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PRIMER

Type2 diabetes mellitus


Ralph A.DeFronzo1, Ele Ferrannini2, Leif Groop3, Robert R.Henry4, William H.Herman5,
Jens Juul Holst6, Frank B.Hu7, C.Ronald Kahn8, Itamar Raz9, Gerald I.Shulman10,
Donald C.Simonson11, Marcia A.Testa12 and Ram Weiss13
Abstract | Type2 diabetes mellitus (T2DM) is an expanding global health problem, closely linked to the
epidemic of obesity. Individuals with T2DM are at high risk for both microvascular complications (including
retinopathy, nephropathy and neuropathy) and macrovascular complications (such as cardiovascular
comorbidities), owing to hyperglycaemia and individual components of the insulin resistance (metabolic)
syndrome. Environmental factors (for example, obesity, an unhealthy diet and physical inactivity) and
genetic factors contribute to the multiple pathophysiological disturbances that are responsible for
impaired glucose homeostasis in T2DM. Insulin resistance and impaired insulin secretion remain the core
defects in T2DM, but at least six other pathophysiological abnormalities contribute to the dysregulation of
glucose metabolism. The multiple pathogenetic disturbances present in T2DM dictate that multiple
antidiabetic agents, used in combination, will be required to maintain normoglycaemia. The treatment must
not only be effective and safe but also improve the quality of life. Several novel medications are in
development, but the greatest need is for agents that enhance insulin sensitivity, halt the progressive
pancreatic cell failure that is characteristic of T2DM and prevent or reverse the microvascular
complications. For an illustrated summary of this Primer, visit: http://go.nature.com/V2eGfN

Type 2 diabetes mellitus (T2DM) is characterized a heterogeneous group with respect to pathophysio
by dysregulation of carbohydrate, lipid and protein logy and are clinically very diverse. Annual conversion
metabolism, and results from impaired insulin secre rates of prediabetes to T2DM range from 3% to 11%
tion, insulin resistance or a combination of both. Of the peryear 3.
three major types of diabetes, T2DM is far more com The clinical presentation, underlying pathophysio
mon (accounting for more than 90% of all cases) than logy and disease progression in patients with diabe
either type1 diabetes mellitus (T1DM) or gestational tes can vary considerably among individuals and, on
diabetes. Over the past few decades, our understand occasion, atypical presentation of symptoms can make
ing of the development and progression of T2DM has clear-cut classification of T2DM difficult. At the time of
evolved rapidly. Its main cause is progressively impaired diagnosis, many patients with T2DM are asymptomatic,
insulin secretion by pancreatic cells, usually upon a whereas others present with severe hyperglycaemia or
background of pre-existing insulin resistance in skel even diabetic ketoacidosis. Latent autoimmune diabe
etal muscle, liver and adipose tissue1 (BOX1). Overt tes in adults4 and maturity-onset diabetes of the young 5
hyperglycaemia is preceded by prediabetes1,2, a high- can masquerade as T2DM. In asymptomatic individu
risk condition that predisposes individuals to T2DM als, the timing and frequency of testing for prediabetes
Correspondence to R.A.D. development (TABLE1). Prediabetes is characterized or T2DM are based on the presence or absence of risk
e-mail: defronzo@uthscsa.edu by any one of the following: impaired fasting glucose factors6. Screening in atrisk individuals is important
Diabetes Division,
(IFG) levels, impaired glucose tolerance (IGT) or because prediabetes is common and ~30% of individu
Department of Medicine,
University of Texas Health
increased glycated haemoglobin A1c (HbA1c) levels. als with T2DM are undiagnosed. Prevention of dia
Science Center, South Texas Individuals with IFG levels are characterized by fasting betes requires identification of individuals who have
Veterans Health Care System plasma glucose levels that are higher than normal but prediabetes and intervention with lifestyle modifica
and Texas Diabetes Institute, do not meet the criteria for the diagnosis of diabetes. tions (weight loss and exercise) plus antidiabetic and
701S.Zarzamoro,
SanAntonio, Texas 78207,
IGT is characterized by insulin resistance in muscle and anti-obesity medications79. The American Diabetes
USA. impaired late (second-phase) insulin secretion after a Association (ADA) Consensus Conference10 recom
meal, whereas individuals with IFG levels manifest mended that high-risk individuals (HbA1c >6.5%;
Article number: 15019
doi:10.1038/nrdp.2015.19
hepatic insulin resistance and impaired early (first- BMI 30kg perm2; age 60years) with IGT or IFG
Published online phase) insulin secretion2. Individuals with prediabetes levels be treated with metformin. Pioglitazone11 and
23 July 2015 have HbA1c levels between 5.76.4%; they represent combined low-dose metformin and rosiglitazone 12

NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 1

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PRIMER

Author addresses
minimize acute and long-term microvascular complica
tions (including retinopathy, nephropathy and neuro
1
Diabetes Division, Department of Medicine, University of Texas Health Science Center, pathy) and macrovascular complications (such as a
South Texas Veterans Health Care System and Texas Diabetes Institute, 701S.Zarzamoro, heart attack and stroke)1719 (TABLE2). T2DM should be
San Antonio, Texas 78207, USA. viewed and treated as a heterogeneous disorder with
2
CNR Institute of Clinical Physiology, Pisa, Italy.
multiple pathophysiological abnormalities, varying
3
Department of Clinical Science Malmoe, Diabetes & Endocrinology, Lund University
Diabetes Centre, Lund, Sweden.
susceptibility to complications and varying clinical
4
University of California, San Diego, Section of Diabetes, Endocrinology & Metabolism, response to therapeutic intervention1719. Ultimately,
Center for Metabolic Research, VA San Diego Healthcare System, San Diego, a true cure for T2DM will require the elucidation of
California,USA. its molecular aetiology and effective interventions to
5
University of Michigan, Ann Arbor, Michigan, USA. combat the obesity epidemic. In this Primer, we dis
6
University of Copenhagen, Kobenhavn, Denmark. cuss the epidemiology, diagnosis, pathophysiology and
7
Department of Nutrition, Harvard T.H.Chan School of Public Health and Department management (present and future) ofT2DM.
ofEpidemiology, Harvard T.H.Chan School of Public Health and Channing Division of
Network Medicine, Brigham and Womens Hospital, Harvard Medical School, Boston, Epidemiology
Massachusetts, USA.
T2DM has become a major global public health con
8
Harvard Medical School and Joslin Diabetes Center, Boston, Massachusetts, USA.
9
Diabetes Unit, Division of Internal Medicine, Hadassah Hebrew University Hospital,
cern (FIG.1). The International Diabetes Federation esti
Jerusalem, Israel. mated that, in 2013, 382million adults aged 2070years
10
Howard Hughes Medical Institute and the Departments of Internal Medicine and worldwide had T2DM, with 80% of those affected living
Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, in low- and middle-income countries20. This number is
Connecticut, USA. expected to rise to 592 million by 2035 (REF.20). Areas
11
Division of Endocrinology, Diabetes and Hypertension, Brigham and Womens Hospital, particularly affected by this disease are China and India,
Harvard Medical School, Boston, Massachusetts, USA. where the prevalence of T2DM has increased dramati
12
Department of Biostatistics, Harvard T.H.Chan School of Public Health, Boston, cally despite the relatively low prevalence of obesity 21.
Massachusetts, USA. Given the same body mass index (BMI), Asians tend
13
Department of Human Metabolism and Nutrition, Braun School of Public Health,
to have a higher percentage of body fat mass, greater
Hebrew University, Jerusalem, Israel.
abdominal obesity and less muscle mass22, which might
explain their increased predisposition to T2DM. In
also are very effective in preventing the conversion of addition, poor nutrition inutero and in early life, com
prediabetes to diabetes. Lifestyle intervention (weight bined with overnutrition in later life, can contribute
loss and exercise) alone, although initially effective, is to the accelerated trajectory of the T2DM epidemic,
associated with weight regain in most individuals1315. especially in populations undergoing rapid nutrition
However, those individuals with prediabetes who transitions, involving changed food habits and reduced
successfully lose weight and maintain a physical activity physical activity. Prevalence of T2DM is slightly higher
programme can be expected to benefit from decreased in men than in women20.
conversion to diabetes16, an improved lipid profile and Epidemiological studies have improved our under
reduced cardiovascular risk, including a reduced risk of standing of the behavioural, lifestyle and biological
developinghypertension. risk factors for T2DM (BOX2). Increasing adiposity, as
T2DM is a complex chronic disorder that requires reflected by higher BMI levels, is the single most impor
continuous medical care, patient self-management for tant risk factor for T2DM (FIG.2). In addition, particu
control of abnormal glucose levels, and multifactorial lar dietary components are associated with a reduced
risk reduction strategies to normalize blood glucose risk of T2DM, independent of body weight, including
levels, lipid profiles and blood pressure to prevent or higher intake of whole grains, green leafy vegetables,
nuts and coffee; lower intake of refined grains, redand
processed meat, and sugar-sweetened beverages;
Box 1 | Glucose homeostasis
andmoderate intake of alcohol23. Physical inactivity is
Following a meal, insulin secretion is stimulated and glucagon secretion is inhibited by a key behavioural risk factor, and both aerobic activ
the combined actions of hyperinsulinaemia and hyperglycaemia. Approximately ity and resistance training are beneficial24. Sedentary
6070% of insulin secretion is dependent on the release of the incretin hormones, behaviour, such as prolonged television watching, is
including glucagon-like peptide1 (GLP1) and gastric inhibitory polypeptide (GIP) by the
associated with increased risk25. Both short (5hours
Lcells and the Kcells in the gut, respectively. Collectively, the changes in glucose,
per night) and long (9hours per night) duration of
insulin and glucagon levels suppress hepatic glucose production, stimulate muscle
glucose uptake and inhibit lipolysis; the latter results in a reduction in the free fatty acid sleep are associated with increased risk26, as is rotating
concentration in blood, which further enhances the effect of insulin on the liver and shift work27. In addition, cigarette smoking is a signifi
muscle. Type 2 diabetes mellitus is associated with major disturbances in all of the cant risk factor for developing T2DM, independent of
preceding physiological responses: insulin secretion is impaired; fasting plasma body weight and other risk factors21. Although genetics
glucagon levels are increased and fail to suppress normally after a meal; basal play an important part in the development of T2DM28,
hepaticglucose production is increased and fails to suppress normally after a meal; the ongoing diabetes epidemic cannot be explained by
muscleglucose uptake is impaired; fasting plasma free fatty acid levels are increased novel genetic mutations but is instead largely explained
and fail to suppress normally following a meal; and the post-meal rise in GLP1 and GIP by the epidemic of obesity 29. Nevertheless, genes deter
isnormal or modestly decreased. However, there is severe cell resistance to the
mine how we respond to changes in the environment,
stimulatory effect of both GLP1 and GIP on insulin secretion.
and viceversa.

