Seminar

Type 2 diabetes across generations: from pathophysiology to prevention and management

Christopher J Nolan, Peter Damm, Marc Prentki

Type 2 diabetes is now a pandemic and shows no signs of abatement. In this Seminar we review the pathophysiology of this disorder, with particular attention to epidemiology, genetics, epigenetics, and molecular cell biology. Evidence is emerging that a substantial part of diabetes susceptibility is acquired early in life, probably owing to fetal or neonatal programming via epigenetic phenomena. Maternal and early childhood health might, therefore, be crucial to the development of eective prevention strategies. Diabetes develops because of inadequate islet -cell and adipose-tissue responses to chronic fuel excess, which results in so-called nutrient spillover, insulin resistance, and metabolic stress. The latter damages multiple organs. Insulin resistance, while forcing cells to work harder, might also have an important defensive role against nutrient-related toxic eects in tissues such as the heart. Reversal of overnutrition, healing of the cells, and lessening of adipose tissue defects should be treatment priorities.

Lancet 2011; 378: 16981 Published Online June 25, 2011 DOI:10.1016/S01406736(11)60614-4 Department of Endocrinology, Canberra Hospital and Australian National University Medical School, Canberra, ACT, Australia (C J Nolan FRACP); Centre for Pregnant Women with Diabetes, Department of Obstetrics, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark (Prof P Damm DMSc); and CRCHUM and Montreal Diabetes Research Center and Department of Nutrition and Department of Biochemistry, University of Montreal, QC, Canada (Prof M Prentki PhD) Correspondence to: Assoc Prof Christopher J Nolan, Department of Endocrinology, Canberrra Hospital, PO Box 11, Woden, ACT 2606, Australia. christopher.nolan@anu.edu.au

Introduction
Type 2 diabetes mellitus is a metabolic disorder of fuel homoeostasis characterised by hyperglycaemia and altered lipid metabolism caused by islet cells being unable to secrete adequate insulin in response to varying degrees of overnutrition, inactivity, consequential overweight or obesity, and insulin resistance. The burden of this disorder is enormous, owing to its rapidly increasing global prevalence, the devastating damage it can do to many organs of the body, and the direct and indirect costs. In this Seminar we discuss developments in the understanding of the pathogenesis of type 2 diabetes from epidemiology, genetics, epigenetics, and molecular cell biology, with emphasis on the emerging role of fetal and neonatal programming, and we underscore the need for a whole-of-life approach to prevention and management.

Epidemiology
A growing non-communicable disease epidemic
The estimated worldwide prevalence of diabetes among adults was 285 million (64%) in 2010, and this value is predicted to rise to around 439 million (77%) by 2030 (table 1).1 Type 2 diabetes is the predominant form and accounts for at least 90% of cases.2 The rise in prevalence is predicted to be much greater in developing than in developed countries (69% vs 20%).1 In developing countries people aged 4060 years (ie, working age) are aected most, compared with those older than 60 years in developed countries.1 This increase in type 2 diabetes is inextricably linked to changes towards a western lifestyle (high-energy diets with reduced physical activity) in developing countries and the rise in the prevalence of overweight and obesity.3,4

however, become greater than that of type 1 diabetes in some ethnic groups, as seen in the USA (121 vs 74 per 100 000 in Asians and Pacic Islanders aged 20 years, and 190 vs 157 per 100 000 in African Americans aged 019 years).8,9 In young people type 2 diabetes associated with obesity frequently remains undiagnosed and is dicult to manage.5 The younger ages at which type 2 diabetes is seen also translates into an increasing number of pregnant women being aected, many of whom are not diagnosed before pregnancy.10,11 Outcomes of pregnancy related to type 2 diabetes are at least similar to or possibly worse than those related to type 1 diabetes, with rates of congenital malformations and perinatal death being high.1214 Poor awareness among health professionals of the risks prompted the International Association of Diabetes in Pregnancy Study Groups (IADPSG) consensus panel on the classication of hyperglycaemic disorders in pregnancy to advise testing women early in pregnancy for overt diabetes.11

The burden of type 2 diabetes: complications and excess mortality

The excess global mortality in 2000 attributable to diabetes overall, most of which was attributable to type 2 diabetes, was 29 million (52%) deaths.15 In 2004, heart disease and stroke were reported on 68% and 16%, respectively, of diabetes-related death certicates in the
Search strategy and selection criteria We searched PubMed with the terms type 2 diabetes, prediabetes, gestational diabetes, obesity, insulin secretion, islet beta-cell dysfunction, beta-cell failure, insulin resistance, epidemiology, susceptibility genes, epigenetics, fetal origins of adult disease, diabetes complications, oral hypoglycaemic agents, incretin therapy, insulin therapy, and combinations of these terms. We selected English language original and review articles mainly published between 2008 and 2011.

Type 2 diabetes in youth and pregnancy

Until 1990, type 2 diabetes was seldom seen in young people and in pregnant women, but this is no longer the case.5,6 In some countries type 2 diabetes is still rare in children and adolescents, for instance in Germany, where prevalence is 23 per 100 000 in people aged 020 years.7 The incidence of type 2 diabetes in young people has,
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2010 Number of adults with diabetes (million) Africa EMME Europe North America South and Central America Southeast Asia West Pacic Worldwide 121 266 554 374 180 587 767 2848 Prevalence (%)*

2030 Number of Prevalence adults with (%)* diabetes (million) 239 517 665 532 296 1010 1128 4387 47% 108% 81% 121% 78% 91% 57% 77%

Percentage increase in number

38% 93% 69% 102% 66% 76% 47% 64%

981% 939% 200% 424% 651% 721% 470% 541%

that a glycated haemoglobin A1c (HbA1c) concentration of 65% or higher can be used to diagnose diabetes.21,22 The committees assessed data that examined the relation between prevalence of diabetes complications, in particular retinopathy, and HbA1c concentrations.21,23 WHO also analysed the DETECT-2 collaboration data of gradable retinal photographs and markers of glycaemic control from 44 623 participants across nine studies (gure 1).21,24 Various international professional bodies and health authorities are considering and adopting these recommendations.

Pathophysiology
A brief overview of normal glucose homoeostasis is presented in gure 2.

Adapted from reference 1 with permission of Shaw and colleagues.1 EMME=Eastern Mediterranean and Middle East. *For each region values are standardised to world age distribution for that year.

