Der Internist

, Volume 46, Issue 7, pp 741–749

Genetik des Typ-2-Diabetes

Schwerpunkt: Genetik in der Inneren Medizin

Zusammenfassung

In den letzten Jahren tritt Diabetes mellitus Typ 2 nahezu epidemisch auf. Weltweit sind mehr als 170 Mio. Menschen betroffen, allein in Deutschland leben ca. 6 Mio. Betroffene. Der Ausbruch der Erkrankung wird sowohl durch Umwelteinflüsse wie Bewegungsmangel und Überernährung, als auch durch genetische Faktoren begünstigt. Trotz aller Anstrengungen der medizinischen Forschung, prädisponierende Risikopositionen des Genoms ausfindig zu machen, ist die kausale Pathogenese des häufigen Nicht-MODY-Typ-2-Diabetes immer noch unklar. Nur wenige Gene sind bis jetzt identifiziert worden, die die individuelle Suszeptibilität für Typ-2-Diabetes verändern (zum Beispiel PPARG, KCNJ11, CAPN10). Oftmals konnten initiale signifikante Ergebnisse in Folgestudien nicht repliziert werden. Vermutlich sind Lokus- und allelische Heterogenität sowie ethnische Differenzen zwischen verschiedenen Populationen erschwerende Faktoren bei der molekulargenetischen Analyse. Untersuchungen an genetisch isolierten Populationen, wie den Pima-Indianern, können bei der Identifizierung von Suszeptibilitätsallelen vorteilhaft sein. Zur Zeit ist es nicht möglich, vom Vorliegen eines bestimmten Suszeptibilitätsallels auf das individuelle Erkrankungsrisiko zu schließen.

Schlüsselwörter

Typ-2-Diabetes Insulinresistenz Hyperglykämie Genetische Polymorphismen 

Genetics of type 2 diabetes

Abstract

In the last years type 2 diabetes has reached almost epidemic proportions. More than 170 million individuals are affected worldwide, about 6 million in Germany. Manifestation of type 2 diabetes is determined by both environmental factors such as lack of physical exercise and overeating and a genetic predisposition. Despite enormous efforts in medical research to identify susceptibility loci and high risk alleles, the genetics of common type 2 diabetes (non-MODY) remain unknown. To date, only a few susceptibility genes have been identified (such as PPARG, KCNJ11, CAPN10). However, replication of initial studies is often difficult. This can be explained by both locus and allelic heterogeneity as well as ethnic differences between different populations. Studies in genetically isolated populations such as the Pima Indians are advantageous to identify susceptibility alleles. Despite some recent advances, it is not possible to predict an individual’s risk of type 2 diabetes based on the presence of a certain disease-risk allele.

