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1 Mechanisms contributing to the development of type 2 diabetes MUTHU K JAYAPAUL, MARK WALKER Abstract We are in the midst of an explosion in the prevalence of type 2 diabetes with a key concern that this will translate into a major future burden of diabetes-related complications. To develop rational and effective means of preventing type 2 diabetes and its complications, we need to understand the mechanisms that predispose to the development of diabetes in at-risk individuals. In this brief review, we provide an overview of the principal metabolic changes that have been identified in at-risk individuals and how they contribute to the progression from normal glucose tolerance (NGT) through to type 2 diabetes. Specifically, both impaired insulin action and defective insulin secretion are key predictors of type 2 diabetes, and both are evident in at-risk individuals well before the development of frank diabetes. These changes are associated with an increased prevalence of adverse cardiovascular risk factors. It is clear, therefore, that the identification of at-risk individuals provides the opportunity to introduce measures to try to prevent the development of type 2 diabetes and the associated cardiovascular disease. Br J Diabetes Vasc Dis 24;4: Key words: type 2 diabetes, impaired glucose tolerance, impaired fasting glycaemia, insulin resistance, beta-cell dysfunction. Correspondence to: Professor Mark Walker School of Clinical Medical Sciences, 4th Floor William Leech Block, The Medical School, Framlington Place, Newcastle-upon-Tyne, NE2 4HH, UK. Tel: +44 () ; Fax: +44 () mark.walker@ncl.ac.uk Figure 1. The prevalence of type 2 diabetes in Pima s categorised by heritage Prevalence (%) Adapted from Knowler et al Non- Half- Full Introduction The global epidemic of diabetes is increasing at an alarming rate and it is predicted that by 225, 333 million people will be suffering from the burden of the disease world-wide. 1 More than 95% of this group will comprise type 2 diabetes. It is well known that type 2 diabetes is preceded by a long asymptomatic period where subjects deteriorate from NGT to IGT and are later diagnosed with type 2 diabetes. This period approximates between 6 1 years depending upon individual subject variation. It has been estimated that there are currently about 314 million subjects with IGT and by 225 a staggering 472 million will have IGT. 1 It is known from epidemiological studies that IGT and IFG are metabolic states with increased risk of future type 2 diabetes, of which at least 3% go on to develop diabetes. 2,3 There is now good evidence that lifestyle or pharmacological interventions at this stage are beneficial in preventing or delaying the onset of diabetes and thereby preventing early development of complications. 4-7 In this review we discuss the mechanisms responsible for the change from NGT to type 2 diabetes. Inherited risk of type 2 diabetes Type 2 diabetes is known to have a strong familial basis and at least 4% of siblings of subjects with type 2 diabetes can expect to develop the disease based on the assumption that survival will be to the age of 8 years. 8 The risk of developing diabetes was estimated as 2.3 to 3.9 times greater in offspring with one or two affected parents, respectively, when compared with offspring with two non-diabetic parents in the Pima population. 9 Further evidence for the genetic nature of the disease comes from a number of twin studies. In one particular study, when monozygotic twins who share identical genetic information were analysed, the concordance rate for type 2 diabetes was increased at 58% compared with the expected prevalence of 1%. 1 The prevalence of type 2 diabetes varies greatly between ethnic populations and in different parts of the world. It remains to be clarified whether this increased risk in certain populations is VOLUME 4 ISSUE 4. JULY/AUGUST

2 Abbreviations GLUT glucose transport HDL-c high density lipoprotein-cholesterol HGO hepatic glucose output IFG impaired fasting glucose IGT impaired glucose tolerance IRS-1 insulin receptor substrate-1 NFG normal fasting glucose NGT normal glucose tolerance PI-3 phosphatidyl-inositol-3 Figure 2. Pathogenesis of type 2 diabetes Figure 3. Extrapolation of data from UKPDS to show the predicted decline in beta-cell function before the diagnosis (time yrs) Beta-cell function (%) Impaired insulin action Type 2 diabetes Raised hepatic glucose output Defective insulin secretion due to common environmental or genetic determinants. The genetic influence is supported by the fact that type 2 diabetes has a higher prevalence in certain populations like American s, Pacific islanders and Asian s. The prevalence is even higher when there is limited foreign genetic mixture as shown in Pima s (figure 1). 