Type 2 diabetes: a failure to contain a chronic fuel surfeit

Chronic fuel surfeit is the primary pathogenic event that drives the development of type 2 diabetes in genetically and epigenetically susceptible people.25,26 Many chronically overnourished and overweight or obese individuals, however, do not develop diabetes at all or develop it very late in life. They remain resistant to type 2 diabetes and safely partition excess calories to subcutaneous adipose tissue (SAT) rather than to the heart, skeletal muscle, liver, and islet cells (gure 3), owing to the following mechanisms: successful islet -cell compensation; maintenance of near-normal blood nutrient concentrations; development of minimal insulin resistance; increased expansion of SAT relative to visceral adipose tissue (VAT); and limited increase in liver fat.27,28 In this way, key organs of the body avoid nutrient-induced damage. Susceptible overnourished individuals develop type 2 diabetes owing to the failure of these adaptive responses to safely dispose of the fuel surfeit (gure 3). The following metabolic defects are crucial to the development of type 2 diabetes: inability of islet cells to compensate for the fuel surfeit; increased glucagon secretion and reduced incretin response; impaired expansion of SAT, hypoadiponectinaemia, and inammation of adipose
IFG and IGT (WHO)* NA IFG 61 and <70 IGT 2 h, 78 and <111 NA Prediabetes (ADA)* 57% and <65% 56 and <70 2 h, 78 and <111 NA GDM and ODP (IADPSG) ODP, 65% GDM, 51, ODP 70 GDM, 1 h 101 2 h, 85 ODP, 111

Table 1: Estimated numbers of adults aged 2079 with any type of diabetes mellitus and prevalence, by region, in 2010 and 2030

USA.16 Furthermore, diabetes is the leading cause of blindness among adults aged 2074 years, and leads to around 44% of end-stage renal failure and 60% of non-traumatic lower-limb amputations in the USA.16 The pattern of complications in Asian populations diers from that in white populations, with more deaths among Asians being attributed to strokes and renal failure.3 Type 2 diabetes is also associated with nonalcoholic fatty liver disease, including non-alcoholic steatohepatitis, polycystic ovarian syndrome, and possibly some malignancies.1720

Diagnosis
Recommendations for diagnostic strategies and criteria for hyperglycaemic disorders, including diabetes, in the general population as well as in pregnant women, have been revised and issued by WHO, the American Diabetes Association (ADA), and the IADPSG (table 2; for a more detailed discussion see webappendix p 1).11,21,22 Of particular note, WHO and ADA have both recommended
Diabetes (WHO and ADA)* HbA1c (%) Fasting plasma glucose (mmol/L) 75 g OGTT post-load plasma glucose (mmol/L) Random glucose (mmol/L) 65% 70 2 h, 111 111 with classic symptoms

See Online for webappendix

ADA=American Diabetes Association. IFG=impaired fasting glucose. IGT=impaired glucose tolerance. GDM=gestational diabetes mellitus. ODP=overt diabetes in pregnancy. IADPSG=International Association of Diabetes in Pregnancy Study Groups. HbA1c=glycated haemoglobin A1c. NA=not applicable. OGTT=oral glucose tolerance testing. *While WHO and ADA diagnostic criteria for diabetes are identical, the approaches to assessment of intermediate hyperglycaemia or prediabetes dier.21,22 Fasting blood sugar of 51 mmol/L and <70 mmol/L at any time of pregnancy is diagnostic of GDM. The usual time of OGTT in pregnancy for GDM is 2428 weeks gestation.11 Screening for ODP by measurement of HbA1c, fasting plasma glucose, or random blood glucose concentration is recommended for the rst antenatal visit. Elevated random plasma glucose values need to be conrmed.11 In the absence of unequivocal hyperglycaemia, results should be conrmed with retesting.

Table 2: Diagnostic criteria for diabetes, IFG, IGT, prediabetes, and gestational diabetes

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16 Prevalence of diabetes-specic retiniopathy (%) 14 12 10 8 6 4 2 0 0 FPG (mmol/L) 2 h PG (mmol/L) HbA1c (%)

FPG 2 h plasma glucose HbA1c

1 17 11 31

2 45 43 46

3 47 49 47

4 48 53 49

5 49 57 50

6 51 60 50

7 52 63 51

8 52 66 52

9 53 69 53

10 11 Vigintile 54 72 53 55 77 54

12 56 80 55

13 57 85 56

14 58 91 57

15

16

17

18

19

20

60 62 64 69 77 101 98 107 119 134 159 199 58 59 61 63 68 79

Figure 1: Prevalence of diabetes-specic retinopathy (moderate to severe) by distribution of FPG, 2 h plasma glucose, and HbA1c concentrations Each vigintile includes individuals with a glycaemia range from the number stated to just below that of the next. FPG=fasting plasma glucose. PG=plasma glucose. HbA1c=glycated haemoglobin A1c. Reproduced from Colagiuri S et al, with permission of Elsevier.24

tissue; increased endogenous glucose production; and development of peripheral insulin resistance.25,26,2934 Importantly, the fuel surfeit is not safely deposited into SAT, such that it has to be disposed of elsewhere. The elsewhere is less healthy VAT and ectopic storage in organs, such as the liver, heart, skeletal muscle, and pancreas, which causes widespread tissue damage.30 Worsening islet -cell function can lead to the need for insulin therapy.

