c h a p t e r

38
Classification and Diagnosis
of Diabetes Mellitus
Michael C. Dennedy, Robert A. Rizza, and Sean F. Dinneen

CHAPTER OUTLINE
DEFINITION, 662 Uncommon Forms of Immune-Mediated
CLASSIFICATION, 663 Diabetes, 668
Type 1 Diabetes,  663 Other Genetic Syndromes Sometimes Associated
Type 2 Diabetes,  665 with Diabetes,  668
Other Specific Types of Diabetes,  665 Gestational Diabetes,  668
Genetic Defects in β Cell Function,  665 DIAGNOSIS, 669
Genetic Defects in Insulin Action,  666 Diagnostic Criteria,  669
Diseases of the Exocrine Pancreas,  667 What Level of Fasting Plasma Glucose
Constitutes Diabetes?  669
Endocrinopathies, 667
What Level of Fasting Plasma Glucose
Drug- or Chemical-Induced Diabetes,  667 Constitutes Normality?  670
Infections, 668 WHERE NEXT?  671

KEY POINTS
• D  iabetes mellitus represents a heterogenous set of disorders that share dysglycemia as
their defining characteristic.
• Diagnosis of diabetes mellitus is based on fasting glucose, glucose measurements
following an oral glucose load, and HbA1c measurements. These values are common to
most forms of the disease with the exception of gestational diabetes mellitus.
• Classification of diabetes mellitus is largely based upon the initial presentation and
underlying pathogenesis, and accurate classification informs the best therapeutic
interventions.
  

nerves. Damage results, at least in part, from the long-

DEFINITION
The term diabetes mellitus does not represent a single dis-
ease entity but rather a set of disease states that share
certain characteristics. Foremost among these is the pres-
ence of elevated plasma glucose levels. As is discussed in
the following section, the presence of hyperglycemia in
a patient is used both to diagnose diabetes and to guide
management decisions, which are directed largely toward
avoiding hyperglycemia. The hyperglycemia itself results
from a combination of defects in insulin secretion, insulin
action, or both.1 An important characteristic of the various
disease states that are labeled as diabetes is the develop-
ment of end-organ damage in vital organs of the body,
including the retina, the renal glomerulus, and peripheral
662
term effects of hyperglycemia and is mediated through
glycation of tissue proteins, increased activity of the
polyol pathway, or other, as yet unrecognized, mecha-
nisms.2 Individual patients vary in their predisposition
to develop these so-called microvascular complications.
Because of this and because of the length of time they
take to develop (frequently decades), the complications
of diabetes cannot be used to classify or diagnose the
disease. People with diabetes are at considerably greater
risk for developing atherosclerotic disease affecting the
coronary, cerebrovascular, peripheral arterial, or other
parts of the circulation. A cause-and-effect relationship
between chronic hyperglycemia and these so-called mac-
rovascular complications of diabetes has not been as

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 38  CLASSIFICATION AND DIAGNOSIS OF DIABETES MELLITUS
clearly established, although evidence linking the two
is accumulating.3 Any definition of diabetes that refers
only to carbohydrate metabolism is incomplete. Oskar
Minkowski is reputed to have first made the association
between the insulin-deficient pancreatectomized state of
his laboratory dogs and the sweet taste of their urine. It
has been suggested that if Minkowski had lacked a sense
of taste but possessed a keen sense of smell, he might
have smelled the ketones on the breath of his animals and
thereby directed diabetes research toward the study of
fat metabolism.4 Disordered fat and protein metabolism
must be included in a complete definition of the disease,
although an emphasis on the pathogenesis of hyperglyce-
mia continues to this day. To define a disease purely in
biochemical terms is to diminish the component of the
disease that leads to much physical, mental, and psycho-
social distress for the many millions of people around the
world who live with it every day. Chronic rheumatic dis-
eases such as rheumatoid arthritis are not associated with
any biochemical hallmark, and their definition is based
largely on patient-derived symptoms and signs. There-
fore, it is important to try to include the patient’s per-
spective in any definition of the chronic disease referred
to as diabetes.
CLASSIFICATION
Before 1979, a classification system for diabetes was
not well established, and many different terms were
used to describe essentially the same clinical entity.
Following publication that year of the report of the
National Diabetes Data Group (NDDG),5 some order
was brought to bear in this area. The recommenda-
tions of the NDDG were subsequently endorsed by
the World Health Organization (WHO) in a publica-
tion in 1980, and minor modifications were later made
in a document published in 1985.6 This classification
in large part was based on pharmacologic treatment
of the disease. Insulin-dependent diabetes mellitus
(IDDM) and non–insulin-dependent diabetes mellitus
(NIDDM) were the two major forms of diabetes that had
been identified. The term insulin-dependent diabetes
mellitus was used to describe patients who typically were
lean at presentation, were prone to ketosis, and required
insulin for survival. The term non–insulin-dependent
diabetes mellitus was used to describe patients who typi-
cally were overweight or obese at presentation, were not
prone to ketosis, and did not require insulin for survival.
The NDDG also had categories for gestational diabetes,
malnutrition-related diabetes mellitus (MRDM), and a
category labeled “other types,” which included certain
forms of diabetes for which a cause had been suggested
at that time. As the terms IDDM and NIDDM became
widely used during the 1980s and 1990s, several prob-
lems became apparent. The main problem arose from the
fact that many patients with NIDDM ended up at some
point in the course of their disease being treated with
insulin and being misclassified as IDDM or having the
rather confusing term insulin-requiring NIDDM applied
to them. In addition, as more information became avail-
able on the causes of the various forms of diabetes, it
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663
became apparent that a classification based on therapy was
not always consistent with new insights into the patho-
genesis of the various forms of diabetes. For this reason,
the American Diabetes Association (ADA) convened an
expert panel in 1995 to address the issue of classification.
This panel published its recommendations in 1997,7 and
these were subsequently endorsed by a WHO consultation
group in a 1998 report.8 The main thrust of this proposal
was to move away from a classification based on therapy
and toward one based on pathogenesis. Four major catego-
ries were proposed: type 1 diabetes, type 2 diabetes, other
specific types of diabetes (including categories for which a
cause has been established), and gestational diabetes. The
details of this classification system, which are outlined in
Table 38-1, are discussed in the following sections.9
Type 1 Diabetes
Type 1 diabetes is characterized by the development of
a state of complete insulin deficiency arising as a conse-
quence of β-cell destruction. In its fully developed form,
patients, if deprived of insulin, will develop ketoacidosis,
coma, and death. Biochemical testing reveals a marked
reduction or complete absence of circulating C-peptide
(a marker of insulin secretion) despite hyperglycemia. The
prevalence of type 1 diabetes in the United States is as
high as 3,000,000 individuals with an annual incidence
of approximately 30,000 new cases.10 Although the peak
incidence occurs in childhood and early adolescence, this
form of diabetes can occur at any age. The incidence of the
disease shows marked regional variation, with the highest
worldwide incidence reported in Scandinavia.11 Epidemi-
ologic and immunologic research has led to the recogni-
tion of two major forms of type 1 diabetes based on the
presence or absence of certain immunologic markers.
Autoimmune Type 1 Diabetes
Autoimmune type 1 diabetes is a prototypic organ-specific
autoimmune disorder. Individuals who develop this form
of diabetes are born with a genetic predisposition to auto-
immune dysfunction, which may manifest in the develop-
ment of other autoimmune conditions such as Addison’s
disease, vitiligo, pernicious anemia, Hashimoto’s thyroid-
itis, and Celiac disease. The genetic predisposition is not
well understood but is known to be linked to the major
histocompatibility locus on chromosome 6.12 The pres-
ence of certain human lymphocyte antigen (HLA) haplo-
types appears to predispose the individual to the disease,
but other HLA haplotypes appear to be protective. In pre-
disposed individuals, a poorly understood environmental
trigger sets off a series of immunologic events that culmi-
nate in selective T cell–mediated destruction of the β cells
of the pancreatic islet. Many antigens have been investi-
gated as potential triggers for the disease. These include
certain viral antigens13 as well as an antigen contained in
cow’s milk protein.14 A large series of investigations has
been carried out for the “Diabetes Autoimmunity Study in
the Young.” These studies initially investigated the early
detection of anti-islet antibodies in children15 and their
role in the prediction of future type 1 diabetes.16,17 The
rate at which β cell destruction occurs varies from indi-
vidual to individual and may be very brief, as is seen when
664 PART 5  DIABETES MELLITUS

