Candidate Genes for Type 2 Diabetes

  • William L. LoweJr.
Part of the Endocrine Updates book series (ENDO, volume 10)

Abstract

The pathogenesis of type 2 diabetes is complex, but is characterized by hyperglycemia secondary to a combination of insulin resistance and pancreatic 0-cell dysfunction that is manifest as inadequate insulin secretion in the face of insulin resistance and hyperglycemia (see Chapters 7 and 8) (1,2). Previous studies have established a clear genetic predisposition for type 2 diabetes (3, 4, 5). The concordance rate among monozygotic twins is 50 to 90% compared to 25 to 35% for dizygotic twins (6). Similarly —30% of offspring of affected individuals develop either type 2 diabetes or impaired glucose tolerance (3, 4, 5). Together, these data are consistent with a significant genetic contribution to the development of type 2 diabetes, but the lack of 100% concordance among monozygotic twins suggests that environmental influences are also important. Moreover, mathematical modeling has suggested that type 2 diabetes is polygenic, i.e., it is inherited in a non-Mendelian fashion and onset of the disease requires the simultaneous presence of a subset of susceptibility genes whose gene products affect insulin production, secretion or sensitivity (3, 4, 5). This has complicated efforts to identify diabetes susceptibility genes for several reasons: (1) the relative contributions of insulin resistance and altered insulin secretion to the pathogenesis of type 2 diabetes probably vary between individuals; (2) because of the above heterogeneity, susceptibility genes likely differ between and within populations; and (3) the effect of any single susceptibility gene on disease risk may be small, making identification of susceptibility genes difficult. Furthermore, environmental factors that still have not been fully defined, but include diet and physical activity, contribute to the development of type 2 diabetes (7, 8, 9). Thus, susceptibility genes for type 2 diabetes may be present in unaffected individuals because they lack a required complement of susceptibility genes or needed environmental factors to induce diabetes.

Keywords

Tyrosine Adenosine Serine Proline Arginine 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Reference