Keywords

Type 2 diabetes Insulin resistance Hyperglycaemia Genetic polymorphisms 

Literatur

  1. 1.
    Zimmet P, Alberti KG, Shaw J (2001) Global and societal implications of the diabetes epidemic. Nature 414 Clinical Queries: 782–787Google Scholar
  2. 2.
    McCarthy MI (2003) Growing evidence for diabetes susceptibility genes from genome scan data. Curr Diab Rep 3: 159–167PubMedGoogle Scholar
  3. 3.
    Sinha R, Fisch G, Teague B et al. (2002) Prevalence of impaired glucose tolerance among children and adolescents with marked obesity. N Engl J Med 346: 802–810PubMedGoogle Scholar
  4. 4.
    Fajans SS, Bell GI, Polonsky KS (2001) Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. N Engl J Med 345: 971–980CrossRefPubMedGoogle Scholar
  5. 5.
    Maassen JA, T Hart LM, Van Essen E et al. (2004) Mitochondrial diabetes: molecular mechanisms and clinical presentation. Diabetes 53 [Suppl 1]: S103–S109PubMedGoogle Scholar
  6. 6.
    Pozzilli P, Di Mario U (2001) Autoimmune diabetes not requiring insulin at diagnosis (latent autoimmune diabetes of the adult): definition, characterization, and potential prevention. Diabetes Care 24: 1460–1467PubMedGoogle Scholar
  7. 7.
    Wei M, Gaskill SP, Haffner SM, Stern MP (1998) Effects of diabetes and level of glycemia on all-cause and cardiovascular mortality. The San Antonio Heart Study. Diabetes Care 21: 1167–1172PubMedGoogle Scholar
  8. 8.
    UK Prospective Diabetes Study (UKPDS) Group (1998) Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352: 854–865CrossRefPubMedGoogle Scholar
  9. 9.
    UK Prospective Diabetes Study (UKPDS) Group (1998) Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352: 837–853CrossRefPubMedGoogle Scholar
  10. 10.
    Nichols GA, Glauber HS, Brown JB (2000) Type 2 diabetes: incremental medical care costs during the 8 years preceding diagnosis. Diabetes Care 23: 1654–1659PubMedGoogle Scholar
  11. 11.
    Pierce M, Keen H, Bradley C (1995) Risk of diabetes in offspring of parents with non-insulin-dependent diabetes. Diabet Med 12: 6–13PubMedGoogle Scholar
  12. 12.
    Tattersal RB, Fajans SS (1975) Prevalence of diabetes and glucose intolerance in 199 offspring of thirty-seven conjugal diabetic parents. Diabetes 24: 452–462PubMedGoogle Scholar
  13. 13.
    Kaprio J, Tuomilehto J, Koskenvuo M et al. (1992) Concordance for type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus in a population-based cohort of twins in Finland. Diabetologia 35: 1060–1067Google Scholar
  14. 14.
    Newman B, Selby JV, King MC, Slemenda C, Fabsitz R, Friedman GD (1987) Concordance for type 2 (non-insulin-dependent) diabetes mellitus in male twins. Diabetologia 30: 763–768PubMedGoogle Scholar
  15. 15.
    Henkin L, Bergman RN, Bowden DW et al. (2003) Genetic epidemiology of insulin resistance and visceral adiposity. The IRAS Family Study design and methods. Ann Epidemiol 13: 211–217PubMedGoogle Scholar
  16. 16.
    Beck-Nielsen H, Vaag A, Poulsen P, Gaster M (2003) Metabolic and genetic influence on glucose metabolism in type 2 diabetic subjects — experiences from relatives and twin studies. Best Pract Res Clin Endocrinol Metab 17: 445–467PubMedGoogle Scholar
  17. 17.
    Hales CN, Barker DJ (1992) Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia 35: 595–601Google Scholar
  18. 18.
    Hattersley AT, Tooke JE (1999) The fetal insulin hypothesis: an alternative explanation of the association of low birth-weight with diabetes and vascular disease. Lancet 353: 1789–1792PubMedGoogle Scholar
  19. 19.
    Weyer C, Bogardus C, Mott DM, Pratley RE (1999) The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest 104: 787–794PubMedGoogle Scholar
  20. 20.
    Parikh H, Groop L (2004) Candidate genes for type 2 diabetes. Rev Endocr Metab Disord 5: 151–176CrossRefPubMedGoogle Scholar
  21. 21.
    Lohmueller KE, Pearce CL, Pike M, Lander ES, Hirschhorn JN (2003) Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet 33: 177–182CrossRefPubMedGoogle Scholar
  22. 22.
    Auwerx J (1999) PPARgamma, the ultimate thrifty gene. Diabetologia 42: 1033–1049Google Scholar
  23. 23.
    Altshuler D, Hirschhorn JN, Klannemark M et al. (2000) The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet 26: 76–80CrossRefPubMedGoogle Scholar
  24. 24.