TABLE 38-1  Classification of Diabetes Mellitus

1. Type 1 diabetes E. Drug or chemical induced

A. Immune-mediated 1. Vacor
B. Idiopathic 2. Pentamidine
2. Type 2 diabetes 3. Nicotinic acid
3. Other specific types 4. Glucocorticoids
A. Genetic defects in β cell function 5. Thyroid hormone
1. HNF-4α (MODY 1) 6. Diazoxide
2. Glucokinase (MODY 2) 7. β-Adrenergic agonists
3. HNF-1α (MODY 3) 8. Thiazides
4. IPF-1 (MODY 4) 9. Second-generation antipsychotics
5. HNF-1β (MODY 5) 10. Protease inhibitors
6. NeuroD1, or BETA 2 (MODY 6) 11. Pasireotide
7. Mitochondrial DNA 12. Others
8. Others F. Infections
B. Genetic defects in insulin action 1. Congenital rubella
1. Type A insulin resistance 2. Cytomegalovirus
2. Leprechaunism 3. Others
3. Rabson-Mendenhall syndrome G. Uncommon forms of immune-mediated diabetes
4. Lipodystrophic diabetes 1. “Stiff-man” syndrome
5. Others 2. Anti-insulin receptor antibodies
C. Diseases of the exocrine pancreas 3. Others
1. Pancreatitis H. Other genetic syndromes sometimes associated with
2. Trauma/pancreatectomy diabetes
3. Neoplasia 1. Down syndrome
4. Cystic fibrosis 2. Klinefelter’s syndrome
5. Hemochromatosis 3. Turner’s syndrome
6. Fibrocalculous pancreatic diabetes 4. Wolfram’s syndrome
7. Others 5. Friedreich’s ataxia
D. Endocrinopathies 6. Huntington’s chorea
1. Cushing’s syndrome 7. Lawrence Moon Biedel syndrome
2. Acromegaly 8. Myotonic dystrophy
3. Glucagonoma 9. Porphyria
4. Pheochromocytoma 10. Prader-Willi syndrome
5. Somatostatinoma 11. Others
6. Aldosteronoma 4. Gestational diabetes mellitus
7. Hyperthyroidism
8. Others
HNF, Hepatocyte nuclear factor; IPF, insulin promoter factor; MODY, maturity-onset diabetes of the young.
From the Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1997;20(7):1183-1197.

type 1 diabetes presents in children or young adults,17,18 or
may be prolonged, as is seen in what has been called latent
autoimmune diabetes in adults.19 Antibodies appear in the
circulation early in the process of β cell destruction.20 These
autoantibodies are believed to be markers (rather than
true instigators) of the immune response. Their presence
can help to classify a newly diagnosed patient with diabe-
tes. In several studies, screening for these autoantibodies
has led to recognition of autoimmune type 1 diabetes in
individuals who otherwise might have been labeled as hav-
ing type 2 diabetes21,22 (see later). Islet cell antibodies, the
first autoantibodies to be discovered, are directed against
a range of islet antigens. The best characterized autoanti-
bodies are those directed against glutamic acid decarbox-
ylase (GAD), an enzyme that is involved in γ-aminobutyric
acid synthesis.23 Isoforms of GAD are found in the central
nervous system and in β cells of the pancreatic islet. Other
autoantibodies include those directed against tyrosine
phosphatases, namely IA-2 and IA-2β, as well as antibod-
ies directed against insulin itself (anti-insulin antibodies).
Autoantibodies are present in 85% to 90% of individu-
als with type 1 diabetes at the time of presentation with
fasting hyperglycemia.15 Childhood-onset type 1 diabetes
is associated with higher levels of autoantibody in serum.
Testing for these autoantibodies is still restricted to a lim-
ited number of laboratories. The most recent recommenda-
tion from the ADA recognizes the utility of autoantibody
testing when aiding the classification of diabetes and states
that while autoantibodies are not recommended for the
routine diagnosis of diabetes, standardized autoantibody
tests can be used for classification of diabetes in adults and
in prospective studies of children at genetic risk for type 1
diabetes after HLA typing at birth.16 The report also states
that the use of insulin antibody testing has no place in the
routine care of patients with diabetes.16
Idiopathic Type 1 Diabetes
The term idiopathic type 1 diabetes is used to describe
a small subset of individuals with type 1 diabetes who
appear not to have an autoimmune basis for their β cell
destruction.24 Other features of this subtype include its
occurrence predominantly in individuals of African-
American or Asian ethnicity, its lack of HLA association,
and its intermittent proneness to ketosis. A number of
different terms, including atypical diabetes, Flatbush dia-
betes, and type 1.5 diabetes, have been used to describe
this form of diabetes. The preferred term in the recent
literature appears to be ketosis-prone type 2 diabetes.25

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 38  CLASSIFICATION AND DIAGNOSIS OF DIABETES MELLITUS
Type 2 Diabetes
Type 2 diabetes represents the most common form of
diabetes. The number of adults with type 2 diabetes has
doubled over the past three decades. Current estimates
for the U.S. population indicate that over 20 million peo-
ple have type 2 diabetes,26,27 while worldwide estimates
for type 2 diabetes reach almost 250 million.27 The con-
dition is characterized by hyperglycemia that results from
a combination of defects in insulin secretion and insulin
action. In any given individual, the degree to which these
defects contribute to hyperglycemia may vary. The dis-
ease usually has its onset after 40 years of age, although
type 2 diabetes is being seen increasingly in young adults
and adolescents.28,29 Although progressive β cell failure is
believed by many to be an important part of the natural
history of this form of diabetes,30 the β cell destruction is
not autoimmune mediated1 and does not progress to the
point at which the patient becomes dependent on insulin
for survival. Ketoacidosis is unusual in this form of dia-
betes, and when it occurs, it usually does so in the setting
of a major intercurrent illness such as myocardial infarc-
tion or stroke, or when treatment with glucocorticoids
is provided. Individuals with type 2 diabetes are not at
increased risk for autoimmune disease but have a higher
prevalence of metabolic abnormalities, including obesity,
hypertension, and a dyslipidemia that is characterized
by hypertriglyceridemia and low levels of high-density
lipoprotein cholesterol. This combination of metabolic
derangements is associated with a marked increase in
risk for atherosclerotic disease. In fact, the prevalence of
atherosclerotic disease in individuals with type 2 diabe-
tes has led to the suggestion that, rather than one lead-
ing to the other, the two conditions may share common
antecedents.3 Insulin resistance may be an important
predisposing factor for both conditions. In recent years,
an inflammatory paradigm of innate immune cell activa-
tion has been proposed as an underlying factor for both
conditions.31
The cause of type 2 diabetes remains to be determined.
Any pathogenetic model of the disease must include both
genetic and environmental factors. Challenges in estab-
lishing the cause of type 2 diabetes include the follow-
ing: (1) The disease lacks an easy-to-define phenotype
and instead is characterized by considerable heteroge-
neity across different ethnic groups; this heterogeneity
often is represented by a spectrum ranging from a pre-
dominant defect in insulin secretion on the one hand to a
predominant defect in insulin action on the other. (2) The
relatively late age of onset makes it difficult to establish
large kindreds and therefore limits genetic studies. (3) No
easy-to-apply methods are available for screening popula-
tions for insulin resistance and defective insulin secretion.
(4) The pathways that are involved in mediating insulin
action are complex and are not fully understood; most
authors believe that a single genetic defect will explain
only a subset of the disease; it is much more likely that
type 2 diabetes represents a set of disorders. Evidence to
support a genetic component of the disease comes from
the strong concordance for the disease that is seen among
monozygotic twins.32 On the other hand, the dramatic
increase in incidence and prevalence of type 2 diabetes
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665
that accompanies the change to a so-called Westernized
lifestyle strongly supports an environmental component
as well.33,27
Other Specific Types of Diabetes
Other specific types of diabetes are included in both
the 1979 NDDG and the 1997 American Diabetes
Association (ADA) classification systems.5,7 A number
of changes occurred in the subtypes of diabetes listed
between the two eras. In particular, the form of diabetes
that is referred to as maturity-onset diabetes of the young
(MODY) has been better defined genetically, and this is
reflected in the 1997 ADA classification system.7 Another
change resulted from removal of MRDM from the clas-
sification and inclusion of fibrocalculous pancreatic dia-
betes (which was previously a subtype of MRDM) as a
disease of the exocrine pancreas. The decision to remove
MRDM as a separate entity resulted from an interna-
tional conference on this subject.34,35 The findings of
the conference did not support a direct cause-and-effect
relationship between protein-calorie malnutrition and
the development of diabetes. Rather, it was thought that
the presence of malnutrition could influence the manner
in which diabetes might present in an otherwise predis-
posed individual.
Genetic Defects in β Cell Function
In the past, the term maturity-onset diabetes of the young
was used to describe a subset of patients with a form of
diabetes characterized by early age of onset of hypergly-
cemia with an autosomal dominant mode of inheritance.
Mutations in certain genes that are involved in regulat-
ing insulin secretion have now been shown to be respon-
sible for the hyperglycemia seen in MODY kindreds.36
Six major forms of MODY have been described,37-40
and their clinical and genetic features are outlined in
Table 38-2 (see Chapter 49). All forms of MODY are
associated with defective insulin secretion without any
significant degree of insulin resistance.41,42 In the case of
glucokinase, the pathophysiologic mechanism is clear,
because the enzyme is involved in phosphorylating glu-
cose, one of the first steps in glucose metabolism. A glu-
cokinase mutation therefore decreases the ability of the
β cell to sense glucose. MODY2 is associated with rela-
tively mild hyperglycemia that is usually amenable to
treatment with diet and exercise. MODY1 and MODY3,
on the other hand, can be associated with more severe
hyperglycemia, a greater likelihood that insulin will be
required for management, and a higher propensity to
develop complications.36 The link between diabetes and
mutations in the genes for hepatocyte nuclear factor
(HNF)-1a, HNF-1β (hepatocyte transcription factors
also expressed in β cells), and HNF-4a (a member of the
steroid-thyroid hormone superfamily and an upstream
regulator of HNF-1 a), appears to involve regulation of
expression of the insulin gene.43 It has been suggested
that MODY may account for between 2% and 5% of
cases of type 2 diabetes.44
Neonatal diabetes is rare and may be transient or per-
manent.45 Several genetic defects have been identified in
these patients. Transient neonatal diabetes results from a
666 PART 5  DIABETES MELLITUS

