,235]. Glycogen synthase mRNA and protein levels, however, are decreased in muscle of type 2 diabetic patients, partly explaining the decreased glycogen synthase activity [235,236]. The major abnormality in glycogen synthase regulation in type 2 diabetes is its lack of dephosphorylation and activation by insulin, as a result of insulin receptor signaling abnormalities (see previous discussion). The glycogen synthase gene has been the subject of intensive investigation, and DNA sequencing has revealed either no mutations or rare nucleotide substitutions that cannot explain the defect in insulin-stimulated glycogen synthase activity [237–239]. The genes encoding the catalytic subunits of PP1 and ISPK-1 have been examined in Pima Indians and Danes with type 2 diabetes [240,241]. Several silent nucleotide substitutions were found in the PP1 and ISPK-1 genes in the Danish population, but the mRNA levels of both genes were normal in skeletal muscle. No structural gene abnormalities in the catalytic subunit of PP1 were detected in Pima Indians. Thus, neither mutations in the PP1 and ISPK-1 genes nor abnormalities in their translation can explain the impaired enzymatic activities of glycogen synthase and PP1 that have been observed in vivo. Similarly, there is no evidence that an alteration in glycogen phosphorylase plays any role in the abnormality in glycogen formation in type 2 diabetes [242]. In summary, glycogen synthase activity is severely impaired in type 2 diabetic individuals, and the molecular cause of the defect most likely is related to impaired insulin signal transduction.

Glycolysis/Glucose oxidation

Glucose oxidation accounts for approximately 90% of total glycolytic flux, whereas anaerobic glycolysis accounts for the other 10%. The two enzymes PFK and PDH play pivotal roles in the regulation of glycolysis and glucose oxidation, respectively. In type 2 diabetic individuals, the glycolytic/ glucose oxidative pathway has been shown to be impaired [243]. Although one study [244] has suggested that PFK activity is modestly reduced in muscle biopsies from type 2 diabetic subjects, most evidence indicates that the activity of PFK is normal [230,235]. Insulin has no effect on muscle PFK activity, mRNA levels, or protein content in either nondiabetic or diabetic individuals [235]. PDH is a key insulin-regulated enzyme with activity in muscle that is acutely stimulated by insulin [245]. In type 2 diabetic patients, insulin-stimulated PDH activity has been shown to be decreased in human adipocytes and in skeletal muscle [245,246]. Obesity and type 2 diabetes mellitus are associated with accelerated FFA turnover and oxidation [1,2,12,247], which would be expected, according to the Randle cycle [248], to inhibit PDH activity and consequently glucose

822 R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

oxidation. Therefore, it is likely that the observed defects in glucose oxidation and PDH activity are acquired secondary to increased FFA oxidation and feedback inhibition of PDH by elevated intracellular levels of acetyl-CoA and reduced availability of NAD. Consistent with this scenario, the rates of basal and insulin-stimulated glucose oxidation are not reduced in the normal glucose-tolerant offspring of two diabetic parents and in the first-degree relatives of type 2 diabetic subjects, whereas it is decreased in overtly diabetic subjects.

Summary

In summary, postbinding defects in insulin action primarily are re- sponsible for the insulin resistance in type 2 diabetes. Diminished insulin binding, when present, is modest and secondary to down-regulation of the insulin receptor by chronic hyperinsulinemia. In type 2 diabetic patients with overt fasting hyperglycemia, a number of postbinding defects have been demonstrated, including reduced insulin receptor tyrosine kinase activity, insulin signal transduction abnormalities, decreased glucose trans- port, diminished glucose phosphorylation, and impaired glycogen synthase activity. The glycolytic/glucose oxidative pathway is largely intact and, when defects are observed, they appear to be acquired secondary to enhanced FFA/lipid oxidation. From the quantitative standpoint, impaired glycogen synthesis represents the major pathway responsible for the insulin resistance in type 2 diabetes and is present long before the onset of overt diabetes, that is, in normal glucose-tolerant, insulin-resistant prediabetic subjects and in individuals with IGT. Recent studies link the impairment in glycogen synthase activation to a defect in the ability of insulin to phosphorylate IRS-1, causing a reduced association of the p85 subunit of PI 3-kinase with IRS-1 and decreased activation of the enzyme PI3K.

References

[1] DeFronzo RA. Pathogenesis of type 2 diabetes mellitus: metabolic and molecular implications for identifying diabetes genes. Diabetes 1997;5:177–269. [2] DeFronzo RA. Lecture Lilly. The triumvirate: beta cell, muscle, liver. A collusion responsible for NIDDM. Diabetes 1988;37:667–87. [3] DeFronzo RA, Jacot E, Jequier E, Maeder E, Wahren J, Felber JP. The effect of insulin on the disposal of intravenous glucose: results from indirect calorimetry. Diabetes 1981;

30:1000–7.

[4] DeFronzo RA, Ferrannini E. Regulation of hepatic glucose metabolism in humans. Diabetes Metab Rev 1987;3:415–59. [5] DeFronzo RA, Gunnarsson R, Bjorkman O, Olsson M, Wahren J. Effects of insulin on peripheral and splanchnic glucose metabolism in non-insulin dependent diabetes mellitus. J Clin Invest 1985;76:149–55. [6] Mari A, Wahren J, DeFronzo RA, Ferrannini E. Glucose absorption and production following oral glucose: comparison of compartmental and arteriovenous-difference methods. Metabolism 1994;43:1419–25.

R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

823

[7] Mandarino L, Bonadonna R, McGuinness O, Wasserman D. Regulation of muscle glucose uptake in vivo. In: Jefferson LS, Cherrington AD, editors. Handbook of physiology. The endocrine system, vol. II The endocrine pancreas and regulation of metabolism. Oxford: Oxford University Press; 2001. p. 803–48. [8] Mitrakou A, Kelley D, Veneman T, Jensen T, Pangburn T, Reilly J, et al. Contribution of abnormal muscle and liver glucose metabolism to postprandial hyperglycemia in NIDDM. Diabetes 1990;39:1381–90. [9] Cherrington AD. Control of glucose uptake and release by the liver in vivo. Diabetes

1999;48:1198–214.

[10] Grill V. A comparison of brain glucose metabolism in diabetes as measured by positron emission tomography or by arteriovenous techniques. Ann Med 1990;22:171–5. [11] Bays H, Mandarino L, DeFronzo RA. Role of the adipocyte, free fatty acids, and ectopic fat in pathogenesis of type 2 diabetes mellitus: peroxisomal proliferator-activated receptor agonsits provide a rational therapeutic approach. J Clin Endocrinol Metab 2004;89:

463–78.

[12] Groop LC, Bonadonna RC, Del Prato S, Ratheiser K, Zych K, Ferrannini E, DeFronzo RA. Glucose and free fatty acid metabolism in non-insulin dependent diabetes mellitus. Evidence for multiple sites of insulin resistance. J Clin Invest 1989;84:205–15. [13] Bergman RN. Non-esterified fatty acids and the liver: why is insulin secreted into the portal vein? Diabetologia 2000;43:946–52. [14] Boden G. Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes 1997;46:3–10. [15] Baron AD, Schaeffer L, Shragg P, Kolterman OG. Role of hyperglucagonemia in maintenance of increased rates of hepatic glucose output in type II diabetics. Diabetes

1987;36:274–83.

[16] DeFronzo RA, Ferrannini E, Hendler R, Wahren J, Felig P. Influence of hyper- insulinemia, hyperglycemia, and the route of glucose administration on splanchnic glucose exchange. Proc Natl Acad Sci USA 1978;75:5173–7. [17] Ferrannini E, Wahren J, Felig P, DeFronzo RA. Role of fractional glucose extraction in the regulation of splanchnic glucose metabolism in normal and diabetic man. Metabolism

1980;29:28–35.

[18] Drucker DJ. Glucagon-like peptides. Diabetes 1998;47:159–69. [19] Holst JJ, Gromada J, Nauck MA. The pathogenesis of NIDDM involves a defective expression of the GIP receptor. Diabetologia 1997;40:984–6. [20] Polonsky KS, Sturis J, Bell GI. Non-insulin-dependent diabetes mellitus: a genetically programmed failure of the beta cell to compensate for insulin resistance. N Engl J Med

1996;334:777–83.

[21] Cerasi E. Insulin deficiency and insulin resistance in the pathogenesis of NIDDM: is a divorce possible? Diabetologia 1995;38:992–7. [22] Sicree RA, Zimmet P, King HO, Coventry JO. Plasma insulin response among Nauruans. Prediction of deterioration in glucose tolerance over 6 years. Diabetes 1987;36:179–86. [23] Saad MF, Knowler WC, Pettitt DJ, Nelson RG, Mott DM, Bennett PH. Sequential changes in serum insulin concentration during development of non-insulin-dependent diabetes. Lancet 1989;i:1356–9. [24] Saad MF, Knowler WC, Pettitt DJ, Nelson RG, Mott DM, Bennett PH. The natural history of impaired glucose tolerance in the Pima Indians. N Engl J Med 1988;319:

1500–5.

[25] Haffner SM, Miettinen H, Gaskill SP, Stern MP. Decreased insulin secretion and increased insulin resistance are independently related to the 7-year risk of NIDDM in Mexican-Americans. Diabetes 1995;44:1386–91. [26] Weyer C, Hanson RL, Tataranni PA, Bogardus C, Pratley RE. A high fasting plasma insulin concentration predicts type 2 diabetes independent of insulin resistance. Evidence for a pathogenic role of relative hyperinsulinemia. Diabetes 2000;49:2094–101.

824 R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

[27] Weyer C, Tataranni PA, Bogardus C, Pratley RE. Insulin resistance and insulin secretory dysfunction are independent predictors of worsening of glucose tolerance during each stage of type 2 diabetes development. Diabetes Care 2000;24:89–94. [28] Pimenta W, Korytkowski M, Mitrakou A, Jenssen T, Yki-Jarvinen H, Evron W, et al. Pancreatic beta-cell dysfunction as the primary genetic lesion in NIDDM. Evidence from studies in normal glucose-tolerant individuals with a first degree NIDDM relative. JAMA

1995;273:1855–61.

Eriksson J, Franssila-Kallunki A, Ekstrand A, Saloranta C, Widen E, Schalin C, et al. Early

metabolic defects in persons at increased risk for non-insulin-dependent diabetes mellitus. N Engl J Med 1989;321:337–43. [30] Reaven GM, Hollenbeck C, Jeng C-Y, Wu MS, Chen Y-DI. Measurement of plasma glucose, free fatty acid, lactate, and insulin for 24 hours in patients with NIDDM. Diabetes

[29]

1988;37:1020–4.

[31] Garvey WT, Olefsky JM, Rubenstein AH, Kolterman OG. Day-long integrated urinary C-peptide excretion. Diabetes 1988;37:590–9. [32] Gastaldelli A, Ferrannini E, Miyazaki Y, Matsuda M, DeFronzo RA. Beta-cell dysfunction and glucose intolerance: results from the San Antonio metabolism (SAM) study. Diabetologia 2004;47:31–9. [33] Hansen BC, Bodkin NH. Heterogeneity of insulin responses: phases leading to type 2 (noninsulin-dependent) diabetes mellitus in the rhesus monkey. Diabetologia 1986;29:

713–9.

[34] Kahn SE. Clinical Review 135. The importance of b -cell failure in the development and progression of type 2 diabetes. J Clin Endocrinol Metab 2001;86:4047–58. [35] Bergman RN, Finegood DT, Kahn SE. The evolution of b-cell dysfunction and insulin resistance in type 2 diabetes. Eur J Clin Invest 2002;32:35–45. [36] Polonsky KS. Lilly Lecture 1994. The beta cell in diabetes: from molecular genetics to clinical research. Diabetes 1995;44:705–17. [37] Bell GI, Polonsky KS. Diabetes mellitus and genetically programmed defects in b -cell function. Nature 2001;414:788–91. [38] McCarthy MI, Froguel P. Genetic approaches to the molecular understanding of type 2 diabetes. Am J Physiol 2002;283:E217–25. [39] Bell GI, Zian K, Newman M, Wu S, Wright L, Fajans S, Spielman RS, Cox NJ. Gene for non-insulin-dependent diabetes mellitus (maturity-onset diabetes of the young subtype) is linked to DNA polymorphism on human chromosome 20q. Proc Natl Acad Sci USA

1991;88:1484–8.

[40] Froguel PH, Zouali H, Vionnet N, Velho G, Vaxillaire M, Sun F, et al. Familial hyperglycaemia due to mutations in glucokinase: definition of a subtype of diabetes mellitus. N Engl J Med 1993;328:697–702. [41] Beck-Nielsen H, Nielsen OH, Pedersen O, Bak J, Faber O, Schmitz O. Insulin action and insulin secretion in identical twins with MODY: evidence for defects in both insulin action and insulin secretion. Diabetes 1988;37:730–5. [42] Mohan V, Sharp PS, Aber VR, Mather HM, Kohner EM. Insulin resistance in maturity- onset diabetes of the young. Diabetes Metab 1988;13:193–7. [43] Elbein SC, Hoffman M, Qin H, Chiu K, Tanizawa Y, Permutt MA. Molecular screening of the glucokinase gene in familial type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 1994;37:182–7. [44] Efendic S, Grill V, Luft R, Wajngot A. Low insulin response: a marker of pre-diabetes. Adv Exp Med Biol 1988;246:167–74. [45] Davies MJ, Metcalfe J, Gray IP, Day JL, Hales CN. Insulin deficiency rather than hyperinsulinaemia in newly diagnosed type 2 diabetes mellitus. Diabet Med 1993;10:

305–12.

[46] Chen K-W, Boyko EJ, Bergstrom RW, Leonetti DL, Newell-Morris L, Wahl PW, et al. Earlier appearance of impaired insulin secretion than of visceral adiposity in the

R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

825

pathogenesis of NIDDM. 5-year follow-up of initially nondiabetic Japanese-American men. Diabetes Care 1995;18:747–53. [47] Arner P, Pollare T, Lithell H. Different etiologies of Type 2 (non-insulin-dependent) diabetes mellitus in obese and non-obese subjects. Diabetologia 1991;34:483–7. [48] Ferrannini E, Natali A, Bell P, Cavallo-Perin P, Lalic N, Mingrone G. Insulin resistance and hypersecretion in obesity. European Group for the Study of Insulin Resistance (EGIR). J Clin Invest 1997;100:1166–73. [49] Banjeri MA, Lebovitz HE. Insulin action in black Americans with NIDDM. Diabetes Care 1992;15:1295–302. [50] Mbanya J-CN, Pani LN, Mbanya DNS, Sobngwi E, Ngogang J. Reduced insulin secretion in offspring of African type 2 diabetic patients. Diabetes Care 2000;23:1761–5. [51] DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 1979;6:E214–23. [52] Hales CN. The pathogenesis of NIDDM. Diabetologia 1994;37:S162–8. [53] Brunzell JD, Robertson RP, Lerner RL, Hazzard WR, Ensinck JW, Bierman EL, et al. Relationships between fasting plasma glucose levels and insulin secretion during intravenous glucose tolerance tests. J Clin Endocrinol 1976;46:222–9. [54] Vague P, Moulin J-P. The defective glucose sensitivity of the B cell in insulin dependent diabetes. Improvement after twenty hours of normoglycaemia. Metabolism 1982;31:

139–42.

[55] Kosaka K, Kuzuya T, Akanuma Y, Hagura R. Increase in insulin response after treatment of overt maturity onset diabetes mellitus is independent of the mode of treatment. Diabetologia 1980;18:23–8. [56] Rossetti L, Giaccari A, DeFronzo RA. Glucose toxicity. Diabetes Care 1990;13:610–30. [57] Unger RH. Lipotoxicity in the pathogenesis of obesity-dependent NIDDM. Genetic and clinical implications. Diabetes 1995;44:863–70. [58] McGarry JD. Banting lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. Diabetes 2002;51:7–18. [59] Shimabukuro M, Zhou Y-T, Levi M, Unger RH. Fatty acid induced b cell apoptosis:

a link between obesity and diabetes. Proc Natl Acad Sci USA 1998;95:2498–502. [60] Bruce DG, Chisholm DJ, Storlien LH, Kraegen EW. Physiological importance of deficiency in early prandial insulin secretion in non-insulin dependent diabetes. Diabetes

1988;37:736–44.

[61] Luzi L. Effect of the loss of first phase insulin secretion on glucose production and disposal in man. Am J Physiol 1989;257:E241–6. [62] Bonner-Weir S. b-cell turnover. Its assessment and implications. Diabetes 2001;50:S20–4. [63] Gautier J-F, Wilson C, Weyer C, Mott D, Knowler WC, Cavaghan M, et al. Low acute insulin secretory responses in adult offspring of people with early onset type 2 diabetes. Diabetes 2001;50:1828–33. [64] Vauhkonen N, Niskanen L, Vanninen E, Kainulainen S, Uusitupa M, Laakso M. Defects in insulin secretion and insulin action in non-insulin-dependent diabetes mellitus are inherited. Metabolic studies on offspring of diabetic probands. J Clin Invest 1997;100:

86–96.

[65] Vaag A, Henriksen JE, Madsbad S, Holm N, Beck-Nielsen H. Insulin secretion, insulin action, and hepatic glucose production in identical twins discordant for non-insulin- dependent diabetes mellitus. J Clin Invest 1995;95:690–8. [66] Barnett AH, Spilipoulos AJ, Pyke DA, Stubbs WA, Burrin J, Alberti KGMM. Metabolic studies in unaffected co-twins of non-insulin-dependent diabetics. BMJ 1981;282:1656–8. [67] Watanabe RM, Valle T, Hauser ER, Ghosh S, Eriksson J, Kohtamaki K, Ehnholm C, Tuomilehto J, Collins FS, Bergman RN, Boehnke M. Familiality of quantitative metabolic traits in Finnish families with non-insulin-dependent diabetes mellitus. Finland-United States Investigation of NIDDM Genetics (FUSION) Study investigators. Hum Hered

1999;49(3):159–68.

826 R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

[68] Rossetti L, Shulman Gi, Zawalich W, DeFronzo RA. Effect of chronic hyperglycemia on in vivo insulin secretion in partially pancreatectomized rats. J Clin Invest 1987;80:

1037–44.

[69] Leahy JL, Bonner-Weir S, Weir GC. Minimal chronic hyperglycemia is a critical determinant of impaired insulin secretion after an incomplete pancreatectomy. J Clin Invest 1988;81:1407–14. [70] Leahy JL, Cooper HE, Weir GC. Impaired insulin secretion associated with near normoglycemia. Diabetes 1987;36:459–64. [71] Robertson RP, Olson IK, Zhang H-J. Differentiating glucose toxicity from glucose desensitization: a new message from the insulin gene. Diabetes 1994;43:1085–9. [72] Prentki M, Corkey BE. Are the beta cell signaling molecules malonyl-CoA and cytosolic long-chain acyl-CoA implicated in multiple tissue defects of obesity and NIDDM? Diabetes 1996;45:273–83. [73] Creutzfeldt W. The incretin concept today. Diabetologia 1979;16:75–85. [74] Drucker DJ. The glucagon-like peptides. Endocrinology [minireview] 2001;142:521–7. [75] Nauck MA, Bartels E, Orskov C, Ebert R, Creutzfeldt W. Additive insulinotropic effects of exogenous synthetic human gastric inhibitory polypeptide and glucagon-like peptide-1- (7–36) amide infused at near-physiological insulinotropic hormone and glucose concentrations. J Clin Endocrinol Metab 1993;76:912–7. [76] Vilsboll T, Krarup T, Deacon CF, Madsbad S, Holst JJ. Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes 2001;50:609–13. [77] Ahren B, Larsson H, Holst JJ. Effects of glucagon-like peptide-1 on islet function and insulin sensitivity in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab

1997;82:473–8.