  1. 1.
    DeFronzo RA. 1997. Pathogenesis of type diabetes: metabolic and molecular implications for identifying diabetes genes. Diabetes Rev 5:177–269.Google Scholar
  2. 2.
    Gerich JE. 1998. The genetic basis of type 2 diabetes mellitus: impaired insulin secretion versus impaired insulin sensitivity. Endocr Rev 19:491–503.PubMedGoogle Scholar
  3. 3.
    Kahn CR, Vicent D, Doria A. 1996. Genetics of non-insulin-dependent (type-II) diabetes mellitus. Annu Rev Med 47:509–31.PubMedGoogle Scholar
  4. 4.
    Lowe WL, Jr. Diabetes Mellitus. In: Jameson JL, editor. Principles of Molecular Medicine. Totowa: Humana Press; 1998. p 433–442.Google Scholar
  5. 5.
    Permutt MA, Chiu K, Ferrer J, Glaser B, Inoue H, Nestorowicz A, Stanley CA, Tanizawa Y. 1998. Genetics of type II diabetes. Recent Prog Horn; Res 53:201–16.Google Scholar
  6. 6.
    Hawkes CH. 1997. Twin studies in diabetes mellitus. Diabet Med 14:347–52.PubMedGoogle Scholar
  7. 7.
    Howard BV. 1997. Dietary fatty acids, insulin resistance, and diabetes. Ann N YAcad Sci 827:215–20.Google Scholar
  8. 8.
    Storlien LH, Baur LA, Kriketos AD, Pan DA, Cooney GJ, Jenkins AB, Calvert GD, Campbell LV. 1996. Dietary fats and insulin action. Diabetologia 39:621–31.Google Scholar
  9. 9.
    Eriksson J, Taimela S, Koivisto VA. 1997. Exercise and the metabolic syndrome. Diabetologia 40:125–35.PubMedGoogle Scholar
  10. 10.
    Naya F.1, Huang HP, Qiu Y, Mutoh H, DeMayo FJ, Leiter AB, Tsai MJ. 1997. Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/neuroD-deficient mice. Genes Dey 11:2323–34.Google Scholar
  11. 11.
    Naya FJ, Stellrecht CM, Tsai MJ. 1995. Tissue-specific regulation of the insulin gene by a novel basic helix-loop-helix transcription factor. Genes Dey 9:1009–19.Google Scholar
  12. 12.
    Malecki MT, Jhala US, Antonellis A, Fields L, Doria A, Orban T, Sand M, Warram JH, Montminy M, Krolewski AS. 1999. Mutations in NEURODI are associated with the development of type 2 diabetes mellitus. Nat Genet 23:323–8.PubMedGoogle Scholar
  13. 13.
    Dupont S, Vionnet N, Chevre JC, Gallina S, Dina C, Seino Y, Yamada Y, Froguel P. 1999. No evidence of linkage or diabetes-associated mutations in the transcription factors BETA2/NEURODI and PAX4 in Type II diabetes in France. Diabetologia 42:480–4.PubMedGoogle Scholar
  14. 14.
    Stoffers DA, Ferrer J, Clarke WL, Habener JF. 1997. Early-onset type-II diabetes mellitus (MODY4) linked to IPF1. Nat Genet 17:138–9.PubMedGoogle Scholar
  15. 15.
    Stoffers DA, Zinkin NT, Stanojevic V, Clarke WL, Habener JE 1997. Pancreatic agenesis attributable to a single nucleotide deletion in the human IPFI gene coding sequence. Nat Genet 15:106–10.PubMedGoogle Scholar
  16. 16.
    Hani EH, Stoffers DA, Chevre JC, Durand E, Stanojevic V, Dina C, Habener JF, Froguel P. 1999. Defective mutations in the insulin promoter factor-1 (IPF-1) gene in late-onset type 2 diabetes mellitus. J Clin Invest 104:R41–8.PubMedGoogle Scholar
  17. 17.
    Macfarlane WM, Frayling TM, Ellard S, Evans JC, Allen LI, Bulman MP, Ayres S, Shepherd M, Clark P, Millward A and others. 1999. Missense mutations in the insulin promoter factor-1 gene predispose to type 2 diabetes. J Clin Invest 104:R33–9.PubMedGoogle Scholar
  18. 18.
    Hansen L, Urioste S, Petersen HV, Jensen JN, Eiberg H, Barbetti F, Serup P, Hansen T, Pedersen O. 2000. Missense mutations in the human insulin promoter factor-1 gene and their relation to maturity-onset diabetes of the young and late-onset type 2 diabetes mellitus in caucasians. J Clin Endocrinol Metab 85:1323–6.PubMedGoogle Scholar
  19. 19.
    Waeber G, Delplanque J, Bonny C, Mooser V, Steinmann M, Widmann C, Maillard A, Miklossy J, Dina C, Hani EH and others. 2000. The gene MAPK8IP1, encoding islet-brain-1, is a candidate for type 2 diabetes. Nat Genet 24:291–5.PubMedGoogle Scholar
  20. 20.
    Bennett ST, Todd JA. 1996. Human type 1 diabetes and the insulin gene: principles of mapping polygenes. Annu Rev Genet 30:343–70.PubMedGoogle Scholar
  21. 21.