11 Pathogenesis of type 2 diabetes Type 2 diabetes is a chronic disorder of carbohydrate and lipid metabolism and is known for its heterogeneity. It is caused by impaired insulin action in muscle and adipose tissue, defective insulin secretion and inadequate suppression of hepatic glucose output (figure 2). During a meal the normal response is to suppress HGO and to enhance glucose uptake in the liver and muscle. This needs an appropriate insulin secretory response and adequate hepatic and muscle insulin sensitivity for glucose uptake. It is important to note that pre-diabetes forms a part of continuum between NGT and diabetes. Many of the abnormalities that characterise the diabetic state, such as insulin resistance and defects in beta-cell function, are evident in at-risk but nondiabetic subjects such as first degree relatives of subjects with type 2 diabetes. It is therefore evident, that these changes evolve long before the development of frank diabetes Years from diagnosis Defects in subjects at risk of type 2 diabetes Beta-cell function One of the most striking observations from the United Kingdom Prospective Diabetes Study (UKPDS) was the significant decrease in beta-cell function of up to 5% of normal, in subjects with a recent diagnosis of type 2 diabetes. 12 Extrapolating the data from the same study suggests that this decline starts approximately 1 12 years before the diagnosis of diabetes (figure 3). It is now universally accepted that beta-cell dysfunction is a hallmark of diabetes and is also related to hyperglycaemia. This dysfunction is manifest through different ways which includes reduced insulin release in response to glucose and other non-glucose secretagogues, changes in pulsatile and oscillatory insulin secretion and an abnormality in the effective conversion of proinsulin to insulin. 13 There is enough evidence to infer that these changes start well before the diagnosis of the disease and most abnormalities have been noted in pre-diabetic individuals. These defects have been identified in high-risk individuals for type 2 diabetes such as subjects with first degree relatives with diabetes and women with a history of gestational diabetes or polycystic ovarian syndrome. 13 Insulin release from the pancreas is biphasic, with the initial brief spike which lasts for 1 minutes called the first phase insulin release. This is followed by a prolonged second phase which plateaux by 2 3 hours. When subjects with IGT were studied by Gerich et al. using the hyperglycaemic clamp technique, 14 they noted significant reductions in both first and second phase insulin secretion. Notably, when NGT subjects with and without a positive family history of diabetes were examined, NGT subjects with a positive family history had significant defects in both phases of insulin secretion. 14 The importance of beta-cell dysfunction in the pathogenesis of pre-diabetes is also emphasised by the defects in the oscillatory insulin release in NGT first degree relatives with type 2 diabetes. 15 Furthermore, increased non-stationarity and disorderliness of rapid pulsatile insulin secre- 228 THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE

3 tion in NGT subjects with a family history of diabetes suggests beta-cell dysfunction is an early and fundamental defect in the development of type 2 diabetes. 16 Muscle Skeletal muscle is responsible for 8% of glucose disposal in peripheral tissues and hence plays an important part in regulating carbohydrate metabolism. In type 2 diabetes the ability of insulin to stimulate glucose uptake, glycogen synthesis and glucose oxidation in skeletal muscle is impaired. 17 These defects have also been identified in pre-diabetic individuals with IGT and glucose tolerant first degree relatives of subjects with type 2 diabetes. 18,19 Rothman et al. studied non-diabetic first degree relatives using magnetic resonance spectroscopy and found evidence of decreased insulin stimulated glucose uptake and glycogen synthesis. 2 The same workers have recently extended their studies by using magnetic resonance spectroscopy to investigate skeletal muscle energy metabolism. 