Genetic and environmental factors

Although the main metabolic defects of type 2 diabetes are present to some degree in most patients, this disorder is highly heterogeneous. Many dierent susceptibility genes have been identied that interact with environmental factors, during gestation, early childhood, and later in life.3,25,3540

Genes
The heritability of type 2 diabetes is high (estimated to be >50%), as indicated by the high concordance rates in monozygotic twins and the notably raised risk in individuals with aected rst-degree relatives.36,4147 Twin studies need to be considered carefully, however, as the intrauterine environments of dizygotic-twin (separate placentas), monozygotic-twin (6070% share one placenta), and singleton pregnancies (one placenta without competition for maternal nutrients) will all be dierent, and this can be a confounder in the interpretation of eects.44 A large study from Sweden on familial risk of type 2 diabetes showed that the relative risks were highest in individuals with at least two aected siblings, irrespective of parental diabetes status.42 This nding
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suggests that a recessive pattern of inheritance from uncommon genetic defects, the sharing of similar intrauterine, postnatal, or both environments by siblings (eg, breastfeeding or bottle feeding or childhood nutrition), or a combination of these factors is important. Genome-wide association studies have helped to raise the number of conrmed diabetes-associated loci to more than 40.36,38,4850 A greater number of these loci are associated with impaired -cell function (KCNJ11, TCF7L2, WFS1, HNF1B, SLC30A8, CDKAL1, IGF2BP2, CDKN2A, CDKN2B, NOTCH2, CAMK1D, THADA, KCNQ1, MTNR1B, GCKR, GCK, PROX1, SLC2A2, G6PC2, GLIS3, ADRA2A, and GIPR) than impaired insulin sensitivity (PPARG, IRS1, IGF1, FTO, and KLF14) or obesity (FTO).38,48,50 Of these, TCF7L2 is the strongest susceptibility locus for type 2 diabetes, being associated with -cell dysfunction.48 Most patients with monogenic forms of diabetes also have gene defects that aect islet -cell function.51,52 Nevertheless, only around 10% of the heritability of type 2 diabetes can be explained by susceptibility loci identied so far, with each locus having a low eect size.36 The remaining heritability might be related to a large number of less common variants (allele frequency <5%) that are dicult to nd with current approaches of genome-wide association studies, and/or epigenetic phenomena.

Early-life environment: fetal and neonatal programming and epigenetic eects

Strong epidemiological and experimental evidence indicates a link between intrauterine growth restriction and adult diseases, such as obesity, hypertension, type 2 diabetes, and cardiovascular disease.44,53 The evidence that
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Fasted Insulin secretion Glucagon secretion Insulin-independent tissues Brain Islets Gut Blood glucose ~4 mmol/L EGP Muscle Liver Insulin-dependent tissues Fat

Glucagon

Fed Insulin secretion Glucagon secretion Insulin-independent tissues Brain Islets Gut Insulin EGP Muscle Liver Insulin-dependent tissues Blood glucose increased Insulin Fat

GLP-1

Insulin

diabetes, adjusted odds ratios were raised for prediabetes or type 2 diabetes in the ospring of women who had gestational diabetes treated by diet (78, 95% CI 26234) or who had type 1 diabetes during pregnancy (40, 131123) at age 22 years.58 The eect of maternal type 1 diabetes was greatest if hyperglycaemia was present in the third trimester (odds ratio per mmol/L glucose 141, 95% CI 104191) and, therefore, the hyperglycaemic intrauterine environment is strongly implicated in the pathogenesis of type 2 diabetes.58 Of potential importance is the nding that vitamin B12 deciency during pregnancy, particularly in women replete for folic acid, has been associated with the development of childhood adiposity and insulin resistance in India.59 Evidence also suggests that breastfeeding is protective against the development of type 2 diabetes before age 21 years.60 Fetal and neonatal programming has been a major area of research activity, with particular interest being paid to the role of epigenetics and fetal origins of adult disease.35,61 Strong evidence from animal studies indicates that early life programming can aect neurohormonal weight control networks and development of pancreatic islets.6264 A glossary of terms relating to this new important eld of epigenetics is provided in panel 1.

Ongoing environmental factors

A westernised lifestyle, which involves a high-energy diet and reduced physical activity, is indisputably linked to the pandemics of obesity and type 2 diabetes. Rates of overweight, obesity, and diabetes rise sharply in populations that move from traditional rural to urban environments.3,39,40,65 Dietary changes are typically from unprocessed, low-energy, high-bre foods to processed, energy-dense foods characterised by high sugar and fat contents.3,6567 Mismatch of epigenetic regulation for a life of low-energy intake when born into a traditional setting with a subsequent high-energy intake associated with the transition to an urban setting may place the transitioning generation at particularly high risk of type 2 diabetes.3,35 Micronutrient imbalances, including deciency in concentrations of vitamin D, vitamin B12 in individuals replete with folic acid, and increased body iron stores have been implicated in the pathogenesis of type 2 diabetes.59,68,69 Evidence also suggests that exposure to synthetic organic pollutants (eg, pesticides and plasticisers) aects endocrine cells and increases the risk of developing type 2 diabetes.70 The gut microbiota, which can be inuenced by events in early life, such as methods of delivery and feeding, and by later life by factors such as use of antibiotics and diet composition, might also contribute to increased risk of type 2 diabetes.71 A potential role for probiotics to alter the gut microbiota in benecial ways is being intensively investigated.71 Increased use of technologies to reduce energy expenditure, including cars, and raised television viewing
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Figure 2: Overview of normal glucose homoeostasis In the fasting state blood glucose concentration is determined by the balance between EGP production, mainly through hepatic glycogenolysis and gluconeogenesis, and use by insulin-independent tissues, such as the brain. EGP prevents hypoglycaemia and is supported by a low insulin-to-glucagon ratio in plasma. The brain is dependent on glucose and, therefore, other tissues, such as heart and skeletal muscle, are mainly provided with non-glucose nutrients (eg, non-esteried fatty acids from adipose tissue lipolysis). In the fed state (meal with carbohydrate) glucose concentrations in the blood rise because of absorption in the gut, which stimulates insulin secretion by islet cells and suppresses glucagon secretion from cells. EGP is suppressed (which helps to curtail total glucose input into blood) and uptake into insulin-sensitive peripheral tissues, such as the heart, skeletal muscle, and adipose tissue is activated (which increases the rate of glucose disposal). Neurohormonal processes include the release of the incretin hormones, such as GLP-1, which increases glucose-stimulated insulin secretion and glucose-suppression of glucagon secretion. Adipose tissue lipolysis is suppressed and anabolic metabolism is promoted. Glucose concentrations become close to the fasting level within 2 h. GLP-1=glucagon-like peptide 1. EGP=endogenous glucose production.