TABLE 38-2  MODY-Related Genes and the Clinical Phenotypes Associated with Mutations in the Genes

Clinical Features of Most Common Clinical Features of

MODY Type Gene Heterozygous State Treatment Molecular Basis Homozygous State
MODY 1 HNF-4α Diabetes; microvascular Oral hypoglycemic Abnormal regulation of gene
complications (in many agent, insulin transcription in β cells, leading
cases); reductions in serum to a defect in metabolic signaling
concentrations of triglyc- of insulin secretion, β cell mass,
erides, apolipoproteins or both
AII and CIII, and Lp(a)
lipoprotein
MODY 2 Glucokinase Impaired fasting glucose, Diet and exercise Defect in sensitivity of β cells to Permanent neo-
impaired glucose tolerance glucose due to reduced glucose natal diabetes
phosphorylation; defect in requiring
hepatic storage of glucose as insulin treat-
glycogen ment
MODY 3 HNF-1α Diabetes, microvascular Oral hypoglycemic Abnormal regulation of gene
complications (in many agent, insulin transcription in β cells, leading
cases), renal glycosuria, to a defect in metabolic signaling
increased sensitivity to of insulin secretion, β cell mass,
sulfonylurea drugs or both
MODY 4 IPF-1 Diabetes Oral hypoglycemic Abnormal transcriptional regula- Pancreatic
agent, insulin tion of β cell development and agenesis and
function neonatal dia-
betes requir-
ing insulin
treatment
MODY 5 HNF-1 β Diabetes; renal cysts and Insulin Abnormal regulation of gene
other abnormalities of renal transcription in β cells, leading
development; progressive to a defect in metabolic signaling
nondiabetic renal dysfunc- of insulin secretion, β cell mass,
tion, leading to chronic or both
renal insufficiency and
failure; internal genital
abnormalities (in female
carriers)
MODY 6 NeuroD1 Diabetes Insulin Abnormal transcriptional regula-
or BETA2 tion of β cell development and
function
BETA2, β cell Ebox transactivator 2; HNF, Hepatocyte nuclear factor; IPF, insulin promoter factor; MODY, maturity-onset diabetes of the young;
NeuroD1, neurogenic differentiation factor 1.
From Fajans SS, Bell GI, Polonsky KS. Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. N Engl J Med.
2001;345:971-980.

defect on ZAC/HYAMI imprinting, and, most notably,
mutations in the adenosine triphosphate (ATP)-sensitive
potassium channel (KATP) of the β cell cause permanent
diabetes.46 The KATP channel comprises two subunits
(Kir6.2 and SUR1), and mutations in these can result
in loss of function (leading to channel closure and neo-
natal hyperinsulinemic hypoglycemia) or gain of func-
tion (leading to channel opening and neonatal diabetes).
Although rare, elucidation of these conditions and the
molecular mechanisms underlying them has improved
our understanding of this area of human biology. More-
over, diabetes arising from KATP channelopathies can
retain sensitivity to the insulin secretagogue effects of
sulfonylureas.47
Other genetic disorders that are associated with
impaired β cell function include certain maternally inher-
ited forms of diabetes with a mutation in mitochondrial
DNA,48 disorders that lead to impaired conversion of
proinsulin to insulin,49 and disorders that lead to synthe-
sis of an aberrant form of the insulin molecule.50 Of the
former conditions, diabetes associated with an A-to-G
transition at the nucleotide pair 3243 in mitochondrial
transfer RNA (tRNA) has been best characterized and
appears to have a wide phenotypic expression from type
2 through to type 1 diabetes. The latter two conditions
are inherited in an autosomal dominant manner and are
associated with relatively mild glucose intolerance.
The ADA in a 2011 position statement has recog-
nized the importance of genetic testing in diagnosis of
some genetic syndromes of β cell function, and states
that measurement of genetic markers for selected diabetic
syndromes, including neonatal diabetes, could provide
valuable information with definition of diabetes-associated
mutations.16 However, the routine measurement of genetic
markers is not of value at the time of diagnosis or manage-
ment of type 1 diabetes.16
Genetic Defects in Insulin Action
For insulin to exert its biological effect, it first must bind
to its receptor on the cell surface. Following receptor
binding, a complex series of postreceptor signaling reac-
tions take place, leading to the hormone’s metabolic and
mitogenic effects. Disruption of some of these postrecep-
tor mediators (e.g., insulin receptor substrate-1) has been

