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Genetic Basis of Type 2 Diabetes Mellitus Implications for Therapy

  • Review Article
  • Published:
Treatments in Endocrinology

Abstract

Type 2 diabetes mellitus represents a multifactorial, heterogeneous group of disorders, which result from defects in insulin secretion, insulin action, or both. The prevalence of type 2 diabetes has increased dramatically worldwide over the past several decades, a trend that has been heavily influenced by the relatively recent changes in diet and physical activity levels. There is also strong evidence supporting a genetic component to type 2 diabetes susceptibility and several genes underlying monogenic forms of diabetes have already been identified. However, common type 2 diabetes is likely to result from the contribution of many genes interacting with different environmental factors to produce wide variation in the clinical course of the disease. Not surprisingly, the etiologic complexity underlying type 2 diabetes has made identification of the contributing genes difficult.

Current therapies in the management of type 2 diabetes include lifestyle intervention through diet modification and exercise, and oral or injected hypoglycemic agents; however, not all individuals with type 2 diabetes respond in the same way to these treatments. Because of variability in the clinical course of the disease and in the responsiveness to pharmacologic therapies, identification and characterization of the genetic variants underlying type 2 diabetes susceptibility will be important in the development of individualized treatment. Findings from linkage analyses, candidate gene studies, and animal models will be valuable in the identification of novel pathways involved in the regulation of glucose homeostasis, and will augment our understanding of the gene-gene and gene-environment interactions, which impact on type 2 diabetes etiology and pathogenesis. In addition, identification of genetic variants that determine differences in antidiabetic drug responsiveness will be useful in assessing a first-line pharmacologie therapy for diabetic patients.

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References

  1. Fauci A, Braunwald E, Isselbacher K, et al. Harrison’s principles of internal medicine. 14th ed. New York (NY): McGraw-Hill Professional, 1998

  2. Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature 2001; 414(6865): 782–7

    Article  PubMed  CAS  Google Scholar 

  3. Green A, Christian Hirsch N, Pramming S. The changing world demography of type 2 diabetes. Diabetes Metab Res Rev 2003; 19(1): 3–7

    Article  PubMed  Google Scholar 

  4. King H, Aubert RE, Herman WH. Global burden of diabetes, 1995–2025: prevalence, numerical estimates, and projections. Diabetes Care 1998; 21(9): 1414–31

    Article  PubMed  CAS  Google Scholar 

  5. Fagot-Campagna A. Emergence of type 2 diabetes mellitus in children: epidemiological evidence. J Pediatr Endocrinol Metab 2000; 13Suppl. 6: 1395–402

    PubMed  Google Scholar 

  6. Gungor N, Arslanian S. Pathophysiology of type 2 diabetes mellitus in children and adolescents: treatment implications. Treat Endocrinol 2002; 1(6): 359–71

    Article  PubMed  Google Scholar 

  7. Dabelea D, Hanson RL, Bennett PH, et al. Increasing prevalence of type II diabetes in American Indian children. Diabetologia 1998; 41(8): 904–10

    Article  PubMed  CAS  Google Scholar 

  8. Hogan P, Dall T, Nikolov P. Economic costs of diabetes in the US in 2002. Diabetes Care 2003; 26(3): 917–32

    Article  PubMed  Google Scholar 

  9. Bougneres P. Genetics of obesity and type 2 diabetes: tracking pathogenic traits during the predisease period. Diabetes 2002; 51Suppl. 3: S295–303

    Article  PubMed  CAS  Google Scholar 

  10. Barnett AH, Eff C, Leslie RD, et al. Diabetes in identical twins: a study of 200 pairs. Diabetologia 1981; 20(2): 87–93

    Article  PubMed  CAS  Google Scholar 

  11. Newman B, Selby JV, King MC, et al. Concordance for type 2 (non-insulin-dependent) diabetes mellitus in male twins. Diabetologia 1987; 30(10): 763–8

    Article  PubMed  CAS  Google Scholar 

  12. Poulsen P, Kyvik KO, Vaag A, et al. Heritability of type II (non-insulin-dependent) diabetes mellitus and abnormal glucose tolerance: a population-based twin study. Diabetologia 1999; 42(2): 139–45