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PRIMER

Table 1 | Diagnostic reference values Mechanisms/pathophysiology


T2DM is a multifactorial disease involving genetic and
Parameters Normal* Prediabetes T2DM environmental factors. The pathophysiological changes
Haemoglobin A1c <5.7%
5.76.4%
6.5% are characterized by -cell dysfunction, insulin resist
<6.0% 6.06.4% ance and chronic inflammation, all of which progres
Fasting plasma glucose <100mg per dl 100125mg per dl 126mg per dl sively hamper control of blood glucose levels and lead
to the development of micro- and macrovascular com
<110mg per dl
110125mg per dl
plications. With respect to hyperglycaemia, at least eight
Twohour plasma OGTT <140mg per dl 140199mg per dl 200mg per dl distinct pathophysiological abnormalities1,37 contribute
OGTT, oral glucose tolerance test; T2DM, type2 diabetes mellitus. *Normal glucose to impaired glucose homeostasis (FIG.3), and these fac
metabolism. American Diabetes Association. World Health Organization. tors are already well established early in the natural his
tory of T2DM. To the ominous octet we can add two
additional pathophysiological abnormalities: activa
Our understanding of the pathophysiology of tion of inflammatory pathways and impaired insulin-
T2DM has been aided by the discovery of novel mediated vasodilation, which both contribute to muscle
disease biomarkers. High blood concentrations of insulinresistance.
pro-inflammatory cytokines, such as Creactive pro
tein, interleukin6 (IL6) and tumour necrosis factor Genetic factors
(TNF), are associated with an increased risk of T2DM30, T2DM clusters in families and is heritable. The relative
whereas a high concentration of adiponectin, which has risk of siblings of a patient with T2DM developing the
anti-inflammatory effects, is associated with a reduced disease compared with families in which none of the sib
risk31. Lower levels of sex hormone-binding globu lings has the disease is ~23, but this figure increases to
lin are associated with increased risk32, as are higher 30 if two siblings have T2DM38. The risk of developing
blood concentrations of branched-chain and aromatic T2DM is higher when the mother has the disease com
amino acids33. Gut flora metabolites might predict pared with when the father has the disease39. The risk
future risk of T2DM because the gut microbiota is of developing T2DM is also markedly increased with a
involved in energy extraction from the diet, modifica BMI of 30 or a non-normal fasting glucose concentra
tion of host gene expression, and increasing metabolic tion of >5.5mmol l1 (REF.40). By comparison, the relative
endotoxaemia (the level of endotoxins in blood) and risk for T1DM is ~15 and the relative risk for maturity-
chronicinflammation34. onset diabetes of the young is ~50. Identification of the
In summary, up to 90% of T2DM cases are poten genes that are responsible for complex polygenic diseases
tially preventable by following a healthy diet, main such as T2DM has been a challenge. A breakthrough
taining a BMI of 25kg per m2, exercising for at least came in 2007 with genome-wide association studies
30minutes per day, avoiding smoking and consuming (GWASs) that reported common genetic variants associ
alcohol in moderation35,36. ated with T2DM. A single-nucleotide polymorphism
(SNP) in TCF7L2 (already reported a year earlier on
the basis of gene linkage analysis) showed the strong
Table 2 | Multifactorial risk reduction outpatient goals of therapy in T2DM est association with T2DM41,42, but SNPs in other genes
Parameter ADA AACE IDF (WDF) have also been shown to be linked to T2DM, includ
Glucose ing in SLC30A8, FTO, CDKAL1, CDKN2A, CDKN2B,
HHEX, IGF2BP2, GCKR and others4244. Subsequent
Fasting glucose (mg per dl) 70130* <110 115
GWASs have increased this list to more than 100 com
2hour postprandial glucose <180* <140 <160 mon variants associated with T2DM45. Most variants are
(mg per dl)
in introns, and it is more correct to talk about genetic
Haemoglobin A1c (%) <7 6.5 <7.0 loci than genes. Accordingly, defining the mechanisms
Lipids by which these loci increase the risk of T2DM is diffi
LDL cholesterol (mg per dl) <70 70 <70 cult. Exceptions are a few variants in exons, which influ
ence the function of the gene, such as SLC30A8 (which
Non-HDL cholesterol (mg per dl) NR <130 <97
encodes a zinc transporter that is required to store insu
<100 lin)46, KCNJ11 (which encodes an ATP-dependent potas
HDL cholesterol (mg per dl) >40 in men >40 in men >39 sium channel) and GCKR (which encodes a glucokinase
>50 in women >50 in women regulatory protein)4345. Intronic variants might influ
ence the expression of a nearby gene (in cis) or a distant
Triglycerides (mg per dl) <150 <150 <200
gene (in trans), but this has been verified only for a small
Blood pressure number of genes, such as a variant in the MTNR1B gene
Systolic pressure/diastolic pressure <140/80* <130/80 130/80 (which encodes a melatonin receptor)47. Cultured human
(mm Hg) islets carrying risk alleles have shown reduced -cell
AACE, Association of Clinical Endocrinologists; ADA, American Diabetes Association; function and survival. Gaining mechanistic insights into
HDL,high-density lipoprotein; IDF, International Diabetes Federation; LDL, low-density these SNPs has proved to be difficult, and animal data
lipoprotein; NR, no recommendation; T2DM, type 2 diabetes mellitus; WDF, World Diabetes
Foundation. *Individualized goals. High-risk or established cardiovascular disease. have not been very informative. For example, the human

Age7080years goal <140/90mmHg, and age >80years goal <150/90mmHg. mutation in SLC30A8 protects against T2DM, whereas it

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PRIMER

predisposes to the disease in mice46. Other animal data insights into the pathogenesis of T2DM. A prospective
have been more rewarding. Linkage to impaired insulin study of ~2,700 individuals, 150 of whom developed
secretion in a polygenic model for T2DM, the GK rat, T2DM during 8years of followup, tested the effect of
was explained by a variant in the ADRA2A gene, result a high genetic risk (highest quartile; 12 risk alleles)
ing in overexpression of the 2Aadrenergic receptor and low genetic risk (lowest quartile; 8 risk alleles) of
in islets48. As pretreatment of human islet cells with an T2DM and showed that all individuals became more
inhibitor of the receptor, yohimbine, normalized insu obese and thereby insulin resistant regardless of high
lin secretion, the authors treated human carriers of the or low genetic risk. However, more high-risk people
variant with the same inhibitor, which resulted in a dose- could not increase their insulin secretion to meet the
dependent improvement in insulin secretion49. Impaired demands imposed by insulin resistance and therefore
-cell function has also been associated with epigenetic developedT2DM52.
modifications50 and microRNA patterns51 that are likely The majority of heritability (85%) cannot be
to increase the fraction of cases in which inheritance is explained by the currently identified SNPs. Alternative
a relevant pathogenetic factor 42. possibilities to explain the heritability are: disease
Notably, these genetic variants only have modest heterogeneity (T2DM may not be a genetically uni
effects, increasing risk by 1020%, and have thus been form disease), geneenvironment interactions and epi
maintained during hundreds of generations. In fact, the genetic mechanisms (DNA methylation and chromatin
majority of non-diabetic people carry risk variants for modifications). Some variants, such as those for KCNQ1
T2DM, and the average frequency of a T2DMassociated (which encodes a voltage-gated potassium channel),
risk allele is 54%45. Despite this high prevalence and only show strong parent-oforigin effects; KCNQ1 is methyl
modest risk increase, these variants have provided novel ated and imprinted in fetal but not in adult life when
inherited from the mother 53.
a
cell function
Insulin resistance is the earliest detectable abnormal
56.3 ity in individuals who are likely to develop T2DM1,54,55.
68.9
22.4% However, overt T2DM does not occur unless cells are
unable to secrete sufficient amounts of insulin to offset
36.8 34.6 the insulin resistance50,56,57. Multiple factors contribute
50.4 67.9 72.1 to cell failure, including ageing 58, genetic abnormali
37.3% 96.2% 123.0 ties45, incretin hormone (glucagon-like peptide1 (GLP1)
70.6%
and gastric inhibitory polypeptide (GIP)) resistance and/
19.8 or deficiency 59,60, lipotoxicity 37,61,62, glucotoxicity 63, insu
41.5 lin resistance leading to cell stress1,37, hypersecretion
World 109.6% 138.2
2013 = 381.8 million
of islet amyloid polypeptide (IAPP)64, reactive oxygen
24.1 201.8
2035 = 591.9 million 38.5 46.0% stress65 and activation of inflammatory pathways37.
Increase = 55% 59.8%
-cell physiology. In human islets, -cells constitute
b 400 ~60% of cells and are intermingled with glucagon-
IGT producing cells (30%), somatostatin-producing
350 T2DM -cells (10%) and pancreatic polypeptide-producing
Number of people (milllions)

300 cells (1%)66. Within the islet, -cells form sparse sub
clusters, which show functional connectivity through
250
gap junctions67. Each islet contains 100500U of insu
200 lin, so that the whole endocrine pancreas (~1million
150
islets, weighing 0.9g) contains 10days worth of sup
ply for a healthy adult 68. -cells communicate with
100 each other and with the other islet endocrine cells
50 through connexin proteins and other cellcell adhe
sion complexes67. Moreover, endocrine cells can influ
0
2013 2035 2013 2035 2013 2035 2013 2035 2013 2035 2013 2035 2013 2035 ence one another via hormones released into the blood.
Africa Europe Middle East North South and South- Western Finally, non-hormonal endocrine cell products (such
and North America Central East Asia Pacic as ATP and zinc) and neurotransmitters influence
Africa and America -cellfunction.
Caribbean
-cells in T2DM. In post-mortem specimens from
Figure 1 | Prevalence of T2DM and IGT. a | In each box,Nature values| Disease
Reviews
the top Primers
are the number
of people with type 2 diabetes mellitus (T2DM) (in millions) in 2013, and the middle patients with T2DM, -cell mass is reduced by 3040%
numbers are an estimate of the number of people expected to have T2DM in 2035. compared with specimens from non-diabetic subjects69.
Thebottom value is the percentage increase from 2013 to 2035. b | Thenumber of people Morphometric measures, however, overlap widely
with T2DM and impaired glucose tolerance (IGT) (in millions) by region for the years 2013 between individuals with or without T2DM, and -cell
and 2035. Data are obtained from the International Diabetes Federation Diabetes Atlas. mass quantification based on insulin immunostaining