[78] D’Alessio DA, Vogel R, Prigeon R, Laschansky E, Koerker D, Eng J, Ensinck JW. Elimination of the action of glucagon-like peptide 1 causes an impairment of glucose tolerance after nutrient ingestion by healthy baboons. J Clin Invest 1996;97:133–8. [79] Nanauck MA, Kleine N, Orskov C, Holst JJ, Willms B, Creutzfeldt W. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7–36 amide) in type 2 (non- insulin-dependent) diabetic patients. Diabetologia 1993;36:741–4. [80] Xu G, Stoffers DA, Habener JF, Bonner-Weir S. Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats. Diabetes 1999;48:2270–6. [81] Kahn SE, Andrikopoulos S, Verchere CB. Islet amyloid. A long-recognized but underappreciated pathological feature of type 2 diabetes. Diabetes 1999;48:241–53. [82] Johnson KH, O’Brien TD, Betysholtz C, Westermark P. Islet amyloid, islet-amyloid polypeptide, and diabetes mellitus. N Engl J Med 1989;321:513–8. [83] Howard CF. Longitudinal studies on the development of diabetes in individual Macaca nigra. Diabetologia 1986;29:301–6. [84] Bretherton-Watt D, Gilbey SG, Ghatei MA, Beacham J, Bloom SR. Failure to establish islet amyloid polypeptide (amylin) as a circulating beta cell inhibiting hormone in man. Diabetologia 1990;33:115–7. [85] Hoppener JWM, Verbeek JS, de Koning EJP, Oosterwijk C, van Hulst KL, Visser- Vernooy HJ, et al. Chronic overproduction of islet amyloid polypeptide-amylin in transgenic mice: lysosomal localization of human islet amyloid polypeptide and lack of marked hyperglycaemia or hyperinsulinaemia. Diabetologia 1993;36:1258–65. [86] Gebre-Medhin S, Olofsson C, Mulder H. Islet amyloid polypeptide in the islets of Langerhans: friend or foe? Diabetologia 2000;43:687–95. [87] Gepts W, Lecompte PM. The pancreatic islets in diabetes. Am J Med 1981;70:105–14. [88] Kloppel G, Lohr M, Habich K, Oberholzer M, Heitz PU. Islet pathology and the pathogenesis of type I and type 2 diabetes mellitus revisited. Surv Synth Path Res 1985;4:

R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

827

[89] Clark A, Wells CA, Buley ID, Cruickshank JK, Vanhegan RI, Matthews DR, et al. Islet amyloid, increased alpha-cells, reduced beta-cells and exocrine fibrosis: quantitative changes in the pancreas in type 2 diabetes. Diabetes Res 1988;9:151–9. [90] Butler AE, Janson J, Bonner-Weir S, Ritzel RA, Butler PC. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 2003;52:102–10. [91] Stefan Y, Orci L, Malaisse-Lagae F, Perrelet A, Patel Y, Unger R. Quantitation of endocrine cell content in the pancreas of non-diabetic and diabetic humans. Diabetes

1982;31:694–700.

[92] Rahier J, Sempoux C, Moulin P, Guiot Y. No decrease of the B cell mass in type 2 diabetic patients. Diabetologia 2000;43(Suppl 1):A65. [93] Janson J, Butler AE, Bonner-Weir S, Ritzel RA, Sultana C, Butler PC. Failure of compensatory increase in new islet formation in humans with type-2 diabetes mellitus. Diabetes 2002;51(Suppl 2):A377. [94] Finegood DT, McArthur D, Kojwang M, Thomas J, Topp BG, Leonard T, et al. b-cell mass dynamics in Zucker diabetic fatty rats: rosiglitazone prevents the rise in net cell death. Diabetes 2000;50:1021–9. [95] Eriksson UJ. Lifelong consequences of metabolic adaptations in utero? Diabetologia

1996;39:1123–5.

[96] Phillips DIW. Insulin resistance as a programmed response to fetal under nutrition. Diabetologia 1996;39:1119–22. [97] Reaven GM, Hollenbeck CB, Chen YDI. Relationship between glucose tolerance, insulin secretion, and insulin action in non-obese individuals with varying degrees of glucose tolerance. Diabetologia 1989;32:52–5. [98] Gulli G, Ferrannini E, Stern M, Haffner S, DeFronzo RA. The metabolic profile of NIDDM is fully established in glucose-tolerant offspring of two Mexican-American NIDDM parents. Diabetes 1992;41:1575–86. [99] Martin BC, Warram JH, Krolewski AS, Bergman RN, Soeldner JS, Kahn RC. Role of glucose and insulin resistance in development of type 2 diabetes mellitus: results of a 25-year follow-up study. Lancet 1992;340:925–9. [100] Hara H, Egusa G Yamakido M, Kawate R. The high prevalence of diabetes mellitus and hyperinsulinemia among the Japanese-Americans living in Hawaii and Los Angeles. Diabetes Res Clin Pract 1994;24(Suppl 1):S37–42. [101] Lillioja S, Nyomba BL, Saad MF, Ferraro R, Castillo C, Bennett PH, et al. Exaggerated early insulin release and insulin resistance in a diabetes-prone population:

a metabolic comparison of Pima Indians and Caucasians. J Clin Endocrinol Metab

1991;73:866–76.

[102] Lillioja S, Mott DM, Howard BV, Bennett PH, Yki-Jarvinen H, Freymond D, Nyomba BL, Zurlo F, Swinburn B, Bogardus C. Impaired glucose tolerance as a disorder of insulin action. Longitudinal and cross-sectional studies in Pima Indians. N Engl J Med 1988;318:

1217–25.

[103] Himsworth HP, Kerr RB. Insulin-sensitive and insulin-insensitive types of diabetes mellitus. Clin Sci (Lond) 1939;4:120–52. [104] Ginsberg H, Kimmerling G, Olefsky JM, Reaven GM. Demonstration of insulin resistance in untreated adult-onset diabetic subjects with fasting hyperglycemia. J Clin Invest 1975;55:454–61. [105] Butterfield WJH, Whichelow MJ. Peripheral glucose metabolism in control subjects and diabetic patients during glucose, glucose-insulin, and insulin sensitivity tests. Diabetologia

1965;1:43–53.

[106] Katz H, Homan M, Jensen M, Caumo A, Cobelli C, Rizza R. Assessment of insulin action in NIDDM in the presence of dynamic changes in insulin and glucose concentration. Diabetes 1994;43:289–96. [107] Bergman RN, Lecture Lilly. Toward physiological understanding of glucose tolerance:

minimal-model approach. Diabetes 1989;38:1512–26.

828 R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

[108] DeFronzo RA, Deibert D, Hendler R, Felig P. Insulin sensitivity and insulin binding to monocytes in maturity-onset diabetes. J Clin Invest 1982;63:939–46.

[109] DeFronzo RA, Sherwin RS, Hendler R, Felig P. Insulin binding to monocytes and insulin action in human obesity, starvation, and refeeding. J Clin Invest 1978;62:204–13. [110] Firth R, Bell P, Rizza R. Insulin action in non-insulin-dependent diabetes mellitus: the relationship between hepatic and extrahepatic insulin resistance and obesity. Metabolism

1987;36:1091–5.

[111] Campbell PJ, Mandarino LJ, Gerich JE. Quantification of the relative impairment in actions of insulin on hepatic glucose production and peripheral glucose uptake in non- insulin dependent diabetes mellitus. Metabolism 1988;37:15–21. [112] Bogardus C, Lillioja S, Howard BV, Reaven G, Mott D. Relationships between insulin secretion, insulin action, and fasting plasma glucose concentration in non-diabetic and noninsulin-dependent subjects. J Clin Invest 1984;74:1238–46.

Del Prato S, Simonson DC, Sheehan P, Cardi F, DeFronzo RA. Studies on the mass effect of

glucose in diabetes. Evidence for glucose resistance. Diabetologia 1997;40:687–97. [114] DeFronzo RA, Ferrannini E, Simonson DC. J Fasting hyperglycemia in non-insulin- dependent diabetes mellitus: contributions of excessive hepatic glucose production and impaired tissue glucose uptake. Metabolism 1989;38:387–95. [115] Huang SC, Phelps ME, Hoffman EJ, Sideris K, Selin CJ, Kuhl DE. Non-invasive determination of local cerebral metabolic rate of glucose in man. Am J Physiol 1980;238:

[113]

E69–82.

[116] Best JD, Judzewitsch RG, Pfeiffer MA, Beard JC, Halter JB, Porte D. The effect of chronic sulfonylurea therapy on hepatic glucose production in non-insulin-dependent diabetes mellitus. Diabetes 1982;31:333–8. [117] Fery F. Role of hepatic glucose production and glucose uptake in the pathogenesis of fasting hyperglycemia in Type 2 diabetes: normalization of glucose kinetics by short-term fasting. J Clin Endocrinol Metab 1994;78:536–42. [118] Jeng C-Y, Sheu WHH, Fuh MM-T, Chen I, Reaven GM. Relationship between hepatic glucose production and fasting plasma glucose concentration in patients with NIDDM. Diabetes 1994;43:1440–4. [119] Waldhausl W, Bratusch-Marrain P, Gasic S, Korn A, Nowotny P. Insulin production rate, hepatic insulin retention, and splanchnic carbohydrate metabolism after oral glucose ingestion in hyperinsulinemic type II (non-insulin dependent) diabetes mellitus. Diabetologia 1982;23:6–15. [120] Nurjhan N, Consoli A, Gerich J. Increased lipolysis and its consequences on gluconeogenesis in noninsulin-dependent diabetes mellitus. J Clin Invest 1992;89:169–75. [121] Stumvoll M, Perriello G, Nurjhan N, Bucci A, Welle S, Jansson P-A, et al. Glutamine and alanine metabolism in NIDDM. Diabetes 1996;45:863–8. [122] Magnusson I, Rothman D, Katz L, Shulman R, Shulman G. Increased rate of gluconeogenesis in type II diabetes: a 13C nuclear magnetic resonance study. J Clin Invest

1992;90:1323–7.

[123] Gastaldelli A, Baldi S, Pettiti M, Toschi E, Camastra S, Natali A, et al. Influence of obesity and type 2 diabetes on gluconeogenesis and glucose output in humans:

a quantitative study. Diabetes 2000;49:1367–73. [124] Clore JN, Stillman J, Sugerman H. Glucose-6-phosphatase flux in vitro is increased in type 2 diabetes. Diabetes 2000;49:969–74. [125] Gerich JE, Meyer C, Woerle HJ, Stumvoll M. Renal gluconeogenesis. Its importance in human glucose homeostasis. Diabetes Care 2001;24:382–91. [126] Ekberg K, Landau BR, Wajngot A, Chandramouli V, Efendic S, Brunengraber H, et al. Contributions by kidney and liver to glucose production in the postabsorptive state and after 60 h of fasting. Diabetes 1999;48:292–8. [127] Moller N, Rizza RA, Ford GC, Nair KS. Assessment of postabsorptive renal glucose metabolism in humans with multiple glucose tracers. Diabetes 2001;50:747–51.

R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

829

[128] Meyer C, Stumvoll M, Nadkarni V, Dostou J, Mitrakou A, Gerich J. Abnormal renal and hepatic glucose metabolism in type 2 diabetes mellitus. J Clin Invest 1998;102:619–24. [129] DeFronzo RA, Ferrannini E, Hendler R, Felig P, Wahren J. Regulation of splanchnic and peripheral glucose uptake by insulin and hyperglycemia. Diabetes 1983;32:35–45. [130] Frayn KN, Coppack SW, Humphreys SM, Whyte PL. Metabolic characteristics of human adipose tissue in vivo. Clin Sci 1989;76:509–16. [131] Ferrannini E, Bjorkman O, Reichard GA Jr, Pilo A, Olsson M, Wahren J, et al. The disposal of an oral glucose load in healthy subjects. Diabetes 1985;34:580–8. [132] Katz LD, Glickman MG, Rapoport S, Ferrannini E, DeFronzo RA. Splanchnic and peripheral disposal of oral glucose in man. Diabetes 1983;32:675–9. [133] Ferrannini E, Simonson DC, Katz LD, Reichard G Jr, Bevilacqua S, Barrett EJ, et al. The disposal of an oral glucose load in patients with non-insulin dependent diabetes. Metabolism 1988;37:79–85. [134] Firth RG, Bell PM, Marsh HM, Hansen I, Rizza RA. Postprandial hyperglycemia in

patients with non-insulin-dependent diabetes mellitus. J Clin Invest 1986;77:1525–32. [135] Kelley D, Mitrakou A, Marsh H, Schwenk F, Benn J, Sonnenberg G, et al. Skeletal muscle glycolysis oxidation, and storage of an oral glucose load. J Clin Invest 1988;81:1563–71.

Jackson RA, Roshania RD, Hawa MI, Sim BM, DiSilvio L. Impact of glucose ingestion on

[136]

hepatic and peripheral glucose metabolism in man: an analysis based on simultaneous use of the forearm and double isotope techniques. J Clin Endocrinol Metab 1986;63:541–9. [137] Ludvik B, Nolan JJ, Roberts A, Baloga J, Joyce M, Bell Jo M, et al. Evidence for decreased splanchnic glucose uptake after oral glucose administration in non-insulin- dependent diabetes mellitus. J Clin Invest 1997;100:2354–61. [138] Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults:

findings from the third National Health and Nutrition Examination Survey. JAMA 2002;

287:356–9.

[139] DeFronzo RA, Ferrannini E. Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and ASCVD. Diabetes Care 1991;14:

173–94.

[140] Reaven GM, Brand RJ, Ida Chen Y-D, Mathur AK, Goldfine I. Insulin resistance and insulin secretion are determinants of oral glucose tolerance in normal individuals. Diabetes 1993;42:1324–32. [141] Diamond MP, Thornton K, Connolly-Diamond M, Sherwin RS, DeFronzo RA. Reciprocal variations in insulin-stimulated glucose uptake and pancreatic insulin secretion in women with normal glucose tolerance. J Soc Gynecol Invest 1995;2:708–15. [142] Reaven GM, Chen Y-DI, Donner CC, Fraze E, Hollenbeck CB. How insulin resistant are patients with non-insulin-dependent diabetes mellitus? J Clin Endocrinol Metab 1985;61:

32–6.

[143] Bogardus C, Lillioja S, Howard BV, Reaven G, Mott D. Relationships between insulin secretion, insulin action, and fasting plasma glucose concentration in non-diabetic and noninsulin-dependent subjects. J Clin Invest 1984;74:1238–46. [144] Dowse GK, Zimmet PZ, Collins VR. Insulin levels and the natural history of glucose intolerance in Nauruans. Diabetes 1996;45:1367–72. [145] Haffner SM, Stern MP, Hazuda HP, Pugh JA, Patterson JK. Hyperinsulinemia in a population at high risk for non-insulin-dependent diabetes mellitus. N Engl J Med 1986;

315:220–4.

[146] Haffner SM, Miettinen H, Stern MP. Insulin secretion and resistance in nondiabetic Mexican Americans and non-Hispanic whites with a parental history of diabetes. J Clin Endocrinol Metab 1996;81:1846–51. [147] Mokdad AH, Ford ES, Bowman BA, Nelson DE, Engelgau MM, Vinicor F, et al. Diabetes trends in the United States, 1990–1998. Diabetes Care 2000;23:1278–83. [148] Thiebaud D, DeFronzo RA, Jacot E, Golay A, Acheson K, Maeder E, et al. Effect of long- chain triglyceride infusion on glucose metabolism in man. Metabolism 1982;31:1128–36.

830 R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

[149] De Kelley, Mandarino LJ. Fuel selection in human skeletal muscle in insulin resistance. A reexamination. Diabetes 2000;49:677–83. [150] Kashyap S, Belfort R, Gastadelli A, Pratipanawatr T, Berria R, Pratipanawatr W, et al. Chronic elevation in plasma free fatty acids impairs insulin secretion in non-diabetic offspring with a strong family history of T2DM. Diabetes 2003;52:2464–74. [151] Carpentier A, Mittelman SD, Bergman RN, Giacca A, Lewis GF. Prolonged elevation of plasma free fatty acids impairs pancreatic beta-cell function in obese nondiabetic humans but not in individuals with type 2 diabetes. Diabetes 2000;49:399–408. [152] Reaven GM. The fourth Musketeer: from Alexendre Dumas to Calude Bernard. Diabetologia 1995;38:3–13. [153] Goodpaster BH, Thaete FL, Kelley BE. Thigh adipose tissue distribution is associated with insulin resistance in obesity and in type 2 diabetes mellitus. Am J Clin Nutr 2000;71:

885–92.

[154] Greco AV, Mingrone G, Giancaterini A, Manco M, Morroni M, Cinti S, et al. Insulin resistance in morbid obesity. Reversal with intramyocellular fat depletion. Diabetes 2002;

51:144–51.

[155] Ryysy L, Hakkinen AM, Goto T, Vehkavaara S, Westerbacka J, Halavaara J, et al. Hepatic fat content and insulin action on free fatty acids and glucose metabolism rather than insulin absorption are associated with insulin requirements during insulin therapy in type 2 diabetic patients. Diabetes 2000;49:749–58. [156] Bajaj M, Surraamornkul S, Piper P, Hardies LJ, Glass L, Cersosimo E, et al. Decreased plasma adiponectin concentrations are closely related to hepatic fat content and hepatic insulin resistance in pioglitazone-treated type 2 diabetic patients. J Clin Endocrinol Metab 2004;89:200–6. [157] Itani SI, Ruderman NB, Schmieder F, Boden G. Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and I j B-a. Diabetes 2002;51:2005–11. [158] Ellis BA, Poynten A, Lowy AJ, Furler SM, Chisholm DJ, Kraegen EW, et al. Long-chain acyl-CoA esters as indicators of lipid metabolism and insulin sensitivity in rat and human muscle. Am J Physiol 2000;279:E554–60. [159] Schmitz-Peiffer C, Craig DL, Biden TJ. Ceramide generation is sufficient to account for the inhibition of the insulin-stimulated PKB pathway in C 2 C 12 skeletal muscle cells pretreated with palmitate. J Biol Chem 1999;274:24202–10. [160] Saltiel AR, Kahn CR. Insulin signaling and the regulation of glucose and lipid metabolism. Nature 2001;414:799–806. [161] Pessin JE, Saltiel AR. Signaling pathways in insulin action: molecular targets of insulin resistance. J Clin Invest 2000;106:165–9. [162] Whitehead JP, Clark SF, Urso B, James DE. Signaling through the insulin receptor. Cur Opin Cell Biol 2000;12:222–8. [163] Ellis LE, Clauser E, Morgan ME, Roth RA, Rutter WJ. Replacement of insulin receptor tyrosine residues 1162 and 1163 compromises insulin-stimulated kinase activity and uptake of 2-dexoyglucose. Cell 1986;45:721–32. [164] Chou DK, Dull TJ, Russell DS, Gherzi R, Lebwohl D, Ullrich A, et al. Human insulin receptors mutated at the ATP-binding site lack protein tyrosine kinase activity and fail to mediate postreceptor effects of insulin. J Biol Chem 1987;262:1842–7. [165] Virkamaki A, Ueki K, Kahn CR. Protein-protein interaction in insulin signaling and the molecular mechanisms of insulin resistance. J Clin Invest 1999;103:931–43. [166] Kerouz NJ, Horsch D, Pons S, Kahn CR. Differential regulation of insulin receptor substrates-1 and -2 (IRS-1 and IRS-2) and phosphatidylinositol 3-kinase isoforms in liver and muscle of the obese diabetic (ob/ob) mouse. J Clin Invest 1997;100:3164–72. [167] Sun XJ, Miralpeix M, Myers MG Jr, Glasheen EM, Backer JM, Kahn CR, et al. The expression and function of IRS-1 in insulin signal transmission. J Biol Chem 1992;267:

22662–72.

R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

831

[168] Cross D, Alessi D, Vandenheed J, McDowell H, Hundal H, Cohen P. The inhibition of glycogen synthase kinase-3 by insulin or insulin-like growth factor 1 in the rat skeletal muscle cell line L6 is blocked by wortmannin but not rapamycin. Biochem J 1994;303:

21–6.

[169] Osawa H, Sutherland C, Robey R, Printz R, Granner D. Analysis of the signaling pathway involved in the regulation of hexokinase II gene transcription by insulin. J Biol Chem 1996;271:16690–4. [170] Lazar DF, Wiese RJ, Brady MJ, Mastick CC, Waters SB, Yamauchi K, Pessin JE, Cuatrecasas P, Saltiel AR. Mitogen-activated protein kinase kinase inhibition does not block the stimulation of glucose utilization by insulin. J Biol Chem 1995;270:20801–7. [171] Dent P, Lavoinne A, Nakielny S, Caudwell FB, Watt P, Cohen F. The molecular mechanisms by which insulin stimulates glycogen synthesis in mammalian skeletal muscle. Nature 1990;348:302–7. [172] Newgard CB, Brady MJ, O’Doherty RB, Saltiel AR. Organizing glucose disposal. Emerging roles of the glycogen targeting subunits of protein phosphatase-1. Diabetes

2000;49:1967–77.

[173] Sheperd PR, Nave BT, Siddle K. Insulin stimulation of glycogen synthesis and glycogen synthase activity is blocked by wortmannin and rapamycin in 3T3L1 adipocytes: evidence for the involvement of phosphoinositide 3 kinase and p70 ribosomal protein S6 kinase. Biochem J 1995;305:25–8. [174] Freidenberg GR, Henry RR, Klein HH, Reichart DR, Olefsky JM. Decreased kinase activity of insulin receptors from adipocytes of non-insulin-dependent diabetic studies.