    Article  PubMed  CAS  Google Scholar 

  13. Klein BE, Klein R, Moss SE, et al. Parental history of diabetes in a population-based study. Diabetes Care 1996; 19(8): 827–30

    Article  PubMed  CAS  Google Scholar 

  14. Knowler WC, Bennett PH, Hamman RF, et al. Diabetes incidence and prevalence in Pima Indians: a 19-fold greater incidence than in Rochester, Minnesota. Am J Epidemiol 1978; 108(6): 497–505

    PubMed  CAS  Google Scholar 

  15. Knowler WC, Pettitt DJ, Savage PJ, et al. Diabetes incidence in Pima Indians: contributions of obesity and parental diabetes. Am J Epidemiol 1981; 113(2): 144–56

    PubMed  CAS  Google Scholar 

  16. Rushforth NB, Bennett PH, Steinberg AG, et al. Diabetes in the Pima Indians: evidence of bimodality in glucose tolerance distributions. Diabetes 1971; 20(11): 756–65

    PubMed  CAS  Google Scholar 

  17. Zimmet P, Dowse G, Finch C, et al. The epidemiology and natural history of NIDDM: lessons from the South Pacific. Diabetes Metab Rev 1990; 6(2): 91–124

    Article  PubMed  CAS  Google Scholar 

  18. Zimmet P, King H, Taylor R, et al. The high prevalence of diabetes mellitus, impaired glucose tolerance and diabetic retinopathy in Nauru: the 1982 survey. Diabetes Res 1984; 1(1): 13–8

    PubMed  CAS  Google Scholar 

  19. Williams RC, Long JC, Hanson RL, et al. Individual estimates of European genetic admixture associated with lower body-mass index, plasma glucose, and prevalence of type 2 diabetes in Pima Indians. Am J Hum Genet 2000; 66(2): 527–38

    Article  PubMed  CAS  Google Scholar 

  20. Korf BR. Genetics in medical practice. Genet Med 2002; 4 (6 Suppl.): 10S–14S

    Article  PubMed  CAS  Google Scholar 

  21. DeFronzo RA, Bonadonna RC, Ferrannini E. Pathogenesis of NIDDM: a balanced overview. Diabetes Care 1992; 15(3): 318–68

    Article  PubMed  CAS  Google Scholar 

  22. Medici F, Hawa M, Ianari A, et al. Concordance rate for type II diabetes mellitus in monozygotic twins: actuarial analysis. Diabetologia 1999; 42(2): 146–50

    Article  PubMed  CAS  Google Scholar 

  23. Grandinetti A, Keawe’aimoku Kaholokula J, Chang HK, et al. Relationship between plasma glucose concentrations and native Hawaiian ancestry: the Native Hawaiian Health Research Project. Int J Obes Relat Metab Disord 2002; 26(6): 778–82

    Article  PubMed  CAS  Google Scholar 

  24. Lillioja S, Mott DM, Zawadzki JK, et al. In vivo insulin action is a familial characteristic in nondiabetic Pima Indians. Diabetes 1987; 36(11): 1329–35

    Article  PubMed  CAS  Google Scholar 

  25. Sakul H, Pratley R, Cardon L, et al. Familiality of physical and metabolic characteristics that predict the development of non-insulin-dependent diabetes mellitus in Pima Indians. Am J Hum Genet 1997; 60(3): 651–6

    PubMed  CAS  Google Scholar 

  26. Martin BC, Warram JH, Rosner B, et al. Familial clustering of insulin sensitivity. Diabetes 1992; 41(7): 850–4

    Article  PubMed  CAS  Google Scholar 

  27. Hanson RL, Imperatore G, Narayan KM, et al. Family and genetic studies of indices of insulin sensitivity and insulin secretion in Pima Indians. Diabetes Metab Res Rev 2001; 17(4): 296–303

    Article  PubMed  CAS  Google Scholar 

  28. Cook JT, Shields DC, Page RC, et al. Segregation analysis of NIDDM in Caucasian families. Diabetologia 1994; 37(12): 1231–40

    Article  PubMed  CAS  Google Scholar 

  29. Elbein SC. Perspective: the search for genes for type 2 diabetes in the post-genome era. Endocrinology 2002; 143(6): 2012–8