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PRIMER

Box 2 | Risk factors for T2DM


fastingfeeding cycles, exercise and stress) on a minute-
tominute basis in order to maintain normal blood
Older age glucose levels, and inter-individual differences affect
Non-white ancestry this adjustment. For example, a lean, insulin-sensitive
Family history of type 2 diabetes mellitus (T2DM) adult might need as little as 0.5U of insulin to dispose
Genetic factors of an oral load of 75g of glucose over 2hours, whereas
Components of the metabolic syndrome (increased waist circumference, increased
an obese, insulin-resistant, glucose-intolerant person
blood pressure, increased plasma triglyceride levels, and low plasma high-density might require 45U to perform the same task (~90fold
lipoprotein (HDL) cholesterol levels and small dense low-density lipoprotein (LDL) inter-individual difference). Invivo tests in humans
cholesterol particles) using intravenous or oral glucose, arginine, sulfonylureas
Overweight or obese (body mass index (BMI)of 25kg per m2) (antidiabetic drugs) or mixed meals have demonstrated
Abdominal or central obesity (independent of BMI) impaired cell function in overt T2DM. However, reli
able quantitation of invivo -cell dysfunction requires
Polycystic ovary syndrome
some form of modelling 78. Absolute insulin secretion in
History of atherosclerotic cardiovascular disease
response to an oral glucose challenge can be normal or
Unhealthy dietary factors (regular consumption of sugary beverages and red meats, even increased in T2DM (FIG.4a), except in long-standing,
and low consumption of whole grains and other fibre-rich foods)
poorly controlled disease, in which absolute insulin
Cigarette smoking secretion is reduced. However, when insulin secretion
Sedentary lifestyle rates are plotted against the concomitant plasma glucose
History of gestational diabetes or delivery of newborns >4kg in weight concentrations, patients with T2DM secrete substan
Presence of acanthosis nigricans (hyperpigmentation of the skin) tially less insulin than non-diabetic controls (FIG.4b).
Some medications This decline in -cell glucose sensing occurs along a
Short and long sleep duration and rotating shift work continuum extending from normoglycaemia through
prediabetes to decompensated diabetes in adults79 and
Psychosocial and economic factors
children80, and is a potent predictor of progression to
diabetes independently of insulin resistance and classic
might lead to underestimation owing to -cell degranu phenotypic predictors79. Absolute insulin secretion is a
lation70. Loss of -cells in T2DM is believed to occur positive antecedent of deteriorating glucose tolerance.
via apoptosis71 and dysregulated autophagy 72. -cell Furthermore, the ability of -cells to respond to the rate
proliferation does not seem to differ between diabetic of increase in plasma glucose concentration (rate sensi
and non-diabetic islets; whether neogenesis is impaired tivity) is impaired in individuals withT2DM79.
in T2DM is uncertain. Vascular disarray and amyloid Antecedent hyperglycaemia and high levels of incre
deposition73 contribute to altered cytoarchitecture in tin hormones (GLP1 and GIP) potentiate glucose-
T2DM islets, especially in patients with long-standing stimulated insulin release in healthy individuals. In
disease. The quantitative functional impact of struc patients with T2DM, glucose-mediated potentiation
tural changes in human T2DM islets is still incom of insulin release is increased compared with normal
pletely defined73. Insulin resistance feeds back to the glucose-tolerant individuals (owing to the hyperglycae
-cell by raising its set point (more insulin is secreted mia); incretin potentiation, however, is severely compro
at any serum level of glucose). This chronic adaptation mised81. The incretin defect is not reversed by reducing
is probably mediated by small increments in circulat the plasma glucose concentration82.
ing glucose levels (such as those that occur in obese Whenever an intervention results in a reduction in
normal glucose-tolerant individuals) as well as by other plasma glucose concentrations, fasting insulin secre
factors, such as raised levels of free fatty acids (FFAs)74. tion rate and total insulin output in response to glucose
In addition, insulin resistance promotes a relative pre are reduced compared with the non-treated condition,
ponderance of cells over -cells74, possibly due to but -cell glucose sensitivity is improved. For example,
selective -cell apoptosis as well as through a process successful bariatric surgery leads to partial recovery of
of dedifferentiation and subsequent redifferentiation -cell function83. This indicates that a -cell mass deficit
and to a progressive loss of cell mass. In culture, islets alone is unlikely to be the cause of diabetes and that,
isolated from patients with T2DM show reduced insulin even in advanced T2DM, many -cells are alive but
release in response to glucose and a higher threshold for stunned or disguised, and therefore amenable to being
the initiation of insulin secretion compared with islets revitalized by intervention84 (FIG.5).
isolated from healthy controls75. Similar changes in insu
lin secretion can be induced in islets isolated from non- Insulin resistance
diabetic individuals by prolonged exposure to increased Obesity and physical inactivity lead to insulin resist
concentrations of FFAs (in particular, palmitate)76 or ance, which together with a genetic predisposition45,
glucose75, and invivo77. place stress on cells, leading to a failure of cell
function and a progressive decline in insulin secre
Insulin secretion. -cells integrate inputs from substrates tion1,2,7,57,85.Insulin resistance precedes T2DM by many
(such as glucose, FFAs, arginine, fructose and amino years1,2,54,55. Insulinresistance is not only present in
acids), hormones and nerve endings to adjust insulin muscle and the liver 1,84,85, the two tissues responsible for
release in response to changing demands (for example, the majority of glucose disposal following carbohydrate

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PRIMER

100 phosphorylation of IRS proteins, which inhibits tyro


Men sine phosphorylation, leading to insulin resistance108,109.
Women
Age-adjusted relative risk

In some cases, serine phosphorylation also increases IRS


75
degradation, further contributing to the insulin resist
ance110. The causes of increased serine phosphorylation
50 are multifactorial, including ectopic lipid accumula
tion, mitochondrial dysfunction, inflammation and
endoplasmic reticulum (ER) stress.
25
Ectopic lipids and PKCs. Ectopic lipid accumulation in
0 muscle37,111 and the liver 37,112114 induces insulin resist
<22 <23 23.0 24.0 25.0 27.0 29.0 31.0 33.0 35 ance by increasing tissue diacylglycerol (DAG) levels115,
23.9 24.9 26.9 28.9 30.9 32.9 34.9 which lead to activation of members of a class of protein
Body mass index (kg per m2) kinaseC (PKC): PKC in muscle107, and PKC116 and
Figure 2 | Association between BMI and T2DM. DataNature
obtained from REFS
Reviews 321,322
| Disease .
Primers
PKC117 in the liver. These PKCs phosphorylate ser
BMI, body mass index; T2DM, type 2 diabetes mellitus. ine residues in IRS proteins, thereby inhibiting insulin
signalling. Genetic knockdown of the genes encoding
PKC in muscle118, PKC116 or PKC117 in the liver, or
ingestion, but also in adipose86,87, kidney 88, gastro of the genes encoding one of the upstream enzymes
intestinal tract 89, vasculature90 and brain91,92 tissues, and involved in DAG production or accumulation 119
pancreatic -cells9395. In muscle, multiple abnormali ameliorates lipid-induced insulin resistance. Consistent
ties contribute to insulin resistance, including defects with this observation, the levels of PKC in muscle and
in insulin signalling, glucose transport, glucose phos of PKC and PKC in the liver are increased in obesity
phorylation, glycogen synthesis, pyruvate dehydro and T2DM116,120,121. In addition, animal models of obe
genase complex activity and mitochondrial oxidative sity andT2DM have increased tissue levels of ceramides,
activity 1,37,95. In the liver, insulin resistance, together which are linked to insulin resistance122. Ceramides and
with insulin deficiency, hyperglucagonaemia, enhanced DAGs might have different roles in promoting insu
glucagon sensitivity and increased substrate (fatty acids, lin resistance depending on the length of fatty acid
lactate, glycerol and amino acids) delivery 9699, leads chains123 and sites of cellular compartmentalization124.
toincreased gluconeogenesis, which is responsible Many treatments that improve insulin sensitivity, such
for the increased basal rate of glucose production and as caloric restriction or thiazolidinediones, also reduce
fasting hyperglycaemia1. Also, insulin resistance in the ectopic lipid content and tissue DAG content.
kidney and augmented renal gluconeogenesis88 con
tribute to fasting hyperglycaemia. Impaired suppres Mitochondrial dysfunction. Mitochondrial dysfunc
sion of hepatic glucose production, decreased hepatic tion has been observed in the liver, muscle, adipose
glucose uptake, muscle insulin resistance, reduced non- tissue and even the brain, including and the hypothala
insulin-mediated glucose uptake100,101 and excessive mus, in rodents and humans with obesity, T2DM and
renal glucose reabsorption102 contribute to postprandial metabolic syndrome125. The cause is both a reduction
hyperglycaemia in T2DM. In addition, insulin resistance in mitochondrial density 119,126 and impaired mitochon
in the vascular endothelium impairs the vasodilating drial functioning secondary to aberrant expression of
effects of insulin, thereby further reducing not only its different components of the oxidative phosphorylation
own delivery but also glucose delivery 103,104. system127129. Altered mitochondrial function contrib
utes to insulin resistance in multiple ways. In adipose
Molecular mechanisms of insulin resistance. Binding tissue, mitochondrial dysfunction has been associated
of insulin to its receptor activates insulin receptor tyro with impaired secretion of adiponectin, a potent insulin-
sine kinase and phosphorylation of a family of insulin sensitizing adipokine127,130,131. In other tissues, mito
receptor substrates (IRSs), especially IRS1 and IRS2 chondrial dysfunction has been suggested to increase
(REF.105) (FIG.6). These phosphorylated IRS proteins levels of reactive oxygen species, which activate redox-
bind to and activate intracellular signalling molecules, sensitive serine kinases to phosphorylate IRS proteins
most important of which is phosphatidylinositol and produce insulin resistance132. Whether mitochon
3kinase (PI3K). PI3K promotes glucose transporter drial dysfunction is the cause or result of insulin resist
type4 (GLUT4) translocation to the plasma mem ance remains a topic of debate133. However, given the
brane, resulting in glucose uptake into skeletal muscle, key role of ectopic lipid deposition in causing insulin
and phosphorylates and inactivates the transcription resistance,mitochondrial dysfunction associated with
factor forkhead box protein O1 (FOXO1), altering reduced mitochondrialfatty acid oxidation is at the very
transcription of downstream genes. Insulin also stim least an important exacerbating factor in this process133.
ulates the RASmitogenactivated protein kinase
(MAPK)pathway. Inflammation. Systemic inflammation is a well-
Insulin resistance in obesity and T2DM has mainly documented contributor to insulin resistance. Increased
been linked to the PI3K pathway 106,107. Insulin resist levels of pro-inflammatory cytokines, such as IL6 and
ance is usually associated with increased serine TNF, and increased numbers of macrophages and other