gestational or overt diabetes in pregnancy can aect diabetes risk in ospring is limited but highly suggestive.54 In longitudinal studies of Pima Indians, among whom the prevalence of obesity-associated type 2 diabetes is very high, ospring of mothers with established disease during pregnancy develop type 2 diabetes earlier than those born to mothers without diabetes.37,55,56 Furthermore, obesity and type 2 diabetes were more frequent among siblings born to the same mother after she developed diabetes.37 In the multiethnic SEARCH for Diabetes in Youth Study, a diagnosis of type 2 diabetes was made at a younger age in children of mothers who had diabetes during pregnancy than of those without diabetes.57 Lastly, in a Danish study, compared with the ospring of mothers without
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times contribute to sedentary lifestyles, which are strongly associated with overweight, obesity, and type 2 diabetes.3,72 Low socioeconomic status and depression also aect risk.73,74 Sleep deprivation and obstructive sleep apnoea are strongly associated with obesity and type 2 diabetes and might have pathogenic roles.75

Resistant Overnutrition, inadequate exercise Chronic fuel surfeit

Susceptible Overnutrition, inadequate exercise Chronic fuel surfeit

Robust islet cells Adequate -cell compensation Normal -cell function

Susceptible islet cells Failed -cell compensation Increased -cell glucagon secretion

Molecular mechanisms: a brief overview Neurohormonal weight control networks

Dysfunction of the mechanisms that control the bodys energy balance and weight and cause overweight and obesity is of major importance in type 2 diabetes pathogenesis. This dysfunction occurs within the complex neurohormonal weight control network of the body in which central signals (from the brainstem and higher cortical centres, eg, cognitive, visual, and other reward cues) and peripheral signals of energy stores (from adipose tissue eg, leptin) or related to hunger (from the gut, eg, ghrelin) and to satiety (from gut and pancreas, eg, vagal aerent neural signals, cholecystokinin, glucagon-like peptide 1 [GLP-1], insulin, and nutrient levels) feed into the hypothalamus and other key areas in the CNS to control appetite, physical activity, and bodyweight.76,77 This network is also highly regulated by the circadian clock, which supports a pathophysiological link between sleep disorders, obesity, and type 2 diabetes.75 Obesity is associated with resistance to the central actions of leptin and insulin.77 Monogenic forms of obesity with severe phenotypes do exist (eg, owing to mutations in LEP, LEPR, MC4R, and POMC), but are uncommon (<5% of all obesity).51 The heritability of obesity is, however, very high, and genome-wide association studies so far have identied 32 common variant loci, yet these only explain an estimated 145% of the variance in body-mass index.78 The identication of rare genetic variants or epigenetic causes is, therefore, necessary to further understand the strong heritability. Hypothalamic weight-control neurons do seem to be notably aected by the environment in early life.62,63 For instance, epigenetic alteration of the regulatory set point for expression of the POMC gene by hypermethylation has been reported in rats overfed early in life.63

Maintenance of normal blood nutrient levels

Elevated nutrient concentrations Postprandial hyperglycaemia

SAT expansion predominates VAT expansion minimal

SAT expansion restricted VAT expansion predominates Hypoadiponectinaemia Inammatory cytokines production

Normal hepatic glucose production Limited liver fat accumulation

Elevated glucose production Hepatic insulin resistance NAFLD/NASH

Normal or minimally impaired insulin sensitivity

Muscle nutrient overload Insulin resistance

Normal ovulation

Polycystic ovarian syndrome Abnormal ovulation

Healthy overweight individual

Type 2 diabetes and complications

Figure 3: Pathway to type 2 diabetes and related complications Complex interactions between the environment early and later in life and the neurohormonal weight control network, especially in the brain, lead to chronic fuel surfeit, which drives the development of type 2 diabetes. Overnourished diabetes-resistant individuals are able to safely contain a chronic fuel overload due to robust islet cells that are able to sustain adequate compensatory insulin secretion as required, and by healthy expansion of SAT. In this way, blood nutrient levels are maintained within the normal range and other tissues, such as the liver, skeletal muscle, heart, and ovaries, are not damaged. In diabetes-susceptible individuals the chronic fuel surfeit is not contained due to islets that are susceptible to failure if overworked and adipose tissue that develops an abnormal phenotype when stressed. The combination results in so-called nutrient spillover into non-adipose tissues and raised concentrations of inammatory cytokines in plasma, which lead to stress and injury in multiple tissues, including the liver, skeletal muscle, heart, and ovaries. Type 2 diabetes eventually develops, which aggravates nutrient-induced tissue injury, including that to the pancreatic islets. The relative contributions of islet cells and adipose tissue to the disease phenotype depends on the underlying mix of genetic and acquired tissue susceptibilities (including epigenetic) of the individual. SAT=subcutaneous adipose tissue. VAT=visceral adipose tissue. NAFLD=non-alcoholic fatty liver disease. NASH=non-alcoholic steatohepatitis.

Islet cells
In human beings islet cells are vulnerable to nutrientinduced damage and, therefore, contribute notably to the development of type 2 diabetes.25,31,33,34 cells have to: maintain synthesis of proinsulin with correct posttranslational modication; ensure secretory granules are ready for secretion; sense nutrient concentrations in blood, mostly via intracellular metabolism with the production of nutrient-secretion coupling factors (gure 4); sense other neurohormonal signals; and appropriately execute insulin granule release via activation of a complex exocytosis machinery. The mechanisms underlying -cell failure, therefore, can be many, varied, and complex.25,26,3234,79 Islet -cell dysfunction
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generally occurs when compensation is required for fuel excess, which can mean that minor deciencies become important.25,80 We have proposed that it is the mix of -cell susceptibility factors that determines the initial mechanism of damage, but that once substantial hyperglycaemia has developed, glucotoxic and glucolipotoxic mechanisms ensue in most patients, resulting in acceleration of the rate of failure.25 One factor peculiar to islet cells in human type 2 diabetes is their propensity to develop islet amyloid polypeptide deposits, but these probably play a part in disease progression rather than initiation.25,79 Studies of -cell failure in rodent models suggest a range of mechanisms, from poor function only, for instance in the Zucker fatty rat 60% pancreatectomy
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Panel 1: Glossary of terms relating to epigenetics Genome: the entire genetic information (genes) for an organism, which is maintained in the nucleotide sequence of DNA; each organism has only one genome Genetic disease: disease caused by common variations (polymorphisms) and mutations (variants whose frequency in the population is <1%) in the nucleotide sequence of the genome Epigenetics: the study of heritable (from cell to daughter cell, parents to ospring, or both) changes in genome function by chemical modications of DNA and DNA-associated proteins that occur without a change in the DNA nucleotide sequence Epigenome: the pattern of genes that can be expressed in a cell type and passed on to daughter cells; multicellular organisms have dierent epigenomes for each cell type Epigenetic imprinting: the epigenetic suppression of certain genesie, the activation or silencing of specic allelesafter fertilisation, dependent on from which parent they were received Epigenetic mechanisms: the organisation of chromatin by enzymes into accessible (open for expression) and inaccessible (closed for expression) congurations through methylation or demethylation of DNA and acetylation or deacetylation of DNA-related histone proteins

in the secretion of glucagon caused by altered incretin action is also possible.86 All these disturbances aggravate hyperglycaemia, but are unlikely to be primary defects in the pathogenesis of type 2 diabetes.29 Gut hormones, including GLP-1, also have roles in CNS regulation of energy balance and appetite.88