    Memisoglu A, Hu FB, Hankinson SE, Liu S et al. (2003) Prospective study of the association between the proline to alanine codon 12 polymorphism in the PPARgamma gene and type 2 diabetes. Diabetes Care 26: 2915–2917PubMedGoogle Scholar
  25. 25.
    Ek J, Andersen G, Urhammer SA et al. (2001) Studies of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2) gene in relation to insulin sensitivity among glucose tolerant caucasians. Diabetologia 44: 1170–1176Google Scholar
  26. 26.
    Muller YL, Bogardus C, Beamer BA, Shuldiner AR, Baier LJ (2003) A functional variant in the peroxisome proliferator-activated receptor gamma2 promoter is associated with predictors of obesity and type 2 diabetes in Pima Indians. Diabetes 52: 1864–1871PubMedGoogle Scholar
  27. 27.
    Stumvoll M, Haring H (2002) The peroxisome proliferator-activated receptor-gamma2 Pro12Ala polymorphism. Diabetes 51: 2341–2347PubMedGoogle Scholar
  28. 28.
    Porzio O, Federici M, Hribal ML et al. (1999) The Gly972→Arg amino acid polymorphism in IRS-1 impairs insulin secretion in pancreatic beta cells. J Clin Invest 104: 357–364PubMedGoogle Scholar
  29. 29.
    Stumvoll M, Fritsche A, Volk A et al. (2001) The Gly972Arg polymorphism in the insulin receptor substrate-1 gene contributes to the variation in insulin secretion in normal glucose-tolerant humans. Diabetes 50: 882–885PubMedGoogle Scholar
  30. 30.
    Ek J, Andersen G, Urhammer SA et al. (2001) Mutation analysis of peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1) and relationships of identified amino acid polymorphisms to Type II diabetes mellitus. Diabetologia 44: 2220–2226CrossRefPubMedGoogle Scholar
  31. 31.
    Gloyn AL, Weedon MN, Owen KR et al. (2003) 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 E23 K variant is associated with type 2 diabetes. Diabetes 52: 568–572PubMedGoogle Scholar
  32. 32.
    Florez JC, Burtt N, de Bakker PI et al. (2004) Haplotype structure and genotype-phenotype correlations of the sulfonylurea receptor and the islet ATP-sensitive potassium channel gene region. Diabetes 53: 1360–1368PubMedGoogle Scholar
  33. 33.
    Rhodes CJ, White MF (2002) Molecular insights into insulin action and secretion. Eur J Clin Invest 32 [Suppl 3]: 3–13Google Scholar
  34. 34.
    Hanson RL, Ehm MG, Pettitt DJ et al. (1998) An autosomal genomic scan for loci linked to type II diabetes mellitus and body-mass index in Pima Indians. Am J Hum Genet 63: 1130–1138CrossRefPubMedGoogle Scholar
  35. 35.
    Elbein SC, Hoffman MD, Teng K, Leppert MF, Hasstedt SJ (1999) A genome-wide search for type 2 diabetes susceptibility genes in Utah Caucasians. Diabetes 48: 1175–1182PubMedGoogle Scholar
  36. 36.
    St.Jean P, Hsueh WC, Mitchell B et al. (2000) Association between diabetes, obesity, glucose and insulin levels in the old order Amish and SNPs on 1q21–23. Am J Hum Genet 67 [Suppl 2]: 1848Google Scholar
  37. 37.
    Wiltshire S, Hattersley AT, Hitman GA et al. (2001) A genomewide scan for loci predisposing to type 2 diabetes in a U.K. 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 69: 553–569PubMedGoogle Scholar
  38. 38.
    Vionnet N, Hani E, Dupont S et al. (2000) Genomewide 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 67: 1470–1480CrossRefPubMedGoogle Scholar
  39. 39.
    Meigs JB, Panhuysen CI, Myers RH, Wilson PW, Cupples LA (2002) A genome-wide scan for loci linked to plasma levels of glucose and HbA(1c) in a community-based sample of Caucasian pedigrees: The Framingham Offspring Study. Diabetes 51: 833–840PubMedGoogle Scholar
  40. 40.
    Xiang K, Wang Y, Zheng T et al. (2002) Genome wide scan for type 2 diabetes susceptibility loci in Chinese. Diabetes 51 [Suppl 2]: A262Google Scholar
  41. 41.
    Mori Y, Otabe S, Dina C et al. (2002) Genome-wide search for type 2 diabetes in Japanese affected sib-pairs confirms susceptibility genes on 3q, 15q, and 20q and identifies two new candidate Loci on 7p and 11p. Diabetes 51: 1247–1255PubMedGoogle Scholar
  42. 42.
    Busfield F, Duffy DL, Kesting JB et al. (2002) A genomewide search for type 2 diabetes-susceptibility genes in indigenous Australians. Am J Hum Genet 70: 349–357PubMedGoogle Scholar
  43. 43.
    Permutt MA, Wasson JC, Suarez BK et al. (2001) A genome scan for type 2 diabetes susceptibility loci in a genetically isolated population. Diabetes 50: 681–685PubMedGoogle Scholar