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PRIMER

Decreased incretin
eect TZDs
Islet
Increased
lipolysis
GLP1 RA
GLP1 RA
DPP4 inhibitor

TZDs Increased
Decreased -cell glucose
GLP1 RA
insulin Increased reabsorption
DPP4 inhibitor
secretion glucagon
-cell secretion SGLT2 inhibitor

Hyperglycaemia

TZDs
Increased Decreased
hepatic glucose uptake
TZDs glucose
Metformin production
GLP1 RA
DPP4 inhibitor Neurotransmitter
Vascular insulin resistance dysfunction IBNF-B
TLR4
Insulin MAPK
At rest Inammation AMPK
TNF
Insulin
ROS
Microvascular recruitment only GLP1 RA Macrophages
1 of 3 capillaries are open at rest

Figure 3 | The ominous octet of hyperglycaemia in T2DM. Insulin resistance in muscle and the
Nature liver, and
Reviews impaired
| Disease Primers
insulin secretion by the pancreatic cells are the core defects in type 2 diabetes mellitus (T2DM). cell resistance to
glucagon-like peptide1 (GLP1) contributes to progressive failure in the function of cells, whereas increased glucagon
levels and enhanced hepatic sensitivity to glucagon contribute to the excessive glucose production by the liver. Insulin
resistance in adipocytes results in accelerated lipolysis and increased plasma free fatty acid (FFA) levels, both of which
aggravate the insulin resistance in muscle and the liver and contribute to cell failure. Increased renal glucose
reabsorption by the sodium/glucose co-transporter 2 (SGLT2) and the increased threshold for glucose spillage in the urine
contribute to the maintenance of hyperglycaemia. Resistance to the appetite-suppressive effects of insulin, leptin, GLP1,
amylin and peptide YY, as well as low brain dopamine and increased brain serotonin levels contribute to weight gain,
which exacerbates the underlying resistance. To the ominous octet must be added vascular insulin resistance and
inflammation, making the decadent decoplet. AMPK, AMP-activated protein kinase; DPP4, dipeptidyl peptidase 4; IB,
inhibitor of NF-B; MAPK, mitogen-activated protein kinase; NF-B, nuclear factor-B; RA, receptor agonist; ROS, reactive
oxygen species; TLR4, Toll-like receptor 4; TNF, tumour necrosis factor; TZDs, thiazolidinediones.

inflammatory cells are observed in adipose tissue, liv Thelper1 (TH1), TH17 and CD8+ Tcells, and a reduc
ers and sera of patients and animals in insulin-resistant tion in the numbers of less-inflammatory cells, such
states134. Pro-inflammatory cytokines induce insulin as M2 macrophages, regulatory T cells (TReg cells) and
resistance by activating downstream kinases, includ TH2 cells145147. Inflammation occurs primarily in adipose
ing IB kinase- (IKK), JUN amino-terminal kinase1 tissue and the liver 142,148. Macrophage infiltration in adi
(JNK1; also known as MAPK8) and p38 MAPK, which pose tissue stimulates lipolysis, and increased levels of
can contribute to the phosphorylation of serine residues IL6 can stimulate hepatic gluconeogenesis and cause
in IRS proteins135,136 and stimulate production of sup hepatic insulin resistance149. Changes in adipose inflam
pressors of cytokine signalling (SOCS), which block the mation have been observed not only in obese mice but
action of IRS proteins137,138. Blocking TNF activity with also in lean mice with differences in genetic predisposi
antibodies or knockout of its receptor improves insulin tion to obesity and insulin resistance150. These inflam
sensitivity in obese mice139, but TNF-specific blocking matory cells themselves are insulin responsive, and
agents do not improve glycaemic control in patients knockout of the insulin receptor in these lineages pro
with T2DM140. Conversely, pharmacological and genetic tects against obesity-induced inflammation and systemic
inhibition of the IKKnuclear factorB (NFB) path insulinresistance151.
way improves insulin sensitivity in mice135,141,142 and Altered lipid metabolism can affect inflammation by
improves glycaemic control in patients with T2DM143, activating Toll-like receptors (TLRs). Indeed, TLR4 is an
albeitmodestly. important component of the innate immune response
Macrophage infiltration in adipose tissue is a key and is activated by fatty acids. Increased FFA levels
aspect of insulin resistance 144 and is characterized can also increase the activity of IKK and JNK, cause
by an increase in the numbers of pro-inflammatory serine phosphorylation of IRS proteins and block IRS
M1 macrophages (classic macrophages) as well as tyrosinephosphorylation152.

NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 7

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PRIMER

ER stress and the UPR. The ER is the major site of syn Diabetic complications
thesis and folding of secreted and integral membrane Diabetic microvascular complications are closely related
proteins. States that increase protein synthesis or dis to the severity and duration of hyperglycaemia164,165.
rupt normal processing create an imbalance between Hyperglycaemia promotes the development of micro
the demand and capacity of the ER, leading to ER vascular complications through the activation of six
stress and the unfolded protein response (UPR). As a major pathways, including enhanced polyol pathway
result, three signalling pathways are activated IRE1, flux, increased formation of advanced glycation end
PRKR-like ER kinase (PERK; also known as EIF2AK3) products (AGEs), increased AGE receptor expression,
and ATF6153 to reduce ER stress by ameliorating activation of PKC isoforms, enhanced hexosamine flux
the UPR response. Pathophysiological states, including and increased intracellular reactive oxygen species166,167.
obesity, hyperlipidaemia and T2DM, disrupt this feed Genetic factors have a pivotal role in determining sus
back loop by increasing phosphorylation of PERK and ceptibility to microvascular complications. T2DM also
IRE1, enhancing splicing of Xbox-binding protein1 affects the macrovasculature, and the incidence of myo
(XBP1) and activating JNK154,155. Conversely, weight cardial infarction, peripheral vascular disease and stroke
loss156 and administration of chemical chaperones that is markedly increased37,168. Reactive oxygen species
reduce ER stress157 are associated with reduced UPR impair angiogenesis, activate several pro-inflammatory
activation. Mechanistically, the UPR is thought to lead pathways and cause epigenetic changes that result in
to insulin resistance through IRE1-dependent activa long-lasting expression of pro-inflammatory genes that
tion of JNK158. Why ER stress develops in obesity is persists after glycaemia is normalized. These same bio
uncertain, but high fatty acid levels can cause ER stress chemical and molecular mechanisms that contribute to
and activate theUPR159. the microvascular complications also contribute to the
Another possible link between obesity and ER stress macrovascular complications166,167.
is the mammalian target of rapamycin (mTOR) signal Accelerated atherosclerotic cardiovascular disease
ling pathway. mTOR, which is involved in the regulation is associated with several risk factors, including insulin
of a wide range of cellular functions, exists in two differ resistance and hyperinsulinaemia, activation of inflam
ent complexes called mTORC1 and mTORC2 (REF.160). matory pathways and the presence of multiple cardio
Increased mTORC1 pathway activation blocks insulin vascular risk factors (such as hypertriglyceridaemia,
signalling pathways by reducing insulin-induced tyro reduced high-density lipoprotein (HDL) cholesterol,
sine phosphorylation of IRS1 and IRS2 (REF.161) and by small dense low-density lipoprotein (LDL) particles169,
increasing degradation of IRS1 (REF.162). Recent studies hypertension, endothelial dysfunction, increased
have demonstrated that the p85 regulatory subunit of plasminogen activator inhibitor1 levels, visceral obesity,
PI3K interacts with XBP1s (the spliced, transcription and non-alcoholic steatohepatitis or non-alcoholic fatty
ally active isoform of XBP1) and promotes the trans liver disease)37,170. Hypertension is twofoldthreefold
location of XBP1s into the nucleus to initiate the ER more common in pe ople with T2DM and greatly
stress response163. increases the risk of macrov ascular complications

a 500 b
NGT
Insulin secretion rate (pmol per min per m2)

450
T2DM
400

350

300

250

200

150

100

50

0
0 20 40 60 80 100 120 140 160 180 0 5 6 7 8 9 10 11 12
Time (min) Plasma glucose (mmol per l)
Figure 4 | Insulin secretion in response to glucose. a | Characteristic insulin secretory response
Nature (reconstructed
Reviews by
| Disease Primers
deconvolution of plasma Cpeptide levels) to oral glucose in patients with type 2 diabetes mellitus (T2DM) and in
body mass index (BMI)-matched non-diabetic individuals. Note the higher fasting secretion rate, the initial blunted
secretory response and the later catchup phase (due to higher glycaemia). b | The insulin secretion rates of panel a
are here plotted against the concomitant plasma glucose concentrations to show the deficit in glucose sensing
inpatients versus normal glucose-tolerant (NGT) controls. Actual experimental data have been averaged and
interpolated to produce thesegraphs.