    Article  PubMed  CAS  Google Scholar 

  30. Fajans SS, Bell GI, Polonsky KS. Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. N Engl J Med 2001; 345(13): 971–80

    Article  PubMed  CAS  Google Scholar 

  31. Stride A, Hattersley AT. Different genes, different diabetes: lessons from maturity-onset diabetes of the young. Ann Med 2002; 34(3): 207–16

    PubMed  CAS  Google Scholar 

  32. Velho G, Froguel P. Genetic, metabolic and clinical characteristics of maturity onset diabetes of the young. Eur J Endocrinol 1998; 138(3): 233–9

    Article  PubMed  CAS  Google Scholar 

  33. Ledermann HM. Is maturity onset diabetes at young age (MODY) more common in Europe than previously assumed [letter]. Lancet 1995; 345(8950): 648

    Article  PubMed  CAS  Google Scholar 

  34. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998; 15(7): 539–53

    Article  PubMed  CAS  Google Scholar 

  35. Yamagata K, Furuta H, Oda N, et al. Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1). Nature 1996; 384(6608): 458–60

    Article  PubMed  CAS  Google Scholar 

  36. Vionnet N, Stoffel M, Takeda J, et al. Nonsense mutation in the glucokinase gene causes early-onset non-insulin-dependent diabetes mellitus. Nature 1992; 356(6371): 721–2

    Article  PubMed  CAS  Google Scholar 

  37. Yamagata K, Oda N, Kaisaki PJ, et al. Mutations in the hepatocyte nuclear factor-lalpha gene in maturity-onset diabetes of the young (MODY3). Nature 1996; 384(6608): 455–8

    Article  PubMed  CAS  Google Scholar 

  38. Stoffers DA, Ferrer J, Clarke WL, et al. Early-onset type-II diabetes mellitus (MODY4) linked to IPF1. Nat Genet 1997; 17(2): 138–9

    Article  PubMed  CAS  Google Scholar 

  39. Horikawa Y, Iwasaki N, Hara M, et al. Mutation in hepatocyte nuclear factor- lbeta gene (TCF2) associated with MODY. Nat Genet 1997; 17(4): 384–5

    Article  PubMed  CAS  Google Scholar 

  40. Malecki MT, Jhala US, Antonellis A, et al. Mutations in NEUROD1 are associated with the development of type 2 diabetes mellitus. Nat Genet 1999; 23(3): 323–8

    Article  PubMed  CAS  Google Scholar 

  41. Froguel P, Zouali H, Vionnet N, et al. Familial hyperglycemia due to mutations in glucokinase: definition of a subtype of diabetes mellitus. N Engl J Med 1993; 328(10): 697–702

    Article  PubMed  CAS  Google Scholar 

  42. Matschinsky FM, Glaser B, Magnuson MA. Pancreatic beta-cell glucokinase: closing the gap between theoretical concepts and experimental realities. Diabetes 1998; 47(3): 307–15

    Article  PubMed  CAS  Google Scholar 

  43. Velho G, Petersen KF, Perseghin G, et al. Impaired hepatic glycogen synthesis in glucokinase-deficient (MODY-2) subjects. J Clin Invest 1996; 98(8): 1755–61

    Article  PubMed  CAS  Google Scholar 

  44. Stoffel M, Duncan SA. The maturity-onset diabetes of the young (MODY1) transcription factor HNF4alpha regulates expression of genes required for glucose transport and metabolism. Proc Natl Acad Sci U S A 1997; 94(24): 13209–14

    Article  PubMed  CAS  Google Scholar 

  45. Okita K, Yang Q, Yamagata K, et al. Human insulin gene is a target gene of hepatocyte nuclear factor-lalpha (HNF-1alpha) and HNF-1beta. Biochem Biophys Res Commun 1999; 263(2): 566–9

    Article  PubMed  CAS  Google Scholar 

  46. Byrne MM, Sturis J, Fajans SS, et al. Altered insulin secretory responses to glucose in subjects with a mutation in the MODY1 gene on chromosome 20. Diabetes 1995; 44(6): 699–704

    Article  PubMed  CAS  Google Scholar 

  47. Shih DQ, Dansky HM, Fleisher M, et al. Genotype/phenotype relationships in HNF-4alpha/MODY1: haplo insufficiency is associated with reduced apolipoprotein (AII), apolipoprotein (CIII), lipoprotein(a), and triglyceride levels. Diabetes 2000; 49(5): 832–7