J Clin Invest 1987;79:240–50. [175] Caro JF, Sinha MK, Raju SM, Ittoop O, Pories WJ, Flickinger EG, et al. Insulin receptor kinase in human skeletal muscle from obese subjects with and without non-insulin dependent diabetes. J Clin Invest 1987;79:1330–7. [176] Caro JF, Ittoop O, Pories WJ, Meelheim D, Flickinger EG, Thomas F, et al. Studies on the mechanism of insulin resistance in the liver from humans with non-insulin-dependent diabetes. Insulin action and binding in isolated hepatocytes, insulin receptor structure, and kinase activity. J Clin Invest 1986;78:249–58. [177] Trichitta V, Brunetti A, Chiavetta A, Benzi L, Papa V, Vigneri R. Defects in insulin- receptor internalization and processing in monocytes of obese subjects and obese NIDDM patients. Diabetes 1989;38:1579–84. [178] Klein HH, Vestergaard H, Kotzke G, Pedersen O. Elevation of serum insulin concentration during euglycemic hyperinsulinemic clamp studies leads to similar activation of insulin receptor kinase in skeletal muscle of subjects with and without NIDDM. Diabetes 1995;344:1310–7. [179] Kashiwagi A, Verso MA, Andrews J, Vasquez B, Reaven G, Foley JE. In vitro insulin resistance of human adipocytes isolated from subjects with non-insulin-dependent diabetes mellitus. J Clin Invest 1983;72:1246–54. [180] Lonnroth P, Digirolamo M, Krotkiewski M, Smith U. Insulin binding and responsiveness in fat cells from patients with reduced glucose tolerance and type II diabetes. Diabetes

1983;32:748–54.

[181] Olefsky JM, Reaven GM. Insulin binding in diabetes. Relationships with plasma insulin levels and insulin sensitivity. Diabetes 1977;26:680–8. [182] Moller DE, Yakota A, Flier JS. Normal insulin receptor cDNA sequence in Pima Indians with non-insulin-dependent diabetes mellitus. Diabetes 1989;38:1496–500.

[183]

Kusari J, Verma US, Buse JB, Henry RR, Olefsky JM. Analysis of the gene sequences of the insulin receptor and the insulin-sensitive glucose transporter (GLUT4) in patients with common-type non-insulin-dependent diabetes mellitus. J Clin Invest 1991;88:1323–30.

[184] Nolan JJ, Friedenberg G, Henry R, Reichart D, Olefsky JM. Role of human skeletal muscle insulin receptor kinase in the in vivo insulin resistance of noninsulin-dependent diabetes and obesity. J Clin Endocrinol Metab 1994;78:471–7.

832 R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

[185] Cusi K, Maezono K, Osman A, Pendergrass M, Patti ME, Pratipanawatr T, et al. Insulin resistance differentially affects the PI 3-kinase and MAP kinase-mediated signaling in human muscle. J Clin Invest 2000;105:311–20. [186] Freidenberg GR, Reichart D, Olefsky JM, Henry RR. Reversibility of defective adipocyte insulin receptor kinase activity in non-insulin dependent diabetes mellitus. Effect of weight loss. J Clin Invest 1988;82:1398–406. [187] Kellerer M, Kroder G, Tippmer S, Berti L, Kiehn L, Mosthaf L, et al. Troglitazone prevents glucose-induced insulin resistance of insulin receptor in rat-1 fibroblasts. Diabetes 1994;43:447–53. [188] Pratipanawatr W, Pratipanawatr T, Cusi K, Berria R, Adams JM, Jenkinson CP, et al. Skeletal muscle insulin resistance in normoglycemic subjects with a strong family history of type 2 diabetes is associated with decreased insulin-stimulated insulin receptor substrate-1 tyrosine phosphorylation. Diabetes 2001;50:2572–8. [189] Krook A, Bjornholm M, Galuska D, Jiang XJ, Fahlman R, Myers MG, et al. Characterization of signal transduction and glucose transport in skeletal muscle from type 2 diabetic patients. Diabetes 2000;49:284–92. [190] Kim Y-B, Nikoulina S, Ciaraldi TP, Henry RR, Kahn BB. Normal insulin-dependent activation of Akt/protein kinase B, with diminished activation of phosphoinositide 3-kinase, in muscle in type 2 diabetes. J Clin Invest 1999;104:733–41. [191] Andreelli F, Laville M, Ducluzeau P-H, Vega N, Vallier P, Khalfallah Y, et al. Defective regulation of phosphatidylinositol-3-kinase gene expression in skeletal muscle and adipose tissue of non-insulin-dependent diabetes mellitus patients. Diabetologia 1999;42:

358–64.

[192] Folli F, Saad JA, Backer JM, Kahn CR. Regulation of phosphatidylinositol 3-kinase activity in liver and muscle of animal models of insulin-resistant and insulin-deficient diabetes mellitus. J Clin Invest 1993;92:1787–94. [193] Hitman GA, Hawrammi K, McCarthy MI, Viswanathan M, Snehalatha C, Ramachan- dran A, et al. Insulin receptor substrate-1 gene mutations in NIDDM: implication for the study of polygenic disease. Diabetologia 1995;38:481–6. [194] Hsueh WA, Law RE. Insulin signaling in the arterial wall. Am J Cardiol 1999;84:21–4J. [195] Jiang ZY, Lin YW, Clemont A, Feener EP, Hein KD, Igarashi M, Yamauchi T, White MF, King GL. Characterization of selective resistance to insulin signaling in the vasculature of obese Zucker (fa/fa) rats. J Clin Invest 1999;104:447–57. [196] Shepherd PR, Kahn BB. Glucose transporters and insulin action. Implications for insulin resistance and diabetes mellitus. N Engl J Med 1999;341:248–57. [197] Garvey WT. Insulin action and insulin resistance: diseases involving defects in insulin receptors, signal transduction, and the glucose transport effector system. Am J Med 1998;

105:331–45.

[198] Gl Bell, Kayano T, Buse JB, Burant CF, Takeda J, Lin D, Fikomoto H, Seino S. Molecular biology of mammalian glucose transporters. Diabetes Care 1990;13:198–200. [199] Joost H-G, Bell GI, Best JD, Birnbaum MJ, Charron MJ, Chen YT, et al. Nomenclature of the GLUT/SLC2A family of sugar/polyol transport facilitators. Am J Physiol Endocrinol Metab 2002;282:E974–6. [200] Rogers PA, Fisher RA, Harris H. An electrophoretic study of the distribution and properties of human hexokinases. Biochem Genet 1975;13:857–66. [201] Matchinsky FM. Banting Lecture 1995. A lesson in metabolic regulation inspired by the glucokinase glucose sensor paradigm. Diabetes 1996;45:223–41. [202] Garvey WT, Huecksteadt TP, Mattaei S, Olefsky JM. Role of glucose transporters in the cellular insulin resistance of type II non-insulin dependent diabetes mellitus. J Clin Invest

1988;81:1528–36.

[203] Zierath JR, He L, Guma A, Odegoard Wahlstrom E, Klip A, Wallenberg-Henriksson H. Insulin action on glucose transport and plasma membrane GLUT4 content in skeletal muscle from patients with NIDDM. Diabetologia 1996;39:1180–9.

R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

833

[204] Krook A, Bjornholm M, Galuska D, Jiang XJ, Fahlman R, Myers MG, et al. Characterization of signal transduction and glucose transport in skeletal muscle from type 2 diabetic patients. Diabetes 2000;49:284–92. [205] Pedersen O, Bak J, Andersen P, Lund S, Moller DE, Flier JS, et al. Evidence against altered expression of GLUT1 or GLUT4 in skeletal muscle of patients with obesity or NIDDM. Diabetes 1990;39:865–70. [206] Eriksson J, Koranyi L, Bourey R, Schalin-Jantti C, Widen E, Mueckler M, et al. Insulin resistance in type 2 (non-insulin-dependent) diabetic patients and their relatives is not associated with a defect in the expression of the insulin-responsive glucose transporter (GLUT-4) gene in human skeletal muscle. Diabetologia 1992;35:143–7. [207] Bonadonna RC, Del Prato S, Saccomani MP, Bonora E, Gulli G, Ferrannini E, et al. Transmembrane glucose transport in skeletal muscle of patients with non-insulin- dependent diabetes. J Clin Invest 1993;92:486–94. [208] Bonadonna RC, Del Prato S, Bonora E, Saccomani MP, Gulli G, Natali A, et al. Roles of glucose transport and glucose phosphorylation in muscle insulin resistance of NIDDM. Diabetes 1996;45:915–25. [209] Cline GW, Petersen KF, Krssak M, Shen J, Hundal RS, Trajanoski Z, et al. Impaired glucose transport as a cause of decreased insulin stimulated muscle glycogen synthesis in type 2 diabetes. N Engl J Med 1999;341:240–6. [210] Williams KV, Price JC, Kelley DE. Interactions of impaired glucose transport and phosphorylation in skeletal muscle insulin resistance. A dose-response assessment using positron emission tomography. Diabetes 2001;50:2069–79. [211] Choi WH, O’Rahilly S, Rees A, Morgan R, Flier JS, Moller DE. Molecular scanning of the insulin-responsive glucose transporter (GLUT 4) gene in patients with non-insulin dependent diabetes mellitus. Diabetes 1991;40:1712–8. [212] Perriott LM, Kono T, Whitesell RR, Knobel SM, Piston DW, Granner DK, et al. Glucose uptake and metabolism by cultured human skeletal muscle cells: rate-limiting steps. Am J Physiol Endocrinol Metab 2001;281:E72–80. [213] Printz RL, Ardehali H, Koch S, Granner DK. Human hexokinase II mRNA and gene structure. Diabetes 1995;44:290–4. [214] Mandarino LJ, Printz RL, Cusi KA, Kinchington P, O’Doherty RM, Osawa H, et al. Regulation of hexokinase II and glycogen synthase mRNA, protein, and activity in human muscle. Am J Physiol 1995;269:E701–8. [215] Vogt C, Ardehali H, Iozzo P, Yki-Jarvinen H, Koval J, Maezono K, et al. Regulation of hexokinase II expression in human skeletal muscle in vivo. Metabolism 2000;49:814–8. [216] Pendergrass M, Koval J, Vogt C, Yki-Jarvinen H, Iozzo P, Pipek R, et al. Insulin-induced hexokinase II expression is reduced in obesity and NIDDM. Diabetes 1998;47:387–94. [217] Ducluzeau P-H, Perretti N, Laville M, Andreelli F, Vega N, Riou J-P, et al. Regulation by insulin of gene expression in human skeletal muscle and adipose tissue. Evidence for specific defects in type 2 diabetes. Diabetes 2001;50:1134–42. [218] Lehto M, Huang X, Davis EM, Le Beau MM, Laurila E, Eriksson KF, et al. Human hexokinase II gene: exon-intron organization, mutation screening in NIDDM, and its relationship to muscle hexokinase activity. Diabetologia 1995;38:1466–74. [219] Laakso M, Malkki M, Kekalainen P, Kuusito J, Deeb SS. Polymorphisms of the human hexokinase II gene: lack of association with NIDDM and insulin resistance. Diabetologia

1995;38:617–22.

[220] Echwald SM, Bjorbaek C, Hansen T, Clausen JO, Vestergaard H, Zierath JR, et al. Identification of four amino acid substitutions in hexokinase II and studies of relationships to NIDDM, glucose effectiveness, and insulin sensitivity. Diabetes 1995;

44:347–53.

[221] Thiebaud D, Jacot E, DeFronzo RA, Maeder E, Jequier E, Felber JP. The effect of graded doses of insulin on total glucose uptake, glucose oxidation, and glucose storage in man. Diabetes 1982;31:957–63.

834 R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

[222] Golay A, DeFronzo RA, Ferrannini E, Simonson DC, Thorin D, Acheson K, et al. Oxidative and non-oxidative glucose metabolism in non-obese Type 2 (non-insulin dependent) diabetic patients. Diabetologia 1988;31:585–91. [223] Lillioja A, Mott DM, Zawadzki JK, Young AA, Abbott WG, Bogardus C. Glucose storage is a major determinant of in vivo ‘insulin resistance’ in subjects with normal glucose tolerance. J Clin Endocrinol Metab 1986;62:922–7. [224] Shulman GI, Rothman DL, Jue T, Stein P, DeFronzo RA, Shulman RG. Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by 13C nuclear magnetic resonance spectroscopy. N Engl J Med 1990;322:223–8. [225] Rothman DL, Magnusson I, Cline G, Gerard D, Kahn CR, Shulman RG, et al. Decreased muscle glucose transport/phosphorylation is an early defect in the pathogenesis of non- insulin-dependent diabetes mellitus. Proc Natl Acad Sci USA 1995;92:983–7. [226] Yki-Jarvinen H, Mott D, Young AA, Stone K, Bogardus C. Regulation of glycogen synthase and phosphorylase activity by glucose and insulin in human skeletal muscle. J Clin Invest 1987;80:95–100. [227] Frame S, Cohen P. GSK3 takes centre stage more than 20 years after its discovery. Biochem J 2001;359(Pt 1):1–16. [228] Cohen P. The Croonian Lecture 1999. Identification of a protein kinase cascade of major importance in insulin signal transduction. Proc R Soc Lond B Biol Sci 1999;354:485–95. [229] Damsbo P, Vaag A, Hother-Nielsen O, Beck-Nielsen H. Reduced glycogen synthase activity in skeletal muscle from obese patients with and without type 2 (non-insulin- dependent) diabetes mellitus. Diabetologia 1991;34:239–45. [230] Mandarino LJ, Wright KS, Verity LS, Nichols J, Bell JM, Kolterman OG, et al. Effects of insulin infusion on human skeletal muscle pyruvate dehydrogenase, phosphofructokinase, and glycogen synthase. Evidence for their role in oxidative glucose metabolism. J Clin Invest 1987;80:655–63. [231] Thorburn AW, Gumbiner B, Bulacan F, Wallace P, Henry RR. Intracellular glucose oxidation and glycogen synthase activity are reduced in non-insulin-dependent (type II)

diabetes independent of impaired glucose uptake. J Clin Invest 1990;85:522–9. [232] Vaag A, Henriksen JE. Beck-Nielsen Decreased insulin activation of glycogen synthase in skeletal muscles in young non-obese Caucasian first-degree relatives of patients with non- insulin-dependent diabetes mellitus. J Clin Invest 1992;89:782–8. [233] Nyomba BL, Freymond D, Raz I, Stone K, Mott DM, Bogardus C. Skeletal muscle glycogen synthase activity in subjects with non-insulin-dependent diabetes mellitus after glyburide therapy. Metabolism 1990;39:1204–10. [234] Pratipanawatr T, Cusi K, Ngo P, Pratipanawatr W, Mandarino LJ, DeFronzo RA. Normalization of plasma glucose concentration by insulin therapy improves insulin- stimulated glycogen synthesis in type 2 diabetes. Diabetes 2002;51:462–8. [235] Vestergaard H, Lund S, Larsen FS, Bjerrum OJ, Pedersen O. Glycogen synthase and phosphofructokinase protein and mRNA levels in skeletal muscle from insulin-resistant patients with non-insulin-dependent diabetes mellitus. J Clin Invest 1993;91:2342–50. [236] Vestergaard H, Bjocbaek C, Andersen PH, Bak JF, Pedersen O. Impaired expression of glycogen synthase mRNA in skeletal muscle of NIDDM patients. Diabetes 1991;40:1740–5.

MajerM,Mott DM,Mochizuki H, Rowles JC, Pederson O, KnowlerWC, et al. Association

[237]

of the glycogen synthase locus on 19q13 with NIDDM in Pima Indians. Diabetologia 1996;

39:314–21.

[238] Orho M, Nikua-Ijas P, Schalin-Jantti C, Permutt MA, Groop LC. Isolatation and characterization of the human muscle glycogen synthase gene. Diabetes 1995;44:1099–105. [239] Bjorbaek C, Echward SM, Hubricht P, Vestergaard H, Hansen T, Zierath J, et al. Genetic variants in promoters and coding regions of the muscle glycogen synthase and the insulin- responsive GLUT4 genes in NIDDM. Diabetes 1994;43:976–83. [240] Bjorbaek C, Fik TA, Echward SM, Yang P-Y, Vestergaard H, Wang JP, et al. Cloning of human insulin-stimulated protein kinase (ISPK-1) gene and analysis of coding regions

R.A. DeFronzo / Med Clin N Am 88 (2004) 787–835

835

and mRNA levels of the ISPK-1 and the protein phosphatase-1 genes in muscle from NIDDM patients. Diabetes 1995;44:90–7. [241] Procharzka M, Michizuki H, Baier LJ, Cohen PTW, Bogardus C. Molecular and linkage analysis of type-1 protein phosphatase catalytic beta-subunit gene: lack of evidence for its major role in insulin resistance in Pima Indians. Diabetologia 1995;38:461–6. [242] Schalin-Jantti C, Harkoenen M, Groop LC. Impaired activation of glycogen synthase in people at increased risk for developing NIDDM. Diabetes 1992;41:598–604. [243] Del Prato S, Bonadonna RC, Bonora E, Gulli G, Solini A, Shank M, et al. Characterization of cellular defects of insulin action in type 2 (non-insulin-dependent) diabetes mellitus. J Clin Invest 1993;91:484–94. [244] Falholt K, Jensen I, Lindkaer Jensen S, Mortensen HB, Volund A, Heding LG, Norskov Petersen P, Falholt W. Carbohydrate and lipid metabolism of skeletal muscle in type 2 diabetic patients. Diabet Med 1988;5:27–31. [245] Mandarino LJ, Madar Z, Kolterman OG, Bell JM, Olefsky JM. Adipocyte glycogen synthase and pyruvate dehydrogenase in obese and type II diabetic patients. Am J Physiol

1986;251:E489–96.

[246] Kelley D, Mokan M, Mandarino L. Intracellular defects in glucose metabolism in obese patients with noninsulin-dependent diabetes mellitus. Diabetes 1992;41:698–706. [247] Groop L, Bonadonna R, Simonson DC, Petrides A, Hasan S, DeFronzo RA. Effect of insulin on oxidative and non-oxidative pathways of glucose and free fatty-acid metabolism in human obesity. Am J Physiol 1992;263:E79–84. [248] Randle PJ, Garland PB, Hales CN, Newsholme EA. The glucose fatty acid cycle: its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1963;i:785–9.

Med Clin N Am 88 (2004) 837–846
Med Clin N Am 88 (2004) 837–846

The metabolic syndrome

Alan J. Garber, MD, PhD a,b, *

a Departments of Medicine, Biochemistry and Molecular Biology, and Molecular and Cellular Biology, Baylor College of Medicine, 6550 Fannin Street, Suite 1045, Houston, TX 77030, USA b Department of Endocrinology, Diabetes, and Metabolism, The Methodist Hospital Houston, TX, USA

The metabolic syndrome is a collection of frequently associated cardio- vascular risk factors that tend to aggregate in selected patient populations and that, together, increase coronary and cardiovascular mortality, and total mortality. The term ‘‘metabolic syndrome’’ has been used variously by disparate organizations to connote different entities. Some, such as the World Health Organization, have used this term to indicate a state of insulin resistance with pervasive dysmetabolism secondary to the state of insulin resistance. Conceptualization of the metabolic syndrome as a unique, high- risk cardiovascular state, as defined by the National Cholesterol Education Program (NCEP), is gaining acceptance as the basis for diagnosing the metabolic syndrome [1]. The NCEP definition is based on clustering multiple metabolic abnormalities associated with insulin resistance but does not require a measure of insulin sensitivity. Table 1 cites the current criteria for the diagnosis of the metabolic syndrome, according to NCEP guidelines. A diagnosis is made by the presence of three or more abnormalities. Although each abnormality may be associated with underlying insulin resistance, no requirement exists for an experimental demonstration of insulin resistance or a measurement of impaired insulin-mediated glucose disposal. Several of these clinical features, such as low high-density lipoprotein (HDL) cholesterol levels and elevations of triglyceride-rich lipoproteins in fasting serum speci- mens, are well known to be interrelated. Furthermore, these conditions also tend to be more prevalent in obese individuals as well as in those with essential hypertension, making this syndrome increasingly prevalent in patients with one or more traditional risk factors for cardiovascular disease.

* Baylor College of Medicine, 6550 Fannin Street, Suite 1045, Houston, TX 77030. E-mail address: agarber@bcm.tmc.edu

0025-7125/04/$ - see front matter 2004 Elsevier Inc. All rights reserved.

doi:10.1016/j.mcna.2004.04.001

838 A.J. Garber / Med Clin N Am 88 (2004) 837–846

Table 1 Definition of metabolic syndrome

Risk factor

Defining level

Abdominal obesity

Men

Waist >40 inches Waist >35 inches 150 mg/dL

Women

Triglycerides

HDL cholesterol

Men

\40 mg/dL \50 mg/dL 130/85 mm Hg 110 mg/dL

Women

Blood pressure

Fasting glucose

NCEP criteria (any 3–5 symptoms).