8 | 2015 | VOLUME 1 www.nature.com/nrdp

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PRIMER

(suchas myocardial infarction, stroke, peripheral vascu


lar disease and congestive heart failure), microvascular
complications (including retinopathy and nephropathy)
and premature death171. Multiple factors contribute Normal Obese
to the increased incidence of hypertension in T2DM,

-cell function
including disturbed blood pressure circadian rhythms
(higher nocturnalblood pressure), impaired blood flow Weight loss
Intervention
autoregulation, stiffening of large arteries, increased
intracellular sodium concentration, increased arterial
sensitivity to angiotensin II, insulin resistance, endothelial
Diabetic
dysfunction, obesity and geneticsusceptibility 172,173.

Diagnosis, screening and prevention


Diagnosis -cell mass
Diagnostic criteria for diabetes have traditionally relied
Figure 5 | Schematic representation of the
Nature Reviews relationship
| Disease Primers
on blood glucose levels. More recently, HbA1c has been between -cell mass and -cell function. In obese
added174 as an integrated measure of long-term gly individuals who are not diabetic, -cell mass is expanded
caemia (the lifespan of a red blood cell is ~120days) (insome proportion to the degree of weight excess), but
(TABLE 1) . However, haemolysis, which reduces red -cell function is comparable to individuals with a normal
blood cell lifespan, can make HbA1c an invalid measure. body mass index (BMI). Preliminary data show that weight
Also, older age, non-white race, high dietary fat intake, loss might cause some reduction in both -cell mass and
alcohol consumption, cigarette smoking, liver disease, function in non-diabetic individuals. Average -cell mass is
kidney disease and iron deficiency can affect HbA1c reduced in type 2 diabetes mellitus (T2DM) regardless of
independently of glycaemia. obesity, but the inter-individual variation is large. -cell
function, however, is profoundly impaired. Intervention,
Although most clinicians agree that diabetes should
such as weight loss and/or antihyperglycaemic treatment,
be defined according to risk of complications, the level improves -cell function but without changes in -cell mass.
of hyperglycaemia associated with complications varies
depending on the complication. Current criteria are
based on maintaining fasting glucose, post-glucose- a first-degree relative with diabetes be screened in pri
load glucose and HbA1c levels below the threshold mary care settings. They also pointed out that most
that is associated with an increased risk of developing racial and ethnic minority groups (African Americans,
diabeticretinopathy 175. Latinos and Hispanics) are at increased risk compared
T2DM diagnosis can be established on the basis of with whites. Other diabetes professional so cieties
an elevated random plasma glucose test (200mgperdl have long recommended opportunistic screening for
with classic symptoms of hyperglycaemia), fasting T2DM within established primary care guidelines in
plasma glucose levels (126mgperdl after at least an high-riskindividuals.
8hour fast), 2hour post-glucose-load glucose level Fasting glucose, post-glucose-load glucose and
(200mg per dl after 75g oral glucose) or HbA1c HbA1c have limitations as screening tests that are
(6.5%) confirmed by repeat testing unless unequivo related to their acceptability (fasting), time consump
cally elevated6 (TABLE2). However, the risk of developing tion (2hour post-glucose-load glucose level) and cost
diabetic nephropathy and distal symmetric peripheral (HbA1c). Some organizations have recommended the
polyneuropathy is already increased with levels of hyper use of risk models and random capillary glucose levels
glycaemia lower than those associated with diabetic as initial screening tests, but these have not been widely
retinopathy 176. In addition, the relationship between adopted180,181. In addition, different cut-off levels to
glycaemia and cardiovascular disease seems to be linear, define prediabetes have been proposed by international
without a clear threshold, which demonstrates the dif organizations182 (TABLE1). The use of lower thresholds
ficulty in using single cut points to diagnose a complex to define increased risk of future diabetes improves
disease state177. sensitivity (that is, the probability of a positive screen
ing test given that the individual is at high risk) but
Screening lowers specificity (that is, the probability of a negative
Screening for a disease is appropriate if the disease is screening test given that the patient is at low risk), and
serious; its natural history is understood; it is detectable decreases the positive predictive value of the test (that is,
in its preclinical stage; the screening test is acceptable, the probability of being at risk given a positive screen
quick, inexpensive and valid; early treatment is more ing test). The 2hour post-glucose-load glucose level of
effective than late treatment; and screening improves 140199mgperdl (IGT) is the most-studied marker for
outcomes178. T2DM meets these criteria, and in 2014 the future diabetes risk, and essentially all randomized clini
US Preventive Services Task Force (USPSTF) issued draft cal trials (RCTs) that have evaluated the efficacy of inter
recommendations supporting screening for abnormal ventions for diabetes prevention have been performed
blood glucose levels and T2DM inadults179. Specifically, in patients with IGT. Data supporting cut-off levels for
the USPSTF recommended that adults 45years of age fasting glucose and HbA1c that define prediabetes are
and those who are overweight or obese, or who have more controversial and differ among organizations.

NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 9

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PRIMER

Prevention the beneficial effects of lifestyle interventions may


RCTs have conclusively demonstrated that intensive persist over time190192. Efforts are underway to imple
lifestyle interventions and medications are effective ment lifestyle interventions in primary care and com
indelaying or preventing the development of T2DM in munity settings. Pharmacological interventions have
high-risk individuals. The evidence base for these inter been less widely applied, perhaps owing to the fact
ventions is extensive and robust (TABLE3). Four large that no me dication is approved by the US FDA for
randomized, controlled clinical trials demonstrated that diabetesprevention.
diet and moderate physical activity designed to achieve
and maintain 57% body weight loss reduce T2DM risk Management
by 2958%16,183185. Lifestyle interventions are associ Management of T2DM is complicated by multiple
ated with improved quality of life (QOL) and are safe, pathophysiological disturbances1,193 (FIG. 3) and the
cost-effective and effective across different ages, gen ABCDE of diabetes management (Age, Body weight,
ders, and racial and ethnic groups, independent of Complications, Duration, Education and Expense, and
the degree of obesity and hyperglycaemia. Metformin Etiology)19. Prevention of microvascular complications
reduces the risk by 2631%184,185, -glucosidase inhibi focuses on glycaemic control164166, whereas prevention
tors (AGIs) reduce risk by 2541%186,187, and thiazoli of macrovascular complications requires correctionof
dinediones reduce risk by 5572%11,188,189. Observational classic cardiovascular risk factors that comprise the
followup of RCT participants has demonstrated that insulin resistance (metabolic) syndrome37 (TABLE3).

Resistin Adipose tissue


Resistin Adiponectin macrophage
PAI1
FA PAI1

Obesity Enlarged
Adiponectin Adipocyte
adipocyte
FA
IL-6 RBP4
FFA TNF
TNF RBP4
TNF IL-6
IL-6
Insulin

Insulin
TLR4 TNFR receptor
P
P
P
P
JNK P
Intracellular
fat Ser-P IRS Tyr-P
IKK
DAG PKC PI3K Insulin action
mTOR
SOCS
ROS

IRE1 UPR
Mitochondria
ER stress XBP1

Nucleus
Muscle or liver cell

Figure 6 | Mechanisms of insulin resistance. In adipocytes, insulin resistance (also caused by increased
Nature Reviews insulin receptor
| Disease Primers
substrate (IRS) serine phosphorylation) and inflammation lead to production and release of free fatty acids (FFAs)
andinsulin-resistance-provoking pro-inflammatory cytokines, such as interleukin6 (IL6), tumour necrosis factor (TNF) and
resistin. Insulin-sensitizing adipokines, such as adiponectin, conversely, ameliorate insulin resistance. Also, retinol-binding
protein 4 (RBP4) increases and might contribute to insulin resistance. Plasminogen activator inhibitor 1 (PAI1) does not
affect insulin resistance but has been implicated in complications of obesity, including accelerated atherosclerosis and
type2 diabetes. These factors contribute to the accumulation of toxic lipid metabolites (diacylglycerol (DAG), ceramides
and acyl-CoAs) in myocytes and hepatocytes, which impair insulin signalling (IRSphosphatidylinositol 3kinase (PI3K)
pathway) and activate inflammatory pathways (JUN amino-terminal kinase (JNK), IB kinase (IKK) and mitogen-activated
protein kinase (MAPK)), which further impair the insulin signal transduction pathway. Mitochondrial dysfunction
predisposing to DAG accumulation and nuclear protein kinase C (PKC) activation as well as generation of reactive oxygen
species (ROS) and increased endoplasmic reticulum (ER) stress further exacerbate the insulin resistance95,125. FA, fatty acid;
mTOR, mammalian target of rapamycin; SOCS, suppressors of cytokine signalling; TLR4, Toll-like receptor 4; TNFR,
TNFreceptor; UPR, unfolded protein response; XBP1, Xbox-binding protein 1.