    Article  PubMed  CAS  Google Scholar 

  48. Byrne MM, Sturis J, Menzel S, et al. Altered insulin secretory responses to glucose in diabetic and nondiabetic subjects with mutations in the diabetes susceptibility gene MODY3 on chromosome 12. Diabetes 1996; 45(11): 1503–10

    Article  PubMed  CAS  Google Scholar 

  49. Pontoglio M, Prie D, Cheret C, et al. HNF1alpha controls renal glucose reabsorption in mouse and man. EMBO Rep 2000; 1(4): 359–65

    Article  PubMed  CAS  Google Scholar 

  50. Stoffers DA, Zinkin NT, Stanojevic V, et al. Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat Genet 1997; 15(1): 106–10

    Article  PubMed  CAS  Google Scholar 

  51. Nishigori H, Yamada S, Kohama T, et al. Frameshift mutation, A263fsinsGG, in the hepatocyte nuclear factor-1beta gene associated with diabetes and renal dysfunction. Diabetes 1998; 47(8): 1354–5

    Article  PubMed  CAS  Google Scholar 

  52. Lindner TH, Njolstad PR, Horikawa Y, et al. A novel syndrome of diabetes mellitus, renal dysfunction and genital malformation associated with a partial deletion of the pseudo-POU domain of hepatocyte nuclear factor-1beta. Hum Mol Genet 1999; 8(11): 2001–8

    Article  PubMed  CAS  Google Scholar 

  53. Naya FJ, Huang HP, Qiu Y, et al. Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in beta2/neuroD-deficient mice. Genes Dev 1997; 11(18): 2323–34

    Article  PubMed  CAS  Google Scholar 

  54. Hegele RA, Cao H, Harris SB, et al. The hepatic nuclear factor-1alpha G319S variant is associated with early-onset type 2 diabetes in Canadian Oji-Cree. J Clin Endocrinol Metab 1999; 84(3): 1077–82

    Article  PubMed  CAS  Google Scholar 

  55. Busch CP, Hegele RA. Genetic determinants of type 2 diabetes mellitus. Clin Genet 2001; 60(4): 243–54

    Article  PubMed  CAS  Google Scholar 

  56. Hani EH, Stoffers DA, Chevre JC, et al. Defective mutations in the insulin promoter factor-1 (IPF-1) gene in late-onset type 2 diabetes mellitus. J Clin Invest 1999; 104(9): R41–8

    Article  PubMed  CAS  Google Scholar 

  57. Froguel P, Vaxillaire M, Sun F, et al. Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus. Nature 1992; 356(6365): 162–4

    Article  PubMed  CAS  Google Scholar 

  58. Vaxillaire M, Boccio V, Philippi A, et al. A gene for maturity onset diabetes of the young (MODY) maps to chromosome 12q. Nat Genet 1995; 9(4): 418–23

    Article  PubMed  CAS  Google Scholar 

  59. Lander ES, Schork NJ. Genetic dissection of complex traits. Science 1994; 265(5181): 2037–48

    Article  PubMed  CAS  Google Scholar 

  60. Hanson RL, Ehm MG, Pettitt DJ, et al. An autosomal genomic scan for loci linked to type II diabetes mellitus and body-mass index in Pima Indians. Am J Hum Genet 1998; 63(4): 1130–8

    Article  PubMed  CAS  Google Scholar 

  61. Elbein SC, Hoffman MD, Teng K, et al. A genome-wide search for type 2 diabetes susceptibility genes in Utah Caucasians. Diabetes 1999; 48(5): 1175–82

    Article  PubMed  CAS  Google Scholar 

  62. Vionnet N, Hani EL, Dupont S, et al. Genome-wide search for type 2 diabetes-susceptibility genes in French whites: evidence for a novel susceptibility locus for early-onset diabetes on chromosome 3q27-qter and independent replication of a type 2-diabetes locus on chromosome 1q21-q24. Am J Hum Genet 2000; 67(6): 1470–80