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 38  CLASSIFICATION AND DIAGNOSIS OF DIABETES MELLITUS
shown to cause diabetes in animals.51 However, very
few human forms of diabetes have been linked clearly to
specific genetic defects in the insulin-signaling cascade.
Leprechaunism and Rabson-Mendenhall syndrome rep-
resent rare congenital disorders of the insulin receptor.52
Both syndromes are associated with diabetes, hyperinsu-
linemia, and altered growth in utero. As the insulin signal-
ing cascade is further defined, it is likely that additional
forms of diabetes will be found to be caused by genetic
defects in insulin action.
The nomenclature associated with clinical syndromes
of severe insulin resistance can be confusing.53,54 The
term type A insulin resistance has been used to describe
a syndrome in which severe insulin resistance is associ-
ated with a skin condition called acanthosis nigricans and
with hyperandrogenism in females. Glucose intolerance
or overt diabetes may or not be present. The term type
B insulin resistance describes a rare syndrome in which
autoantibodies to the insulin receptor lead to insulin
resistance and hyperinsulinemia (see later). Also associ-
ated with insulin resistance are the lipodystrophies (see
Chapter 37); several forms of lipodystrophic diabetes
have been characterized,55 and in some cases, their genetic
basis has been established and novel therapeutic interven-
tions have been utilized.56 Several novel forms of familial
partial lipodystrophy are now well characterized and are
associated with severe insulin resistance. Interestingly,
syndromes of partial lipodystrophy often masquerade as
obesity and are characterized clinically by a redistribu-
tion of fat to facial and abdominal areas with lipoatrophy
of the femerogluteal region and lower limbs. Numerous
mutations have been described in individuals with partial
lipodystrophy ranging from mutations of LMNA (lamin
A/C), encoding the filament laminin, to nuclear receptors
(PPARγ) to rarer mutations in lipid droplet–associated
proteins such as CIDEC (cell death–inducing DFFA-like
effector c) and Perlipin 1.54
The use of genetic testing in the classification of genetic
syndromes of insulin action remains an area for evalua-
tion within subspecialized services at this time. The ADA
have recommended that routine genetic testing in patients
with type 2 diabetes has no current role, stating that these
studies should be confined to the research setting and
evaluation of specific syndromes.16
Diseases of the Exocrine Pancreas
Hyperglycemia can occur during an episode of acute
pancreatitis and is associated with a poor prognosis. It is
unusual for permanent diabetes to develop following a sin-
gle episode of acute pancreatitis. Furthermore, removal of
up to 90% of the pancreas does not always cause diabetes.
On the other hand, diabetes has been reported in associa-
tion with very small pancreatic adenocarcinomas, leading
some investigators to speculate that these tumors produce
some diabetogenic factor or factors.57 Five percent to 15%
of patients with cystic fibrosis develop diabetes.58 Insulin
replacement in cystic fibrosis–related diabetes (CFRD) is
often challenging, as these individuals retain insulin sensi-
tivity and are prone to hypoglycemic episodes. Moreover,
insulin requirement in the setting of CFRD is compli-
cated by malabsorption, the associated need for enteral
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667
feeding as well as by infectious exacerbations associated
with underlying bronchiectasis.59 Hemochromatosis can
cause diabetes.60 Because glucose tolerance may improve
with phlebotomy, this condition represents an important,
potentially reversible cause of diabetes. Fibrocalculous
pancreatic diabetes is seen mainly in the tropics and is
associated with abdominal pain and calcification of the
pancreas on abdominal imaging.61 The natural history of
this form of diabetes has been established,62 along with a
genetic marker of the disease.63
Endocrinopathies (See Chapter 42)
Cortisol, growth hormone, glucagon, and the catechol-
amines (epinephrine and norepinephrine) can antagonize
insulin action. Tumors that produce these hormones in
excess lead to Cushing’s syndrome, acromegaly, gluca-
gonoma, and pheochromocytoma, respectively. Although
all of these conditions are associated with a degree of glu-
cose intolerance, overt diabetes develops only in a subset
of patients. The importance of recognizing these second-
ary forms of diabetes lies in the fact that resection of the
underlying tumor can cure diabetes. The hyperglycemia
that is seen in the setting of aldosterone-producing ade-
nomas and somatostatinomas results from alteration of
insulin secretion. An added challenge to diabetes mellitus
arising from endocrinopathy is that somatostatin ana-
logues often used to control conditions such as growth
hormone excess and, more recently, glucocorticoid excess
can induce diabetes in their own right (described in the
following section).
Drug- or Chemical-Induced Diabetes
Certain compounds are toxic to β cells. These include
the rat poison vacor and the antipneumocystis drug
pentamidine. The hyperglycemia that results from these
agents is usually not reversible. Thiazide diuretics can
inhibit insulin secretion by causing hypokalemia, and
this effect may be picked up on an oral glucose toler-
ance test as early as 4 weeks following the initiation of
therapy. However, these agents do not induce diabetes
mellitus in the absence of underlying susceptibility.64
Glucocorticoids and nicotinic acid cause hyperglyce-
mia by impairing insulin action. Glucocorticoid excess,
whether endogenous or exogenous, is also independently
associated with many so-called secondary complications
of diabetes such as atherosclerosis and cardiovascular
disease.65 Protease inhibitors (PIs) commonly used in
the treatment of individuals with human immunodefi-
ciency virus infection can cause hyperglycemia. This
effect of PIs probably results from inducing a form of
partial lipodystrophy that selects the face and limbs,
while causing fat accumulation in the region around
the waist.66 The so-called atypical or second-generation
antipsychotics are associated with metabolic disorders
including overt diabetes mellitus. The ADA published
a consensus statement highlighting this association and
identifying the need for clinical research in this area.67
The pathophysiologic mechanisms underlying the met-
abolic derangements are beginning to be elucidated.68
Finally, somatostatin analogues, often used in the treat-
ment of endocrinopathy and neuroendocrine tumors,
668 PART 5  DIABETES MELLITUS
also cause inhibited insulin release. This is particularly
true for pasireotide, an agent that has a broader selectiv-
ity across the somatostatin receptor subtypes. In endo-
crinopathies associated with insulin resistance such as
Cushing’s disease or acromegaly, use of these agents
may result in overt diabetes.69
Infections
Certain viral infections, including rubella70 and cox-
sackie B virus,71 have been associated with diabetes.
Some studies suggest that a viral infection can trigger
autoimmune destruction of β cells in genetically pre-
disposed individuals, leading to autoimmune type 1
diabetes.
Uncommon Forms of Immune-Mediated Diabetes
The stiff-man syndrome is a rare neurologic syndrome
characterized by spasticity of the axial muscles. It is asso-
ciated with very high titers of anti-GAD antibodies, and
up to one third of patients develop diabetes.72 Autoan-
tibodies directed against the insulin receptor represent
another rare cause of diabetes (referred to as type B insu-
lin resistance).73 These antibodies have the potential to
change from being receptor antagonists (causing insulin
resistance) to being receptor agonists (leading to poten-
tially life-threatening hypoglycemia). Spontaneous remis-
sion of antibody production can occur. The syndrome is
typically seen in African-American females in association
with other autoimmune diseases (most commonly sys-
temic lupus erythematosus).
Other Genetic Syndromes Sometimes Associated
with Diabetes
Many of the genetic syndromes listed under H in Table
38-1 are known to be associated with diabetes. Wolfram’s
syndrome, also known as DIDMOAD (reflecting the
components of the disorder; diabetes insipidus, diabetes
mellitus, optic atrophy, and deafness), is a rare autosomal
recessive disorder caused by mutations in the WFS1 gene
on the short arm of chromosome 4. Polymorphisms in
the WFS1 gene have been linked to an increased risk for
type 2 diabetes,74 providing an example of how the study
of rare disorders can improve our understanding of com-
mon conditions.
Gestational Diabetes
Gestational diabetes (GDM) is a common medical com-
plication of pregnancy and is defined as diabetes with
onset or first recognition during pregnancy. The original
criteria for diagnosis of GDM were chosen to identify
women for whom there was a greater risk for postpar-
tum persistence of hyperglycemia. Dysglycemia during
pregnancy is associated with complications for both
mother and fetus. Fetal/neonatal complications include
large for gestational age birth weight, macrosomia,
and neonatal hypoglycemia. Maternal complications
include higher rates of cesarean section.74-77 Appropri-
ate diagnosis and management of gestational diabetes
potentially reduces the incidence of these related com-
plications. The Hyperglycaemia and Adverse Pregnancy
Outcome (HAPO) study aimed to clarify the relationship
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TABLE 38-3  Screening for and Diagnosis of
Gestational Diabetes Mellitus*
In women not previously diagnosed with overt diabetes, perform
a 75-g OGTT (with measurement of plasma glucose fasting and
at 1 and 2 hours post–glucose load) at 24 to 28 weeks gestation.
The OGTT should be performed in the morning after an overnight
fast of at least 8 hours.
The diagnosis of gestational diabetes mellitus is made when any
of the following plasma glucose values are exceeded:
Fasting ≥92 mg/dL (5.1 mmol/L)
1 hour post–75-g oral glucose ≥180 mg/dL (10.0 mmol/L)
2 hours post–75-g oral glucose ≥153 mg/dL (8.5 mmol/L)
*There is no consensus regarding universal screening versus screening
in “at-risk” individuals.
OGTT, Oral glucose tolerance test.
Diagnosis based on IADPSG recommendations and endorsed by the
ADA.
From International Association of Diabetes and Pregnancy Study
Groups Consensus Panel. International Association of Diabetes
and Pregnancy Study Groups Recommendations on the Diagnosis
and Classification of Hyperglycemia in Pregnancy, Diabetes Care.
33:676–682, 2010; American Diabetes Association: Diagnosis and
classification of diabetes mellitus. Diabetes Care. 2013;36:S67-S74.
between adverse pregnancy outcomes and maternal glu-
cose levels (below the threshold for overt GDM).78 The
results from this study suggested that updated threshold
values were necessary to develop an “outcomes-based”
system for diagnosis of GDM. Consequently, the Inter-
national Association of Diabetes and Pregnancy Study
Groups (IADPSG) have published a consensus statement
that sets out updated recommendations for the diagno-
sis of GDM using the 75-g oral glucose tolerance test
(OGTT), performed between 24 and 28 weeks (Table
38-3).79 Recent controversies have arisen regarding the
use of the IADPSG criteria. The National Institutes of
Health have recommended retaining the traditional, so-
called “2-step approach” of diagnosis for GDM with a
1-hour 50-g OGTT, followed by a 3-hour 100-g OGTT.
However, there are sufficient data to support the use of
IADPSG criteria, which have now been endorsed by the
ADA and WHO.80,81
The prevalence of gestational diabetes increases
in parallel with the prevalence of type 2 diabetes in a
population. Previous data from a large U.S. health care
organization described a prevalence of 7.4 cases per 100
pregnancies.75 Using diagnostic thresholds, as set out by
the IADPSG, the prevalence of GDM is higher, between
11% and 12.5%.78,79,82 Moreover, when applied to large
population-based cohorts, GDM diagnosed by IADPSG
criteria is associated with a higher incidence of adverse
maternal and neonatal outcomes, validating the chosen
threshold values.82
Risk factors for GDM include age (it is more common
among older women), ethnicity (higher rates are seen
among women from ethnic groups with a high incidence
of type 2 diabetes), prepregnancy body mass index (the
risk increases with degree of obesity), parity (the risk
increases with the number of previous pregnancies), and
family history of diabetes. A previous pregnancy that was
complicated by GDM or a history of delivery of a macro-
somic infant also represents a strong risk factor for future
GDM as well as a future diagnosis of type 2 diabetes.77,83

