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Genetics of Types 2 Diabetes Mellitus

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Genetics of Types 2 Diabetes Mellitus Genetics of type 2 diabetes mellitus Genetics of type 2 diabetes mellitus WY So, MCY Ng, SC Lee, T Sanke, HK Lee, JCN Chan Type 2 diabetes mellitus is a heterogeneous disease that is caused by both genetic and environmental factors. Only a minority of cases of type 2 diabetes are caused by a single-gene defect, such as maturity- onset diabetes of youth (mutated MODY gene), syndrome of insulin resistance (insulin receptor defect), and maternally inherited diabetes and deafness (mitochondrial gene defect). The genetic component of the more common form of type 2 diabetes is probably complex and involves the interactions of multiple genes and environmental factors. The candidate gene approach has identified several genes that regulate insulin signalling and secretion, but their contributions to diabetes are small. Recent genome scan studies have been conducted to identify major susceptibility loci that are linked with type 2 diabetes. This information would provide new insights into the identification of novel genes and pathways that lead to this complex disease. HKMJ 2000;6:69-76 Key words: Amyloid metabolism; Diabetes mellitus, non-insulin-dependent/genetics; DNA, mitochondrial; Insulin/ deficiency; Insulin resistance/genetic; Mutation Introduction Insulin Growth hormone, The maintenance of the blood glucose concentration cortisol, within a narrow range (between 3 and 7 mmol/L) ↑ Glycogen synthesis catecholamines, ↑ Lipogenesis glucagon irrespective of the pathophysiological circumstances, ↑ Glucose transport depends on the intricate relationships between the ↓ Lipolysis ↑ Glycogen breakdown actions of insulin—the only hormone that reduces ↓ Gluconeogenesis ↑ Lipolysis ↓ ↑ blood glucose level—and those of counter-regulatory Glycogenolysis Gluconeogenesis hormones. The latter group of hormones comprises growth hormone, catecholamines, cortisol, and gluca- gon, all of which tend to elevate blood glucose levels Glucose homeostasis (Fig 1). Insulin reduces the blood glucose level by enhancing glucose uptake, mainly in the muscle and Fig 1. The roles of insulin and counter-regulatory liver, thereby promoting glucose oxidation and glyco- hormones in the regulation of glucose homeostasis gen synthesis. Insulin also inhibits lipolysis and hep- atic glucose production, and facilitates energy storage hyperglycaemia owing to a combination of insulin by promoting lipogenesis. Type 2 diabetes mellitus resistance and changed insulin secretion.1 As a result, is a heterogeneous disease characterised by chronic there is insufficient insulin action to keep the blood glucose level within normal limits. More than 85% of all cases of diabetes mellitus are type 2 diabetes.2 This Divisions of Clinical Pharmacology and Endocrinology, Department disease affects not only the elderly and middle-aged of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong people, but also increasingly, young people, especially WY So, MRCP in non-Caucasian populations. MCY Ng, PhD SC Lee, PhD JCN Chan, FRCP The development of diabetes: nature or First Department of Medicine, Wakayama University of Medical nurture? Science, Japan T Sanke, MD Department of Internal Medicine, Seoul National University College Genes play an important role in the development of of Medicine, South Korea diabetes mellitus, particularly type 2 diabetes.3 Un- HK Lee, MD like autoimmune type 1 diabetes mellitus, no clear Correspondence to: Dr WY So relationship has been described between the human HKMJ Vol 6 No 1 March 2000 69 So et al common genotype that is present in most populations Specific types of diabetes mellitus and which has now been rendered detrimental by (1) Genetic defects of β-cell function changes in lifestyle. Identifying the genetic com- α (a) Chromosome 20, HNF-4 (MODY1) ponents of type 2 diabetes not only provides insight (b) Chromosome 7, glucokinase (MODY2) (c) Chromosome 12, HNF-1α (MODY3) into the mechanisms of diabetes, but also allows the (d) Chromosome 13, IPF-1 (MODY4) identification of susceptible individuals, for whom an (e) Chromosome 17, HNF-1β (MODY5) early diagnosis can be made and suitable treatment (f) Mitochondrial DNA mutation (g) Others subsequently given. (2) Genetic defects in insulin action (a) Type A insulin resistance Insulin resistance (b) Leprechaunism (c) Rabson-Mendenhall syndrome Insulin resistance means an impaired biological (d) Lipoatrophic diabetes (e) Others response to insulin by one or more of its target tissues, the consequence is reduced glucose disposal in (3) Diseases of exocrine pancreas response to insulin. Insulin exerts its biological effect (4) Endocrinopathies via binding to its receptor, which resides on the cell (5) Drug-induced