Adipose tissue and inammation

The need to have fat that can expand for metabolic health is exemplied by two extremes in white adipose tissue: rare disorders in which this type of fat is absent, such as congenital and acquired lipodystrophies, can lead to severe metabolic syndrome, whereas some very obese individuals do not develop metabolic syndrome at all.8991 Thus, healthy white adipose tissue prevents nutrient spillover to other tissues and protects against metabolic disease.30 White adipose tissue in metabolic syndrome or type 2 diabetes is abnormal in multiple ways: distribution favours VAT; reduced adipocyte dierentiation and adiponectin expression and secretion; suppression of lipolysis by insulin is impaired; increased expression and secretion of inammatory cytokines (eg tumour necrosis factor , interleukin-1, and monocytechemoattractant protein-1); and increased tissue inammation (eg, macrophage inltrates).92,93 Decline in secretion of adiponectin and raised concentrations of inammatory cytokines and non-esteried fatty acids aggravate insulin resistance in muscle and are pathogenic in non-alcoholic steatohepatitis.20,93 The discovery of functional brown adipose tissue in adult human beings raises the possibility for an overlooked role of this tissue in human energy homoeostasis and a preventive role in type 2 diabetes.94 The detectability of this tissue in humans lessens with increasing age and is decreased in individuals with high body-mass index and fasting plasma glucose values.94 Genome-wide association studies have shown that only 01% of variation in fat distribution (waist circumference and waist-to-hip ratio) can be explained genetically, and, therefore, genetic dierences aecting this aspect of adipose tissue seem unlikely between obese people who do and do not develop type 2 diabetes.95 Regional dierences in gene expression of preadipocytes, however, persist in cells in culture after several passes, which suggests that these cells have epigenetic memory.96 Furthermore, preadipocytes from people with type 2 diabetes have an intrinsic gene expression prole that also persists after two passages.97 Thus, the early-life environment could aect adipose tissue phenotype. Additionally, abnormalities in adipose tissue might be induced by hyperglycaemia and, therefore, could occur downstream from -cell impairment.89,92

model,81 to substantial loss of -cell mass in the Sprague Dawley intrauterine growth restriction model.82 The latter model is of particular interest because Sprague Dawley rats are normally very resistant to the development of diabetes. The loss of islet -cell mass in this intrauterine growth restriction model has been linked to epigenetic downregulation of Pdx1, a pancreatic homoeobox transcription factor essential for normal -cell dierentiation.64 Loss of 4060% of -cell mass has been seen in pancreas samples from people with impaired fasting glucose and type 2 diabetes, but less than 24% at 5 years after disease onset has also been reported.83,84 Whether a subset of people with type 2 diabetes have predominant functional deciencies in cells without loss of mass is unknown, but this may have implications for treatment.

Glucagon secretion and incretin eect

Glucagon secretion and the incretin eect, which involves GLP-1 and gastric inhibitory polypeptide, are disturbed in type 2 diabetes.29,85,86 Glucagon secretion is increased during fasting and fails to suppress after meals.86 The incretin eect, which is the added increase in insulin secretion from an oral glucose compared to a glycaemia-matching intravenous glucose load, is severely impaired.85 The latter feature could be caused by impaired GLP-1 production (although the overall evidence for this is not strong) and reduced sensitivity of cells to gastric inhibitory polypeptide.29,87 Dysfunction
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The liver
Increases in endogenous glucose production, predominantly of hepatic origin, are a major determinant of fasting
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hyperglycaemia in type 2 diabetes. Lack of suppression of production after eating contributes to fed-state hyperglycaemia.26 The mechanisms underlying this dysregulation are complex, involving increased supply of gluconeogenic substrate from peripheral tissues, an eect of raised concentrations of non-esteried fatty acids to activate hepatic gluconeogenesis, and the hepatic response to raised concentrations of glucagon.26,98 Type 2 diabetes is strongly associated with non-alcoholic fatty liver diseaseeach is highly predictive of the other19,20 and is a determinant of its severity and that of nonalcoholic steatohepatitis, and of liver-related mortality.20 Nevertheless, the liver does not seem to be a primary cause of type 2 diabetes.

Glucose

Islet -cell Pyruvate PDH PC OAA Acetyl-CoA Mitochondrial metabolism TCA Cycle PYR shuttles NADPH Citrate Mal-CoA FA oxidation Ca2+ Glycolysis + + Glycerol-3-P Intracellular signals + + Glycerolipids (MAG, DAG, TG) LC-CoA GL/FA cycling NEFA Glycerol