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PRIMER

Table3 | Intervention to delay or prevent T2DM development* glycerophosphate dehydrogenase210,211. In a study carried
out in the United Kingdom and United States, cardio
Intervention Risk reduction (%) Refs vascular events were significantly reduced in a small
Lifestyle (body weight reduction of 57%) 2958 183185 group of 344 obese patients with diabetes who were
Metformin 2631 184,185 treated withmetformin212.
Lifestyle and metformin 28 185
Drugs that increase insulin secretion. Sulfonylureas aug
Acarbose (glucosidase inhibitor) 25 186 ment insulin secretion, and the resulting hyperinsulinae
Voglibose (glucosidase inhibitor) 41 187 mia overcomes insulin resistance, leading to a decline in
Troglitazone 55 188 fasting plasma glucose levels and HbA1c. However, after
the initial decline, HbA1c rises progressively because
Rosiglitazone 60 189
sulfonylureas have no long-term protective effect on
Pioglitazone 72 11 cell function1,207,209 and might even accelerate failure
T2DM, type 2 diabetes mellitus. *In people with impaired glucose tolerance. ofcell function213. Sulfonylureas commonly cause
hypoglycaemia and are associated with weight gain,
and some retrospective studies suggest that they might
Ideally, HbA1c should be reduced to as close to nor increase cardiovascular events214,215. Compared with
mal without causing adverse effects, of which hypo glibenclamide, the short-acting sulfonylurea, gliclazide
glycaemia is the greatest concern16,17,19,193,194. Patients has been associated with a reduced risk of all-cause
with T2DM with HbA1c levels persistently <6.5% do mortality and cardiovascular death and is less likely to
not develop retinopathy 195. Because obesity and physi cause weight gain and hypoglycaemia216. Stepwise addi
cal inactivity are insulin-resistant states associated with tion of sulfonylurea to metformin, or vice versa, is associ
tissue fat overload (lipotoxicity)37,61, lifestyle modifica ated with progressive failure of cell function and rise in
tion should be a basic component of all intervention HbA1c217. However, because they are inexpensive, met
programmes16,17. However, despite initial weight loss, formin and sulfonylureas remain the most commonly
most patients regain lost weight over the subsequent prescribed oral antidiabetic agents worldwide.
12years1315. Further, despite successful weight loss, Meglitinides (repaglinide and nateglinide) are short-
~50% of obese individuals with prediabetes still progress acting insulin secretagogues that require administration
to overt diabetes192. Thus, most obesity experts recom before each meal. Although related with less hypoglycae
mend concomitant anti-obesity medications to help to mia than sulfonylureas, they do not prevent the progres
promote and maintain weight loss. Mobilization of fat sive decline in cell function and rise in HbA1c that is
from the liver and muscle, and cells improves hepatic associated withT2DM.
and muscle insulin sensitivity and cell function37,196,197.
Insulin sensitizers. Thiazolidinediones (pioglitazone
Antidiabetic medications and rosiglitazone) are the only true insulin-sensitizing
Achievement of durable glycaemic control requires agents1,37,217,218. They enhance insulin action in skeletal
antidiabetic medications that reverse the pathophysio and cardiac muscle, the liver and adipocytes1,37,217219, and
logical defects that are present in T2DM1,198. Because no exert a potent effect on cells to augment and preserve
single medication reverses the multiple abnormalities, insulin secretion220222. Multiple mechanisms mediate
combination therapy has gained widespread accept their insulin-sensitizing effects: increased insulin signal
ance and will continue to grow 1,198201. Normalization ling; stimulation of several intracellular steps involved
of HbA1c at the time of diagnosis results in improved in glucose metabolism (GLUT4, glycogen synthase and
long-term glycaemic control7,8,200,202,203. For prediabetes, pyruvate dehydrogenase); stimulation of peroxisome pro
pharmacological therapy with thiazolidinediones11,204, liferator-activated receptor- (PPAR); PPAR coactiva
GLP1 receptor agonists205, metformin192 and AGIs186 tor1 (PGC1) activation leading to increased fat oxidation;
effectively prevents or delays the progression of IGT to proliferation of subcutaneous adipocytesand activation
diabetes(TABLE4). of genes involved in lipogenesis; fat redistribution from
visceral to subcutaneous stores; reduced plasma levels of
Metformin. Metformin is the most commonly pre FFAs; a reduction in circulating inflammatory cytokines;
scribed antidiabetic medication worldwide and works and an increase in adiponectin levels1,61,217,218. The com
by suppressing hepatic glucose production, leading to a bined insulin-sensitizing and cell stimulatory effects of
reduction in fasting plasma glucose levels and HbA1c206. thiazolidinediones explain their durable action, which
Metformin has no effect on cell function206,207 and, in was shown to be up to 5years in the ADOPT study,
the absence of weight loss, does not improve muscle and their ability to reduce HbA1c209,221,222. Pioglitazone
insulin sensitivity 206; thus, after an initial decrease, favourably affects many components of insulin resistance
HbA1c rises progressively 207209. The mechanisms by (metabolic) syndrome217,218 and reduced the MACE end
which metformin suppresses hepatic glucose produc points (myocardial infarction, stroke and cardiovascular
tion remain unclear but include inhibition of mito death) in the PROactive study 223. Adverse events (includ
chondrial complex I, activation of AMP-activated ing fluid retention, fat mass gain and trauma-relatedfrac
protein kinase (AMPK), and inhibition of glycolytic tures in post-menopausal women) are doserelated, and
and/or gluconeogenic enzymes and mitochondrial doses >30mgperday should be avoided224. Weight gain

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PRIMER

is common with thiazolidinediones, but the greater GLP1 receptor agonists (exenatide, liraglutide, albiglu
the weight gain, the greater the decrease in HbA1c tide, lixisenatide and dulaglutide) cause a pharmacological
and thegreater the improvements in insulin sensitiv increase in plasma GLP1 levels, markedly augment insulin
ity andcell function220,221. Concerns about the link secretion and inhibit glucagon secretion236,237. The increase
between bladder cancer and pioglitazone have been dis in the levels of plasma insulin and the decrease in those of
pelled by a 6year followup in the PROactive study 225 glucagon effectively suppress hepatic glucose production236
and a recently completed 10year US FDA-mandated and cause a durable reduction for up to 3years in
study 226. In a review of approximately onemillion people HbA1c237,238. GLP1 receptor agonists promote weight loss
from six populations, no increase in bladder cancer (resulting in improved insulin sensitivity), delay gastric
was observed with either pioglitazone (hazard ratio: emptying (which is accelerated in patients with new-onset
1.011.04) or rosiglitazone (hazard ratio: 1.001.01)227. diabetes), correct endothelial dysfunction, reduce blood
pressure, improve the plasma lipid profile and reduce
GLP1 modulators. T2DM is associated with severe GLP1 Creactive protein levels238,239. Combination therapy with
resistance in -cells60,228,229. Dipeptidyl peptidase 4 (DPP4) a GLP1 receptor agonist plus basal insulin has been shown
inhibitors (sitagliptin, saxagliptin, linagliptin, alogliptin to be very effective in reducing HbA1c while preventing
and vildagliptin) prolong the half-life of endogenously the weight gain associated with insulin therapy, without
secreted GLP1. As DPP4 inhibitors do not increase (only an increased risk of hypoglycaemia240. Nausea and vomit
prolong) plasma GLP1 levels, their ability to augment ing are the most common side effects with GLP1 receptor
insulin secretion and reduce HbA1c is modest230,231. Their agonists, but these are usually mild and dissipate within
primary effect to improve glycaemic control is mediated 48weeks. An increased incidence of pancreatitis has not
by inhibition of glucagon secretion and reduction in basal been observed in large healthcaredatabases234,235,241.
hepatic glucose production232. DPP4 inhibitors have an
excellent safety profile233. Concerns about pancreatitis have Targeting intestinal and renal glucose absorption. AGIs
not been substantiated in prospective trials233. Two large (acarbose and voglibose) slow the rate of carbohydrate
cardiovascular outcome studies have demonstrated a haz absorption in the intestine and increase meal-stimulated
ard ratio of 1.0 for the primary end point (MACE) for both GLP1 secretion. The HbA1clowering effect of AGIs is
alogliptin234 and saxagliptin235, although a 27% increase in modest and comparable to the effect of DPP4 inhibi
the incidence of hospitalization for congestive heart failure tors. In a review of 41RCTs in the Cochrane Database242,
was observed with saxagliptin compared with placebo. The AGIs reduced HbA1c by 0.8%, which is similar to the
results of TECOS (sitagliptin) and ELIXIR (lixisenatide) HbA1clowering effect of gliptins (0.70.8%) in two
presented at the ADA National Science Meeting (2015) different meta-analyses243,244. However, AGIs have been
also showed a hazard ratio of ~1.0 for the primary cardio shown to decrease the conversion of prediabetes to dia
vascular end point. Many cardiovascular outcome trials betes in the STOP NIDDM trial186. Adverse effects of
with the newer antidiabetic agents are ongoing, and results AGIs are related to the gastrointestinal tract (diarrhoea,
will be reported during the next 23years. abdominal pain, nausea and vomiting).

Table4 | Characteristics of major classes of currently available antidiabetic agents


Drugs Glycaemic Durability Mechanism of action Body CV risk CV safety Side effects
efficacy weight factors
(HbA1c)
Metformin No HGP Possibly beneficial212 GI and lactic acidosis
Sulfonylureas No Insulin secretion Neutral Possibly Hypoglycaemia
detrimental214,216
TZDs Yes Insulin sensitivity * Probably beneficial223 Fluid retention
(pioglitazone)
cell function Bone fractures
DPP4 inhibitors No Glucagon secretion Neutral Neutral Neutral234,235 None
Insulin secretion (weak)
SGLT2 Not known Glucosuria Unknown Genital mycotic infections
inhibitors
Glucotoxicity Volume-related
AGIs Not known Carbohydrate absorption Neutral Neutral Possibly beneficial 186
GI
GLP1 receptor Yes Insulin secretion Not known Nausea and vomiting
agonists
Glucagon secretion
Insulin Yes HGP Neutral Neutral257 Hypoglycaemia
Glucose uptake in muscle
, decreased; , increased; AGIs, -glucosidase inhibitors; CV, cardiovascular; DPP4, dipeptidyl peptidase 4; GI, gastrointestinal; GLP1, glucagon-like peptide1;
HbA1c, haemoglobin A1c; HGP, hepatic glucose production; SGLT2, sodium/glucose co-transporter 2; TZDs, thiazolidinediones. *The greater the weight gain,
thegreater the improvements in insulin secretion and insulin sensitivity. Requires increasing insulin dose. The number of arrows defines severity.