21 They found that mitochondrial oxidation was decreased in insulin resistant first degree relatives, and this in turn was associated with an increase in intramyocellular lipid content. They proposed that the defect of mitochondrial function may represent the primary defect in skeletal muscle and that the decreased oxidative function leads to the accumulation of intramyocellular lipid and secondary insulin resistance. In individuals with IGT as in type 2 diabetic individuals the most proximal defect in the signalling pathway has been identified as the inability of insulin to stimulate tyrosine phosphorylation of its receptor. New defects in the activation of IRS-1 and reduced ability to associate with the p85 subunit of PI-3 kinase have been identified recently Other studies have noted the ability of PI-3 kinase to induce GLUT4 translocation and to activate GLUT4 transporter is impaired. 23,25 Work on human skeletal muscle cultures from insulin resistant NGT first degree relatives of subjects with type 2 diabetes by our group identified a defect in insulin mediated glucose uptake. The retention of this defect of insulin action in cultured muscle cells suggest that there may be an inherited basis. 26 Liver Type 2 diabetes is characterised by a raised fasting blood glucose that is associated with raised HGO. In normal individuals HGO is suppressed markedly with even small increments of insulin. In individuals with diabetes this sensitivity appears to be diminished in spite of hyperinsulinaemia. Results from studies on pre-diabetic individuals have been variable and inconclusive. In individuals with IGT, post-absorptive HGO remains in the normal range, possibly because post-absorptive hyperinsulinaemia overcomes hepatic insulin resistance. However, immediately following a meal, plasma insulin concentrations may be inadequate to suppress HGO. 27 Roberston et al. and Lillioja et al. identified reduced hepatic insulin sensitivity as a cause of raised HGO but in these studies no attempts were made to exclude confounding factors such as differing portal insulin levels. 28,29 Berrish et al. co-infused insulin, glucagon and somatostatin (which suppresses endogenous insulin and glucagon release) to achieve comparable portal insulin and glucagon levels and then performed euglycaemic clamps. 3 Under these conditions, hepatic insulin sensitivity was comparable in subjects with IGT and NGT. These data suggest that the impaired hepatic insulin sensitivity is a late feature in the pathogenesis of type 2 diabetes. Relative importance of decreased insulin secretion and insulin resistance The relationship between insulin secretion and insulin action is complex 31 and there is an on-going debate concerning the relative importance of impaired insulin secretion and insulin resistance in the development of type 2 diabetes. Unfortunately, much of the argument has been based on information from cross-sectional studies which, by their very nature, cannot identify predictors of disease. However, a number of longitudinal studies have been conducted to identify the key metabolic predictors of diabetes. Lillioja et al. prospectively studied 2 Pima s with NGT and IGT and the results were reported after a mean follow-up of 5.3 years. 32 These individuals had a mean age of 26 years and had undergone detailed metabolic studies which included a hyperinsulinaemic euglycaemic clamp. At the end of the study 38 individuals had developed type 2 diabetes. Insulin sensitivity was the strongest predictor for new onset diabetes even after correction for differences in adiposity. However, a subsequent study in the Pima population reported that both a decreased acute insulin response to glucose and insulin resistance were independent risk factors for the progression from NGT to IGT and for the progression from IGT to type 2 diabetes. 33 Haffner et al. also identified defective insulin action and insulin secretion, measured by fasting insulin, as predictors of type 2 diabetes in NGT and IGT in Mexican-Americans. 34 The balance of evidence, therefore, indicates that both impaired insulin secretion and insulin resistance are independent predictors for the development of type 2 diabetes. Are IGT and IFG different? Recent work published by Weyer et al. demonstrated defects in insulin secretion, action and endogenous glucose output in prediabetic individuals. 35 Specifically, subjects with IGT and IFG had similar impairments in insulin action, but the subjects with IFG had a greater impairment in early phase insulin secretion and a higher rate of endogenous glucose output. Van Haeften and colleagues used the hyperglycaemic clamp technique to measure first phase and second phase insulin responses and insulin sensitivity in individuals with IFG compared to individuals with NFG and type 2 subjects. 36 As shown in figure 4, there was a progressive decline in both phases of insulin response with deterioration in glucose tolerance. When IGT and IFG are compared with reference to total and cardiovascular mortality from epidemiological data, there is a continuous positive relationship for fasting and two-hour plasma glucose values that even extend below the current thresholds for IGT and IFG. But when analysed after correction for other cardiovascular risk factors such as BMI, blood pressure, cholesterol VOLUME 4 ISSUE 4. JULY/AUGUST