  44. 44.
    Duggirala R, Blangero J, Almasy L et al. (1999) Linkage of type 2 diabetes mellitus and of age at onset to a genetic location on chromosome 10q in Mexican Americans. Am J Hum Genet 64: 1127–1140PubMedGoogle Scholar
  45. 45.
    Ghosh S, Watanabe RM, Valle TT et al. (2000) The Finland-United States investigation of non-insulin-dependent diabetes mellitus genetics (FUSION) study. I. An autosomal genome scan for genes that predispose to type 2 diabetes. Am J Hum Genet 67: 1174–1185PubMedGoogle Scholar
  46. 46.
    Ehm MG, Karnoub MC, Sakul H et al. (2000) Genomewide search for type 2 diabetes susceptibility genes in four American populations. Am J Hum Genet 66: 1871–1881PubMedGoogle Scholar
  47. 47.
    Lindgren CM, Mahtani MM, Widen E et al. (2002) Genomewide search for type 2 diabetes mellitus susceptibility loci in Finnish families: the Botnia study. Am J Hum Genet 70: 509–516PubMedGoogle Scholar
  48. 48.
    Luo TH, Zhao Y, Li G et al. (2001) A genome-wide search for type II diabetes susceptibility genes in Chinese Hans. Diabetologia 44: 501–506CrossRefPubMedGoogle Scholar
  49. 49.
    Pratley RE, Thompson DB, Prochazka M et al. (1998) An autosomal genomic scan for loci linked to prediabetic phenotypes in Pima Indians. J Clin Invest 101: 1757–1764PubMedGoogle Scholar
  50. 50.
    Cox NJ (2001) Challenges in identifying genetic variation affecting susceptibility to type 2 diabetes: examples from studies of the calpain-10 gene. Hum Mol Genet 10: 2301–2305PubMedGoogle Scholar
  51. 51.
    Horikawa Y, Oda N, Cox NJ et al. (2000) Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nat Genet 26: 163–175CrossRefPubMedGoogle Scholar
  52. 52.
    Ma H, Fukiage C, Kim YH et al. (2001) Characterization and expression of calpain 10. A novel ubiquitous calpain with nuclear localization. J Biol Chem 276: 28525–28531PubMedGoogle Scholar
  53. 53.
    Suzuki K, Hata S, Kawabata Y, Sorimachi H (2004) Structure, activation, and biology of calpain. Diabetes 53 [Suppl 1]: S12–S18PubMedGoogle Scholar
  54. 54.
    Rasmussen SK, Urhammer SA, Berglund L et al. (2002) Variants within the calpain-10 gene on chromosome 2q37 (NIDDM 1) and relationships to type 2 diabetes, insulin resistance, and impaired acute insulin secretion among Scandinavian Caucasians. Diabetes 51: 3561–3567PubMedGoogle Scholar
  55. 55.
    Horikawa Y, Oda N, Yu L et al. (2003) Genetic variations in calpain-10 gene are not a major factor in the occurrence of type 2 diabetes in Japanese. J Clin Endocrinol Metab 88: 244–247PubMedGoogle Scholar
  56. 56.
    Evans JC, Frayling TM, Cassell PG et al. (2001) Studies of association between the gene for calpain-10 and type 2 diabetes mellitus in the United Kingdom. Am J Hum Genet 69: 544–552CrossRefPubMedGoogle Scholar
  57. 57.
    Bosque-Plata L, Aguilar-Salinas CA, Tusie-Luna MT et al. (2004) Association of the calpain-10 gene with type 2 diabetes mellitus in a Mexican population. Mol Genet Metab 81: 122–126PubMedGoogle Scholar
  58. 58.
    Song Y, Niu T, Manson JE, Kwiatkowski DJ, Liu S (2004) Are variants in the CAPN10 gene related to risk of type 2 diabetes? A quantitative assessment of population and family-based association studies. Am J Hum Genet 74: 208–222CrossRefPubMedGoogle Scholar
  59. 59.
    Weedon MN, Schwarz PE, Horikawa Y et al. (2003) Meta-analysis and a large association study confirm a role for calpain-10 variation in type 2 diabetes susceptibility. Am J Hum Genet 73: 1208–1212CrossRefPubMedGoogle Scholar
  60. 60.
    Baier LJ, Permana PA, Yang X et al. (2000) A calpain-10 gene polymorphism is associated with reduced muscle mRNA levels and insulin resistance. J Clin Invest 106: R69–R73PubMedGoogle Scholar
  61. 61.
    Sreenan SK, Zhou YP, Otani K et al. (2001) Calpains play a role in insulin secretion and action. Diabetes 50: 2013–2020PubMedGoogle Scholar
  62. 62.
    Tripathy D, Eriksson KF, Orho-Melander M, Fredriksson J, Ahlqvist G, Groop L (2004) Parallel manifestation of insulin resistance and beta cell decompensation is compatible with a common defect in Type 2 diabetes. Diabetologia 47: 782–793Google Scholar
  63. 63.
    Ong KK, Phillips DI, Fall C et al. (1999) The insulin gene VNTR, type 2 diabetes and birth weight. Nat Genet 21: 262–263CrossRefPubMedGoogle Scholar