Plasma membrane receptors ACh-R GLP-1-R GIP-R FFAR1 -ADR-R SSN-R

ATP/ADP

K ATP channel m

Skeletal and cardiac muscle

The traditional view emphasises a pathogenic role for skeletal-muscle insulin resistance in type 2 diabetes, but we believe that this idea needs careful reconsideration. Type 2 diabetes is a disease of relative inactivity and overnutrition with failure of the body to safely contain fuel excess. As discussed above, this failure can be explained by islet -cell and adipose tissue deciencies, with secondary contributions from the liver. So does muscle insulin resistance per se play a causal role in type 2 diabetes pathogenesis? Skeletal muscle inactivity (lack of exercise) certainly contributes to fuel surfeit, but this is not a consequence of insulin resistance. Rather, insulin resistance is downstream from failure to contain the fuel surfeit. Skeletal muscle in individuals with type 2 diabetes is nutrient replete, or even nutrient overloaded, such that it responds with insulin resistance as protection against steatosis or metabolic stress of the tissue.30,31,99 Even with short-term overfeeding, attuned to having a feast, skeletal and cardiac muscles develop insulin resistance to divert excess nutrients to safe storage in adipose tissue.101,102 Thus, if skeletal and cardiac muscle insulin resistance is protective against nutrient toxicity, attempts to directly reverse it without concomitant nutrient detoxication, or to override it by forcing nutrients into muscle (eg, by aggressive insulin therapy) could be harmful. An important issue that should be considered separately from insulin resistance, however, is that the number and function of muscle mitochondria are decient in individuals with type 2 diabetes and their rst-degree relatives.103 This feature could have genetic causes, be acquired early in life, or could merely be a consequence of chronic inactivity.103 Treatments that promote mitochondrial biogenesis, function, or both, in muscle, rather than those that increase insulin sensitivity directly, could be benecial in people with type 2 diabetes. The eects would mimic those of exercise, which lessens insulin requirements and -cell exhaustion. The indirect eect is improvements in insulin sensitivity of skeletal muscle as the cells revert from needing to keep energy out to taking it in.
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Voltage-gated Ca2+ channel Ca

2+

Insulin exocytosis

NEFA

Figure 4: Role of islet -cell metabolic activation by fuels and neurohormonal agonists in insulin secretion Glucose is metabolised via glycolysis to pyruvate and in the mitochondria to acetyl-CoA, which is then oxidised in the TCA cycle. These actions lead to an increased cytosolic ratio of ATP to ADP, which closes the K+ATP channels, depolarises the plasma membrane potential, and opens voltage-gated Ca+ channels, causing inux of Ca+ and the triggering of insulin-granule exocytosis. Pyruvate from glucose can also be metabolised via PC into the anaplerosis-cataplerosis pathway. Anaplerosis refers to the processes by which Krebs cycle intermediates in the mitochondrion are replenished or increased, whereas cataplerosis refers to their egress from the mitochondrion. Changes in concentrations of cataplerosis-derived signalling molecules, including NADPH from pyruvate shuttles, and citrate-derived Mal-CoA, can lead to augmentation of insulin secretion. Glucose interacts with NEFA by promoting activity in a GL/FA cycle when raised concentrations of Mal-CoA, via the anaplerosis pathway, inhibits partitioning of LC-CoA into FA oxidation, which increases the availability of the LC-CoA for esterication. Glucose also provides glycerol-3-phosphate, which is necessary for FA esterication. Glycerolipids are rapidly hydrolysed by lipases back to NEFA and glycerol to create the GL/FA cycle process. This cycle produces lipid signalling molecules, such as diacylglycerols, that enhance glucose-stimulated insulin secretion. Aminoacids, such as glutamine and leucine, also interact with the glucose metabolism pathways to increase the coupling signals produced by glucose alone. The cell responds to other neurohormonal and metabolic extracellular signals via various plasma membrane receptors. PC=pyruvate carboxylase. PDH=pyruvate dehydrogenase. Ach-R=acetylcholine receptor. GIP-R=gastric inhibitory polypeptide receptor. GLP-1-R=glucagon-like peptide-1 receptor. FFAR1=free-fatty-acid receptor-1. -ADR-R=2-adrenergic receptor. SSN-R=somatostatin receptor. OAA, oxaloacetate; CoA=coenzyme A. MAG, monoacylglycerides; DAG=diacylglycerides. TG=triacylglycerides. m=change in plasma membrane potential. Mal-CoA=malonyl-CoA. LC-CoA=long-chain acyl-CoA. GL=glycerolipid. FA=fatty acid. NEFA=non-esteried fatty acids.

Prevention and management

The pandemic of type 2 diabetes, along with its high human and economic costs, is showing no signs of abatement and, therefore, new approaches are urgently needed to prevent, slow the progression, and limit the consequences of this disease. Changes need to be based on knowledge of the pathophysiology and to take into account new insights from genetic and epigenetic studies. A whole-of-life approach is indicated, particularly for prevention.

Early life
Events and lifestyle in early life might substantially aect susceptibility to type 2 diabetes. Fetal and neonatal programming might contribute substantially to susceptibility to obesity, -cell and adipose tissue
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Major transitions in life

Pregnancy 0 weeks Mother Years Baby Years Early GDM At risk of GDM Undiagnosed Untreated 28 weeks GDM treated

40 weeks

Populations rapidly transitioning from traditional to westernised lifestyles deserve particular attention to prevent disastrous increases in diabetes prevalence (the match-mismatch paradigm of metabolic disease35), as has been seen in regions such as Asia. Improvements in maternal public health programmes in pretransition and post-transition populations and provision of education to relevant groups about the risks of rapidly adopting western lifestyles could be considered.

Figure 5: Timelines for prevention of gestational and permanent diabetes Owing to guidelines, women are frequently not diagnosed and do not receive interventions for gestational diabetes until around 28 weeks gestation. Thus, the fetus might have been exposed to an adverse intrauterine environment during the previous two trimesters. Before pregnancy mothers could optimise their health, which might be helped by health checks, advice, and public health programmes. Mothers with gestational diabetes are at high risk of permanent diabetes after pregnancy. This period yields an opportunity for diabetes prevention, including gestational diabetes in later pregnancies. Most health advice given after gestational diabetes is directed at the mother, but advice for the whole family could achieve reductions in the risk of diabetes for multiple generations simulatenously. GDM=gestational diabetes mellitus.

Gestational diabetes
A pandemic of gestational diabetes accompanies that of obesity and type 2 diabetes.11,104 The new IADPSG recommendations for diagnosis of hyperglycaemia in pregnancy include early screening for overt diabetes, but most cases of gestational diabetes are still diagnosed between 24 and 28 weeks gestation (gure 5).11 Most women, therefore, do not receive dietary and lifestyle advice or receive insulin therapy, if required, until late in the pregnancy. Two clinical trials have shown that late diagnosis and management are associated with better obstetric outcomes,105,106 but whether the childs risk of developing metabolic diseases later in life is reduced by this approach is unknown. The Australian Carbohydrate Intolerance Study in Pregnant Women showed that, although the standard intervention for gestational diabetes greatly lowered macrosomia rates, it had no eect on body-mass index in children aged 45 years.107 The window of opportunity to alter adverse fetal programming might arise earlier than 28 weeks gestation, or the neonatal or early childhood periods could be crucial in the determination of later metabolic health, such that a broader approach might be needed to protect the osrping (gure 5). Many mothers with gestational diabetes progress to overt diabetes later in life.104,108,109 In an Australian study, the risk of developing type 2 diabetes after gestational diabetes was 96 times greater at 15 years than that in women who had been pregnant without gestational diabetes.108 Whether public health eorts to encourage women to adopt healthy lifestyles before pregnancy would be the most useful preventive approach, and how best to help mothers and their families to sustain healthy lifestyles after pregnancy needs to be assessed.