4 Figure 4. Plasma insulin levels during 18-min hyperglycaemic glucose clamps (1 mmol/l) in subjects with NGT, IFG and type 2 diabetes Key messages Plasma insulin (pmol/l) NGT (n=28) IFG (n=24) Type 2 (n=15) Geometric mean (95% CI) Adapted from van Haeften et al and smoking, the two-hour plasma glucose value was a better predictor than fasting glucose concentration. 37,38 However, a population-based cross-sectional study, 39 Heldgaard et al., recently demonstrated a similar cardiovascular risk factor profile in Danish subjects with IFG and IGT. Clearly, more studies are needed in this area to predict and target appropriate individuals with higher risk. Cardiovascular risk in subjects at increased risk of type 2 diabetes The review so far has tended to focus on aspects of carbohydrate metabolism in subjects at risk of type 2 diabetes. However, it is well documented that at-risk subjects such as the non-diabetic relatives of type 2 diabetic families have an increased prevalence of other adverse metabolic and anthropometric characteristics. We and others 4,41 have shown that such relatives tend to be more obese compared to subjects with no family history of type 2 diabetes and have associated abnormalities of lipid metabolism. 42 It is likely that both shared lifestyle and genetic factors contribute to the increased prevalence of obesity that in turn will contribute to the insulin resistance. In addition, obesity is a feature of the metabolic syndrome that includes other adverse cardiovascular risk factors such as abnormal glucose tolerance, raised triglyceride and low HDL-c levels, high blood pressure and insulin resistance. 43 The prevalence of these and other adverse cardiovascular risk factors is increased in the non-diabetic, but atrisk, relatives, of type 2 diabetic families. 44,45 This highlights that these subjects are predisposed not only to type 2 diabetes, but also to cardiovascular disease. Summary It is evident that many of the metabolic defects that characterise Non-diabetic first degree relatives of patients with type 2 diabetes have a three-fold increased life-time risk of developing diabetes compared to the background population IGT and IFG are metabolic states with increased risk of type 2 diabetes Impaired insulin action and defective insulin secretion are key metabolic features that predict the development of type 2 diabetes in at-risk subjects The defects of insulin action and insulin secretion are evident in at-risk individuals for long periods before the development of frank diabetes Strategies for preventing type 2 diabetes and its complications need to focus on trying to delay/avoid the deterioration in insulin action and insulin secretion in at-risk individuals and to correct the adverse cardiovascular risk profile type 2 diabetes are present in non-diabetic but at-risk subjects, such as first-degree relatives of type 2 diabetic patients, well before the development of the diabetic state. Defining these defects is important for the future development of rational and targeted measures for the prevention of both type 2 diabetes and the associated cardiovascular disease. References 1. IDF: Diabetic Atlas Second Edition. International Diabetes Federation, Kohler C, Temelkova-Kurktschiev T, Schaper F, Fucker K, Hanefeld M. (Prevalence of newly diagnosed type 2 diabetes, impaired glucose tolerance and abnormal fasting glucose in a high risk population. Data from the RIAD study using new diagnostic criteria for diabetes). Dtsch Med Wochenschr 1999;124: Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997;2: Pan XR, Li GW, Hu YH et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care 1997;2: Tuomilehto J, Lindstrom J, Eriksson JG et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 21;344: Knowler WC, Barrett-Connor E, Fowler SE et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 22;346: Holman RR, North BV, Tunbridge FK. Possible prevention of type 2 diabetes with acarbose or metformin. Diabetes 2;49(suppl 1):45-P. 8. Kobberling JTH. Empirical risk figures for first degree relatives of noninsulin dependent diabetics. Academic Press London: Knowler WC, Pettitt DJ, Savage PJ, Bennett PH. Diabetes incidence in Pima indians: contributions of obesity and parental diabetes. Am J Epidemiol 1981;113: Newman B, Selby JV, King MC, Slemenda C, Fabsitz R, Friedman GD. 23 THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE

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