The metabolic syndrome, as defined by the NCEP, is not to be confused with the insulin resistance syndrome or the presence of underlying insulin resistance, although such resistance is likely in patients with the metabolic syndrome. Insulin resistance is an evolving entity, which may or may not be associated with aspects of dysmetabolism secondary to prolonged insulin resistance that appear later. A useful example of this evolution is the slow, progressive decline of pancreatic b -cell function under conditions of ongoing or worsening insulin resistance. This decline leads ultimately to hypergly- cemia and a clinical diagnosis of type 2 diabetes. Many years are required for the evolution of this process before diabetes can be diagnosed [2]. There is, therefore, an antecedent period of compensated hyperinsulinemic euglycemia in which patients clearly are insulin resistant but in whom dysmetabolism of carbohydrates may be difficult to detect. A similar latency may also exist with respect to the evolution of dyslipidemia secondary to impaired clearance of triglyceride-rich lipoproteins or accelerated removal or delayed synthesis of HDL cholesterol. For example, teenaged women with polycystic ovary syndrome clearly have, as part of the underlying pathogenesis of this disorder, an important element of insulin resistance. However, at the time of diagnosis, these young women rarely have obvious hypertriglyceridemia, low HDL cholesterol, or overtly abnormal carbohy- drate metabolism. With prolonged persistence of unrelieved insulin re- sistance, however, they do have a much higher likelihood of developing the stigmata of the metabolic syndrome. Thus, it may therefore be possible that the metabolic consequence of early b -cell failure in the presence of prolonged insulin resistance leads to the abnormal metabolism required to diagnose the metabolic syndrome. A weaker association exists between insulin resistance and essential hypertension. Various authors have concluded that approximately 50% to 75% of patients with essential hypertension have underlying insulin resistance. Whether such resistance begins before the onset of hypertension is somewhat unclear, although obesity is a clear risk factor for the

A.J. Garber / Med Clin N Am 88 (2004) 837–846

839

development of hypertension, and obesity is also a risk factor for the development of insulin resistance. It is likely that the insulin resistance

precedes the hypertension in such cases, although not in all cases of essential hypertension, even when hypertension is fully developed. Although it is currently under reexamination, impaired fasting glucose (a fasting glucose 110 mg/dL) is one of the five diagnostic criteria used for determining the presence of the metabolic syndrome. In contrast, some authors have suggested that patients with otherwise normal fasting glucose levels may demonstrate impaired glucose tolerance at the point of a 2-hour postglucose challenge, during an oral glucose tolerance test. Although a recent consensus development conference of the American College of Endocrinology recommended the inclusion of a 2-hour postglucose value of greater than 140 mg/dL as a potential alternative to the 110-mg/dL fasting glucose level, this addition has not been included in current definitions of the metabolic syndrome because glucose tolerance testing is believed to be too difficult for practitioners and potentially impractical in routine clinical settings. However, physicians may wish to offer such testing where possible

to clarify patient status with the metabolic syndrome and to ascertain

potential impairments of carbohydrate metabolism or even overt diabetes. Suggestions have been made to modify diagnostic criteria for the metabolic syndrome by including elevated levels of highly sensitive C- reactive protein as a potential criterion for the diagnosis of the metabolic

syndrome [3]. Although individuals with three or more criteria for metabolic syndrome were clearly shown to have increased levels of C-reactive protein, such elevations of C-reactive protein may not be independent of the underlying insulin resistance, which is surely present in patients having three or more diagnostic features of the metabolic syndrome. Thus, the use

of elevated C-reactive protein may overlap existing diagnostic components

and, therefore, may not add additional insight about the nature of any underlying dysmetabolism. Instead, the use of highly sensitive C-reactive

proteins as an additional estimate of cardiovascular risk, independent of the underlying diagnosis of the metabolic syndrome, should be retained as potentially more useful than by its inclusion within the metabolic syndrome.

A diagnosis of the metabolic syndrome is, however, tantamount to a

diagnosis of excess cardiovascular risk, whether or not C-reactive proteins are elevated. In the Nurses Health Survey, event-free survival in individuals with the metabolic syndrome was clearly lower than in individuals without the metabolic syndrome [2]; however, it should also be noted that individuals with elevated C-reactive protein and a diagnosis of metabolic syndrome had even lower rates of event-free survival than did individuals with the metabolic syndrome but with low levels of C-reactive protein. Thus, a diagnosis of the metabolic syndrome based on the criteria of the NCEP is highly effective in predicting excess cardiovascular risk. For example, in an analysis of the Framingham Study offspring, diagnosis of the metabolic syndrome approximately doubled cardiovascular risk for males

840 A.J. Garber / Med Clin N Am 88 (2004) 837–846

and tripled such risk for females with the metabolic syndrome compared with those without the metabolic syndrome. A greater adverse cardiovas- cular impact of the metabolic syndrome was seen by Lakka et al [4] in the Kuoppio Study (see [4]), in which a diagnosis of the metabolic syndrome increased coronary artery mortality and cardiovascular mortality by three- fold and doubled total mortality in this patient population. An even greater cardiovascular risk was noted in the Mexico City Study. The metabolic syndrome may also be an outstanding risk predictor of future diabetes. In the Framingham Offspring Study, a recent analysis suggested that a diagnosis of the metabolic syndrome predicted a fivefold 8-year future risk of diabetes in males and a sixfold increase in the future risk of diabetes in females. Although the accuracy of the metabolic syndrome as a predictor of excess risk of cardiovascular disease is not surprising, its robust ability to predict an excess risk of future diabetes is, in fact, somewhat unexpected. This degree of accuracy may provide insight into the precise nature of the ‘‘metabolic syndrome.’’ Because it is likely that the metabolic syndrome describes at least one aspect of underlying insulin resistance (clearly the period in which multiple metabolic abnormalities have evolved, likely secondary to b-cell failure resulting from an underlying insulin resistance state), then the metabolic syndrome presents a slice in time in the evolution of the insulin resistant state into an area of gross pathology, such as type 2 diabetes or clinical atherosclerosis. Therefore, the metabolic syndrome likely characterizes a state in time of latent underlying disease evolution that may be viewed as preclinical diabetes or preclinical atherosclerosis. Based in large measure on epidemi- ologic analyses, such a diagnosis clearly represents a high probability transition state in the evolution from normality to gross pathology resulting from insulin resistance. It is important to recognize a transition state because transition states are generally more reversible than end-stage pathology. Alternatively, one may view the high predictability of the metabolic syndrome of future type 2 diabetes as the likelihood that the metabolic syndrome is already type 2 diabetes. This view derives from the observation that glucose is a continuous variable that proceeds from completely normal to completely abnormal, with the diagnosis of diabetes being a somewhat arbitrary event in the middle of this evolution. Prior expert committees have set arbitrary diagnostic criteria for type 2 diabetes at levels of 126 mg/dL, based in part on the recognized increase in the development of the typical or classic microvascular complications of diabetes, such as retinopathy. Nonetheless, although it is an expert opinion, the diagnosis point for diabetes remains arbitrary. This is not to say that diabetes may not occur at an earlier point or at lower glucose levels before the development of very substantial rates of hyperglycemia. As seen in the special analysis of the NHANES III database, there was a fivefold increase in the incidence of retinopathy in the fasting glucose interval of 110 to 119 mg/dL compared with the interval of 100 to 109 mg/dL. It is therefore

A.J. Garber / Med Clin N Am 88 (2004) 837–846

841

possible that much lower levels of fasting hyperglycemia may be associated with milder degrees of type 2 diabetes than the level currently used for the diagnosis of type 2 diabetes (126 mg/dL). Similarly, the United Kingdom Prospective Diabetes Study (UKPDS) used a fasting glucose level of 108 mg/dL to diagnose diabetes and encountered a 21% incidence of retinop- athy in their newly diagnosed patients [5]. The metabolic syndrome may overlap, to a variably greater extent, the diagnosis of type 2 diabetes and may ultimately be replaced by a more aggressive diagnosis of this disorder. The prevalence of the metabolic syndrome is truly staggering. Although there may be an epidemic of type 2 diabetes in the United States, the proportion of Americans with the metabolic syndrome is far larger. Using the criteria of the NCEP and applied to the results of the NHANES III database updated to the 2000 census, Ford et al [6] estimated that approximately 47 million Americans met the current criteria of the metabolic syndrome. As high as 40% of the population 60 years and older have the metabolic syndrome. The syndrome is higher in minority patients compared with white patients. The number of Americans with the metabolic syndrome clearly exceeds the number of Americans with type 2 diabetes and those with impaired glucose tolerance. Thus, the number at risk for the future development of type 2 diabetes is much greater than previously suspected. Indeed, the striking prevalence of the metabolic syndrome in the US population, together with its extraordinary predictability of future diabetes, may be a useful rationale for aggressive interventions with regard to treatment of the metabolic syndrome, not only as a high-risk cardiovascular state, but also, as a serious premonitory state of type 2 diabetes. Either or both of these views clearly justifies intervention, both with regard to hygienic measures, such as lifestyle modification including diet and exercise, together with the possibility of pharmacologic intervention to interdict the evolution to type 2 diabetes and to mitigate the excess risk of cardiovascular events.

Obesity

The foundation of the metabolic syndrome is excess deposition of adipose tissue in visceral or abdominal compartments, which gives rise to an underlying insulin resistant state. Although the NCEP definition of the metabolic syndrome does not directly measure insulin sensitivity, much of the diagnostic criteria outlined previously are associated with the dysme- tabolism of insulin resistance. Insulin resistance may be directly addressed by lifestyle modification. Such modifications include regular, vigorous aerobic exercise as frequently as possible. The insulin sensitizing benefits of exercise require, for example, five or more sessions per week of approximately 3 to 5 miles per day, consisting of a brisk walking pace of 3 to 4 miles per hour. Light-weight training is also useful in supporting muscle bulk and assisting with weight reduction. Of course, before

842 A.J. Garber / Med Clin N Am 88 (2004) 837–846

beginning regular daily exercise, patients with high risk of coronary disease should undergo exercise cardiac testing to exclude subclinical or atypical coronary ischemia. Exercise alone without aggressive calorie restriction is usually insufficient

to produce weight loss. Indeed, exercise may increase appetite, which may

more than compensate for the increased caloric expenditure and oxygen

consumption associated with the exercise. For that reason, aggressive dietary modification with limitation of concentrated sweets, saturated fats, and reduction of portion sizes seems essential if weight reduction is to be achieved. Weight reduction to achieve a body mass index (BMI) less than 30

is essential if the metabolic syndrome is to be modified. Nonobese but

overweight individuals have a substantially reduced risk of the metabolic syndrome. Of course, reduction of overweight individuals to normal weight ( 27 BMI) would be ideal, but this level may be difficult to achieve in the markedly obese population in whom even small degrees of weight loss would be beneficial for many of the parameters of the metabolic syndrome, especially the hypertriglyceridemia and hyperglycemia. Lifestyle modification with diet and exercise greatly magnifies the effect of pharmacologic agents designed to intervene in dyslipidemia, hypertension, or abnormal carbohydrate tolerance. Because the metabolic syndrome is also a high-risk predictor of future diabetes, intervention to prevent the development of overt type 2 diabetes seems appropriate. The role of diet and

exercise as part of a thorough lifestyle modification program is unsurpassed for prevention of type 2 diabetes in patients with impaired glucose tolerance. Although they are not strictly the same as the patient population with the metabolic syndrome, patients in the Diabetes Prevention Program (DPP) showed a 58% reduction in the risk of development of type 2 diabetes by

a 7% loss of body weight and regular daily exercise. Pharmacologic

therapies were also useful for the prevention of type 2 diabetes because these therapies may have reduced the underlying insulin resistance. These therapies, however, will be discussed later as part of future considerations in the management of the metabolic syndrome. Pharmacologically assisted weight loss may also be considered. Orlistat (Xenical) therapy reduces fat absorption, produces a 3% to 8% weight loss, and reduces the development of type 2 diabetes. It should be considered for those failing life style modifications.

Treatment of dyslipidemia

The metabolic syndrome does not necessarily include hypercholesterol- emia, as characterized by a markedly increased mass of low-density lipoprotein (LDL) cholesterol. Instead, a shift in the size distribution of LDL particles toward a smaller, denser and inherently more atherogenic LDL particle, as the result of the underlying insulin resistance state, seems

A.J. Garber / Med Clin N Am 88 (2004) 837–846

843

present in many of these patients. Diagnosis that focuses on hypertriglycer- idemia and low HDL cholesterol levels aids in recognizing that these factors traditionally herald the presence of a severe, underlying redistribution of LDL particle size toward a smaller, more atherogenic particle size. Because patients with the metabolic syndrome represent a high-risk cardiovascular state, precise quantitation of this state by assessment of the 10-year cardiovascular risk using the Framingham risk engine (found on the NHLBI website) is most useful in determining appropriate action regarding reduction of LDL mass. Risks greater than 20% per 10 years equate to an extremely high risk state, equivalent to the risk of known coronary disease, and therefore merit reduction of LDL cholesterol below 100 mg/dL, using interventions with statins. Use of a statin should not be predicated on

a titration of slight elevations to just below 100 mg/dL. Instead, if the

decision is made to intervene with a b -hydroxy- b -methylglutaryl-coenzyme

A (HMG-CoA) reductase inhibitor, then a full dose, designed to produce

a 30% to 40% reduction of LDL mass, such as 40 mg of pravastatin or

simvastatin, should be used. This recommendation reflects, in part, results from randomized controlled trials demonstrating that such doses custom- arily produce a significant reduction in coronary events of approximately 30% or more and also the recognition that in high-risk patients with minimally elevated LDL levels there may likely be an altered particle distribution of LDL cholesterol, which may merit a somewhat more aggressive therapeutic intervention. For example, in the Heart Protection Study, patients with LDL cholesterol less than 100 mg/dL at the time of randomization benefited equally from 40 mg of simvastatin, with pro- portionate reductions in coronary event reduction, as did those patients with substantially higher levels of LDL cholesterol at the time of randomization to simvastatin. Once LDL goals have been attained, then residual elements of the dyslipidemia should be addressed. The second treatment goal for the

management of dyslipidemia should be correction of low levels of HDL cholesterol. This goal may be attained by lowering triglycerides with a fibric acid derivative if these triglycerides are substantially elevated ( 250 mg/dL). Previously, the use of gemfibrozil was encouraged, owing to the publication of two large-scale interventional trials demonstrating coronary event reduction with gemfibrozil. Recently, however, it has been recognized that gemfibrozil inhibits the glucuronidation of many statins thereby raising statin blood levels, resulting in elevated serum levels of such statins. This may considerably complicate safety considerations in the use of gemfibrozil

in patients already treated with HMG-CoA reductase inhibitors. Thus, in

such patients, fenofibrate (Tricor) is preferred. The smallest possible dose that produces acceptable modification of triglyceride levels should be used.

In those patients with low HDL cholesterol ( 40 mg/dL in males; 50 mg/dL in females) in whom triglycerides are not markedly elevated, direct intervention with nicotinic acid may be useful. Generally, for every 1 g of

844 A.J. Garber / Med Clin N Am 88 (2004) 837–846

nicotinic acid administered, a 10% increase in HDL cholesterol can be expected. Nicotinic acid, used as part of a treatment program with statins, has produced remarkable event reductions in trials such as HATS. Presently, combination therapy tablets using lovastatin and slow-release nicotinic acid are available and prove effective for correcting dyslipidemia in patients with the metabolic syndrome. Treatment with nicotinic acid should be initiated and titrated slowly to avoid precipitating overt symptomatology secondary to the vasoreactive effects of nicotinic acid or to suddenly decompensate glycemic control owing to the increased insulin resistance resulting from nicotinic acid therapy. If carbohydrate tolerance deteriorates during nicotinic acid therapy, antidiabetic therapy should be instituted early and aggressively to restrain hyperglycemia from complicating the underlying metabolic syndrome or from producing a recrudescence of the hyper- triglyceridemia or the low HDL cholesterol. In patients with overt hyperglycemia, thiazolidinediones are preferred for correction of hypergly- cemia in patients with low HDL cholesterol. Nicotinic acid should be withheld until at least 6 months of antidiabetic therapy has been completed with thiazolidinediones, such as rosiglitazone or pioglitazone. Biguanides, such as metformin, may also be useful in improving insulin sensitivity and preventing weight gain in patients on nicotinic acid and thiazolidinediones. Combination therapy products of both rosiglitazone and metformin may be especially useful as initial treatment for new onset hyperglycemia in such patients, with secondary adverse effects of hyperglycemia as the consequence of nicotinic acid therapy.

Treatment of hypertension

Numerous agents have been established as excellent first-line therapies for hypertension in patients with diabetes and in nondiabetic patients with dyslipidemia. Ramipril, used in the HOPE Study, showed excellent antiatherogenic effects in diabetic patients with one additional coronary risk factor and in patients with coronary disease. Captopril and atenolol were equally effective for macrovascular risk reduction in patients with diabetes in the UKPDS. Calcium channel blockers such as felodipine (Plendil) also proved effective in diabetic patients in the HOT Trial. Finally, thiazide diuretics were found to be useful in the ALLHAT Study. Thus, a variety of agents can be chosen for patients with diabetes. Because most patients with type 2 diabetes evolve from a preexisting metabolic syndrome, the use of antihypertensive agents might be expected in patients with the metabolic syndrome, as they have been proven to be efficacious in patients with diabetes. Because endothelial dysfunction is an important part of the underlying insulin resistance state, which appears to be widely present in the metabolic syndrome, angiotensin-converting enzyme inhibitors and aldo- sterone receptor antagonists are useful in improving hypertension and

A.J. Garber / Med Clin N Am 88 (2004) 837–846

845

relieving endothelial dysfunction in this population. Other agents may be equally efficacious in improving hypertension but may lack the ability to improve insulin resistance or endothelial dysfunction. These agents, in- cluding thiazide diuretics, b -blockers, cardioselective b -blockers, and potassium channel blockers, should be reserved for second and third line (or beyond) therapies. Part of the clinical issue in patients with diabetes is that the treatment target for antihypertensive therapy is a diastolic pressure less than 80 mm Hg. Attainment of such a target, which probably should extend to patients with prediabetic states, such as the metabolic syndrome, is the need for multiple antihypertensive agents, including an average of three, needed for diabetic patients in the United States, and at least two or more in the UKPDS. Thus, much of the discussion revolving around which one of a number of the foregoing antihypertensive agents should be considered the best antihypertensive agent in the metabolic syndrome or other prediabetic states is rendered moot and obviated by the fact that most of these agents will be required in combination to achieve the kinds of blood pressure targets now envisioned for such patients. One should therefore consider beginning with an angiotensin-converting enzyme or angiotensin II receptor blocker. A rapid dose escalation to include b -blockers, thiazide diuretics, calcium channel blockers, and other agents should be introduced to gain rapid control of the hypertensive state and improve endothelial dysfunction in these patients.

Treatment of impaired carbohydrate tolerance

The central diagnostic point of abnormal carbohydrate tolerance used in the NCEP 2001 Guidelines is a fasting glucose level greater than 110 mg/dL. This is known as impaired fasting glucose and may or may not be accompanied by impaired glucose tolerance (2-hour postchallenge glucose 140–199 mg/dL). Although impaired glucose tolerance is clearly associated with the presence of underlying insulin resistance, impaired fasting glucose may or may not be associated with insulin resistance. It is, instead, more likely to be associated with declining b -cell function. There are no prospective randomized trials suggesting that pharmacologic therapy of impaired fasting glucose yields treatment benefits either with regard to prevention of adverse coronary outcomes or the prevention of progression to type 2 diabetes. Nonetheless, it seems clear that pharmacologic modification may present a successful approach to this particular health problem because pharmacologic intervention with regard to impaired glucose tolerance has been demonstrated to be successful with regard to the prevention of type 2 diabetes. Studies such as the DPP and the TRIPOD studies have demonstrated efficacy of both metformin, in the former, and a thiazolidinediones in the latter, with regard to diabetes prevention. The thiazolidinediones therapy arm of the DPP study showed a striking, prolonged benefit of thiazolidinediones therapy. It would therefore suggest

846 A.J. Garber / Med Clin N Am 88 (2004) 837–846

that in patients failing beneficial lifestyle modifications or having insufficient benefit from lifestyle interventions, chemoprevention of diabetes may be warranted. On the other hand, it is completely unknown whether chemo- prevention of diabetes with metformin or thiazolidinediones, or both, would have a beneficial effect with regard to the adverse cardiovascular outcomes associated with the metabolic syndrome. Future studies to clarify this important point are clearly necessary.

Summary

The metabolic syndrome is a collection of cardiovascular risk factors that denote a high-risk multifactorial adverse cardiovascular state, which is largely the result of obesity and the resulting insulin resistance. It is diagnosed by the presence of multiple risk factors, such as hypertriglycer- idemia, low HDL cholesterol, hypertension, essential hypertension, abnor- mal fasting glucose levels, and abdominal or visceral obesity. This state also denotes a high-risk state for the evolution to type 2 diabetes. Treatment for the metabolic syndrome should be focused primarily on lifestyle modifica- tion, with reduction of the underlying obesity and insulin resistance. The treatment of individual coronary risk factors is clearly warranted in such patients because the metabolic syndrome represents a high-risk cardiovas- cular state equal to 20% or greater 10-year risk of coronary disease. In such patients, it may be possible that impaired glucose tolerance also exists. This diagnosis requires a glucose tolerance test to be performed. Chemopreven- tion of deterioration of impaired glucose tolerance to a future diabetic state has been successful with metformin or thiazolidinediones, as well as with aggressive lifestyle modification. Indeed, combination of both chemo- prevention and lifestyle modification may prevent future cases of diabetes if instituted early in the course of diagnosis of impaired glucose tolerance. Whether such treatments benefit the adverse cardiovascular outcomes remain to be decided.