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PRIMER

Sodium/glucose cotransporter2 (SGLT2) inhibitors (sulfonylureas) and insulin254,255. According to the ADA,
(dapagliflozin, canagliflozin and empagliflozin) block hypoglycaemia is defined as a plasma glucose level of
glucose absorption in the proximal renal tubule245,246. <70mgperdl. Most cases are mild, but severe hypo
They decrease the maximum renal glucose reabsorp glycaemia (requiring third-party assistance for recov
tive capacity and, importantly, reduce the blood glucose ery) has been reported in 510% or more of individuals
threshold (to <40mgperdl) at which glucose spills into treated with sulfonylureas and insulin. Hypoglycaemia
the urine102. The increased glucose removal from the has been associated with myocardial infarction, ven
body via glucosuria leads to a reduction in plasma glu tricular arrhythmias, stroke and weight gain254256. In the
cose, which results in the amelioration of glucotoxicity, ACCORD study, the incidence of severe hypoglycaemia
with improved cell function and enhanced insulin and weight gain was 3.1% and 3.5%, respectively, in the
sensitivity as a consequence247,248. Their glucose-lowering intensively treated group, and the study was stopped early
efficacy is equivalent to that of metformin, and loss of because of an increased incidence of sudden death257.
calories in urine (4 calories per gram glucose) promotes Risk factors for hypoglycaemia include use of insulin or
weight loss of ~2.53.0kg 245. Because SGLT2 inhibitors sulfonylureas, missed meals, strenuous exercise, alcohol
also suppress sodium transport, they cause mild extra consumption, interaction with other drugs, advanced age
cellular volume depletion and reduce blood pressure and renal or hepatic disease.
(~56mmHg in systolic pressure and ~12mmHg in
diastolic pressure). Their glucose-lowering efficacy is off Cardiovascular comorbidities
set by: increased glucose absorption by SGLT1, which can Controversy has arisen about the optimal treatment
reabsorb ~3040% of filtered glucose following SGLT2 goal for hypertension in T2DM based on results of the
blockade249, and paradoxical stimulation of endogenous ACCORD trial258, which reported that targeting a systolic
glucose production associated with increased glucagon blood pressure of <120mmHg did not reduce the com
and reduced insulin secretion247,248. SGLT2 inhibitors can posite primary outcome of cardiovascular events and was
be combined with all antidiabetic medications, includ associated with more adverse events. This led to a reap
ing insulin. The efficacy of SGLT2 inhibitors is reduced praisal of optimal blood pressure levels to a less-stringent
when the estimated glomerular filtration rate declines to target of 140/90mmHg259. However, in ACCORD, patients
<4560mlperminper1.73m2. Adverse effects include targeted to a systolic blood pressure of <120mmHg experi
genital mycotic infections in female patients, balanitis in enced 40% fewer strokes258, and a meta-analysis of 40RCTs
uncircumcized male patients, urinary tract infections and (n=100,354 participants) reported that a 10mmHg
volume-related side effects in older patients and individ decrease in systolic blood pressure was associated with a
uals taking diuretics. Recently, cases of euglycaemic relative risk reduction (RRR) of 27% for stroke, 13% RRR
ketoacidosis have been described with SGLT2 inhibitors, for death, 12% RRR for coronary heart disease events, 13%
primarily in T1DM, but also in T2DM. The potential of RRR for retinopathy and 17% RRR for albuminuria260.
SGLT2 inhibitors to prevent diabetic nephropathy is Hyperglycaemia is a relatively weak risk factor for cardio
being studied250. Combined SGLT2 andSGLT1 inhibitor vascular disease in T2DM164, and the anti-atherogenic
therapy has considerable appeal. When SGLT2 is blocked, effect of HbA1c reduction might take >10years to mani
modest inhibition (~30%) of SGLT1 can increase gluco fest 165. Dyslipidaemia is a major risk factor for cardio
suria by ~80%249. Furthermore, 30% inhibition of gut vascular disease in T2DM, and hypercholesterolaemia
SGLT1 produces an acarbose-like effect, which further should be treated aggressively (TABLE2).
reduces HbA1c by 0.50.6%249.
Quality of life
Adding insulin. If oral or injectable antidiabetic agents T2DM imposes a substantial physical and psychological
fail to normalize HbA1c, patients with T2DM can be burden on patients, resulting in reduced health status
treated with insulin, but large doses (>80100 units per and QOL. The relationship between improvements in
day) are often required251. Combining insulin therapy HbA1c, reduced symptoms of hypoglycaemia and hyper
with thiazolidinediones or metformin can improve gly glycaemia, and enhanced QOL was clearly demonstrated
caemic control and enable insulin dose reduction. The more than 15years ago261. Since then, many classes
combination of GLP1 receptor agonists with basal insulin ofglucose-lowering medications and different typesof
therapy causes robust HbA1c reduction, while reducing insulin have been approved, but few comparative-
insulin dose and promoting weight loss252. Combining effectiveness studies exist to guide treatment choices on
SGLT2 inhibitors with insulin also effectively reduces the basis of patientcentred outcomes such asQOL262.
HbA1c, decreases insulin dose, promotes weight loss The complexity, burden and adverse effects of dia
and reduces hypoglycaemia253. In new-onset T2DM, betes therapies reduce QOL, satisfaction and adher
intensive insulin therapy 202,203 to reverse the metabolic ence to therapy, often leading to suboptimal glycaemic
decompensation, such as glucotoxicity and lipotoxicity, control. However, comparative longitudinal studies
has proved effective in maintaining glycaemic control assessing patient-centred outcomes are relatively rare.
(HbA1c ~6.0%) for long periods. Moreover, when they are used, assessments often lack the
measurement properties such as sensitivity, responsive
Hypoglycaemia ness and ability to detect changes that are meaningful to
Hypoglycaemia is a potential adverse effect of all patients263. As the number of approved diabetes treat
antidiabetic agents, especially insulin secretagogues ments increases, therapeutic decisions will be made on

NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 13

2015 Macmillan Publishers Limited. All rights reserved


PRIMER

Measurement domains
Biological and physiological Symptom status Functional status Health perceptions

Individual modiers
Genetic Personality and coping Cultural Environmental

Patient-centred measures
Mobility
Physical Pain intensity Social and
symptoms Activities of role function
Pathophysiological daily living Quality
mechanism Fatigue of life
Mental Emotional
impairments Memory loss Cognitive well-being
functioning
Assessment methods
Laboratory Remote clinical Electronic daily Questionnaires Web-based online
and imaging monitoring diaries and surveys communities

Figure 7 | Illustration of the four major concepts in patient-reported outcomes. The domains, individual modifiers
Nature Reviews | Disease Primers
and assessment methods for the multidimensional quality-oflife construct are shown in relation to selected
patient-centred measures.

the basis of outcomes such as QOL, satisfaction and Outlook


treatment adherence. Therefore, future diabetes research Long-term normalization of blood glucose levels in
should be designed to gather high-quality scientific evi T2DM depends on delaying or reversing failure of cell
dence of comparative treatment effectiveness on the basis function to ensure appropriate insulin secretion and on
of patient-centred outcomes. improving insulin resistance. New avenues for treatment
QOL is multifaceted and can be assessed using sev are currently in development268 and might, in combination
eral techniques (FIG.7). Effective measurement of patient- with existing drugs, bring change and enhance our ability
centred outcomes poses challenges for clinical researchers, to control glycaemia. Our ability to prevent and reverse
when deciding among the hundreds of available generic advanced microvascular and macrovascular complica
and disease-specific questionnaires (for example, see tions is limited, and new strategies, some currently under
PROQOLID (http://www.qolid.org/proqolid)). Although investigation, will be required to close thisgap(FIG.8).
QOL outcomes measured through structured, clinic-
based, self-administered questionnaires have been found to Insulin secretion
be responsive to the effects of therapeutic interventions Progression from altered glucose metabolism to overt
such as symptoms of diabetes, changes in HbA1c, adverse diabetes occurs as the reduction in cell mass and func
effects, weight changes and glycaemic variability 264,265 tion is further aggravated. Thus, an attractive intervention
they are artificially restrictive and typically undertaken is one that will halt the progressive decline in cell mass
in the clinic at relatively infrequent intervals. and function and prevent the need for exogenous insu
Using newer electronic and mobile computing techno lin replacement that otherwise follows1. Agents that sup
logies, monitoring QOL in real time is now feasible, and press inflammation, including IL1 blockers and salsalate
offers a more efficient and accurate way to collect data (apotent inhibitor of NFB), have shown some promise
and broaden the scientific assessment of QOL data to real- in improving glycaemic control and cell function143,269,270.
time surveillance and remote monitoring. Smartphones MicroRNAs play a pivotal part in the physiological and
and tablets are much more effective for reporting acute pathological processes involved in glucose metabolism
diabetes-related and treatment-related events such as by post-transcriptional regulation of gene expression.
hypoglycaemia, gastrointestinal symptoms, cognitive Particular microRNAs can regulate cell function271,
problems and sleep disturbances than older technolo exposing key regulatory signalling pathways involved in
gies266. Furthermore, they allow for dynamic question restoration of cell mass, and provide a promising strat
naires, bridging the gap between more-sensitive but egy for improving insulin secretion and cell health in
more-burdensome longer static questionnaires and T2DM. Identification of novel insulin secretagogues
less-sensitive but less-burdensome shorter forms by that act directly on cells and enteroendocrine Kcells
using item response theory and computer adaptive test and Lcells in the intestine are under investigation, and
ing 267. Most recently, big data methods have been used members of the Gprotein-coupled class of receptors have
in patient-centred outcomes research for analysing elec shown promise272. GLP1 receptor agonists induce cell
tronic health records, web-based, crowd-sourced social proliferation in rodents273, but studies in humans have not
media databanks, and intensively longitudinal, electronic demonstrated a similar effect237. A series of novel signal
remote patient-monitoring databases transmitted through ling pathways have been reported to be strongly associated
glucose, blood pressure, weight and activity devices. These with cell mass restoration. For example, the PI3K PKC
methods provide promising research opportunities for pathway has been shown to augment glucose-mediated
capturing patient functioning and feelings in real time cell proliferation, and activation of PKC may provide
and in real-life environments. a novel approach to increase human cell proliferation274.

14 | 2015 | VOLUME 1 www.nature.com/nrdp

2015 Macmillan Publishers Limited. All rights reserved


PRIMER

Glucose-stimulated insulin secretion However, multiple glucokinase activators have failed


Mitochondrial metabolism is essential for normal cell because of lack of efficacy or adverse effects280. Glucagon
function275. APPL1 proteins are reported to influence receptor antagonists have shown good clinical efficacy,
mitochondrial function and cells by maintaining the although cell hyperplasia and increased levels of
expression of several key genes involved in mitochondrial hepatic aminotransferases may limit their usefulness281.
biogenesis276. APPL1 also contributes to the regulation of Gluconeogenic inhibitors have shown some efficacy282284,
both first and second phases of glucose-stimulated insulin but safety issues (hypoglycaemia and lactic acidosis) are
secretion276 and therefore has potential as a therapeutic a concern.
target for antiT2DM drug discovery. Other agents that Islet transplantation faces many hurdles285, but encap
improve mitochondrial function, including the regulators sulated islets hold promise286. The practicality of trans
of NAD-dependent protein deacetylase sirtuin1, peroxi forming stem cells into insulin-secreting cells that are
some proliferator-activated protein kinase and uncoupl responsive to glucose287 is a long way off. The creation of
ing protein2 (UCP2), may prove to be effective in the stem cells that imitate natural healthy cells represents
therapeutic intervention of T2DM277279. another option287. However, the concept that stressed
Glucokinase is a key therapeutic target and serves as cells in patients with diabetes dedifferentiate into other
the glucose sensor and glycolysis activator in cells. islet cells raises hopes for reversing thisprocess288.