  64. 64.
    Huxtable SJ, Saker PJ, Haddad L et al. (2000) Analysis of parent-offspring trios provides evidence for linkage and association between the insulin gene and type 2 diabetes mediated exclusively through paternally transmitted class III variable number tandem repeat alleles. Diabetes 49: 126–130PubMedGoogle Scholar
  65. 65.
    Knowler WC, Bennett PH, Hamman RF, Miller M (1978) Diabetes incidence and prevalence in Pima Indians: a 19-fold greater incidence than in Rochester, Minnesota. Am J Epidemiol 108: 497–505PubMedGoogle Scholar
  66. 66.
    Baier LJ, Hanson RL (2004) Genetic studies of the etiology of type 2 diabetes in Pima Indians: hunting for pieces to a complicated puzzle. Diabetes 53: 1181–1186PubMedGoogle Scholar
  67. 67.
    Baier L, Kovacs P, Wiedrich CH et al. (2002) Positional cloning of an obesity/diabetes susceptibility gene(s) on chromosome 11 in Pima Indians Journal: Am N Y Acad SCT 967: 258–264Google Scholar
  68. 68.
    Baier LJ, Muller YL, Kovacs P et al. (2003) Methods to identify obesity and type 2 diabetes mellitus susceptibility genes in Pima Indians Journal: Progress in Obesity Reseach 9: 365–369Google Scholar
  69. 70.
    Hsueh WC, Mitchell BD, Aburomia R et al. (2000) Diabetes in the Old Order Amish: characterization and heritability analysis of the Amish Family Diabetes Study. Diabetes Care 23: 595–601PubMedGoogle Scholar
  70. 71.
    Mills GW, Avery PJ, McCarthy MI et al. (2004) Heritability estimates for beta cell function and features of the insulin resistance syndrome in UK families with an increased susceptibility to type 2 diabetes. Diabetologia 47: 732–738Google Scholar
  71. 72.
    Poulsen P, Kyvik KO, Vaag A, Beck Nielsen H (1999) Heritability of type II (non-insulin-dependent) diabetes mellitus and abnormal glucose tolerance — a population-based twin study. Diabetologia 42: 139–145Google Scholar
  72. 73.
    Freeman MS, Mansfield MW, Barrett JH, Grant PJ (2002) Heritability of features of the insulin resistance syndrome in a community-based study of healthy families. Diabet Med 19: 994–999PubMedGoogle Scholar
  73. 74.
    Lehtovirta M, Kaprio J, Forsblom C, Eriksson J, Tuomilehto J, Groop L (2000) Insulin sensitivity and insulin secretion in monozygotic and dizygotic twins. Diabetologia 43: 285–293Google Scholar
  74. 75.
    Watanabe RM, Valle T, Hauser ER et al. (1999) Familiarity of quantitative metabolic traits in Finnish families with non-insulin-dependent diabetes mellitus. Finland-United States Investigation of NIDDM Genetics (FUSION) Study investigators. Hum Hered 49: 159–168PubMedGoogle Scholar
  75. 76.
    Bergman RN, Zaccaro DJ, Watanabe RM et al. (2003) Minimal model-based insulin sensitivity has greater heritability and a different genetic basis than homeostasis model assessment or fasting insulin. Diabetes 52: 2168–2174PubMedGoogle Scholar
  76. 77.
    Jenkins AB, Samaras K, Carey DG, Kelly P, Campbell LV (2000) Improved indices of insulin resistance and insulin secretion for use in genetic and population studies of type 2 diabetes mellitus. Twin Res 3: 148–151PubMedGoogle Scholar
  77. 78.
    Elbein SC, Hasstedt SJ, Wegner K, Kahn SE (1999) Heritability of pancreatic beta-cell function among nondiabetic members of Caucasian familial type 2 diabetic kindreds. J Clin Endocrinol Metab 84: 1398–1403CrossRefPubMedGoogle Scholar
  78. 79.
    Hong Y, Weisnagel SJ, Rice T et al. (2001) Familial resemblance for glucose and insulin metabolism indices derived from an intravenous glucose tolerance test in Blacks and Whites of the HERITAGE Family Study. Clin Genet 60: 22–30PubMedGoogle Scholar
  79. 80.
    Sakul H, Pratley R, Cardon L, Ravussin E, Mott D, Bogardus C (1997) Familiarity of physical and metabolic characteristics that predict the development of non-insulin-dependent diabetes mellitus in Pima Indians. Am J Hum Genet 60: 651–656PubMedGoogle Scholar

Copyright information

© Springer Medizin Verlag 2005

Authors and Affiliations

  • Y. Böttcher
    • 1
  • P. Kovacs
    • 1
  • A. Tönjes
    • 1
  • M. Stumvoll
    • 1
    • 2
  1. 1.Medizinische Klinik IIIUniversitätsklinikum Leipzig
  2. 2.Medizinische Klinik und Poliklinik IIIUniversitätsklinikumLeipzig

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