    Article  PubMed  CAS  Google Scholar 

  63. Wiltshire S, Hattersley AT, Hitman GA, et al. A genome-wide scan for loci predisposing to type 2 diabetes in a UK population (the Diabetes UK Warren 2 Repository): analysis of 573 pedigrees provides independent replication of a susceptibility locus on chromosome 1q. Am J Hum Genet 2001; 69(3): 553–69

    Article  PubMed  CAS  Google Scholar 

  64. Hsueh WC, St Jean PL, Mitchell BD, et al. Genome-wide and fine-mapping linkage studies of type 2 diabetes and glucose traits in the old order Amish: evidence for a new diabetes locus on chromosome 14q11 and confirmation of a locus on chromosome 1q21-q24. Diabetes 2003; 52(2): 550–7

    Article  PubMed  CAS  Google Scholar 

  65. Xiang K. Search for type 2 diabetes susceptibility genes in Chinese, 2002 [abstract]. Diabetes Res Clin Pract 2002; 56Suppl. 1: SY019

    Google Scholar 

  66. Ghosh S, Watanabe RM, Hauser ER, et al. Type 2 diabetes: evidence for linkage on chromosome 20 in 716 Finnish affected sib pairs. Proc Natl Acad Sci U S A 1999; 96(5): 2198–203

    Article  PubMed  CAS  Google Scholar 

  67. Bowden DW, Sale M, Howard TD, et al. Linkage of genetic markers on human chromosomes 20 and 12 to NIDDM in Caucasian sib pairs with a history of diabetic nephropathy. Diabetes 1997; 46(5): 882–6

    Article  PubMed  CAS  Google Scholar 

  68. Zouali H, Hani EH, Philippi A, et al. A susceptibility locus for early-onset non-insulin dependent (type 2) diabetes mellitus maps to chromosome 20q, proximal to the phosphoenolpyruvate carboxykinase gene. Hum Mol Genet 1997; 6(9): 1401–8

    Article  PubMed  CAS  Google Scholar 

  69. Klupa T, Malecki MT, Pezzolesi M, et al. Further evidence for a susceptibility locus for type 2 diabetes on chromosome 20q13.1-q13.2. Diabetes 2000; 49(12): 2212–6

    Article  PubMed  CAS  Google Scholar 

  70. Permutt MA, Wasson JC, Suarez BK, et al. A genome scan for type 2 diabetes susceptibility loci in a genetically isolated population. Diabetes 2001; 50(3): 681–5

    Article  PubMed  CAS  Google Scholar 

  71. Mahtani MM, Widen E, Lehto M, et al. Mapping of a gene for type 2 diabetes associated with an insulin secretion defect by a genome scan in Finnish families. Nat Genet 1996; 6: 90–4

    Google Scholar 

  72. Shaw JT, Lovelock PK, Kesting JB, et al. Novel susceptibility gene for late-onset NIDDM is localized to human chromosome 12q. Diabetes 1998; 47(11): 1793–6

    Article  PubMed  CAS  Google Scholar 

  73. Ehm MG, Karnoub MC, Sakul H, et al. Genome-wide search for type 2 diabetes susceptibility genes in four American populations. Am J Hum Genet 2000; 66(6): 1871–81

    Article  PubMed  CAS  Google Scholar 

  74. Hanis CL, Boerwinkle E, Chakraborty R, et al. A genome-wide search for human non-insulin-dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2. Nat Genet 1996; 13(2): 161–6

    Article  PubMed  CAS  Google Scholar 

  75. Horikawa Y, Oda N, Cox NJ, et al. Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nat Genet 2000; 26(2): 163–75

    Article  PubMed  CAS  Google Scholar 

  76. Malecki MT, Moczulski DK, Klupa T, et al. Homozygous combination of calpain 10 gene haplotypes is associated with type 2 diabetes mellitus in a Polish population. Eur J Endocrinol 2002; 146(5): 695–9

    Article  PubMed  Google Scholar 

  77. Cassell PG, Jackson AE, North BV, et al. Haplotype combinations of calpain 10 gene polymorphisms associated with increased risk of impaired glucose tolerance and type 2 diabetes in South Indians. Diabetes 2002; 51(5): 1622–8

    Article  PubMed  CAS  Google Scholar 

  78. Baier LJ, Permana PA, Yang X, et al. A calpain-10 gene polymorphism is associated with reduced muscle mRNA levels and insulin resistance. J Clin Invest 2000; 106(7): R69–73