References

[1] Executive summary of the Third Report of the National Cholesterol Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486–97. [2] Lebovitz H. Diabetes Reviews 1999. [3] Ridker PM, et al. Circulation 2003;107:391–7. [4] Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 2002;288:2709–16. [5] United Kingdom Prospective Diabetes Study No. 34. Lancet 1998. [6] Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults:

findings from the third National Health and Nutrition Examination Survey. JAMA 2002;

Med Clin N Am 88 (2004) 847–863
Med Clin N Am 88 (2004) 847–863

Oral antidiabetic agents: 2004

Harold E. Lebovitz, MD *

Department of Medicine, State University of New York Health Science Center at Brooklyn, 450 Clarkson Avenue, Brooklyn, NY 11203, USA

The 1980s and 1990s were marked by unprecedented advances in knowledge about the pathogenesis of type 2 diabetes and its chronic complications. Landmark intervention studies in type 2 diabetic patients proved that intensive control of glycemia, blood pressure, and plasma lipids significantly decreased microvascular and macrovascular complications [1–4]. New drugs were introduced that decreased blood glucose, blood pressure, and low-density lipoprotein cholesterol levels. The Steno II research study performed from 1993 through 2001 showed that the use of contemporary treatments to implement aggressive blood glucose, blood pressure, plasma lipid, and antithrombotic target goals in type 2 diabetic patients with microalbuminuria resulted in a greater than 50% reduction in clinically relevant macrovascular and microvascular complications [5]. Given these impressive advances it is somewhat surprising that several recent publications comparing the characteristics and treatment profiles of diagnosed type 2 diabetic populations in the National Health and Nutrition Examination Surveys of 1988 to 1994 and 1999 to 2000 show a worsening of the characteristics and no significant improvement in either glycemic control or total metabolic control [6,7]. The difference between the two surveys shows that type 2 diabetes has increased in males more than females, is occurring at a younger age, and with a body mass index that is higher (Table 1). Treatment has changed in that diet-only therapy decreased from 27.4% to 20.2% of the type 2 diabetic population. Insulin-only therapy decreased from 24.2% to 16.4%, oral antidiabetic agents increased from 45.4% to 52.5%, and combination oral antidiabetic agent plus insulin increased from 3.1% to 11%. Adequate glycemic control as estimated by hemoglobin (Hb) A 1c less than 7% decreased from 44.5% of the population in 1988 to 1994 to 35.8% in 1999 to 2000.

* 416 Henderson Avenue, Staten Island, NY 10310. E-mail address: hlebovitz@attglobal.net

0025-7125/04/$ - see front matter 2004 Elsevier Inc. All rights reserved.

doi:10.1016/j.mcna.2004.05.002

848 H.E. Lebovitz / Med Clin N Am 88 (2004) 847–863

Table 1 Comparison of characteristics of adult diabetic patients 20 years and older in NHANES III (1988–1994) and NHANES 1999–2000

 

NHANES III

NHANES 1999–2000

Prevalence of diabetes Age standardized (%) Men (%) BMI (kg/m 2 ) Age at diagnosis of diabetes Race Non-Hispanic white (%) Other races (%)

5.4

6.1

43.2

50

29.9

32.3

50.7

46.7

74.6

59.8

25.4

40.2

Abbreviation: BMI, body mass index. Data from Saydah SH, Fradkin J, Cowie CC. Poor control of risk factors for vascular disease among adults with previously diagnosed diabetes. JAMA 2004;291:335–42; and Koro CE, Bourgeois N, Bowlin SJ, Fedder DO. Glycemic control from 1988 to 2000 among US adults diagnosed with type 2 diabetes. Diabetes Care 2004;27:17–20.

More detailed analyses of the National Health and Nutrition Examina- tion Surveys 1999 to 2000 data set show that only 37% of the diabetic population had a HbA 1c less than 7% with 63% having a HbA 1c greater than 7% and 37.2% one greater than 8% [7]. In that same survey 40.4% had a blood pressure greater than 140/90 mm Hg; 51.8% had a total cholesterol greater than or equal to 200 mg/dL. Only 7.3% of the diabetic population had HbA 1c less than 7%, blood pressure less than 130/80 mm Hg, and total cholesterol less than 200 mg/dL. Understanding the causes responsible for this failure to improve the metabolic regulation of type 2 diabetic patients is critical to designing more effective treatment strategies. Table 2 delineates the causes into patient- related, health care provider–related, disease-related, and therapeutic agent– related. Patient-related causes include the enormous increase in obesity that has occurred in the last 10 years [8] and the large problem with patients’ failure to comply with treatment programs designed to achieve metabolic regulation. Health care provider causes include failure to recognize the importance of early aggressive treatment and a lack of understanding of the

Table 2 Causes responsible for failure to improve metabolic control in type 2 diabetic patients

Responsible cause

Example

Patient

Increasing obesity of the population Difficulty in compliance with complicated regimens Lack of understanding importance of early aggressive control Failure to understand significance of multiple defects Progressive beta cell failure Inability to restore normal physiology Side effects

Health care provider

Disease

Therapeutic agents

H.E. Lebovitz / Med Clin N Am 88 (2004) 847–863

849

interaction of the pathogenic mechanisms responsible for type 2 diabetes, which dictate that combination drug therapy is almost essential to achieve glycemic and blood pressure control. A recent report from Kaiser- Permanente Northwest noted that a nonrandomized retrospective 1994 to 2002 database analysis identified that it took an average of 14 months before type 2 diabetic patients who were on metformin monotherapy and had HbA 1c greater than 8% were switched or had additional therapies added to their regimen [9]. For patients taking sulfonylurea monotherapy the average time was 20 months. The most important disease-related cause is the progressive nature of the loss of beta cell function, which seems to be characteristic of type 2 diabetes [10]. Therapeutic agent–related causes include the inability of many agents to modify metabolic processes to restore normal physiologic regulation [11] and the occurrence of significant side effects that limit the use of many agents [12].

The importance of early aggressive treatment

The major pathogenetic mechanisms that are responsible for the metabolic abnormalities of type 2 diabetes are insulin resistance, deficient insulin secretion, and glucose and lipid toxicity. Time course studies have shown that insulin resistance occurs early and although subtle changes in beta cell function are noted quite early, clinically significant insulin secretory inadequacy follows several years later [13]. Glucose and lipid toxicity further contribute to insulin resistance and beta cell insufficiency after derangement of intermediary metabolism has occurred. Several clinical observations dictate that both the clinical course of type 2 diabetes and the development of microvascular complications are most favorably altered by very early and aggressive treatment of both the insulin resistance and the hyperglycemia. Several intervention studies in individuals with impaired glucose tolerance have shown that decreasing the compen- satory hyperinsulinemia presumably by reducing insulin resistance or lowering postprandial plasma glucose rises can delay or prevent the development of new-onset type 2 diabetes [14–17]. In the one study (TRIPOD study), the data show that reducing insulin resistance markedly decreased the rate of loss of beta cell function [16]. These data suggest that early interventions that decrease the stress of increased insulin secretion on the beta cell can delay or prevent the progressive decline of beta cell function in type 2 diabetic patients. Preservation of endogenous insulin secretory function is associated with better glycemic control. The initial treatment of type 2 diabetic patients with insulin resistance should be to decrease the insulin resistance. Hyperglycemia is the primary cause of microvascular complications in all diabetic patients. Both the Diabetes Control and Complication Trial (DCCT) in type 1 diabetic patients and the United Kingdom Diabetes

850 H.E. Lebovitz / Med Clin N Am 88 (2004) 847–863

Prevention Study (UKPDS) in type 2 diabetic patients showed that intensive glycemic control compared with ordinary glycemic control significantly reduced clinically relevant retinopathy, nephropathy, and neuropathy [1,18]. For every 1% decrease in HbA 1c there was approxi- mately a 30% decrease in microvascular complications. It is apparent in examining the time course of the development of the microvascular complications that the intensive treatment had to be in place for 3 to 4 years in the DCCT or 9 years in the UKPDS before any benefit became evident [1,18]. These data suggested that the damage caused by early hyperglycemia takes several years before its impact lessens. The concept that the vascular bed has a memory of its previous exposure to blood glucose levels and that this memory plays a major role in the blood vessels’ biology for many subsequent years has been confirmed by the Epidemi- ology of Diabetic Complications Study [19]. The Epidemiology of Diabetic Complications Study is a long-term follow-up of the patients who participated in the DCCT study. At the conclusion of the DCCT both the intensively treated and the ordinarily treated type 1 diabetic cohorts returned to their primary care centers for their long-term care. Most of the patients in both cohorts agreed to return to the research centers once a year to have examinations for HbA 1c and retinal and kidney function. Within 2 or 3 years of care in their primary care centers the two cohorts had mean HbA 1c of approximately 8%. That is, the intensively treated group could not continue to achieve mean HbA 1c values of 7.1% to 7.2% outside of the intensive research setting. The ordinary control cohort was allowed to be more aggressive in their management and they improved from their previous mean HbA 1c of 9%. In years 4 to 7 both cohorts had mean HbA 1c of approximately 8.1%. Despite the equal HbA 1c , the rate of progression of retinopathy continued to be twofold greater and nephropathy sixfold greater in follow-up years 5 and 6 in the former ordinary control cohort than the former intensively treated cohort. These data strongly support the concept that early aggressive glycemic control is essential to maximally reduce microvascular complications.

Strategies for treating hyperglycemia in type 2 diabetic patients

Management of the metabolic abnormalities of patients with type 2 diabetes involves correction of hyperglycemia, blood pressure, lipid abnormalities, and the components of the metabolic syndrome. This article deals selectively with the management of hyperglycemia by oral agents, although it is obvious that such management interfaces with combination and insulin treatment and must take into account their associated effects on the other metabolic abnormalities. This being the case, the following principles must be considered when implementing any treatment program for hyperglycemia.

H.E. Lebovitz / Med Clin N Am 88 (2004) 847–863

851

1. Type 2 diabetes needs to be diagnosed as early as possible, preferably in the presymptomatic phase by screening if possible.

2. Insulin resistance or the presence of the metabolic syndrome should be an indication to start treatment. Lifestyle modification should be the first line of intervention. Pharmacologic treatment can be considered if impaired glucose tolerance is present and should be implemented if type 2 diabetes is diagnosed and lifestyle modification has been inadequate to normalize glycemic control.

3. Combination therapy with oral agents that have different modes of action should be initiated in type 2 diabetic patients if and when the HbA 1c exceeds 6.5%.

4. Most oral antidiabetic agents provide 75% or more of their antihy- perglycemic activity at 50% of the maximally recommended dose. Because side effects are frequently dose related, the use of submaximal doses of two agents with different modes of actions achieves better glycemic control with fewer side effects than maximal doses of a single agent.

5. In choosing oral agents in treating hyperglycemia, consideration should be given in each patient to their potential nonglycemic metabolic effects.

6. If a combination of two oral agents is insufficient to achieve a target glycemic goal of HbA 1c less than or equal to 7%, addition of a third oral agent is unlikely to achieve it if the HbA 1c is greater than or equal to 8% to 8.5%. If the HbA 1c exceeds 8% to 8.5% the addition of basal insulin before the evening meal or at bedtime or neutral protamine Hagedorn insulin at bedtime is preferable.

7. The percent decrease in HbA 1c with every oral therapy is directly cor- related with the baseline HbA 1c when the treatment is started. That is, the greatest drop occurs with the highest baseline values and the lowest decrease with the lowest baseline values.

Specific oral therapies: agents to treat insulin resistance

Two classes of oral antidiabetic agents reduce insulin resistance:

biguanides (metformin) and thiazolidinediones (pioglitazone and rosiglita- zone) [19]. These agents decrease insulin resistance by different mecha- nisms and have preferential effects on different tissues [20–22]. The thiazolidinediones act primarily on adipose tissue to decrease the meta- bolic consequences of obesity. It seems that increases in visceral adipose tissue result in excessive release of free fatty acids and cytokines (eg, tumor necrosis factor- a ) and reduce release of the adipose tissue hormone adiponectin. The result is altered hepatic metabolism and interference in the transmission of the insulin signal within insulin-sensitive cells. These effects are responsible for the insulin resistance associated with obesity. The thiazolidinediones act on adipose tissue to decrease plasma free fatty

852 H.E. Lebovitz / Med Clin N Am 88 (2004) 847–863

acids, decrease tumor necrosis factor- a secretion, and improve adiponectin secretion, all of which improve insulin action in muscle, adipose tissue, and liver. Metformin increases insulin action directly in insulin-sensitive cells by a still undetermined mechanism. Metformin exerts a major effect in increasing insulin sensitivity in liver and only a minor effect in skeletal muscle [23]. Thiazolidinediones have a major effect in increasing insulin sensitivity in muscle and a somewhat lesser effect in liver [23]. Overall thiazolidinediones are about 70% more effective as a total body insulin sensitizer than metformin [24]. Improvement in insulin sensitivity in insulin-resistant type 2 diabetic patients allows endogenous insulin to be more effective and treatment of such patients with insulin sensitizers improves glycemic control. The magnitude of improvement depends on the amount of beta cell function that is present at the time therapy is started. The mean decrease in HbA 1c that occurs with either metformin or thiazolidinedione monotherapy in patients with a mean baseline HbA 1c of approximately 9% is 1.5% [25]. About 30% of such patients achieve a HbA 1c less than or equal to 7% on maximal doses of sensitizing drugs. In the remainder of the patients, insulin secretory function is too low and either insulin secretagogues or insulin replacement needs to be added to the insulin sensitizer to achieve target glycemic goals. The addition of insulin secretagogues to insulin sensitizers can decrease HbA 1c an additional 1% to 1.4% [26]. The addition of an insulin sensitizer to an insulin treatment regimen can decrease HbA 1c by

a mean of 0.8% to 1.2% [27] but the amount is influenced by how much the insulin dose is reduced.

There are several significant advantages to using insulin sensitizers as part

of the therapeutic treatment program. As monotherapy, thiazolidinediones

or metformin do not cause serious hypoglycemia because endogenous insulin secretion is still glucose dependent. Even therapy combining

a thiazolidinedione and metformin is rarely associated with hypoglycemia

[28]. Treatment of insulin-resistant type 2 diabetic patients with insulin sensitizers improves many of the components of the metabolic syndrome [20,21]. The effects of metformin and thiazolidinediones on the components of the metabolic syndrome differ significantly as shown in Table 3. The

effects of the two thiazolidinediones, pioglitazone and rosiglitazone, seem to be quite similar. There have been some reports suggesting that pioglitazone has a greater effect in reducing plasma triglycerides than does rosiglitazone; however, these have not been well-designed studies and there is need for

a double-blind, randomized head-to-head comparator study to validate

whether there is any significant difference. Metformin is the only drug used

to treat hyperglycemia that has been shown to reduce macrovascular complications of type 2 diabetes [2]. Metformin treatment of overweight type 2 diabetic patients in the UKPDS reduced cardiovascular-related deaths (42%) and myocardial infarctions (39%). Sulfonylurea treatment and insulin treatment had no significant benefits on those cardiovascular

H.E. Lebovitz / Med Clin N Am 88 (2004) 847–863

853

Table 3 Comparison of the effects of thiazolidinediones and metformin on insulin resistance and the components of the Metabolic Syndrome

Activity

Metformin

Thiazolidinediones

Glycemic control FPG HbA 1c FPI Body weight Visceral fat Insulin sensitivity Peripheral Liver Dyslipidemia LDL cholesterol LDL particle size HDL cholesterol Triglyceride Lipoprotein (a) FFA Endothelial function Vasodilation Blood pressure Adhesion molecules Muscle proliferation Procoagulant state

##

##

##

##

#

##

#

"

#

0

""

""

"

"

0

"

""

#

0

"

##

"

""

0

#

#

#

PAI-1

#

#

Fibrinogen

Inflammation

C-reactive protein

#

##

Mesangial function

Microalbuminuria

0

#

Abbreviations: FFA, free fatty acid; FPG, fasting plasma glucose; FPI, fasting plasma insulin; HDL, high-density lipoprotein; LDL, low-density lipoprotein; PAI, plasminogen activator inhibitor. 0, no effect; #, decrease; ##, marked decrease; ", increase; "", marked increase. Data from Lebovitz HE, Banerji MA. Treatment of insulin resistance in diabetes mellitus. Eur J Pharmacol 2004;490:135–46.

events even though they lowered HbA 1c the same 0.6% as metformin. Clinical trials examining the effects of thiazolidinedione treatment on the development of clinical cardiovascular events in type 2 diabetic patients are in progress. There are additional major differences between the effects of thiazoli- dinediones and metformin. Metformin treatment is usually associated with some weight loss. Most clinical studies show a mean weight loss with metformin treatment of approximately 1 to 2 kg [29]. Thiazolidinedione treatment is usually associated with a mean weight gain of 1.5 kg at

854 H.E. Lebovitz / Med Clin N Am 88 (2004) 847–863

intermediate doses and 3.5 kg at high doses [30]. The side effects of metformin include abdominal discomfort and diarrhea, which occur in 10% to 20% of patients on maximal doses, and a very rare occurrence of lactic acidosis [29]. The gastrointestinal symptoms can be minimized by initiating metformin therapy with 500 mg with the evening meal, increasing the dose to 500 mg twice a day, and slowly titrating the dose to 1000 mg twice a day with meals. The longer-acting preparations, such as Glucophage XR, cause less gastrointestinal side effects. The few cases of metformin-induced lactic acidosis that have been reported occurred in individuals with decreased renal function, symptomatic heart failure on therapy, or an underlying metabolic acidosis [31]. The major side effects of thiazolidinedione treatment are an increase in adipose tissue and fluid retention. The increase in adipose tissue is selective for the subcutaneous region [32]. The visceral adipose tissue either is unchanged or decreases slightly. The fluid retention manifests itself as mild to moderate peripheral edema, which occurs in 4% of patients on monotherapy [33]. When thiazolidinediones are combined with insulin, edema is seen in approxi- mately 15% of the patients [33]. A rare type 2 diabetic patient on thiazolidinediones develops heart failure. Such patients are usually older, are on maximal doses of the thiazolidinedione, are also taking insulin, and have a prior history of cardiovascular disease or renal failure [33]. The mechanism seems to be the increase in plasma volume in type 2 diabetic patients who had asymptomatic compensated heart failure. Treatment of the fluid retention with loop diuretics is of limited benefit. Angiotensin-converting enzyme inhibitors and aldosterone antagonists have been used with limited success to treat the fluid retention [33]. According to a recent consensus panel convened by the American Diabetes and American Heart Associations patients who are at risk for developing congestive heart failure and could benefit from thiazolidine- dione treatment should be started on very low doses, titrated up slowly, and have careful monitoring of body weight and edema [33]. If excess weight gain or edema is noted despite attempts to treat it, the thiazolidinedione should be discontinued. Metformin is administered twice a day and the maximal benefits on glycemic control are seen at 2000 mg/d. Pioglitazone is administered once daily in doses of 15, 30, or 45 mg/d. Rosiglitazone is administered either once or twice a day in doses ranging from 2, 4, or 8 mg/d.