Intestine Brain Kidney


K and L
enteroendocrine Bariatric surgery
cells
Bile acid
sequestrants

Microbiome
Microbiome mediators
(probiotics)
Fusion proteins (GLP1 with
Metformin FGF21, glucagon, GIP and PYY)
Lower bowel Appetite suppressants SGLT2 and SGLT1 inhibitors
delayed release

Muscle Liver

FGF1 MPC1 and MPC2 inhibitors FGF1 PDHK2 Acetyl-CoA inhibitors


PDHK4 inhibitors PTP1B inhibitors FGF21 inhibitors Glucagon receptor antagonist
Anti-inammatory MicroRNA modulators FXR ligands Obeticholic acid Glucokinase activator
agents AMPK activation AMPK Gluconeogenic Glycogen synthase activator
PPAR modulators Imeglimin activators inhibitors Glycogen phosphorylase inhibitors

Pancreas Adipose tissue Cell

-cell
Nucleus
-cell Mitochondrion
Glucagon
inhibitors
GLP1 MPC1
DAG MicroRNA and MPC2
Glucokinase activators Glucose-responsive PPAR modulators inhibitors
New GLP1 receptor insulin analogues Anti-inammatory VCP2
agonists Closed-loop agents DGAT1 activators
Sirtuin activators insulin delivery PGC1 activators and DGAT2 MicroRNA AMPK
-cell activation Stem cells AMPK activators inhibitors silencing activators

Figure 8 | Potential therapeutic targets in T2DM management. Schematic representation of the different targets in
Nature Reviews | Disease Primers
type 2 diabetes mellitus (T2DM) organized per tissue. AMPK, AMP-activated protein kinase; DAG, diacylglycerol; DGAT,
DAG acyltransferase; FGF, fibroblast growth factor; FXR, farnesoid X nuclear receptor; GIP,gastric inhibitory polypeptide;
GLP1, glucagon-like peptide 1; MPC, mitochondrial pyruvate carrier; PDHK, pyruvate dehydrogenase kinase; PGC1,
PPAR coactivator1; PPAR, peroxisome proliferator-activated receptor-; PTP1B, protein tyrosine phosphatase 1B;
PYY,peptide YY; SGLT, sodium/glucose co-transporter; VCP2, viral citrullinated peptide 2.

NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 15

2015 Macmillan Publishers Limited. All rights reserved


PRIMER

In patients with T2DM who have minimal cell and bile acid sequestrants309 might prove to be useful in
reserves, intensive continuous subcutaneous insulin infu treating T2DM. Novel fusion proteins, including GLP1
sion has proved to be very effective289. In contrast to the with fibroblast growth factor21, glucagon, GIP or pep
accuracy needed for insulin delivery in insulin-sensitive tideYY, which promote weight loss and enhance insulin
T1DM, the larger doses of insulin and underlying insu sensitivity in rodents, are in development310. Inhibitors of
lin resistance in T2DM enable the use of much simpler protein tyrosine phosphatase 1B, a cytosolic non-receptor
pump devices. Hopefully, this will result in the introduc PTPase that has been implicated as a negative regulator
tion of less-sophisticated and low-price pumps into the of insulin signal transduction, have received interest 311.
market. Conversely, closed-loop insulin delivery systems Several microRNAs are upregulated in diabetes and
that consist of an insulin pump that delivers insulin based obesity, and their silencing improves insulin sensitivity312.
on an algorithm whose inputs are derived from a con Specific microbiome profiles render individuals prone
tinuous glucose monitor are advancing quickly in clini to develop obesity and altered glucose metabolism313. The
cal studies289,290, and this might be an attractive option ability to identify protective microbiome profiles might
for insulin-dependent, poorly controlled T2DM. Insulin provide a key to the development of obesity and diabe
administration via injection is a limiting factor for its tes interventions. It remains to be determined whether
broader use. Inhaled insulin with improved pharmaco specific dietary components are involved in microbiome
kinetic and pharmacodynamic profiles makes this option changes and induce unfavourable transitions. Probiotics
more appealing to patients291. Another attractive option is or pharmacological manipulation of microbiome ele
oral insulin, which is currently in clinical trials and hope ments that favour more healthy flora may prove to be
fully will mature into a simple and safe alternative for useful in stemming the twin epidemics of obesity and
insulin delivery 292. T2DM313. Surgical rearrangement of the gastrointestinal
tract has shown remarkable efficacy in treating obese
Insulin sensitivity patients with T2DM307,314. Development of minimally
There is a major need for novel insulin-sensitizing agents, invasive reversible procedures, such as the duodenal
and many new agents show promise in humans. New sleeve and temporary mucosal barriers, might replace
metformin preparations target the lower bowel, effec surgery in the nearfuture.
tively reducing HbA1c while minimizing metformin
exposure293. In addition, selective PPAR modula Comorbidities
tors have shown some efficacy as insulin sensitizers294. There is great need to address short- and long-term dia
Compounds targeting mitochondrial proteins (mito betic complications. The most promising therapy for
chondrial pyruvate carrier 1 (MPC1) and MPC2) have the near future is the use of drug combinations (dual or
shown efficacy 295. Derivatives of fibroblast growth fac triple) that address the pathophysiological abnormalities
tor1 improve hepatic and muscle insulin sensitivity in responsible for cell dysfunction and insulin resistance
animals296 and reduce plasma glucose levels in patients and that normalize plasma glucose levels198200 (FIG.3). The
with T2DM297. Inhibitors of pyruvate dehydrogenase optimal candidates for this therapy are patients at the very
kinase 4 (PDHK4) increase pyruvate oxidation in early stage of their disease or at the prediabetesstate7.
muscle and reduce the supply of gluconeogenic precur Hypoglycaemia remains a critical barrier for intensi
sors (lactate and alanine) to the liver, whereas inhibition fication of care, especially in patients who require insu
of PDHK2 in the liver decreases gluconeogenesis298. lin, and poses serious immediate and long-term risks.
Imeglimin, the first member of a new tetrahydrotriazine- Continuous glucose monitoring with pre-set alarms
containing class of oral antidiabetics (glimins), has mod and use of therapeutic agents or regimens that minimize
est HbA1clowering efficacy and augments both insulin the risk of hypoglycaemia are available options. A self-
sensitivity and insulin secretion299,300. UCP2 activators regulating insulin that is responsive to blood sugar levels
have similarly been shown to improve hepatic and muscle (SmartCells) is currently under development.
insulin sensitivity in rodents. Treatment of established microvascular complica
Accumulation of toxic lipid metabolites (DAG, fatty tions remains a major unmet need. Anti-VEGF (vascu
acid acyl-CoAs and ceramides) in muscle and the liver lar endothelial growth factor) therapy has changed the
causes severe insulin resistance. Inhibitors of DAG acyl outcome in many patients with advanced retinopathy,
transferase1 (DGAT1) and DGAT2 have yielded con but more novel therapies are needed. Cpeptide replace
flicting results301,302. Blockade of denovo lipogenesis with ment therapy 315 and ocular inhibition of kallikreins
inhibitors of acetyl-CoA carboxylase reduces liver fat and and kinin receptor antagonists offer new therapeutic
increases hepatic insulin sensitivity in preclinical stud avenues316. Angiotensin-converting enzyme inhibitors
ies303. Liver-targeted mitochondrial uncouplers have been and angiotensin II receptor blockers slow progression of
shown to reduce liver fat and content and improve insu nephropathy but do not reverse it317. Endothelin inhibi
lin sensitivity in mice304,305. Weight loss drugs (topiramate tors or agents that prevent AGE accumulation are in
and phentermine extended-release, lorcaserin, bupro PhaseIII studies for prevention of microvascular compli
pionand naltrexone, and high-dose liraglutide) promote cations318,319. SGLT2 inhibitors also are being investigated
fat removal from muscle and the liver and improve insu for the prevention of diabetic nephropathy 250. Although
lin sensitivity and glycaemic control in T2DM306. Bariatric we have agents that can ameliorate symptoms of diabetic
surgery provides long-term remission of T2DM307. The neuropathy, there is a need for molecules that will prevent
farnesoid X nuclear receptor ligand obeticholic acid308 its development and progression.

16 | 2015 | VOLUME 1 www.nature.com/nrdp

2015 Macmillan Publishers Limited. All rights reserved


PRIMER

Cardiovascular morbidity and mortality, the major cardiovascular risk in T2DM remain obscure. As T2DM
cause of death in T2DM, is increased twofoldthreefold is an inflammatory disease, an anti-inflammatory
in patients with T2DM320. Hyperglycaemia is a weak approach initiated early in combination with normali
risk factor for cardiovascular disease, and the factors zation of cardiovascular risk factors17 before the clini
(other than hypertension, dyslipidaemia and enhanced cal appearance of macrovascular disease may prove to
coagulation) that are responsible for the increased beeffective.

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insulin secretion and improves cell function in 315. Bhatt,M. P., Lim,Y.-C. & Ha,K.-S. Cpeptide Squibb, Janssen; Speakers Bureau - AstraZeneca, Novo
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304. Tao,H., Zhang,Y., Zeng,X., Shulman,G.I. & Jin,S. with type2 diabetic nephropathy. J.Am. Soc. Nephrol. and is a consultant/advisory board member for Glaxo, Smith,
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mitochondrial uncoupling improves diabetic 320. Boussageon,R. etal. Effect of intensive glucose M.A.T. has no conflict of interest; (9) R.W. serves as a
symptoms in mice. Nat. Med. 20, 12631269 lowering treatment on all cause mortality, consultant for Medtronics and Kamada and is on the
(2014). cardiovascular death, and microvascular events speakers bureau for Medtronics and Novo Nordisk; (10) F.H.
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targeted mitochondrial uncoupler. Cell Metab. 18, 321. Colditz,G.A., Willett,W.C., Rotnitzky,A. advisory boards for Merck and Novartis and he has received
740748 (2013). &Manson,J.E. Weight gain as a risk factor for clinical research grant support from Gilead Pharmaceuticals; (12)
306. Garvey,W.T. etal. Two-year sustained weight loss diabetes mellitus in women. Ann. Intern. Med. 122, D.C.S. has no conflict of interest; (13) I.R. Advisory Board:
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