    Article  PubMed  CAS  Google Scholar 

  79. Lynn S, Evans JC, White C, et al. Variation in the calpain-10 gene affects blood glucose levels in the British population. Diabetes 2002; 51(1): 247–50

    Article  PubMed  CAS  Google Scholar 

  80. Orho-Melander M, Klannemark M, Svensson MK, et al. Variants in the calpain-10 gene predispose to insulin resistance and elevated free fatty acid levels. Diabetes 2002; 51(8): 2658–64

    Article  PubMed  CAS  Google Scholar 

  81. Sreenan SK, Zhou YP, Otani K, et al. Calpains play a role in insulin secretion and action. Diabetes 2001; 50(9): 2013–20

    Article  PubMed  CAS  Google Scholar 

  82. Altshuler D, Hirschhorn JN, Klannemark M, et al. The common PPARgamma Prol2Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet 2000; 26(1): 76–80

    Article  PubMed  CAS  Google Scholar 

  83. Deeb SS, Fajas L, Nemoto M, et al. A Pro12Ala substitution in PPARgamma2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nat Genet 1998; 20(3): 284–7

    Article  PubMed  CAS  Google Scholar 

  84. Lohmueller KE, Pearce CL, Pike M, et al. Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet 2003; 33(2): 177–82

    Article  PubMed  CAS  Google Scholar 

  85. Gloyn AL, McCarthy MI. The genetics of type 2 diabetes. Best Pract Res Clin Endocrinol Metab 2001; 15(3): 293–308

    Article  PubMed  CAS  Google Scholar 

  86. Sesti G. Searching for type 2 diabetes genes: prospects in pharmacotherapy. Pharmacogenomics J 2002; 2(1): 25–9

    Article  PubMed  CAS  Google Scholar 

  87. Desvergne B, Wahli W. Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev 1999; 20(5): 649–88

    Article  PubMed  CAS  Google Scholar 

  88. Harris PK, Kletzien RF. Localization of a pioglitazone response element in the adipocyte fatty acid-binding protein gene. Mol Pharmacol 1994; 45(3): 439–45

    PubMed  CAS  Google Scholar 

  89. Tontonoz P, Hu E, Graves RA, et al. mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer. Genes Dev 1994; 8(10): 1224–34

    Article  PubMed  CAS  Google Scholar 

  90. Nolte RT, Wisely GB, Westin S, et al. Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma. Nature 1998; 395(6698): 137–43

    Article  PubMed  CAS  Google Scholar 

  91. Maeda N, Takahashi M, Funahashi T, et al. PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes 2001; 50(9): 2094–109

    Article  PubMed  CAS  Google Scholar 

  92. Yamauchi T, Kamon J, Waki H, et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 2001;7(8): 941–6

    Article  PubMed  CAS  Google Scholar 

  93. Picard F, Auwerx J. PPAR(gamma) and glucose homeostasis. Annu Rev Nutr 2002; 22: 167–97

    Article  PubMed  CAS  Google Scholar 

  94. Miles PD, Barak Y, Evans RM, et al. Effect of heterozygous PPARgamma deficiency and TZD treatment on insulin resistance associated with age and high-fat feeding. Am J Physiol Endocrinol Metab 2003; 284(3): E618–26

    PubMed  CAS  Google Scholar 

  95. Okuno A, Tamemoto H, Tobe K, et al. Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese Zucker rats. J Clin Invest 1998; 101(6): 1354–61

    Article  PubMed  CAS  Google Scholar 

  96. Yen CJ, Beamer BA, Negri C, et al. Molecular scanning of the human peroxisome proliferator activated receptor gamma (hPPAR gamma) gene in diabetic Caucasians: identification of a Pro12Ala PPAR gamma 2 missense mutation. Biochem Biophys Res Commun 1997; 241(2): 270–4

    Article  PubMed  CAS  Google Scholar 

  97. Miles PD, Barak Y, He W, et al. Improved insulin-sensitivity in mice heterozygous for PPAR-gamma deficiency. J Clin Invest 2000; 105(3): 287–92

    Article  PubMed  CAS  Google Scholar 

  98. Ristow M, Muller-Wieland D, Pfeiffer A, et al. Obesity associated with a mutation in a genetic regulator of adipocyte differentiation. N Engl J Med 1998; 339(14): 953–9