or chemical-induced diabetes surface of target tissues.3 The insulin receptor consists (6) Infections of two α chains and two β chains, which are connected (7) Uncommon forms of immune-mediated diabetes by disulphide bridges. The binding of insulin to one (8) Other genetic syndromes of the extracellular α chains leads to the autophos- (a) Down’s syndrome phorylation of multiple tyrosine molecules in the (b) Friedreich’s ataxia intracellular domain of the β chain. The phosphorylated (c) Huntington’s chorea (d) Klinefelter’s syndrome receptor then transfers the message inside the cell by (e) Laurence-Moon-Biedl syndrome phosphorylating tyrosine residues on insulin receptor (f) Myotonic dystrophy substrate-1 (IRS-1). This intracellular protein is (g) Porphyria (h) Prader-Willi syndrome considered to play a central role in the intracellular (i) Turner’s syndrome signal cascade that is involved in glucose uptake and (j) Wolfram’s syndrome glycogen synthesis. The IRS-1 also transfers the (k) Others growth-promoting and mitogenic signals of insulin to the nucleus, thereby stimulating protein synthesis. leukocyte antigen genes and type 2 diabetes. In studies of monozygotic twins, the concordance rate for type 2 Defects in the insulin-signalling pathway, owing to diabetes has been reported to be 90% or more, even in mutations in the insulin receptor gene or the presence twins with a major difference in body weight.4 There of antibodies to the insulin receptor or insulin itself, are also marked racial differences in the prevalence are rare causes of insulin resistance.9 Polymorphisms of type 2 diabetes; prevalence rates in populations in the IRS-1 gene have been associated, although not such as Asians and American Indians are particularly strongly, with insulin resistance in various popu- high.5,6 A minority of cases of type 2 diabetes, such as lations.10,11 Further support comes from studies of maturity-onset diabetes of youth (MODY), result from knockout animal models.12,13 Familial studies in Pima mutations in a single gene.7 Some specific subgroups Indians and other populations show the clustering of diabetes caused by genetic defects of β-cell function of risk factors related to insulin resistance,6,14 thus or insulin action have also been described (Box).3 The suggesting that genetic factors may contribute to the majority of cases of type 2 diabetes, however, are development of insulin resistance. Other factors such multifactorial in origin, and different combinations as obesity, postmenopausal state, exercise, drug use of several genes that interact with non-genetic factors (glucocorticoids, β-blockers, and adrenergic agents), contribute to the development of hyperglycaemia.3,8 and infections may also influence the development of insulin resistance.1,15 The apparent genetic heterogeneity seems sur- prising in view of the similarity in the pathogenesis Most studies show that defective glucose oxidation of type 2 diabetes in different populations. Hence, and glycogen synthesis in muscle are the major the genetic origins of type 2 diabetes may be diverse. causes of insulin resistance in type 2 diabetes.1,16 The disease may represent maladaptation to and se- These observations may be in part explained by fuel lection of different genotypes in response to different competition—namely, an increased level of free fatty evolutionary pressures, rather than be derived from a acids competing with glucose as energy substrates. 70 HKMJ Vol 6 No 1 March 2000 Genetics of type 2 diabetes mellitus Increased levels of free fatty acids can also induce Maturity-onset diabetes of youth insulin resistance by reducing the hepatic clearance of insulin and enhancing gluconeogenesis through the Blood glucose is the main secretagogue for insulin Randle cycle.17 More recent evidence suggests that secretion. In response to a high blood glucose level, a long-chain fatty acids may modulate gene tran- specific glucose transporter in the β cells, glucose scription or directly affect the activity of glycogen transporter-2, facilitates the uptake of glucose into the synthase.18 Furthermore, adipose tissue produces a cell. Glucose is then phosphorylated by glucokinase pro-inflammatory cytokine, tumour necrosis factor α, to glucose-6-phosphate, the first rate-limiting step in which can inhibit insulin signalling by inhibiting the glycolysis. As a result of glycolysis and mitochondrial phosphorylation of the insulin receptor and IRS-1.19 oxidative phosphorylation, adenosine triphosphate Other cytokines such as interleukin-6 may also induce (ATP) is produced and facilitates the closure of the endothelial dysfunction, which in turn can contribute transmembrane potassium channels. The subsequent to the clustering of cardiovascular risk factors, as depolarisation of the cell membrane causes
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