Specific oral therapies: agents to increase insulin secretion

In insulin-resistant type 2 diabetes, hyperglycemia occurs when insulin secretion is inadequate to overcome the degree of insulin resistance that is present. The natural history of the development of type 2 diabetes is a progressive decline in beta cell function. This was clearly documented in

H.E. Lebovitz / Med Clin N Am 88 (2004) 847–863

855

the UKPDS, which also showed that this decline in beta cell function was not altered by treatment with diet, metformin, sulfonylureas, or insulin [10]. The decline in beta cell function is caused by a decreased ability of glucose to cause closure of an ATP-dependent potassium channel in the plasma membrane of beta cell [34,35]. The normal mechanism for glucose stimulation of insulin secretion involves the following steps [34,35]. Glucose from the plasma compartment is rapidly transported into the beta cell, phosphorylated, and metabolized to generate ATP. Special enzymes in the beta cell (Glut-2 glucose transporter and glucokinase) allow this process to occur quantitatively so that the intracellular ATP:ADP ratio accurately reflects the plasma glucose concentration. The plasma membrane of the beta cell contains a potassium channel whose function is regulated by the ATP:ADP ratio and a voltage-dependent calcium channel. When the plasma glucose is low the potassium channel is open and extruding potassium from the beta cell. The plasma membrane is appropriately polarized and the calcium channel is closed. As the plasma glucose rises, the ATP:ADP ratio increases, which causes the ATP-dependent potassium channels to close. Closure of the ATP-dependent potassium channel causes depolarization of the adjacent plasma membrane, which results in opening of the voltage- dependent calcium channels in that portion of the depolarized membrane. The open calcium channels allow calcium to be transported from the extracellular compartment into the cytoplasm of the beta cell. Increases in cytosolic calcium ion concentrations linearly increase the release of insulin from the beta cell granule into the plasma compartment. The impaired release of insulin, which is characteristic of the early stages of type 2 diabetes, is a delayed and impaired ability of plasma glucose fluctuations appropriately to regulate closure of the ATP-dependent potassium channel. As the duration of type 2 diabetes increases, the functional defect in beta cells is compounded by an increase in apoptosis and a decrease in beta cell mass. The mechanism responsible for the decrease in mass is unclear but the consequence is that type 2 diabetic patients become more insulin deficient with time. In the first 4 or 5 years after the onset of clinical type 2 diabetes the functional defect in insulin secretion can be ameliorated by pharmacologic agents, which act directly on the ATP-dependent potassium channel and augment its closure by glucose. These agents are the insulin secretagogues, of which there are three distinct classes in clinical use: (1) sulfonylureas, (2) meglitinides, and (3) phenylalanine derivatives. All of these agents interact with the regulatory subunit of the ATP-dependent potassium channel and directly stimulate its closure [34,36]. There are subtle differences in the specific binding site and characteristics of binding among the three classes of insulin secretagogues, which modulate differences in their pattern of insulin release [35,37]. The commonly prescribed sulfonylureas include glyburide, glipizide, and glimepiride. The glyburide is formulated as regular and micronized. The

856 H.E. Lebovitz / Med Clin N Am 88 (2004) 847–863

glipizide is formulated as short acting and slow release. Table 4 lists these formulations and their characteristics. The meglitinide that is available is repaglinide and the phenylalanine derivative that is marketed is nateglinide. Their characteristics are also listed in Table 4. The clinically relevant insulin secretory defects in type 2 diabetes are (1) a 30- to 60-minute delay in meal-mediated insulin secretion, (2) a deficient quantity of insulin secretion, and (3) a progressive loss in beta cell function with time [34,36,38]. Administration of sulfonylureas does not significantly alter the delay in meal-mediated insulin secretion. Sulfonylurea treatment augments fasting insulin secretion and the second or late phase (after 60 minutes) of meal-mediated insulin secretion [34,36]. The consequence of these pharmacologic actions is a lowering of the fasting plasma glucose but very little decrease in the postprandial plasma glucose excursion. Sulfonylureas do not stimulate insulin biosynthesis. The two new insulin secretagogues, repaglinide [39,40] and nateglinide [41,42], were specifically designed to increase early meal-mediated insulin secretion. They are able to do so because they are rapidly absorbed and have rapid binding kinetics to the regulatory subunit of the ATP-dependent potassium channel [35,37,39–42]. They can be taken at the time of the meal and are able to facilitate early meal-mediated insulin secretion. This provides for a lower early and a shorter duration of postprandial glucose rise. These insulin secretagogues in contrast to sulfonylureas decrease the postprandial plasma glucose excursions [39–43].

Table 4 Properties of commonly prescribed insulin secretagogues

 

Duration

Generic name

Daily dose

of action

Comments

Glyburide

2.5–20 mg

>24 h

Absorption is incomplete and variable Hypoglycemia is the most common and severe Blocks ischemic preconditioning More consistent absorption

Glyburide

1–8 mg

>24 h

micronized

Glipizide

2.5–20 mg

>12 h

Relatively short acting Hypoglycemia less severe and about half as frequent as glyburide Hypoglycemia and weight gain reported to be quite low Hypoglycemia frequency and severity \ half that of glyburide No interference with ischemic preconditioning Low incidence of hypoglycemia Weight gain less than with sulfonylureas Very low incidence of hypoglycemia Little data on weight gain

Glipizide-

5–20 mg

24 h

GITS

Glimepiride

1–8 mg

24 h

(Amaryl)

Repaglinide

1–4 mg with each meal 60–120 mg with each meal

5–6 h

(Prandin)

Nateglinide

3–4 h

(Starlix)

H.E. Lebovitz / Med Clin N Am 88 (2004) 847–863

857

Sulfonylurea drugs have a long duration of action because of their pharmacokinetic properties and their binding kinetics to the regulatory subunit of the ATP-dependent potassium channel [34,36]. Repaglinide has a prolonged low-affinity binding to the regulatory subunit of the ATP- dependent potassium channel, and although it has a rapid onset of insulin release it also continues stimulating some insulin secretion for several hours, which explains its additional effect in lowering fasting plasma glucose [37,44]. In contrast, nateglinide has a rapid onset and short duration of insulin secretory action because it rapidly dissociates from the regulatory subunit of the ATP-dependent potassium channel [37,41]. Its beneficial effects are primarily in lowering postprandial plasma glucose excursions

[41].

Understanding the pharmacology of the various insulin secretagogues explains the differences in their clinical effects (Table 5) [34,36]. Sulfonylur- eas have a prolonged duration of action. Their primary beneficial effects are to decrease fasting and between-meal hyperglycemia. They have minimal effects on postprandial glucose excursions. Because of their prolonged actions they can lead to severe fasting and late postprandial hypoglycemia [34,45,46]. This is particularly so when meals are delayed or missed [47]. Severe sulfonylurea-induced hypoglycemia is a rare complication that is more likely to occur in older individuals and in those with underlying cardiovascular or kidney disease [36,45,46]. When it occurs, patients need treatment for several days in an emergency ward or intensive care unit. Glyburide treatment has been reported to have a significantly greater frequency of severe hypoglycemia than other sulfonylureas [34,45,46]. Nateglinide has only minor effects on fasting and between-meal hyper- glycemia but is very effective in reducing postprandial glucose excursions [41,48]. Because of its rapid onset and short duration of action it must be taken with each meal. A major advantage is that missed meals and delayed meals are unlikely to cause significant hypoglycemia. Indeed, reported rates of hypoglycemia are quite low. Because of its minimal effects on fasting hyperglycemia nateglinide is usually given in combination with other antihyperglycemic agents [42]. Repaglinide has properties that combine the benefits of both sulfonylur- eas and nateglinide. It primarily facilitates early meal-mediated insulin secretion but it also has some modest prolonged insulin secretory function [43,44,47]. As a result, it lowers fasting plasma glucose and also decreases postprandial glucose excursions [40,44]. It is taken with each meal. If meals are delayed or missed there is a minimal likelihood of having significant hypoglycemia [47]. Clinical trials comparing treatment with repaglinide versus a sulfonylurea show similar degrees of glycemic control with repaglinide causing somewhat less hypoglycemia and weight gain [44]. The beneficial effects of sulfonylureas on glycemic control occur during the first several years following diagnosis. The effects decrease with duration of diabetes. In the UKPDS trial the percentage of type 2 diabetic patients

858 H.E. Lebovitz / Med Clin N Am 88 (2004) 847–863

Table 5 Comparison of classes of insulin secretagogues

 

Sulfonylureas

Repaglinide

Nateglinide

Dosing FPG PPG excursion PP insulin secretion Hypoglycemia Weight gain HbA 1c Cost

Once or twice daily # 50 to 60 mg/dL Slight effect " late phase Fasting and late PP 1 to 3 kg # 1.5%

With each meal

With each meal # 20 mg/dL Major effect 10 min to 4 h Uncommon ? # 0.8% Expensive

# 50 to 60 mg/dL Moderate effect " early and late phases Less than sulfonylureas Less than sulfonylureas # 1.5%

Inexpensive Expensive

Abbreviations: FPG, fasting plasma glucose; PP, postprandial; PPG, postprandial plasma glucose excursion.

that achieved HbA 1c less than 7% on sulfonylurea monotherapy decreased from 50% after 3 years to 34% after 6 years to 24% after 9 years [49]. Many type 2 diabetic patients need insulin replacement therapy rather than insulin secretagogue therapy after 5 to 10 years of clinical disease [50,51].

Specific oral therapies: agents to delay carbohydrate digestion and absorption

Postprandial plasma glucose levels are determined by the nutrients being ingested, the gastrointestinal hormones being secreted in response to the nutrients, pancreatic insulin and glucagon secretion, and the responsiveness of the liver and peripheral tissues to the secreted insulin and glucagons. Changing the digestion of complex carbohydrates decreases the rate of monosaccharide absorption and lowers postprandial plasma glucose and, secondarily, plasma insulin levels [52]. Complex carbohydrates are digested to oligosaccharides in the small intestine by pancreatic lipase. The oligosaccharides are then cleaved to monosaccharides by a group of enzymes ( a -glucosidases) located in the brush border of the enterocytes and the monosaccharides are absorbed [52]. Normally, most of the digestion and absorption of carbohydrates occurs in the duodenum and upper jejunum. Competitive inhibitors of the a -glucosidase enzymes have been made and when given to diabetic patients decrease the postprandial plasma glucose rise [52–54]. These drugs decrease the rate of digestion of oligosaccharides in the duodenum and upper jejunum. The oligosaccharides proceed through the small intestine where they are slowly cleaved and absorbed. This results in a decrease in the mean peak postprandial glucose of approximately 50 mg/dL [52–54]. The mean fasting plasma glucose during chronic therapy with a -glucosidase inhibitors is reduced approximately 20 mg/dL and the mean HbA 1c by 0.5% [52–54].

H.E. Lebovitz / Med Clin N Am 88 (2004) 847–863

859

The major a -glucosidase inhibitor used is acarbose, which is a nonabsorb- able agent. The recommended dose is 50 mg taken with the start of each meal. The distal jejunum and ileum normally have very low concentrations of a -glucosidase enzymes, which means that during the initiation of treatment much of the undigested oligosaccharide passes into the colon where it is metabolized by the bacteria to short-chain fatty acids, hydrogen, methane, and carbon dioxide. That causes the side effects of abdominal pain, diarrhea, and flatulence. The side effects can be minimized by initiating therapy with 25 mg with the evening meal. After a week or so the dose can be increased to 25 mg with breakfast and the evening meal. If minimal or no symptoms occur the dose titration can be slowly increased to 50 mg with each meal. Occasional patients may require 100 mg with each meal. Dose increases are determined by the 1-hour postprandial plasma glucose levels, which ideally should be less than or equal to 180 mg/dL. Acarbose and miglitol are the a -glucosidase inhibitors on the market. The usual dose is 50 mg with each meal. The a -glucosidase inhibitors can be combined with all other classes of antihyperglycemic therapy.

Combination therapies

Combination therapy should be the treatment of choice in most patients with type 2 diabetes. Acceptance of the importance of combination therapy has spawned the production of several fixed combinations, such as glyburide and metformin (Glucovance), metformin and glipizide (Metaglip), metfor- min and rosiglitazone (Avandemet), and glimepiride and rosiglitazone (Avandaril). These fixed combinations provide for better compliance and lower cost because they require one copay. The use of metformin and a thiazolidinedione provides maximum effects on insulin resistance with diminished side effects. This combination is quite useful in patients in the early stages of hyperglycemia when insulin resistance is the predominant defect and insulin secretion is still well maintained. In the more advanced stages of hyperglycemia when insulin secretory deficiency is more marked, a combination of an insulin secretagogue and one or more insulin sensitizers is more appropriate. a -Glucosidase inhibitors or nategli- nide can be added specifically to improve recalcitrant postprandial hyperglycemia. The choice between adding a third oral agent or adding basal insulin therapy should be dictated by the cost and the magnitude of the HbA 1c at the time the therapy change is being considered.

Summary

The appropriate management of patients with type 2 diabetes presents many challenges to health care providers. The disease is increasing at

860 H.E. Lebovitz / Med Clin N Am 88 (2004) 847–863

alarming rates because of the population’s changing lifestyle. The first several years of type 2 diabetes are likely to be unrecognized and untreated. The pathophysiology of type 2 diabetes dictates that treatment of insulin resistance should be an early and central focus for every therapeutic program. Effective treatment of insulin resistance can slow the rate of beta cell deterioration and improve the cardiovascular risk factors, which are part of the metabolic syndrome. When beta cell function deteriorates it is necessary to improve insulin availability either by adding an insulin secretagogue or providing insulin replacement. Treatment must focus on control of both fasting and postprandial plasma glucose levels if glycemic targets are to be met and chronic complications are to be avoided. Appropriate control of blood pressure, lipids, and the predilection to thrombotic disease are equally important targets. The pharmacologic tools currently available are capable of allowing most patients with type 2 diabetes to achieve good metabolic control. Implementation of early combination therapy is essential if glycemic targets are to be met.

References

[1] UK Prospective Diabetes Study Group. Intensive blood-glucose control with sulphony- lureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837–53. [2] UK Prospective Diabetes Study Group. Effect of intensive blood glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854–65. [3] Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension:

principal results of the Hypertension Optimal Treatment (HOT) randomized trial. Lancet

1998;351:1755–62.

[4] Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomized placebo-controlled trial. Lancet 2002;360:7–22. [5] Gaede P, Vedel P, Larsen N, Jensen GVH, Parving H-H, Pederson O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med

2003;348:383–93.

[6] Saydah SH, Fradkin J, Cowie CC. Poor control of risk factors for vascular disease among adults with previously diagnosed diabetes. JAMA 2004;291:335–42. [7] Koro CE, Bourgeois N, Bowlin SJ, Fedder DO. Glycemic control from 1988 to 2000 among US adults diagnosed with type 2 diabetes. Diabetes Care 2004;27:17–20. [8] Flegal KM, Carroll MD, Ogden CL, Johnson CL. Prevalence and trends in obesity among US adults, 1999–2000. JAMA 2002;288:1723–7. [9] Brown N. Diabetes 2003;(Suppl 1):A61–2. [10] UK Prospective Diabetes Study Group. Overview of 6 years therapy of type 2 diabetes:

a progressive disease (UKPDS 16). Diabetes 1995;44:1249–58. [11] Lebovitz HE. Insulin secretogogues: sulfonylueas, meglitinides and phenylalanine deriva- tives. In: LeRoith D, Taylor SI, Olefsky JR, editors. Diabetes mellitus: a fundamental and clinical text. 3rd edition. Philadelphia: Lippincott Williams & Wilkins; 2004. p. 1107–22. [12] Lebovitz HE. Oral therapies for diabetic hyperglycemia. Endocrinol Metab Clin North Am 2001;30:909–33.

H.E. Lebovitz / Med Clin N Am 88 (2004) 847–863

861

[13] Weyer C, Bogardus C, Mott DM, Pratley RE. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest 1999;104:787–94. [14] Tuomilehto J, Lindstrom J, Eriksson JG, Hamalainen H, Ilanne-Parikka P, Keinanen- Kiukaanniemi S, et al. Finnish Diabetes Preventation Group. Preventation of type 2 diabetes by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001;344:1343–50. [15] Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. Diabetes Prevention Program Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393–403. [16] Buchanan TA, Xiang AH, Peters RK, Kjos SL, Marroquin A, Goico J, et al. Preservation of pancreatic b-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women. Diabetes 2002;51:2796–803. [17] Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laasko M. STOP-NIDDM Trial Research Group. Acarbose for the prevention of type 2 diabetes the STOP-NIDDM randomized trial. Lancet 2002;359:2072–7. [18] Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977–86. [19] Writing Team For The Diabetes Control And Complications Trial/Epidemiology Of Diabetes Interventions And Complications Research Group. Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: the Epidemiology of Diabetes Interventions and Complications (EDIC) study. JAMA 2003;290:2159–67. [20] Lebovitz HE, Banerji MA. Treatment of insulin resistance in diabetes mellitus. Eur J Pharmacol 2004;440:135–46. [21] Lebovitz HE. Rationale for and role of thiazolidinediones in type 2 diabetes mellitus. Am J Cardiol 2002;90:34G–41G. [22] Lebovitz HE. Treating hyperglycemia in type 2 diabetes: new goals and strategies. Cleve Clin J Med 2002;69:809–20. [23] Inzucchi SE, Maggs DG, Spollett GR, Page SL, Rife FS, Walton V, et al. Efficacy and metabolic effects of metformin and troglitazone in type 2 diabetes mellitus. N Engl J Med

1998;338:867–72.

[24] Yu JG, Kruszynska YT, Mulford MI, Olefsky JM. A comparison of troglitazone and metformin on insulin requirements in euglycemic intensively insulin-treated type 2 diabetic patients. Diabetes 1999;48:2414–21. [25] Lebovitz HE, Dole JF, Patwardhan R, Rappaport EB, Freed MI. Rosiglitazone monotherapy is effective in patients with type 2 diabetes. J Clin Endocrinol Metab 2001;

86:280–8.

[26] Kipnes MS, Krosnick A, Rendell MS, Egan JW, Mathisen AL, Schneider RL. Pioglitazone hydrochloride in combination with sulfonylurea therapy improves glycemic control in type 2 diabetes mellitus: a randomized, placebo-controlled study. Am J Med 2001;111:

10–7.

[27] Raskin P, Rendell M, Riddle MC, Dole JF, Freed MI, Rosenstock J, for the Rosiglitazone Clinical Trials Study Group. A randomized trial of rosiglitazone therapy in patients with inadequately controlled insulin-treated type 2 diabetes. Diabetes Care 2001;

24:1226–32.

[28] Fonseca V, Rosenstock J, Patwardhan R, Salzman A. Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus: a randomized controlled trial. JAMA 2000;283:1695–702. [29] Bailey CJ, Turner RC. Drug therapy: metformin. N Engl J Med 1996;334:574–9. [30] Lebovitz HE, Banerji MA. Insulin resistance and its treatment by thiazolidinediones. Recent Prog Horm Res 2001;56:265–94.

862 H.E. Lebovitz / Med Clin N Am 88 (2004) 847–863

[31] DeFronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulin- dependent diabetes mellitus. N Engl J Med 1995;333:541–9.

[32] Kelley IE, Walsh K, Han TS, et al. Effect of a thiazolidinedione compound on body fat and fat distribution of patients with type 2 diabetes. Diabetes Care 1999;22:288–93.

Nesto RW, Bell D, Bonow RO, Fonseca V, Grundy SM, Horton ES, et al. Thiazolidinedione

use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. October 7, 2003. Circulation 2003;

108:2941–8.

[33]

[34] Lebovitz HE, Melander A. Sulfonylureas: basic aspects and clinical use. In: DeFronzo R, editor. International textbook of diabetes. 3rd edition. Chichester (UK): John Wiley and Sons Ltd; 2004. [35] Fuhlendorff J, Rorsman P, Kofod H, Brand CL, Rolin B, MacKay P, et al. Stimulation of insulin release by repaglinide and glibenclamide involves both common and distinct processes. Diabetes 1998;47:345–51. [36] Lebovitz HE. Insulin secretogogues: sulfonylueas, meglitinides and phenylalanine deriva- tives. In: LeRoith D, Taylor SI, Olefsky JR, editors. Diabetes mellitus: a fundamental and clinical text. 3rd edition. Philadelphia: Lippincott Williams & Wilkins; 2004. p. 1107–22. [37] Hu S, Wang S, Fanelli B, Bell PA, Dunning BE, Geisse S, et al. Pancreatic b -cell KATP channel activity and membrane-binding studies with nateglinide: a comparison with sulfonylureas and repaglinide. J Pharmacol Exp Ther 2000;293:444–52. [38] Pimenta W, Korytkowski M, Mitrakou A, et al. Pancreatic beta-cell dysfunction as the primary genetic lesion in NIDDM: evidence from studies in normal glucose-tolerant individuals with a first-degree NIDDM relative. JAMA 1995;273:1855–61. [39] Guay DRP. Repaglinide, a novel, short-acting hypoglycemic agent for type 2 diabetes mellitus. Pharmacotherapy 1998;18:1195–204. [40] Jovanovic L, Dailey G III, Huang W-C, Strange P, Goldstein BJ. Repaglinide in type 2 diabetes: a 24-week fixed-dose efficacy and safety study. J Clin Pharmacol 2000;40:

49–57.

[41] Hanefeld M, Dickinson S, Bouter KP, Guitard C. Rapid and short-acting mealtime insulin secretion with nateglinide controls both prandial and mean glycemia. Diabetes Care 2000;

23:202–7.