    Article  PubMed  CAS  Google Scholar 

  99. Barroso I, Gurnell M, Crowley VE, et al. Dominant negative mutations in human PPARgamma associated with severe insulin resistance, diabetes mellitus and hypertension. Nature 1999; 402(6764): 880–3

    PubMed  CAS  Google Scholar 

  100. Yamauchi T, Kamon J, Waki H, et al. The mechanisms by which both heterozygous peroxisome proliferator-activated receptor gamma (PPARgamma) deficiency and PPARgamma agonist improve insulin resistance. J Biol Chem 2001; 276(44): 41245–54

    Article  PubMed  CAS  Google Scholar 

  101. Weyer C, Bogardus C, Mott DM, et al. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest 1999; 104(6): 787–94

    Article  PubMed  CAS  Google Scholar 

  102. Pearson ER, Velho G, Clark P, et al. Beta-cell genes and diabetes: quantitative and qualitative differences in the pathophysiology of hepatic nuclear factor-1alpha and glucokinase mutations. Diabetes 2001; 50Suppl. 1: S101–7

    Article  PubMed  CAS  Google Scholar 

  103. Pearson ER, Liddell WG, Shepherd M, et al. Sensitivity to sulphonylureas in patients with hepatocyte nuclear factor-lalpha gene mutations: evidence for pharmacogenetics in diabetes. Diabet Med 2000; 17(7): 543–5

    Article  PubMed  CAS  Google Scholar 

  104. Roses AD. Genome-based pharmacogenetics and the pharmaceutical industry. Nat Rev Drug Discov 2002; 1(7): 541–9

    Article  PubMed  CAS  Google Scholar 

  105. Buchanan TA, Xiang AH, Peters RK, et al. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women. Diabetes 2002; 51(9): 2796–803

    Article  PubMed  CAS  Google Scholar 

  106. Gloyn AL, Weedon MH, Owen KR, et al. Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variants is associated with type 2 diabetes. Diabetes 2003; 52: 568–72

    Article  PubMed  CAS  Google Scholar 

  107. Love-Gregory L, Wasson J, Lin J, et al. E23K single nucleotide polymorphism in the islet ATP-sensitive potassium channel gene (Kir6.2) contributes as much to the risk of type II diabetes in Caucasians as the PPARgamma Pro12Ala variant. Diabetologia 2003; 46(1): 136–7

    PubMed  CAS  Google Scholar 

  108. Nielsen EM, Hansen L, Carstensen B, et al. The E23K variant of Kir6.2 associates with impaired post-OGTT serum insulin response and increased risk of type 2 diabetes. Diabetes 2003; 52(2): 573–7

    Article  PubMed  CAS  Google Scholar 

  109. Schwanstecher C, Meyer U, Schwanstecher M. KIR6.2 polymorphism predisposes to type 2 diabetes by inducing overactivity of pancreatic beta-cell ATP-sensitive K+ channels. Diabetes 2002; 51: 875–9

    Article  PubMed  CAS  Google Scholar 

  110. Wagenaar LJ, Kuck EM, Hoekstra JB. Troglitazone: is it all over? Neth J Med 1999; 55(1): 4–12

    Article  PubMed  CAS  Google Scholar 

  111. Watkins PB, Whitcomb RW. Hepatic dysfunction associated with troglitazone. N Engl J Med 1998; 338(13): 916–7

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This review was written during National Institute of Health fellowships for both authors (no funding source). The authors have no conflicts of interest that are directly relevant to the content of this review.

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  1. Research Program, Genetic Basis of Human Disease Division, Translational Genomics Research Institute, 400 North Fifth Street, Suite 1600, Phoenix, Arizona, 85004, USA

    Johanna K. Wolford

  2. Department of Clinical Physiology, Baker Heart Institute, Melbourne, Victoria, Australia

    Barbora Vozarova de Courten

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Correspondence to Johanna K. Wolford.

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Wolford, J.K., de Courten, B.V. Genetic Basis of Type 2 Diabetes Mellitus Implications for Therapy. Mol Diag Ther 3, 257–267 (2004). https://doi.org/10.2165/00024677-200403040-00007

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