-cell function and mass

Type 2 diabetes

NGT

Prediabetes

Diet and metformin Time (years)

+Other agents required

+Insulin required

Figure 6: Natural history of type 2 diabetes and possible inadequacies of the standard therapeutic approach Type 2 diabetes mellitus is a progressive disease in which islet -cell function and mass decrease and metabolic stress and tissue injuries worsen over time. The current approaches to diabetes management are largely based on the expectation of this pattern. Thus, treatments are increased or added only if glycaemic therapy is inadequate (ie, glycated haemoglobin A1c remains above target). A change in the main goals of therapy towards healing of the pathogenic defects, with the aim of preventing and altering the natural history of the disease, might improve outcomes and be more cost eective. NGT=normal glucose tolerance.

dysfunctions and the metabolic syndrome. As these acquired susceptibility factors are potentially preventable, major focuses of basic and translational research should be directed towards maternal, neonatal, and early childhood health. Care needs to be taken, however, not to introduce interventions at critical stages of development without evidence of short-term and long-term safety and ecacy. In the meantime, maintenance of good health during gestation and into early childhood through appropriate diet and exercise, good-quality obstetric, neonatal, and paediatric care, and breastfeeding should be supported, particularly in lower-socioeconomic groups, which are at the highest risk.
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Prediabetes
Prediabetes, in which glucose tolerance, fasting glucose, or both are impaired, is associated with increased probability of incident diabetes (~34% increase in risk in 75 years) and cardiovascular disease (~11% in 10 years).110 Eective management of prediabetes can prevent or delay the onset of both these disorders. Lifestyle interventions (improved diet, increased exercise, or both) can lower the risk of incident diabetes by 2859%,111115 but adherence outside clinical trials is a challenge. Pharmacotherapy with -glucosidase inhibitors, metformin, and
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thiazolidinediones can also eectively lower the risk of incident diabetes, but whether these drugs are truly preventive or treat early symptoms is unclear.114,116118 Owing to high prevalence rates, public health approaches are clearly required.

Panel 2: Desired characteristics of glycaemic control therapies in type 2 diabetes The therapy, in addition to achieving target HbA1c, should: Be disease modifying (ie, reverse one or more of the underlying pathophysiological processes) (i) Reduce chronic fuel surfeit (ii) Protect islet -cells from progressive failure (iii) Prevent adipose tissue dysfunction, including abnormal fat distribution and inammation (iv) Restore normal islet -cell function and incretin physiology (v) Restore normal regulation of hepatic glucose production (vi) Enhance skeletal muscle mitochondrial function/ oxidative metabolism (vii) Enhance energy expenditure and thermogenesis Sustain good metabolic control with low therapy-associated unwanted eects Enhance quality of life of patients Reduce diabetes microvascular and macrovascular complications Reduce diabetes-related mortality (includes cardiovascular disease-related), and all-cause mortality
HbA1c=glycated haemoglobin A1c.

Established diabetes
The clinical management of established type 2 diabetes involves optimum control of factors that cause complications, such as blood glucose and lipid concentrations, blood pressure, bodyweight, and smoking, as well as regular screening for and appropriate management of microvascular (eye, renal, and neural) and macrovascular (coronary, cerebral, and peripheral) complications. Local practice guidelines, such as the ADA Clinical Practice Recommendations 2011,119 should be used. Glycaemic control of type 2 diabetes becomes more dicult over time as islet -cell failure is progressive (gure 6).25,26 All current guidelines for treatment of hyperglycaemia are largely structured around this expected decline with the main aim of maintaining optimum HbA1c levels. Extension of the therapeutic goals to include the reversal of pathophysiology might now be possible, as suggested by Defronzo.26 The key problems to focus on are chronic fuel surfeit, including the brain control of energy homoeostasis, islet -cell dysfunction, the health of adipose tissues and fat partitioning, and regulation of endogenous glucose production (panel 2). Reduction of the chronic fuel surfeit is extremely challenging because it is linked to the CNS and reward mechanisms. Improvements in diet and exercise should be pursued in all patients and can achieve good results in the rst year, but success is dicult to sustain.112,120 For morbidly obese individuals, bariatric surgery should be considered early in the disease course, before the islet -cell mass is irreversibly damaged. The outcome should be rapid normalisation of blood glucose control.121 For moderately obese people, GLP-1 mimetics (eg, exenatide, liraglutide) should be considered for use early, as they reduce appetite, promoting some weight loss, as well as protecting the islet cells.4,122 GLP-1 has multiple positive eects on cells and the body: the incretin eect; antiapoptotic and proliferative eects on cells (in rodents; whether the same eects arise in human beings is unknown); reduction of appetite; slowed absorption of nutrients through delaying gastric emptying; and possible protective eects on the vascular endothelium.123,124 Early use of GLP-1 mimetics in moderately to severely obese patients holds the promise of healing the islet -cells, although the longterm unknown risks of serious side-eects (eg, malignancy, pancreatitis) need to be weighed up against the known consequences of poor glycaemic control and progressive -cell dysfunction (eg, renal failure, amputations, and cardiac death) in high-risk patients.122
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Eorts to nd new treatments for obesity must continue. The disorder is dicult to treat because agents that aect the CNS carry the risk of severe adverse eects, such as depression.125 For the islet cell, the GLP-1 mimetics are again the most promising for reversing pathophysiology. For lessobese patients, however, increasing endogenous GLP-1 by treatment with the orally available dipeptidyl-peptidase IV inhibitors early after onset of type 2 diabetes might be benecial,4,122 but these drugs become less eective with increasing duration of disease. Sulphonylureas have no known disease-modifying eects and, although not conclusively proven, might hasten -cell decline.126 They also cause weight gain and hypoglycaemia126 and, therefore, use should be curtailed. Metformin and the thiazolidinediones could also have some direct and indirect protective eects on cells.127,128 The only agents available with a healing eect that act on adipose tissue are the thiazolidinediones (pioglitazone and rosiglitazone).26 They activate peroxisome proliferatoractivated receptor , which improves dierentiation of fat cells.129 Thiazolidinediones promote SAT expansion, reduce lipolysis and expression and secretion of cytokines as well as adipose tissue inammation, and increase reesterication of fatty acids and expression and secretion of adiponectin.129132 These drugs also lead to sustained good glycaemic control in patients with type 2 diabetes.26,126 The use of thiazolidinediones, however, can lead to weight gain (albeit with more healthy SAT than unhealthy
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VAT), oedema, cardiac failure, and osteopenia with distal fractures, and rosiglitazone is possibly associated with cardiac adverse eects.126,133135 Low doses, however, might have a much better safety prole while maintaining some ecacy. In a diabetes prevention study of 2 mg rosiglitazone combined with 500 mg metformin twice daily for 3 years,117 and a 12-week study of 75 mg pioglitazone daily in patients with type 2 diabetes and poor glycaemic control,136 both drugs showed signicantly benecial eects. Metformin that lowers glucose concentrations mainly through eects on endogenous glucose production is benecial in patients with type 2 diabetes.26,137 This drug should continue to be used in combination with other drugs. Insulin therapy clearly has a place in the treatment of patients who have become insulin decient and have poorly controlled type 2 diabetes, and possibly to stabilise disease in the very early stages, if used for only a short time.138 The benets of long-term insulin therapy started early in the type 2 diabetes disease process, however, is unclear. Insulin does not directly reverse the pathophysiological processes of this disease and most patients gain weight26 and are at risk of hypoglycaemia. If insulin therapy overrides insulin resistance in muscle, it also has the potential to cause insulin-mediated nutrient toxic eects by promoting excess glucose uptake in the face of high lipid concentrations (glucolipotoxic eects).30,31 Insulin-mediated tissue injury, particularly of the heart, could have caused the unexpected mortality in the aggressive glycaemic control group of the The Action to Control Cardiovascular Risk in Diabetes study.139 Changes in treatment strategies must be supported by strong evidence. Carefully designed clinical trials are needed to test new approaches, especially early use of GLP-1 mimetic agents or dipeptidyl-peptidase IV inhibitors in combination with thiazolidinediones at substantially reduced doses. Long-term safety is also a major consideration (panel 2). With further progress in unravelling the pathogenic roles of genes and epigenomic phenomena in type 2 diabetes, pharmacogenomic and pharmacoepigenomic studies might eventually yield treatment choices that can be personalised for individual patients.