TABLE 38-4  Diagnostic Thresholds for
Diabetes and Lesser Degrees of Impaired Glucose
Regulation*
Fasting Plasma 2-Hour Plasma
Category Glucose Glucose
Normal <100 mg/dL <140 mg/dL
(<5.6 mmol/L) (<7.8 mmol/L)
IFG 100-125 mg/dL* — ❖
(5.6-6.9 mmol/L)
IGT — 140–199 mg/dL*
(7.8–11.0 mmol/L)
Diabetes ≥126 mg/dL† ≥200 mg/dL
(≥7.0 mmol/L) (≥11.1 mmol/L)
IFG, Impaired fasting glucose; IGT impaired glucose tolerance.
*When both tests are performed, IFG or IGT should be diagnosed only
if diabetes is not diagnosed by the other test.
†A diagnosis of diabetes needs to be confirmed on a separate day.
¶The test should be performed in a laboratory using a method that is
NGSP (or equivalent) certified and standardized to the DCCT assay.
❖HbA1c values between 5.7% and 6.4% represent a category for
“sub-diabetic, high-risk state”9,86,97
In fact, the rising tide of obesity, unhealthy lifestyle, and
type 2 diabetes presents a significant challenge in discern-
ing type 2 diabetes first presenting during pregnancy from
GDM. Hence postpartum testing of glycemia is necessary
in all women with a diagnosis of GDM.9,79,83 Screening
for GDM presents a further challenge and currently there
is no consensus on whom should be screened.79,84 In some
countries (e.g., the United States), universal screening
is undertaken routinely, whereas in other regions (e.g.,
parts of Europe), only women who are believed to be at
high risk are screened.
DIAGNOSIS
Diagnostic Criteria
The modern-day classification of diabetes is based on clin-
ical presentation combined with (in some cases) genetic
and autoantibody testing. The diagnosis of diabetes is
based on measurement of glucose and/or glycated hemo-
globin (HbA1c). A historical perspective is necessary to
understand how we got to this point. The Expert Com-
mittee of the ADA, in their 1997 report, recommended
changes in the diagnostic criteria used for diabetes, in
addition to recommending changes in the classification
system.7 These recommendations were subsequently
endorsed by the WHO8 (Table 38-4). Major changes
included a reduction in the fasting plasma glucose cut
point used to diagnose diabetes from 140 mg/dL to 126
mg/dL and a recommendation to use fasting plasma glu-
cose rather than an OGTT for diagnosis. The ability to
use casual (i.e., random) plasma glucose levels in patients
with hyperglycemic symptoms was retained, as was the
requirement that in asymptomatic individuals, a diagnosis
should be based on testing carried out on more than
one occasion. The ADA report based its criteria on use
of the fasting plasma glucose level, and the WHO report
included equivalent cut points for whole-blood venous and
capillary glucose.8 The Expert Committee of the ADA
published two further reports in 2003 and 2009.85,86
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38  CLASSIFICATION AND DIAGNOSIS OF DIABETES MELLITUS 669
While recommendations regarding diagnostic criteria for
diabetes on the basis of fasting glucose, OGTT, and random
glucose have remained unchanged, the 2009 report also
added recommendations for use of HbA1c in the diagnosis
of diabetes mellitus (see Table 38-4). These updated
HbA1c¶ recommendations for HbA1c have subsequently been
≤5.0%
included in ADA Clinical Practice Recommendations.9
In the 1997 report, the ADA also introduced a new
system for classifying the intermediate zone between nor-
mal glucose tolerance and overt diabetes.7 A new cate-
gory called impaired fasting glucose (IFG) was introduced
≥6.5% along with the pre-existing category of impaired glucose
tolerance (IGT). The presence of one or both of these
categories is often referred to as pre-diabetes, although
this term has never been formally endorsed by any of
the Expert Committees, who have instead preferred the
description “sub-diabetic, high risk state.”
While threshold values for the diagnosis of diabetes
were originally formulated based on the risk for devel-
oping retinopathy, the basis for the “diagnosis” of these
intermediate categories of hyperglycemia is the risk for
developing overt diabetes; hence the terminology “Cate-
gories of Increased Risk for Diabetes.”86 The diagnosis of
intermediate levels of hyperglycemia uses threshold val-
ues of fasting glucose (IFG: 100 to 125 mg/dL) or 2-hour
glucose following a 75-g glucose load (IGT: 140 to 199
mg/dL). An intermediate level of HbA1c (5.7% to 6.4%)
has also been suggested as an indicator of future onset of
diabetes in “at-risk” individuals.9,86 The threshold values
for the diagnosis of intermediate levels of hyperglycemia
have been a considerable matter of debate, and there is
no overall consensus between the ADA and the WHO for
threshold values of fasting glucose. The main questions of
clinical relevance are: (1) What constitutes diabetes? and
(2) What constitutes “normal”? We will address both of
these questions now.
What Level of Fasting Plasma Glucose
Constitutes Diabetes?
The development of microvascular changes, particularly
in the retina, is one of the hallmarks of diabetes melli-
tus. Because these complications can take many years to
develop, it is not possible to use their presence to diag-
nose the condition. Instead, the level of plasma glucose
that confers a risk for occurrence of these changes is used
for diagnostic purposes. At the time the 1997 report was
written, the best estimate of this level was fasting plasma
glucose of 126 mg/dL. This value was based on data
from three epidemiologic studies involving Pima Indians,
Egyptians, and a U.S. national sample.7 In all three stud-
ies, there appeared to be a threshold of risk (i.e., a level
below which the risk for retinopathy was negligible, and
above which the risk rose steeply). In the 2003 report of
the expert committee, reference was made to a separate
analysis of Pima Indian data, suggesting that the thresh-
old at which retinopathy risk increased might be lower
than that previously reported.87 However, the presence
of a threshold was not disputed, and the 126 mg/dL cut
point for diagnosis remained in place. An analysis of data
from two cross-sectional Australian cohort studies and
one longitudinal U.S. cohort study has raised doubt about
670 PART 5  DIABETES MELLITUS

BLUE MOUNTAINS EYE STUDY (N = 3162) the presence of a retinopathy threshold (Fig. 38-1).88 All
50 three studies used multiple-field digital retinal photogra-
Any retinopathy phy to identify retinopathy, a more sophisticated method
40 Moderate retinopathy than that used in earlier studies that informed the ADA
expert committee decision. The risk for retinopathy in all
three studies appeared to be continuous across the entire
Percentage

30
range of plasma glucose, with up to 10% of individu-
20 als demonstrating some degree of retinopathy at levels of
fasting plasma glucose well within the range considered
normal. These data are consistent with an earlier report
10
from the Diabetes Prevention Program, which also identi-
fied retinopathy in individuals with impaired glucose tol-
0
erance.89 Taken together, these data suggest that current
diagnostic criteria may need further revision. Nonethe-
7–

6. 5–

7. 3–

7. 1–

8. 9–

9. 7–

10 .5–

3
.6

0.
≤4

4.

5.

6.

7.

7.

8.
4

.2
9
2

≥1
5.

less, the current threshold values for glucose in the diag-

A Fasting plasma glucose (mmol/L)
nosis of diabetes have remained unchanged in the most
Number with any 89 165 42 15 4 9 3 5 32 recent recommendations.8,86
retinopathy
Number with 7 14 2 3 3 0 0 2 16 The most significant new recommendation from the
moderate retinopathy
2009 Expert Committee of the ADA was the inclusion
Total 866 1604 420 105 39 30 16 12 70
of an HbA1c value ≥6.5% as a criterion for the diagnosis
AUSTRALIAN DIABETES, OBESITY AND of diabetes.86 The measurement of HbA1c has been the
LIFESTYLE STUDY (N = 2265)
mainstay of the assessment of glycemic control in clini-
40
cal practice for many years. However, as a consequence
of poor standardization of the assay in the past, HbA1c
30 results could not previously be compared across popula-
Percentage

tions. Standardization of the HbA1c assay has been com-

20 pleted in the United States. A further complication of the
use of HbA1c in the diagnosis of diabetes is the recommen-
10 dation by the International Federation of Clinical Chem-
ists that the units used for reporting results be changed
0 from percentage (as used in DCCT aligned assays in the
United States) to millimoles per mole (mmol/mol). This
5. 7–

6. 5–

7. 3–

7. 1–

8. 9–

9. 7–

10 .5–

3
.6

recommendation has been adopted by many (but not all)

0.
≤4

4.

5.

6.

7.

7.

8.