[42] Horton ES, Foley J, Clinkingbeard C, Foley J, Mallow S, Shen S. Nateglinide alone and in combination with metformin improves glycemic control by reducing mealtime glucose levels in type 2 diabetes. Diabetes Care 2000;23:1660–5. [43] Owens DR, Ismail I, Luzio SD, et al. Increased prandial insulin secretion after administration of a single preprandial oral dose of repaglinide in patients with type 2 diabetes. Diabetes Care 2000;23:518–23. [44] Marbury T, Huang W-C, Strange P, Lebovitz HE. Repaglinide versus glyburide: a one year comparison trial. Diabetes Res Clin Pract 1999;43:155–66. [45] Shorr RI, Ray WA, Daugherty WA, et al. Individual sulfonylureas and serious hypoglycemia in older people. J Am Geriatr Soc 1996;44:751–5. [46] Van Staa T, Abenhaim L, Monette J. Rates of hypoglycemia in users of sulfonylureas. J Clin Epidemiol 1997;50:735–41. [47] Damsbo P, Marbury TC, Clauson P, Windfeld K. A double-blind randomized comparison of meal-related glycemic control by repaglinide and glyburide in well-controlled type 2 diabetic patients. Diabetes Care 1999;22:789–94. [48] Walter YH, Spratt DI, Garreffa S, McLeod JF. Mealtime glucose regulation by nateglinide in type-2 diabetes mellitus. Eur J Clin Pharmacol 2000;56:129–33. [49] Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirements for multiple therapies (UKPDS 49). JAMA 1999;281:2005–12. [50] Yki-Jarvinen H, Dressler A, Zieman M. Study Group HOE 901/3002. Less nocturnal hypoglycemia and better post dinner glucose control with bedtime insulin glargine

H.E. Lebovitz / Med Clin N Am 88 (2004) 847–863

863

compared with bedtime NPH insulin during combination therapy in type 2 diabetes. Diabetes Care 2001;23:1130–6. [51] Yki-Jarvinen H, Ryysy L, Nikkila K, Tulokas T, Vanamo R, Heikkila M. Comparison of bedtime insulin regimens in patients with type 2 diabetes mellitus: a randomized, controlled trial. Ann Intern Med 1999;130:389–96. [52] Lebovitz HE. Alpha-glucosidase inhibitors as agents in the treatment of diabetes. Diabetes Reviews 1998;6:132–45. [53] Chiasson JL, Josse R, Hunt J, Palmason C, Rodger NW, Ross SA, et al. The efficacy of acarbose in the treatment of patients with non-insulin dependent diabetes mellitus. Ann Intern Med 1994;121:928–35. [54] Holman RR, Cull CA, Turner RC. A randomized double-blind trial of acarbose in type 2 diabetes shows improved glycemic control over 3 years. Diabetes Care 1999;22:960–4.

Med Clin N Am 88 (2004) 865–895
Med Clin N Am 88 (2004) 865–895

Insulin therapy in type 2 diabetes

Trent Davis, MD, Steven V. Edelman, MD *

Section of Diabetes/Metabolism, Veterans Affairs San Diego HealthCare System, 3350 La Jolla Village Drive 111G, San Diego, CA 92161, USA

Diabetes mellitus affects approximately 18 million people in the United States, which is approximately 6% of the overall population, and over 800,000 new cases are diagnosed annually [1]. Diabetes may actually be more endemic than these figures indicate because there are no symptoms in the early stages of the disease, and potentially one undiagnosed individual exists for every one that is identified [2]. Of the total diabetic population, 85% to 90% of individuals have type 2 diabetes whereas 10% to 15% have type 1 diabetes [3]. Type 2 diabetes leads to a tremendous amount of death and disability and uses a large portion of the health care dollar [4]. Although diabetes is associated with multiple disorders with distinct pathologic mechanisms, insulin resistance is the common denominator and is associated with several comorbidities, including obesity, hypertension, and vascular disease. The natural history of the disease is often complicated by various microvascular and macrovascular sequelae that can lead to blindness, end-stage renal disease, lower-extremity amputation, and atherosclerosis resulting in heart attack or stroke [3,5]. Although most of the human suffering is caused by end-stage microvascular disease, 80% of diabetics die of macrovascular cardiovascular disease. There is now clear evidence from the United Kingdom Prospective Diabetes Study (UKPDS) and the Kumamoto study that improved glycemic control through intensive diabetes management delays the onset and significantly retards the progression of microvascular complications in patients with type 2 diabetes mellitus [6,7]. The results from the UKPDS are reassuring in that, although intensive treatment with insulin was associated with increased weight gain and hypoglycemia, there is no evidence of any harmful effect of insulin on cardiovascular outcomes, which has been a controversial issue. An epidemiologic analysis of the UKPDS

* Corresponding author. E-mail address: svedelman@vapop.ucsd.edu (S.V. Edelman).

0025-7125/04/$ - see front matter 2004 Elsevier Inc. All rights reserved.

doi:10.1016/j.mcna.2004.04.005

866 T. Davis, S.V. Edelman / Med Clin N Am 88 (2004) 865–895

data shows a continuous association between the risk of cardiovascular complications and glycemia, such that for every percentage point of decrease in HbA 1c (eg, from 9% to 8%), there is a 25% reduction in diabetes-related deaths, a 7% reduction in all-cause mortality, and an 18% reduction in combined fatal and nonfatal myocardial infarction [6]. To achieve glycemic goals in patients with type 2 diabetes, we now have multiple pharmacologic agents with different mechanisms of action, in- cluding sulfonylureas, meglitinides, metformin, a-glucosidase inhibitors, thiazolidinediones, and insulin. It must be emphasized, however, that unlike patients with type 1 diabetes, who have no significant insulin secretion and hence require insulin therapy from the onset of their disease, a prominent feature in the early stages of the disease for patients with type 2 diabetes is insulin resistance with hyperinsulinemia. Therefore, improving insulin sensitivity be means of caloric restriction, exercise, and weight management early in the disease process will benefit type 2 diabetics. When these measures fail, glycemic goals can often be achieved with oral agents used alone or in combination with each other. When patients are diagnosed late in the natural history, however, there is progressive loss of pancreatic beta-cell function and endogenous insulin secretion, making diurnal glycemic control difficult. At this late stage, most patients require exogenous insulin therapy to achieve optimal glucose control. The American Diabetes Association (ADA) now recommends that the glycemic objective for patients with type 2 diabetes to normalize glycemia and glycosylated hemoglobin concentrations should be similar to that for type 1 diabetes.

Pathogenesis and natural history of type 2 diabetes

Of the Americans diagnosed with type 2 diabetes, 80% to 90% are obese, and the remainder are lean [8]. The genesis of hyperglycemia in type 2 diabetes involves a triad of abnormalities: excessive hepatic glucose pro- duction, impaired pancreatic insulin secretion, and peripheral resistance to insulin action, occurring principally in liver and muscle tissue [9]. The severity of these abnormalities and their contribution to the degree of hyperglycemia can vary considerably, causing heterogeneity in the metabolic expression of the diabetic state. Such differences are best exemplified by the lean and obese varieties of type 2 diabetes, which have the same underlying pathophysiologic basis but differ in the extent to which each abnormality contributes to the development of the hyperglycemic state. Of these ab- normalities, peripheral insulin resistance to insulin action and impaired pancreatic beta-cell secretion are early and primary abnormalities, whereas increased hepatic glucose production is a late and secondary manifestation. Early in their disease, patients with type 2 diabetes compensate for increased insulin resistance at the tissue level by increasing pancreatic beta-cell insulin secretion [10]. When this compensation is no longer adequate to overcome

T. Davis, S.V. Edelman / Med Clin N Am 88 (2004) 865–895

867

the insulin resistance, blood glucose levels begin to rise. Over the course of the disease, endogenous insulin levels slowly begin to decrease and, ultimately, many patients with type 2 diabetes are unable to achieve optimal glycemic control with oral agents [11]. In subjects with type 2 diabetes who are lean, impaired insulin secretion is the predominant defect, and insulin resistance tends to be less severe than in the obese variety [12]. On the other hand, insulin resistance and hyper- insulinemia are the classical abnormalities of obese persons with type 2 diabetes [12]. In type 2 diabetes, insulin secretion is often excessive compared with the nondiabetic situation but is still insufficient to overcome the insulin resistance that is present. It is important to understand and appreciate these fundamental differences when considering insulin therapy in type 2 diabetes. Based on this knowledge, lean type 2 diabetic subjects usually fail oral agents faster and will require considerably less insulin to control their hyperglycemia than their obese counterparts. In contrast, large doses of exogenous insulin are the rule in the obese form of this disorder when euglycemia is desired [13]. The need for large amounts of exogenous insulin in obese type 2 diabetes also raises the question of the most appropriate methods of insulin delivery. Under normal circumstances, insulin is secreted from the pancreas into the portal vein, going directly to the liver in which a large first-pass extraction of portal insulin occurs [14]. When insulin is injected subcutaneously, absorption occurs directly into the peripheral circulation, without the initial effects of hepatic extraction. Therefore, the tissues are exposed to greater levels of insulin than if insulin was provided by the portal route. Because the primary target of exogenous insulin is the liver, type 2 diabetes may be uniquely suited to delivery of insulin through the portal vein. Such a situation occurs when insulin is delivered intraperitoneally, and the majority of insulin is absorbed into the portal circulation [15]. Intraperitoneal insulin delivery systems will not be discussed in this section, however, this method holds considerable promise in type 2 diabetes because of the more physiologic delivery of insulin and because of selective and effective inhibition of hepatic glucose output, with less peripheral insulinemia than occurs with subcutaneous insulin injections [16].

Intensive insulin therapy

Successful insulin management requires an educated and motivated patient, as well as the participation of a multidisciplinary health care team. Intensive insulin therapy requires a substantial input of physician and support staff time, which has a significant economic impact on the health care system [17]. Although long-term data on costs are not yet available, projections suggest that substantial savings from the high costs of end- stage disease could be achieved by following ADA guidelines [18].

868 T. Davis, S.V. Edelman / Med Clin N Am 88 (2004) 865–895

Furthermore, as discussed later, we now have the opportunity to use combinations of insulin and a variety of oral antidiabetic agents with differing mechanisms of action. The use of these potent combinations permit us to safely and effectively lower blood glucose levels and to achieve ADA target glycemic levels with relatively low risk for hypogly- cemia or weight gain. In addition to the natural history of type 2 diabetes, there is heterogeneity in the pathophysiology of type 2 diabetes mellitus that may influence when patients require insulin. Some patients who have been diagnosed with type 2 diabetes may actually have a condition more closely related to insulin- dependent or type 1 diabetes, with severe insulinopenia. Many of these pa- tients have been shown to have islet cell antibody positivity or antibodies to glutamic acid decarboxylase, with a decreased C-peptide response to glucagon stimulation and a propensity for primary oral medication failure [19]. These individuals are now labeled with the condition latent autoimmune diabetes in adults [20]. There are also wide geographic and racial differences that may influence the need for insulin therapy. For example, Asian patients with type 2 diabetes tend to be thinner, are diagnosed with diabetes at an earlier age, fail oral hypoglycemic agents much sooner, and are more sensitive to insulin therapy than the classic centrally obese patient in the United States and some parts of Europe [21]. The goals of therapy should be tailored to individual patients. Candidates for intensive management should be motivated, compliant, and educable, and be without other medical conditions and physical limitations that preclude accurate and reliable home glucose monitoring (HGM) and insulin administration; caution is advised in patients who are aged or have hypo- glycemic unawareness. Other limitations to achieving normoglycemia may include high titers of insulin antibodies, especially in patients with a history of intermittent use of insulin of animal origin. The site of insulin injection also may change the pharmacokinetics, and absorption can be highly variable, especially if lipohypertrophy is present. The periumbilical area has been shown to be one of the most desirable areas to inject insulin because of the rapid and consistent absorption kinetics observed at this location; however, rotating the injection site is usually advised [22]. It is also advisable to inject in the same body location for a certain meal time (ie, triceps fat pad for breakfast, abdomen for lunch, and upper thighs for dinner) [23]. In summary, before starting insulin therapy, the patient should be well educated in the techniques of HGM, proper insulin administration, and self- adjustment of the insulin dose, if appropriate, as well as knowledgeable about dietary and exercise strategies, including carbohydrate counting. The patient and family members also need to be informed about hypoglycemia prevention, recognition, and treatment. Initial and ongoing education by a diabetes management team, including a certified diabetes educator, is crucial for long-term success and safety.

T. Davis, S.V. Edelman / Med Clin N Am 88 (2004) 865–895

869

Insulin treatment strategies

Combination therapy

Combination therapy usually refers to the use of daytime oral antidia- betic agents together with a single injection of intermediate or long-acting insulin at bedtime. Several studies [24–36] have looked at the safety and efficacy of combination therapy. For many of the reasons mentioned earlier, the analysis of studies to evaluate the efficacy and safety of combination therapy is difficult. Several review articles using meta-analysis conclude that combination therapy results in only modest improvements in glucose con- trol and contribute to increased medical costs of diabetes management compared with insulin therapy alone. These earlier studies, however, were conducted when sulfonylureas were the only available type of oral agent. Because of heterogeneity in type 2 diabetes together with variability in the design and clinical situations of previous studies, however, the use of meta- analysis may be inappropriate for making generalized statements regarding this form of therapy [27,37]. Based on several recent reports, the use of combination therapy has been quite successful in selected patients, especially with the newer oral agents used alone or together with insulin [26–

29,35,36,38–41].

For a number of practical reasons, combination therapy may be beneficial. The patient does not need to learn how to mix different types of insulin, and patient compliance and acceptance are better with a single injection than with multiple injections of insulin. Combination therapy also requires a lower total dose of exogenous insulin than regimens of two or three injections per day. Combination therapy also contributes to less weight gain and peripheral hyperinsulinemia. Last, combination therapy is ideally suited to suppress excessive hepatic glucose production overnight. The rationale for combination therapy with insulin and sulfonylureas is based on the assumption that, if evening insulin lowers the fasting glucose concentration to normal, then daytime oral agents will be more effective in controlling postprandial hyperglycemia and maintaining euglycemia throughout the day. Metabolic profiles of patients who have type 2 diabetes have demonstrated that fasting blood glucose contributes significantly to daytime hyperglycemia [42]. In addition, the fasting blood glucose concen- tration is highly correlated with the degree of hepatic glucose production during the early morning hours [13]. Hepatic glucose output is directly decreased by insulin [43] and indirectly inhibited by the ability of insulin to reduce adipose tissue lipolysis, with lower concentrations of free fatty acids and gluconeogenesis [41]. Also, the peak of bedtime intermediate-acting insulin coincides with the onset of the dawn phenomenon (early morning resistance to insulin caused by diurnal variations in growth hormone and possibly in levels of norepinephrine), which usually occurs between 3 and 7 AM. Bedtime insulin also increases the morning serum insulin

870 T. Davis, S.V. Edelman / Med Clin N Am 88 (2004) 865–895

concentration and may assist in reducing the post-breakfast glucose rise in addition to the fasting value.

Combination of insulin and sulfonylurea agents

In one of the first large studies demonstrating the efficacy of insulin/ sulfonylurea combination therapy, Yki-Jarvinen et al [38] compared com- bination therapy with regimens of two and four insulin injections per day in patients with type 2 diabetes. These patients were on submaximal doses of glyburide (12.5 mg/d), glipizide (20 mg/d), and metformin ( 1.4 g/d), with fasting blood glucose concentrations at approximately 225 mg/dL and mean fasting serum C-peptide values of 0.66 nmol/L. After 3 months, all treatment groups had similar reductions in mean diurnal glucose con- centrations and glycosylated hemoglobin levels (1.6%–1.9%) compared with the control group, who were taking oral agents alone. The group treated with a combination of oral agents and bedtime neutral protamine Hagedorn (NPH) insulin, however, had the least weight gain (1.2 0.5 kg) of any group and a 50% to 65% lower increment in mean diurnal serum-free insulin concentrations. There was no evidence of severe hypoglycemia with combination therapy, and patient acceptance was excellent. Several other recent publications [26,28,29,31,34,40] also support the additional efficacy and safety of combination therapy in patients who are inadequately controlled by oral hypoglycemic agents alone. A recent study conducted by Riddle and Schneider [36] demonstrates the efficacy and safety of a combination consisting of 70% NPH insulin and 30% regular insulin (70/30) insulin at dinnertime and sulfonylurea therapy. In this study, 145 type 2 diabetics with uncontrolled hyperglycemia (fasting plasma glucose level [FPG] 180–300 mg/dL), on maximum sulfonylurea therapy (glimepir- ide, 8 mg orally, twice daily) were randomized to placebo plus insulin or glimepiride plus insulin for 6 months. The dose of 70/30 insulin at dinnertime was titrated to keep fasting fingerstick capillary blood glucose to less than 120 mg/dL. At 24 weeks, HbA 1c levels decreased significantly and similarly in both groups ( 9.9%–7.6%). The combination therapy group, however, needed nearly 35% less insulin than the insulin-only group (49 versus 78 units) and achieved glycemic control faster, with fewer dropouts (3% versus 15%, P \ 0.01). Surprisingly, weight gain was similar ( 4.0 kg) in both groups.

Insulin and metformin

Weight gain is a constant occurrence in most clinical trials in which insulin or sulfonylureas, or both agents, are used to treat type 2 diabetes. Although it was attenuated with combination therapy with sulfonylureas in the study by Yki-Jarvinen [38], weight gain remains a problem because it can exacerbate insulin resistance and hyperinsulinemia. The use of metformin in

T. Davis, S.V. Edelman / Med Clin N Am 88 (2004) 865–895

871

this situation may prove advantageous because its use is associated with reduced weight gain. The safety and efficacy of metformin in combination with insulin has been demonstrated in a recent multicenter study by Yki-Jarvinen et al [35]. In this placebo-controlled study, 96 type 2 diabetics who were poorly controlled with oral sulfonylurea therapy (mean glycosylated hemoglobin value 9.9% 0.2%; mean fasting plasma glucose level 214 5 mg/dL) were randomized to 1 year of treatment with bedtime intermediate-acting insulin plus either glyburide (10.5 mg), metformin (2 g), glyburide and metformin, or a second injection of intermediate-acting insulin in the morning. Patients were taught to adjust the bedtime insulin dose on the basis of fasting glucose measurements. At 1 year, body weight remained unchanged in patients receiving bedtime insulin plus metformin (mean change 0.9 1.2 kg) but increased by 3.9 0.7 kg, 3.6 1.2 kg, and 4.6 1.0 kg, respectively, in patients receiving bedtime insulin plus glyburide, bedtime insulin plus both oral drugs, and bedtime and morning insulin. In addition, the greatest decrease in the glycosylated hemoglobin value was observed in the bedtime insulin and metformin group (from 9.7 0.4% to 7.2 0.2%, a difference of 2.5 0.4 percentage points) at 1 year (P 0.001 compared with baseline and P 0.05 compared with other groups). This group also had significantly fewer symptomatic and biochemical cases of hypoglycemia (P 0.05) than the other groups. The authors conclude that combination therapy with bedtime insulin plus metformin not only prevents weight gain but also seems superior to other bedtime insulin regimens, with respect to improvements in glycemic control and frequency of hypoglycemia. In a more recent study [44] of approximately 390 type 2 diabetics, the combination of insulin and metformin led to a significant improvement in glycemic control that was greater than with insulin alone. The mean daily glucose level decreased from 141 34 to 137 31 mg/dL in the insulin-only group (mean decrease 0.16; 95% confidence interval [CI]; 10–4 mg/dL) and from 141 40 to 140 31 mg/dL in the metformin group (P = 0.006 versus placebo; mean decrease 1.04; 95% CI; 27 to 9 mg/dL). The mean daily glucose level decreased by 13 mg/dL more in the metformin group compared with the placebo group Fig 1.

Insulin and thiazolidinediones

The glitazones are potent insulin sensitizers and are, therefore, well suited for use in insulin-resistant patients with type 2 diabetes. In several early studies, troglitazone was documented to not only improve glycemic control but also to reduce exogenous insulin requirements in obese patients with type 2 diabetes [45,46]; however, troglitazone was withdrawn from the US market as a result of an increased risk of severe idiosyncratic liver damage. Presently there are two glitazones available, rosiglitazone and pioglitazone, for clinical use in the US, and several more are in development.

872 T. Davis, S.V. Edelman / Med Clin N Am 88 (2004) 865–895

T. Davis, S.V. Edelman / Med Clin N Am 88 (2004) 865–895 Fig. 1. ( A

Fig. 1. (A) Blood glucose levels measured at home. (B) Change in blood glucose levels measured at home. Data are means with SD error bars. For each time point indicated, the first and the second bars show values at baseline and the third and the fourth show values at 16 weeks. Blood glucose levels in the metformin group compared with the placebo group are all significantly lower at 16 weeks (P 0.05). The change in glucose values is also significantly greater in the metformin than in the placebo group at all times during the day (P 0.05). (From Wulffele MG, Kooy K, Lehert P. Bets D Ogterop JC, Van Der Burg BB, Donker AJM, Stehouwer CDA. Combination of insulin and metformin in the treatment of type 2 diabetes. Diabetes Care 2002;25(12):2133–40; with permission.)

In one 16-week study, Rubin et al [47] demonstrated that the daily addition of 15 and 30 mg of pioglitazone to the regimen of patients receiving a median dose of 61 units of insulin resulted in mean FPG reductions of 36 and 49 mg/ dL and HbA 1c reductions of 0.7% and 1.0%, respectively, compared with placebo. The insulin-sparing properties of rosiglitazone were shown in a 6- month study conducted by Raskin et al [48]. They demonstrated that the addition of 2 and 4 mg orally twice daily of rosiglitazone improved HbA 1c

T. Davis, S.V. Edelman / Med Clin N Am 88 (2004) 865–895

873

levels by 0.6% and 1.2%, respectively, compared with placebo, in 312 patients with type 2 diabetes who were uncontrolled on approximately 70 units of insulin daily (baseline HbA 1c 9%). Moreover, insulin requirements were also reduced by approximately 5 and 10 units, respectively, in the two groups treated with rosiglitazone, in keeping with the insulin sensitizing effects of the glitazones. In summary, both rosiglitazone and pioglitazone improve glucose control in poorly controlled, insulin-treated patients with type 2 diabetes mellitus. There have been no reports of insulin added to subjects treated with glitazones alone.