latent autoimmune diabetes in adults might have increased susceptibility to -cell dysfunction. Early use of insulin might be appropriate and, indeed, necessary in many of these patient groups, excluding those with some forms of monogenic diabetes.

Conclusions
To turn around the pandemic of type 2 diabetes and its eect on lives and economies worldwide is necessary, but is a major challenge for modern society. An improved understanding of the pathogenesis and natural history is crucial to focus eorts appropriately. Substantial evidence of safety and ecacy of candidate prevention and treatment strategies must be provided before they can be widely implemented. We propose that the whole of patients lives need to be considered for eective disease management, and particularly in prevention for reversal of the pandemic. A continued broad but coordinated multidisciplinary approach is needed that involves scientists, public health practitioners, educators, clinicians, and the people at risk, with support from government authorities and non-governmental organisations.
Contributors All authors contributed to the literature search and the content of this Seminar. CJN wrote the rst draft of the paper and all authors contributed to the writing of the nal version. Conicts of interest CJN has received speakers fees from Eli Lilly, GlaxoSmithKline, Merck Sharp Dhome, Norvartis, and Servier, and PD and CJN from Novo Nordisk. MP declares that he has no conicts of interest. Acknowledgments We thank Viviane Delghingaro and Jee-Hye Kim for initial preparation of gures and Sharyn Wragg for her graphic design assistance. PD has received funding from Novo Nordisk and Novo Nordisk Foundation. References 1 Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract 2010; 87: 414. 2 Gonzalez EL, Johansson S, Wallander MA, Rodriguez LA. Trends in the prevalence and incidence of diabetes in the UK: 19962005. J Epidemiol Community Health 2009; 63: 33236. 3 Chan JC, Malik V, Jia W, et al. Diabetes in Asia: epidemiology, risk factors, and pathophysiology. JAMA 2009; 301: 212940. 4 Colagiuri S. Diabesity: therapeutic options. Diabetes Obes Metab 2010; 12: 46373. 5 Reinehr T, Kiess W, Kapellen T, Wiegand S, Holl RW. Children with diabetes mellitus type 2 in Europe: an underserved population. Arch Dis Child 2010; 95: 954. 6 McIntyre HD, Thomae MK, Wong SF, Idris N, Callaway LK. Pregnancy in type 2 diabetes mellitusproblems & promises. Curr Diabetes Rev 2009; 5: 190200. 7 Neu A, Feldhahn L, Ehehalt S, Hub R, Ranke MB. Type 2 diabetes mellitus in children and adolescents is still a rare disease in Germany: a population-based assessment of the prevalence of type 2 diabetes and MODY in patients aged 020 years. Pediatr Diabetes 2009; 10: 46873. 8 Liu LL, Yi JP, Beyer J, et al. Type 1 and Type 2 diabetes in Asian and Pacic Islander U.S. youth: the SEARCH for Diabetes in Youth Study. Diabetes Care 2009; 32 (suppl 2): S13340. 9 Mayer-Davis EJ, Beyer J, Bell RA, et al. Diabetes in African American youth: prevalence, incidence, and clinical characteristics: the SEARCH for Diabetes in Youth Study. Diabetes Care 2009; 32 (suppl 2): S11222.

Lean and elderly patients

Although Asian patients with type 2 diabetes are frequently leaner than patients of other ethnic origins, fuel surfeit is still likely to be seen and will cause relative visceral adiposity (webappendix p 1).3,66 Some patients, however, have type 2 diabetes without fuel surfeit. These patients are often elderly and probably have some susceptibility to islet -cell dysfunction, but the disease may well be caused by age-related decline in function. Latent autoimmune diabetes in adults needs to be excluded in these patients.140 Non-elderly adult patients who are lean and do not have monogenic diabetes or
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