.2
9
4

≥1

B Fasting plasma glucose (mg/dL) European countries. The diagnostic value of ≥6.5% (for
Number with any 5 46 51 28 15 9 5 5 46 DCCT aligned assays) was chosen based on its associa-
retinopathy tion with the inflection point for retinopathy, upon which
Number with 0 1 2 4 3 3 1 0 12
moderate retinopathy the fasting and 2-hour glucose values have been chosen.
Total 57 616 694 384 146 75 48 28 134 HbA1c offers a useful so-called “chronic measurement”
upon which to base the diagnosis of diabetes. Measure-
MULTI-ETHNIC STUDY OF ment does not require the patient to fast or consume a
ATHEROSCLEROSIS (N = 6079)
glucose load. However, these benefits must be balanced
50
with consideration of the higher cost of the assay as well
40 as errors associated with high red bloo cell turnover states
and hemoglobinopathies.
Percentage

30
What Level of Fasting Plasma Glucose
20 Constitutes Normality?
10
Less straightforward than diagnosing overt diabetes has
been the characterization of intermediate levels of (what
0 has been termed) dysglycemia. At what level does one
cross the boundary between normal and abnormal? Glu-
5. 7–

6. 5–

7. 3–

7. 1–

8. 9–

9. 7–

10 .5–

3
.6

0.

cose is a continuous variable, and therefore choosing a cut

≤4

4.

5.

6.

7.

7.

8.

.2
9
4

≥1

C Fasting plasma glucose (mg/dL) point to define the upper limit of normal fasting glucose
Number with any 59 327 241 98 47 44 30 20 93 (and the lower limit of impaired fasting glucose) while
retinopathy informed by clinical risk and observation, is ultimately
Number with 7 6 2 5 8 16 6 8 38
moderate retinopathy arbitrary. The Expert Committee in its 1997 report, chose
Total 358 2732 1794 520 207 128 82 66 192 a value of 110 mg/dL but revised this value to 100 mg/
Figure 38-1  Prevalence of retinopathy across a wide range of fasting dL in 2003.85 The updated lower recommendation was
plasma glucose levels in three epidemiologic studies using digital retinal based on receiver operator characteristic (ROC) curve
photography to screen the retina. (Data from Wong TY, Liew G, Tapp analyses of the ability of various baseline levels of fasting
RJ, et al. Relation between fasting glucose and retinopathy for diagno-
sis of diabetes: three population-based cross-sectional studies. Lancet.
plasma glucose to predict future diabetes. ROC curves
2008;371:736–743.)

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 38  CLASSIFICATION AND DIAGNOSIS OF DIABETES MELLITUS
were derived from cohort studies available to the com-
mittee at the time but were not published in the report.
A factor that undoubtedly influenced the committee
was a desire to achieve “equivalence” (in terms of pre-
dicting future diabetes) between impaired fasting glucose
and impaired glucose tolerance. The term equivalence can
be considered as cross-sectional or prospective. In cross-
sectional terms, complete equivalence would amount to
those patients with impaired fasting glucose also having
impaired glucose tolerance. This was not the case when the
cut point was at 110 mg/dL and still is not the case with
the cut point at 100 mg/dL. In fact, it has been suggested
that these two states of “pre-diabetes” may be different
biological entities, with altered insulin action and altered β
cell function contributing in different ways to their patho-
genesis.90 A lesser degree of cross-sectional equivalence
would be a situation in which population prevalences of
impaired fasting glucose and impaired glucose tolerance
are the same. Lowering the cut point to 100 mg/dL did
help move things toward equivalence by this definition.
In prospective terms, equivalence amounts to an equal
ability of these two intermediate states of hyperglycemia
to predict future events, such as overt diabetes and car-
diovascular disease or mortality. This is the point about
which most of the controversy has arisen. A large Euro-
pean epidemiologic consortium published data clearly
demonstrating that 2-hour plasma glucose following an
OGTT was superior to fasting plasma glucose in predict-
ing future cardiovascular events.91 Members argued that
the OGTT should not be discarded from clinical practice
or from epidemiologic research. A large number of stud-
ies have looked at the ability of fasting plasma glucose to
predict future diabetes. One of these, the Baltimore Longi-
tudinal Study of Aging (BLSA), followed a cohort of more
than 800 subjects with serial OGTTs for up to 20 years.92
Investigators documented the natural history of pro-
gression from normal glucose tolerance to intermediate
states of hyperglycemia to overt diabetes. Many subjects
reverted to normal from intermediate states of hyperglyce-
mia, but in general, a slow, steady progression to diabetes
was seen, with male gender and obesity increasing risk. By
altering the threshold that was used to define the lower
limit of impaired fasting glucose, BLSA investigators
showed that much of the “discrepancy” between rates of
progression from impaired fasting glucose versus impaired
glucose tolerance to overt diabetes was a function of the
threshold used rather than of any inherent biological dif-
ference between the two states of hyperglycemia. Using
the definition of a threshold that we discussed previously,
one would expect that the cut point between normal and
impaired fasting glucose would be associated with a sig-
nificant increase in risk. This is not the case. Several inves-
tigators have demonstrated that risk for future diabetes
and risk for cardiovascular events increase across the con-
tinuum of glucose levels from normal through impaired
fasting glucose or impaired glucose tolerance.93-96 There
does not appear to be a threshold of risk.
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671
Has HbA1c added clarity to this area? The Expert
Committee position statement from 2009 declared that
HbA1c values of 6.0% to 6.4% represented a category
that is described as a “sub-diabetic, high risk state.”86
The ADA, in their 2013 position statement, set out that
“it is reasonable to consider an A1c range between 5.7 and
6.4% as identifying individuals with high risk for future
diabetes, to whom the term pre-diabetes may be applied.”
8,86 These HbA
1c thresholds are based upon the future
risk for developing diabetes, rather than cardiovascular
complications relating to diabetes. The choice of thresh-
old HbA1c values are informed by data from the National
Health and Nutrition Examination Surveys (NHANES)
as well as the Diabetes Prevention Programme (DPP) in
which study participants with “pre-diabetes” had HbA1c
values between 5.5% and 6.0% (NHANES) or a mean
HbA1c of 5.9% (DPP).8,89 Several prospective studies
were systematically reviewed in a large meta-analysis that
included a combined sample of 44,203 individuals. The
results of this meta-analysis were published since the last
meeting of the Expert Committee, and they have been
used in resolving the updated HbA1c threshold values for
the identification of a so-called “sub-diabetic, high risk
state.”8,97 The HbA1c may actually represent a more pow-
erful predictor of type 2 diabetes than fasting glucose.
Ultimately, HbA1c, like fasting glucose, is a continuous
variable, and its association with future risk for diabetes
or macrovascular or microvascular outcomes is curvilin-
ear. Hence the choice of the appropriate inflection point
at which to “draw a line in the sand” is likely to remain
an area of controversy and debate.
WHERE NEXT?
Classification and diagnosis of diabetes has become ever
more complicated as our understanding of this heteroge-
nous set of conditions, underpinned by chronic hypergly-
cemia, increases. The appropriate diagnosis, classification
and appropriate management of diabetes, while guided
by various position statements, requires clinical acumen.
This is even truer in light of the gray area that represents
so-called pre-diabetes, a categorization applicable princi-
pally to individuals at risk for type 2 diabetes. It remains
the most sensible to address the diagnosis of pre-diabetes
by taking a holistic approach and considering body mass
index, lipid profile, blood pressure, as well as various gly-
cemic threshold. In light of the global obesity epidemic,
perhaps we should be more liberal with our advice (and
interventions) regarding healthy lifestyle, rather than
waiting for members of the population to cross arbitrary
thresholds.
  