Insulin and a -glucosidase inhibitors

The addition of acarbose to insulin therapy may be an option in patients who have pronounced postprandial hyperglycemia. The first long-term controlled study to demonstrate a beneficial effect of acarbose in patients on insulin therapy was reported by Chiasson et al [49]. Of the total number of patients in this study, 91 were receiving insulin and had glycosylated hemoglobin values greater than 7%. Postprandial plasma glucose levels at 90 minutes were significantly reduced to 282 mg/dL with the addition of acarbose, compared with 331 mg/dL seen with insulin alone. Glycosylated hemoglobin values decreased by 0.4% in the acarbose group, but, as ex- pected, no significant decreases in fasting plasma glucose levels were seen. Acarbose may be initiated in patients on insulin treatment by starting with a low dose of 25 mg with breakfast and titrating up by 25 mg weekly to 50 to 100 mg three times daily with meals (100 mg three times daily for patients 60 kg body weight), depending on gastrointestinal tolerance and efficacy.

Insulin glargine and oral agents

The long-acting analog insulin glargine was studied in comparison with NPH insulin in 756 patients with type 2 diabetes in an open-label, 24-week, multicenter study [50]. In this study, patients who were inadequately controlled on oral agents including sulfonylurea, metformin, and glitazones were randomized to receive either bedtime insulin glargine or NPH insulin, and the doses were adjusted to obtain a target fasting glucose level of less than 100 mg/dL (5.6 mmol/L). At the conclusion of the trial, the median daily dose of insulin was approximately 0.45 IU/kg of body weight in both groups. The two forms of insulin produced a similar improvement in HbA 1c (6.96 versus 6.97%) and similar reductions in fasting glucose levels (117 versus 120 mg/dL); however, the incidence of mild nocturnal hypoglycemia was significantly lower among patients treated with insulin glargine than in the group treated with NPH insulin (P \ 0.001) [50]. There was a reduction of approximately 45% of nocturnal hypoglycemia with glargine compared

874 T. Davis, S.V. Edelman / Med Clin N Am 88 (2004) 865–895

with NPH [50]. Treatment with NPH or glargine in addition to oral therapy in type 2 diabetic patients resulted in a decrease of fasting glucose in both groups, reaching a plateau by 12 weeks. HbA 1c declined at a predictably slower rate, stabilizing after 18 weeks (Fig. 2) [50].

slower rate, stabilizing after 18 weeks ( Fig. 2 ) [50] . Fig. 2. ( A

Fig. 2. (A) FPG and (B) HbA 1c during the study. Values in both figures are means; error bars indicate SE. (From Riddle MC, Rosenstock J, Gerich J. The Treat-to-Target Trial: Randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care 2003;26(11):3080–6; with permission.)

T. Davis, S.V. Edelman / Med Clin N Am 88 (2004) 865–895

875

Selection of patients most likely to succeed on combination treatment

The most common type of patient in whom combination therapy will succeed is the one who is failing oral treatment without significant glucose toxicity and has some evidence of responsiveness to oral agents. Patients have a higher likelihood of success using combination therapy if they are obese, have had overt diabetes for less than 10 to 15 years, are diagnosed with type 2 diabetes after the age of 35, do not have fasting blood glucose

values consistently over 250 to 300 mg/dL, and have evidence of endogenous insulin secretory ability. Although standard measurement conditions and C- peptide concentrations have not been established for this clinical situation,

a fasting C-peptide concentration ( 0.2 nmol/L) or glucagon-stimulated

level ( 0.40 nmol/L) indicates some degree of endogenous insulin secretory ability [51,52]. Patients with type 2 diabetes diagnosed before the age of 35

more often have atypical forms of diabetes. Patients who have had diabetes for more than 10 to 15 years tend to have a greater chance of beta-cell exhaustion and, thus, tend to be less responsive to oral hypoglycemic agents and combination therapy. Thin patients are more likely to be hypoinsuli- nemic and often respond inadequately to oral agents, which lead to combination therapy failure. In addition, markedly elevated fasting glucose concentration is often associated with a concomitant decrease in endoge- nous insulin secretory ability, which renders oral agents ineffective. The actual number of patients who might respond favorably to combination therapy is unknown but is estimated to be between 20% and 40%.

Initiating combination therapy

Calculation of the initial bedtime dose of intermediate-acting insulin can be based on clinical judgment or various formulas based on the fasting blood glucose concentration or body weight. For example, the average fasting blood glucose (mg/dL) can be divided by 18 or body weight (kg) can be divided by 10 to calculate the initial dose of NPH or insulin glargine to be started at bedtime [43]. Also, 5 to 10 units of insulin can be safely started for thin patients, and 10 to 15 units can be started for obese patients at bedtime, as an initial estimated dose. In either case, the dose is increased in increments of 2 to 5 units every 3 to 4 days until the morning fasting blood glucose concentration is consistently in the range of 70 to 120 mg/dL [53]. The best time to give the evening injection of intermediate-acting insulin

is between 10 PM and midnight. Insulin glargine has been shown to be

effective when taken either in the morning or evening. Many reliable pa- tients can make their own adjustments using HGM. Based on the results of HGM, combination therapy can be altered to reduce hyperglycemia at identified times during the day. For example, a common situation seen with daytime oral agents and bedtime intermediate- acting insulin therapy is an improvement in the fasting, pre-lunch, and pre- dinner blood sugar values, although the post-dinner blood glucose

876 T. Davis, S.V. Edelman / Med Clin N Am 88 (2004) 865–895

concentration remains excessively high ( 200 mg/dL). In this clinical situation, an injection of premixed insulin (70/30 or 75/25 mix) can be given before dinner instead of a bedtime dose of intermediate- or long-acting insulin. This regimen will often improve the post-dinner blood glucose values because the premixed insulin contains rapid-acting analogs yet allows overnight glucose control secondary to the intermediate-acting component. With this regimen, however, one must be more cautious about early morning hypoglycemia because the intermediate-acting insulin given before dinner will exert its peak effect earlier. In the experience of these authors, this has not been a major clinical problem in obese patients with type 2 diabetes compared with those with type 1 diabetes mellitus. Normally the dose of bedtime intermediate- or long-acting insulin can be converted to the dose of premixed insulin, dose per dose, and adjustments can be made through HGM.

Dose adjustment

Once the fasting blood glucose concentrations are consistently in a desir- able range, the pre-lunch, pre-dinner, and bedtime blood sugar values must be monitored to determine if the oral hypoglycemic agents are maintaining daylong glycemia. It is recommended that after the addition of evening insulin patients continue to take the maximal dose of the oral sulfonylurea agent. If the daytime blood glucose concentrations become excessively low, the dose of oral medication must be reduced. The morning dose of sul- fonylurea should be reduced or discontinued first. This situation is common because glucose toxicity may be reduced because of improved glucose control, leading to enhanced sensitivity to both oral agents and insulin. If the pre-lunch and pre-dinner blood glucose concentrations remain exces- sively high on combination therapy, it is likely that the oral agents are not contributing significantly to glycemic control throughout the day. In this situation, a more conventional or intensive regimen of two injections per day is indicated.

Multiple-injection regimens

One of the most common insulin regimens used in type 2 diabetes mellitus is the split-mixed regimen consisting of a pre-breakfast and pre-dinner dose of intermediate- and fast-acting insulin. This split-mixed regimen of two injections per day is often inadequate for patients with type 1 or lean patients with type 2 diabetes and can result in persistent early morning hypoglycemia and fasting hyperglycemia. Such problems do not appear to occur as frequently in obese type 2 diabetes. This is likely caused by pathophysiologic differences, particularly in endogenous insulin secretory ability, insulin resistance, and counter-regulatory mechanisms in type 1 and type 2 diabetes.

T. Davis, S.V. Edelman / Med Clin N Am 88 (2004) 865–895

877

In a landmark trial with type 2 diabetes by Henry et al [54], daylong gly- cemia and glycosylated hemoglobin were essentially normalized by 6 months of intensive treatment with a split-mixed insulin regimen. In this study, 14 typical obese patients with type 2 diabetes mellitus (age 59 2 years; duration of diabetes 7 2 years; body mass index 31 2 kg/m 2 ; fasting blood glucose concentration 283 13 mg/dL) failing therapy with oral antidiabetic agents were intensively managed with pre-breakfast and pre- dinner NPH and regular insulin over a 6-month period. The insulin dose was adjusted based on HGM results of four injections per day. Glycemic control was rapidly achieved within 1 month and was maintained for the duration of the study. The average total insulin dose needed to maintain glycemic control approached 100 units per day, with approximately 50% of the total dose required before breakfast and 50% before dinner. The ratio of NPH to regular insulin was approximately 75%:25%. There was a very low incidence

of mild hypoglycemic reactions, which decreased as the study progressed,

and no reactions were severe or required assistance. In addition, patient compliance and sense of well being were excellent. Near-normalization of the glycosylated hemoglobin, however, led to some adverse effects in these patients. The mean serum insulin concentration obtained during 24-hour metabolic profile studies increased from 308 80 pmol/L at baseline to 510 102 pmol/L (P 0.05) at completion of the 6-month study. The exacerbation of hyperinsulinemia by exogenous insulin therapy was strongly

correlated with weight gain throughout the study. Despite biweekly visits with the study dietitian and instructions to reduce the daily caloric intake,

a mean weight gain of approximately 9 kg or 18.8 pounds occurred.

Interestingly, the total daily insulin dose was 86 þ 13 units at 1 month and 100 þ 24 units at 6 months, despite minimal additional improvement in

glycemic control during that period. Most of the improvement in glycemic control was caused by the suppression of basal hepatic glucose production (from 628 þ 44 to 350 þ 17 l mol/m 2 /min, P 0.001), with a more modest but significant improvement in peripheral glucose uptake (from 1418 þ 156

to 1657 þ 128 l mol/m 2 /min, P 0.05), as determined by the glucose clamp

technique. This study emphasizes a number of important aspects of intensive glucose control with insulin in obese subjects with type 2 diabetes. First, the average daily dose of insulin needed to control such patients approximates 1 unit per kilogram of body weight. Second, the total daily insulin requirement can be split equally between the pre-breakfast and pre-dinner injections. Third, the split-mixed regimen in patients with type 2 diabetes is usually devoid of the common problems seen with this regimen in type 1 diabetes, particularly early morning hypoglycemia and fasting (pre-prandial) hyperglycemia. Fourth, both severe and mild hypoglycemic events are much less fre- quent in patients with type 2 compared with patients with type 1 diabetes undergoing intensive insulin therapy. And finally, weight gain with

878 T. Davis, S.V. Edelman / Med Clin N Am 88 (2004) 865–895

peripheral hyperinsulinemia occurs, which may contribute to metabolic and vascular complications. A similar but larger 3-month clinical trial [38] compared a split-mixed combination with a multiple-injection regimen consisting of pre-meal regular and bedtime NPH insulin injections. Both the split-mixed and multiple-injection regimen treatment groups achieved equivalent and near- normal glycosylated hemoglobin values. These therapies, however, were associated with weight gain of 0.8 0.05 and 2.9 0.05 kg, a 39% and 36% increase in mean diurnal serum-free insulin levels, and a total daily insulin dose of 43 and 45 units, respectively. The authors demonstrated that the change in body weight was negatively correlated with the change in glycosylated hemoglobin values and positively correlated with the mean diurnal serum-free insulin values. The differences between these two studies with regard to total insulin requirements, mean insulin concentrations, and weight gain are primarily the result of differences in patient characteristics. Patients in the latter study were leaner (body mass index 29 versus 31 kg/ m 2 ), had lower baseline fasting blood glucose values (225 versus 283 mg/dL) and reduced baseline mean diurnal serum-free insulin values (138 versus 308 pmol), and were previously treated with submaximal doses of sulfonylureas, compared with the patients in the former study. In addition, the latter study was conducted over a shorter period of time (3 months versus 6 months). Another long-term (5-year) clinical trial using a split-mixed regimen of two injections per day in 102 nonobese type 2 diabetic patients demonstrated that excellent glycemic control could be achieved with intensive split-dose insulin without significant hypoglycemia but at the expense of progressive weight gain [55]. All these studies clearly demonstrate the efficacy of various insulin regimens and the adverse consequences of such therapy.

Premixed insulin approach: rapid-acting insulin analogs

Rapid-acting insulin analogs are also available as manufactured, pre- mixed insulin formulations. One such insulin preparation is Humalog Mix 75/25, which is a fixed-ratio mixture of 25% rapid-acting insulin lispro and 75% novel protamine-based intermediate-acting insulin called neutral protamine lispro (NPL). NPL was developed to solve the problem of instability with prolonged storage that occurs with NPH combined with insulin. Studies of the pharmacokinetic and pharmacodynamic profiles of NPL show they are comparable to those of NPH insulin [56]. Humalog Mix 75/25 was studied in comparison to premixed human insulin 70/30 in 89 patients with type 2 diabetes in a 6-month randomized, open-label, two-period crossover study [57]. All patients had been previously treated with mixed insulin therapies, including short- or rapid-acting and an intermediate- or long-acting insulin, twice daily for at least 30 days before enrollment. During a 2 to 4 week lead-in period, patients were treated with

T. Davis, S.V. Edelman / Med Clin N Am 88 (2004) 865–895

879

human insulin 70/30. The patients were randomized to receive one of two treatment sequences: therapy twice per day with Humalog Mix 75/25 in- jected before morning and evening meals for 3 months, after which they were crossed over to receive human insulin 70/30 using the same dosing frequency for an additional 3 months, or the alternate treatment sequence. Patients performed self-monitoring blood glucose (SMBG) at scheduled intervals during the study period (preprandial, 2-h postprandial, and occasional 3 AM readings) and recorded this information along with any hypoglycemic episodes in a study diary. Mean insulin doses were similar or identical between treatments. Blood glucose values after the morning meal were significantly lower during treatment with Humalog Mix 75/25 (Humalog Mix 75/25 8.95 2.17 versus human insulin 70/30 10.00

2.28 mmol/L, P = 0.017). Treatment with Humalog Mix 75/25 produced

similar significant blood glucose results 2 hours after the evening meal as

well (Humalog Mix 75/25 9.28 2.15 versus human insulin 70/30 10.27

2.76 mmol/L, P = 0.014). Blood glucose results at other time points, HbA 1c

levels, daytime hypoglycemia, and nocturnal hypoglycemia were not sig- nificantly different between treatments. Compared with human insulin 70/ 30, twice-daily injections of Humalog Mix 75/25 in patients with type 2 diabetes resulted in improved postprandial glycemic control after the morning and evening meals, similar overall glycemic control, and the added convenience of administration immediately before meals. Insulin aspart, another rapid-acting insulin analog, is available in a premixed formulation with a protamine-retarded insulin aspart called Novolog Mix 70/30 (70% insulin aspart protamine suspension and 30% insulin aspart). A comparison study [58] of the pharmacokinetic and pharmacodynamic parameters of the Novolog Mix 70/30 and human insulin 70/30 in healthy patients showed that the faster onset and greater peak action of insulin aspart was preserved in the aspart mixture. Another study [59] compared premixed aspart mixture 70/30 with premixed human insulin 70/30 administered twice daily in a randomized 12-week open-label trial in 294 patients with type 1 and type 2 diabetes. Patients were instructed to inject the human insulin 70/30 30 minutes before morning and evening meals and the premixed aspart mixture 10 minutes

before morning and evening meals. SMBG levels and hypoglycemia incidence were recorded in diaries. Patients required a small increase in the total daily aspart mixture dose compared with human insulin 70/30 (mean difference at 12 weeks [95% CI 0.01; 0.05]), P 0.01; 0.03 U/kg. There was no significant difference in HbA 1c between groups, yet the mean blood glucose values after treatment with the aspart mixture showed statistically significant treatment differences after breakfast, before lunch, after dinner, and at bedtime. Blood glucose values were approximately 1.0 mmol/L lower compared with the human insulin 70/30 group at each time point (P 0.05). The incidence of hypoglycemia was not found to be different between the two groups, and weight gain was not significant during

880 T. Davis, S.V. Edelman / Med Clin N Am 88 (2004) 865–895

the study period with either type of insulin. Treatment with twice-daily premixed aspart mixture 70/30 resulted in similar overall glycemic control; yet postprandial control improved without additional hypoglycemia and with injections immediately before meals compared with premixed human insulin 70/30 given 30 minutes before the meal. In a more recent study that focused on changes in lipid levels, Schwartz et al [60] compared insulin 70/30 mix taken twice per day plus metformin versus triple oral therapy (secretagogues, metformin, and thiazolidine- diones) and clearly demonstrated that insulin plus metformin are superior in lowering total cholesterol and triglycerides levels. The baseline values for total cholesterol, low-density lipoprotein, high-density lipoprotein, and triglycerides indicated no differences between the triple OHA and insulin/ metformin groups. By the end of the study (week 24) significant decreases in total cholesterol and triglycerides were evident in the insulin plus metformin group (P = 0.038 and 0.033, respectively, compared with the triple oral therapy group). Subjects in the triple oral therapy group showed a small increase in cholesterol and less of a decrease in triglyceride levels [60]. For glucose control, both groups had similar FPG values at the beginning of the study. After 24 weeks of treatment, the changes from baseline mean FPG values were 55 and 65 mg/dL for the triple oral therapy and insulin plus metformin, respectively [60]. Baseline HbA 1c values were 9.62 1.25% for subjects in the triple oral therapy and 9.65 1.62% in the insulin group. HbA 1c values at weeks 2 and 6 demonstrated the efficacy of both treatments; however, insulin plus metformin treatment achieved improvements in HbA 1c values at weeks 2 and 6 (9.03 1.35% and 8.11 1.20%, respectively) that were significantly greater than the response to triple oral therapy (P = 0.001 and 0.001, respectively). At weeks 12 and 24, no statistically significant difference in HbA 1c between the two groups were observed (final values at week 24 were 7.59 1.4% for triple oral therapy and 7.59 1.25% for insulin plus metformin [P = 0.772]) (Fig. 3) [60]. Along with SMBG, the use of rapid-acting premixed insulin analogs is convenient and can be beneficial in reducing postprandial hyperglycemia and in helping patients achieve glycemic control without the increased incidence of hypoglycemia. In addition, protocols are currently underway to assess the efficacy of using rapid-acting premixed insulin analogs three times per day before breakfast lunch and dinner, based on HGM data. This regimen is more related to a basal bolus strategy discussed below.

Basal–bolus strategy

The basal–bolus insulin strategy, which can be used in patients with either type 1 or type 2 diabetes, incorporates the concept of providing continuous basal insulin levels throughout the day and night with brief increases in insulin levels at the time of meal ingestion by bolus doses.

T. Davis, S.V. Edelman / Med Clin N Am 88 (2004) 865–895

881

Davis, S.V. Edelman / Med Clin N Am 88 (2004) 865–895 881 Fig. 3. ( A

Fig. 3. (A) Mean FPG values at screening and weeks 12 and 24 by treatment group. No statistically significant changes were observed between the triple oral therapy () and insulin plus metformin ( ). (B) Mean SEM changes for the total cholesterol, HDL, LDL, and triglycerides at week 24. * Statistically significant (P 0.05) reduction in total cholesterol and triglyceride levels in the insulin plus metformin group compared with the triple oral therapy group. HDL, high-density lipoprotein; LDL, low-density lipoprotein; OHA, XXX. (From Schwartz S, Sievers R, Strange P Lyness W, Hollander P. Insulin 70/30 mix plus metformin versus triple oral therapy in the treatment of type 2 diabetes after failure of two oral drugs:

efficacy, safety, and cost analysis. Diabetes Care 2003;26(8):2598–603; with permission.)

The use of pre-meal regular insulin with bedtime NPH as the basal insulin has been a common strategy for intensive insulin therapy in the United States, but because regular insulin should be administered 20 to 40 minutes before meals, a risk of hypoglycemia exists if the meal is delayed. If regular

882 T. Davis, S.V. Edelman / Med Clin N Am 88 (2004) 865–895

insulin is given just before a meal, high postprandial glucose levels and delayed hypoglycemia may result. A strategy that provides for some flexibility in the mealtime administration of insulin with the use of rapid- acting insulin analogs, lispro or aspart, administered immediately before meals, and long-acting insulin, such as glargine, ultralente, lente, or NPH as the basal insulin. These regimens that use multiple doses of intermediate- acting insulin such as NPH can be associated with unpredictable nocturnal hypoglycemia and day-to-day instability of blood glucose patterns in part because of intrapatient variability of the effect of subcutaneous injected insulin and the patient’s peak action profile [61]. NPH, which exhibits peak action 5 to 7 hours after administration, has also been used in combination with rapid-acting insulin analogs, commonly given at least twice daily, although the disadvantages of NPH used in this manner are similar to those associated with Ultralente