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REFERENCES 25. Umpierrez GE, Kitabchi AE. Ketosis-prone type 2 diabetes mel-
litus. Ann Intern Med. 2006;144:350–357.
1. Kahn SE. The relative contributions of insulin resistance and beta-
26. Cowie C, Rust KF, Byrd-Holt DD, et al. Prevalence of diabetes
cell dysfunction to the pathophysiology of type 2 diabetes. Diabe-
and impaired fasting glucose in adults in the US population. Dia-
tologia. 2003;46:3–19.
betes Care. 2006;29:1263–1268.
2. Brownlee M. Biochemistry and molecular cell biology of diabetic
27. Danaei G, Finucane MM, Lu Y, et al. National, regional, and
complications. Nature. 2001;414:813–820.
global trends in fasting plasma glucose and diabetes prevalence
3. Nathan DM, Cleary PA, Backlund J-YC, et al. Intensive diabetes
since 1980: systematic analysis of health examination surveys and
treatment and cardiovascular disease in patients with type 1 dia-
epidemiological studies with 370 country-years and 2.7 million
betes. N Engl J Med. 2005;353:2643–2653.
participants. Lancet. 2011;378:31–40.
4. McGarry J. What if Minkowski had been ageusic? An alternative
28. Mokdad AH, Bowman BA, Ford ES, et al. The continuing epi-
angle on diabetes. Science. 1992;258:766–770.
demics of obesity and diabetes in the United States. JAMA.
5. National Diabetes Data Group. Classification and diagnosis of
2001;286:1195–1200.
diabetes mellitus and other categories of glucose intolerance. Dia-
29. D’Adamo E, Caprio S. Type 2 diabetes in youth: epidemiology
betes. 1979;28:1039–1057.
and pathophysiology. Diabetes Care. 2011;34:S161–S165.
6. World Health Organization. Diabetes Mellitus: Report of a WHO
30. Rudenski A, Hadden D, Atkinson A, et al. Natural history of
study group. Geneva: World Health Organization; 1985.
pancreatic islet β-cell function in type 2 diabetes mellitus stud-
7. Report of the Expert Committee on the Diagnosis and Classifica-
ied over six years by homeostasis model assessment. Diabet Med.
tion of Diabetes Mellitus. Diabetes Care. 1997;20:1183–1197.
1988;5:36–41.
8. Alberti KGMM, Zimmet PZ. Definition, diagnosis, and classifica-
31. Shapiro H, Pecht T, Shaco-Levy R, et al. Adipose tissue foam
tion of diabetes mellitus and its complications. Part 1: Diagno-
cells are present in human obesity. J Clin Endocrinol. 2013;98:
sis and classification of diabetes mellitus. Provisional report of a
1173–1181.
WHO consultation. Diabet Med. 1998;15:539–553.
32. Barnett A, Eff C, Leslie R, et al. Diabetes in identical twins: a
9. American Diabetes Association. Diagnosis and classification of
study of 200 pairs. Diabetologia. 1981;20:87–93.
diabetes mellitus. Diabetes Care. 2013;36:S67–S74.
33. Knowler W, Saad M, Pettitt D, et al. Determinants of diabetes
10. LaPorte R, Matsushima M, Chang Y. Prevalence and incidence
mellitus in the Pima Indians. Diabetes Care. 1993;16:216–227.
of insulin-dependent diabetes. In: National Diabetes Data Group,
34. Hoet J, Tripathy B, Rao R, et al. Malnutrition and diabetes in the
ed. Diabetes in America. Bethesda, MD: National Institutes of
tropics. Diabetes Care. 1996;19:1014–1017.
Health; 1995:37–46.
35. Tripathy B, Samal K. Overview and consensus statement on dia-
11. Harjutsalo V, Sjoberg L, Tuomilehto J. Time trends in the inci-
betes in tropical areas. Diabetes Metab Rev. 1997;13:63–76.
dence of type 1 diabetes in Finnish children: a cohort study. Lan-
36. Fajans SS, Bell GI, Polonsky KS. Molecular mechanisms and
cet. 2008;371:1777–1782.
clinical pathophysiology of maturity-onset diabetes of the young.
12. Buzzetti R, Quattrocchi C, Nistico L. Dissecting the genetics of
N Engl J Med. 2001;345:971–980.
type 1 diabetes: relevance for familial clustering and differences in
37. Yamagata K, Furuta H, Oda N, et al. Mutations in the hepato-
incidence. Diabetes Metab Rev. 1998;14:111–128.
cyte nuclear factor-4-alpha gene in maturity-onset diabetes of the
13. Dahlquist G. The aetiology of type 1 diabetes: an epidemiological
young (MODY 1). Nature. 1996;384:458–460.
perspective. Acta Paediatr. 1998;425:5–10.
38. Froguel P, Vaxillaire M, Sun F, et al. Close linkage of glucokinase
14. Scott F, Norris J, Hubert K. Milk and type 1 diabetes: exam-
locus on chromosome 7p to early-onset non-insulin-dependent
ining the evidence and broadening the focus. Diabetes Care.
diabetes. Nature. 1992;356:162–164.
1996;19:379–383.
39. Yamagata K, Oda N, Kaisaki P, et al. Mutations in the hepato-
15. Robles DT, Eisenbarth GS, Wang T, et al. Identification of chil-
cyte nuclear factor-1-alpha gene in maturity-onset diabetes of the
dren with early onset and high incidence of anti-islet autoantibod-
young (MODY 3). Nature. 1996;384:455–458.
ies. Clin Immunol. 2002;102:217–224.
40. Stoffers D, Ferrer J, Clarke W, et al. Early-onset type-II diabetes
16. Barker JM. Prediction of Autoantibody Positivity and Progression
mellitus (MODY 4) linked to IPF1. Nat Genet. 1997;117:138–139.
to Type 1 Diabetes: Diabetes Autoimmunity Study in the Young
41. Byrne M, Sturis J, Menzel S, et al. Altered insulin secretory re-
(DAISY). J Clin Endocrinol Metab. 2004;89:3896–3902.
sponse to glucose in diabetic and nondiabetic subjects with muta-
17. Steck AK, Johnson K, Barriga KJ, et al. Age of islet autoantibody
tions in the diabetes susceptibility gene MODY 3 on chromosome
appearance and mean levels of insulin, but not GAD or IA-2 auto-
20. Diabetes. 1996;45:1503–1510.
antibodies, predict age of diagnosis of type 1 diabetes: diabetes auto-
42. Clement K, Pueyo M, Vaxillaire M, et al. Assessment of insu-
immunity study in the young. Diabetes Care. 2011;34:1397–1399.
lin sensitivity in glucokinase-deficient subjects. Diabetologia.
18. Ludvigsson J, Carlsson A, Deli A, et al. Decline of C-peptide dur-
1996;39:82–90.
ing the first year after diagnosis of Type 1 diabetes in children and
43. Habener J, Stoffers D. A newly discovered role of transcription
adolescents. Diabetes Res Clin Pract. 2013;100:203–209.
factors involved in pancreas development and the pathogenesis of
19. Zimmet P, Tuomi T, Mackay R, et al. Latent autoimmune diabe-
diabetes mellitus. Proc Assoc Am Physicians. 1998;110:12–21.
tes mellitus in adults (LADA): the role of antibodies to glutamic
44. Velho G, Froguel P. Maturity-onset diabetes of the young
acid decarboxylase in diagnosis and prediction of insulin depen-
(MODY), MODY genes and non-insulin-dependent diabetes mel-
dency. Diabet Med. 1994;11:299–303.
litus. Diabetes Metab. 1997;23:34–37.
20. Bingley PJ, Williams AJ, Gale EA. Optimized autoantibody-based
45. Sperling MA. Neonatal diabetes mellitus: from understudy to cen-
risk assessment in family members: implications for future inter-
ter stage. Curr Opin Pediatr. 2005;17:512–518.
vention trials. Diabetes Care. 1999;22:1796–1801.
46. Du X, Ounissi-Benkalha H, Loder MK, et al. Overexpression
21. Molbak A, Christau B, Marner B, et al. Incidence of insulin-de-
of ZAC impairs glucose-stimulated insulin translation and se-
pendent diabetes mellitus in age groups over 30 years in Denmark.
cretion in clonal pancreatic beta-cells. Diabetes Metab Res Rev.
Diabet Med. 1994;11:650–655.
2012;28:645–653.
22. Humphrey A, McCarty D, Mackay I, et al. Autoantibodies to glu-
47. Sperling MA. ATP-sensitive potassium channels—neonatal diabe-
tamic acid decarboxylase and phenotypic features associated with
tes and beyond. N Engl J Med. 2006;355:507–510.
early insulin treatment in individuals with adult-onset diabetes
48. Walker M, Turnbull D. Mitochondrial related diabetes: a clinical
mellitus. Diabet Med. 1998;15:113–119.
perspective. Diabet Med. 1997;14:1007–1009.
23. Willis J, Scott R, Brown L, et al. Islet cell antibodies and antibod-
49. O’Rahilly S, Gray H, Humphreys P, et al. Impaired processing of
ies against glutamic acid decarboxylase in newly diagnosed adult-
prohormones associated with abnormalities of glucose homeosta-
onset diabetes mellitus. Diabetes Res Clin Prac. 1996;33:89–97.
sis and adrenal function. N Engl J Med. 1995;333:1386–1390.
24. Maldonado M, Hampe CS, Gaur LK, et al. Ketosis-prone diabetes:
50. Haneda M, Polonsky K, Bergenstal R, et al. Familial hyperin-
dissection of a heterogeneous syndrome using an immunogenetic
sulinemia due to a structurally abnormal insulin: definition of
and beta-cell functional classification, prospective analysis and
an emerging new clinical syndrome. N Engl J Med. 1984;310:
clinical outcomes. J Clin Endocrinol Metab. 2003;88:5090–5098.
1288–1294.

671.e1

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For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.
671.e2 REFERENCES
51. Bruning J, Winnay J, Bonner-Weir S, et al. Development of a novel
polygenic model of NIDDM in mice heterozygous for IR and IRS-
1 null alleles. Cell. 1997;88:561–572.
52. Taylor S. Lilly lecture: Molecular mechanisms of insulin resis-
tance: lessons from patients with mutations in the insulin-receptor
gene. Diabetes. 1992;41:1473–1490.
53. Tritos NA, Mantzoros CS. Syndromes of severe insulin resistance.
J Clin Endocrinol Metab. 1998;83:3025–3030.
54. Parker VER, Savage DB, O’Rahilly S, Semple RK. Mechanistic
insights into insulin resistance in the genetic era. Diabet Med.
2011;28:1476–1486.
55. Joffe BI, Panz VR, Raal FJ. From lipodystrophy syndromes to dia-
betes mellitus. Lancet. 2001;357:1379–1381.
56. Arioglu E, Duncan-Morin J, Sebring N, et al. Efficacy and safety
of troglitazone in the treatment of lipodystrophy syndromes. Ann
Intern Med. 2000;133:263–274.
57. Gullo L, Pezzilli R, Morselli-Labate A, Group IPCS. Diabetes and
the risk of pancreatic cancer. N Engl J Med. 1994;331:81–84.
58. Moran A, Doherty L, Wang X, Thomas W. Abnormal glucose
metabolism in cystic fibrosis. Pediatrics. 1998;133:10–17.
59. Kelly A, Moran A. Update on cystic fibrosis. J Cyst Fibros.
2013;12:318–331.
60. Phelps G, Chapman I, Hall P, et al. Prevalence of genetic haemo-
chromatosis among diabetic patients. Lancet. 1989;2:233–234.
61. Yajnik C, Shelgikar K, Naik S, et al. The ketoacidosis-resistance
in fibro-calculous-pancreatic-diabetes. Diabetes Res Clin Pract.
1993;15:149–156.
62. Mohan V, Barman KK, Rajan VS, et al. Natural history of endo-
crine failure in tropical chronic pancreatitis: a longitudinal follow-
up study. J Gastroenterol Hepatol. 2005;20:1927–1934.
63. SPINK1 is a susceptibility gene for fibrocalculous pancreatic dia-
betes in subjects from the Indian subcontinent. Am J Hum Genet.
2002;71:964–968.
64. Stears AJ, Woods SH, Watts MM, et al. A double-blind, placebo-
controlled, crossover trial comparing the effects of amiloride and
hydrochlorothiazide on glucose tolerance in patients with essen-
tial hypertension. Hypertension. 2012;59:934–942.
65. Neary NM, Booker OJ, Abel BS, et al. Hypercortisolism is associ-
ated with increased coronary arterial atherosclerosis: analysis of
noninvasive coronary angiography using multidetector computer-
ized tomography. J Clin Endocrinol Metab. 2013;98:2045–2052.
66. Margolis AM, Heverling H, Pham PA, Stolbach A. A review of the
toxicity of HIV medications. J Med Toxicol. 2014;10:26–39.
67. American Diabetes Association. Consensus development confer-
ence on antipsychotic drugs and obesity and diabetes. Diabetes
Care. 2004;27:596–601.
68. Ader M, Kim SP, Catalano KJ, et al. Metabolic dysregulation with
atypical antipsychotics occurs in the absence of underlying dis-
ease: a placebo-controlled study of olanzapine and risperidone in
dogs. Diabetes. 2005;54:862–871.
69. Colao A, Petersenn S, Newell-Price J, et al. A 12-month phase
3 study of pasireotide in Cushing’s disease. N Engl J Med.
2012;366:914–924.
70. Forrest J, Menser M, Burgess JA. High frequency of diabe-
tes mellitus in young patients with congenital rubella. Lancet.
1971;2:332–334.
71. King M, Bidwell D, Shikh A, et al. Coxsackie-B-virus-specific IgM
responses in children with insulin-dependent (juvenile-onset; type
1) diabetes mellitus. Lancet. 1983;1:1397–1399.
72. Solimena M, De Camilli P. Autoimmunity to glutamic acid de-
carboxylase (GAD) in stiff-man syndrome and insulin-dependent
diabetes mellitus. Trends Neurosci. 1991;14:452–457.
73. Arioglu E, Andewelt A, Diabo C, et al. Clinical course of the syn-
drome of autoantibodies to the insulin receptor (Type B insulin
resistance): a 28-year perspective. Medicine. 2002;8:87–100.
74. Sandhu MS, Weedon MN, Fawcett KA, et al. Common variants
in WFS1 confer risk of type 2 diabetes. Nat Genet. 2007;39:
951–953.
75. Lawrence JM, Contreras R, Chen W, Sacks DA. Trends in the
prevalence of preexisting diabetes and gestational diabetes mel-
litus among a racially/ethnically diverse population of pregnant
women, 1999–2005. Diabetes Care. 2008;31:899–904.
Downloaded for Ainun Jariah Muliadi (ainunjariahmuliadi98@gmail.com) at Universitas Muslim Indonesia from ClinicalKey.com by Elsevier on May 14, 2018.
For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.
76. Persson B, Hanson U. Neonatal morbidities in gestational diabetes
mellitus. Diabetes Care. 1998;21:B79–B84.
77. Dornhorst A, Rossi M. Risk and prevention of type 2 diabetes
in women with gestational diabetes. Diabetes Care. 1998;21:
B43–B49.
78. HAPO Study Cooperative Research Group, Metzger BE, Lowe LP,
et al. Hyperglycemia and adverse pregnancy outcomes. N Engl J
Med. 2008;358:1991–2002.
79.  International Association of Diabetes and Pregnancy Study
Groups Consensus Panel. International Association of Diabetes
and Pregnancy Study Groups Recommendations on the Diagnosis
and Classification of Hyperglycemia in Pregnancy. Diabetes Care.
2010;33:676–682.
80. National Institutes of Health. NIH Consensus Development Con-
ference on Diagnosing Gestational Diabetes Mellitus. NIH Con-
sensus Development Conference Statements. 2013;28:1–36.
81. McIntyre HD. Diagnosing Gestational Diabetes Mellitus: rationed
or rationally related to risk? Diabetes Care. 2013;36:2879–2880.
82. O’Sullivan EP, Avalos G, O’Reilly M, et al. Atlantic Diabetes
in Pregnancy (DIP): the prevalence and outcomes of gestational
diabetes mellitus using new diagnostic criteria. Diabetologia.
2011;54:1670–1675.
83. O’Reilly MW, Avalos G, Dennedy MC, et al. high prevalence of
abnormal glucose tolerance post partum is reduced by breast-
feeding in women with prior gestational diabetes mellitus. Eur J
Endocrinol. 2011;165:953–959.
84. Simmons D, Moses RG. Gestational diabetes mellitus: to screen
or not to screen?: Is this really still a question? Diabetes Care.
2013;36:2877–2878.
85. The Expert Committee on the Diagnosis and Classification of Dia-
betes Mellitus. Follow-up report on the diagnosis of diabetes mel-
litus. Diabetes Care. 2003;26:3160–3167.
86. The International Expert Committee. International Expert Com-
mittee Report on the Role of the A1c Assay in the Diagnosis of
Diabetes. Diabetes Care. 2009;32:1327–1334.
87. Gabir MM, Hanson RL, Dabelea D, et al. Plasma glucose and
prediction of microvascular disease and mortality. Diabetes Care.
2000;23:1113–1118.
88. Wong TY, Liew G, Tapp RJ, et al. Relation between fasting glu-
cose and retinopathy for diagnosis of diabetes: three population-
based cross-sectional studies. Lancet. 2008;371:736–743.
89. Diabetes Prevention Program Research Group. The prevalence
of retinopathy in impaired glucose tolerance and recent-onset
diabetes in the Diabetes Prevention Program. Diabet Med.
2007;24:137–144.
90. Abdul-Ghani MA, Triphany D, DeFronzo RA. Contributions of
β-cell dysfunction and insulin resistance to the pathogenesis of im-
paired glucose tolerance and impaired fasting glucose. Diabetes
Care. 2006;29:1130–1139.
91. The DECODE Study Group, the European Epidemiology Study
Group. Glucose tolerance and cardiovascular mortality: compari-
son of fasting and 2-hour diagnostic criteria. Arch Intern Med.
2001;161:397–404.
92. Meigs JB, Muller DC, Nathan DM, et al. The natural history
of progression from normal glucose tolerance to type 2 dia-
betes in the Baltimore Longitudinal Study of Aging. Diabetes.
2003;52:1475–1484.
93. Dinneen S, Maldonado D, Leibson C, et al. Effects of changing di-
agnostic criteria on the risk of developing diabetes. Diabetes Care.
1998;21:1408–1413.
94. Nichols GA, Hillier TA, Brown JB. Progression from newly ac-
quired impaired fasting glucose to type 2 diabetes. Diabetes Care.
2007;30:228–233.
95. Tirosh A, Shai I, Tekes-Manova D, et al. Normal fasting plasma
glucose levels and type 2 diabetes in young men. N Engl J Med.
2005;353:1454–1462.
96. Khaw KT, Wareham N, Bingham S, et al. Association of hemo-
globin A1c with cardiovascular disease and mortality in adults: the
European prospective investigation into cancer in Norfolk. Ann
Intern Med. 2004;141:413–420.
97. Zhang X, Gregg EW, Williamson DF, et al. A1c level and future
risk of diabetes: a systematic review. Diabetes Care. 2010;33:
1665–1673.