    Bell GI, Selby MJ, Rutter WJ. 1982. The highly polymorphic region near the human insulin gene is composed of simple tandemly repeating sequences. Nature 295:31–5.PubMedGoogle Scholar
  22. 22.
    Vafiadis P, Bennett ST, Colle E, Grabs R, Goodyer CG, Polychronakos C. 1996. Imprinted and genotype-specific expression of genes at the IDDM2 locus in pancreas and leucocytes. J Autoimmun 9:397–403.PubMedGoogle Scholar
  23. 23.
    Bennett ST, Wilson AJ, Cucca F, Nerup J, Pociot F, McKinney PA, Barnett AH, Bain SC, Todd JA. 1996. IDDM2-VNTR-encoded susceptibility to type I diabetes: dominant protection and parental transmission of alleles of the insulin gene-linked minisatellite locus. JAutoimmun 9:415–21.Google Scholar
  24. 24.
    Ahmed S, Bennett ST, Huxtable SJ, Todd JA, Matthews DR, Gough SC. 1999. INS VNTR allelic variation and dynamic insulin secretion in healthy adult non-diabetic Caucasian subjects. Diabet Med 16:910–7.PubMedGoogle Scholar
  25. 25.
    Dunger DB, Ong KK, Huxtable SJ, Sherriff A, Woods KA, Ahmed ML, Golding J, Pembrey ME, Ring S, Bennett ST and others. 1998. Association of the INS VNTR with size at birth. ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood. Nat Genet 19:98–100.PubMedGoogle Scholar
  26. 26.
    Hales CN, Barker DJ, Clark PM, Cox LJ, Fall C, Osmond C, Winter PD. 1991. Fetal and infant growth and impaired glucose tolerance at age 64. BMJ 303:1019–22.PubMedGoogle Scholar
  27. 27.
    Ong KK, Phillips DI, Fall C, Poulton J, Bennett ST, Golding J, Todd JA, Dunger DB. 1999. The insulin gene VNTR, type 2 diabetes and birth weight. Nat Genet 21:262–3.PubMedGoogle Scholar
  28. 28.
    Spielman RS, Ewens WJ. 1996. The TDT and other family-based tests for linkage disequilibrium and association. Am J Hum Genet 59:983–9.PubMedGoogle Scholar
  29. 29.
    Huxtable SJ, Saker PJ, Haddad L, Walker M, Frayling TM, Levy JC, Hitman GA, O’Rahilly S, Hattersley AT, McCarthy MI. 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 49:126–30.PubMedGoogle Scholar
  30. 30.
    Paquette J, Giannoukakis N, Polychronakos C, Vafiadis P, Deal C. 1998. The INS 5’ variable number of tandem repeats is associated with IGF2 expression in humans. J Biol Chem 273:14158–64.PubMedGoogle Scholar
  31. 31.
    Miki T, Nagashima K, Seino S. 1999. The structure and function of the ATP- sensitive K+ channel in insulin-secreting pancreatic beta-cells. J Mol Endocrinol 22:113–23.PubMedGoogle Scholar
  32. 32.
    Aguilar-Bryan L, Bryan J. 1999. Molecular biology of adenosine triphosphate-sensitive potassium channels. Endocr Rev 20:101–35.PubMedGoogle Scholar
  33. 33.
    Meissner T, Beinbrech B, Mayatepek E. 1999. Congenital hyperinsulinism: molecular basis of a heterogeneous disease. Hum Mutat 13:351–61.PubMedGoogle Scholar
  34. 34.
    Inagaki N, Gonoi T, Clement JP, Namba N, Inazawa J, Gonzalez G, Aguilar-Bryan L, Seino S, Bryan J. 1995. Reconstitution of IKATP: an inward rectifier subunit plus the sulfonylurea receptor. Science 270:1166–70.PubMedGoogle Scholar
  35. 35.
    Stern MP, Duggirala R, Mitchell BD, Reinhardt OC, Benavides E, Blangero J, P. OC. 1996. Evidence for linkage of regions on chromosomes 6 and 11 to plasma glucose concentrations in Mexican Americans. Genome Res 6:724–734.PubMedGoogle Scholar
  36. 36.
    Elbein SC, Bragg KL, Hoffman MD, Mayorga RA, Leppert MF. 1996. Linkage studies of NIDDM with 23 chromosome 11 markers in a sample of whites of northern European descent. Diabetes 45:370–5.PubMedGoogle Scholar
  37. 37.
    Lindner T, Gragnoli C, Schulze J, Rietzsch H, Petzold C, Schroder HE, Cox NJ, Bell GI. 1997. The 31-cM region of chromosome 11 including the obesity gene tubby and ATP-sensitive potassium channel genes, SURI and Kir6.2, does not contain a major susceptibility locus for NIDDM in 127 non-Hispanic white affected sibships. Diabetes 46:1227–9.PubMedGoogle Scholar
  38. 38.
    Hani EH, Clement K, Velho G, Vionnet N, Hager J, Philippi A, Dina C, Inoue H, Permutt MA, Basdevant A and others. 1997. Genetic studies of the sulfonylurea receptor gene locus in NIDDM and in morbid obesity among French Caucasians. Diabetes 46:688–94.PubMedGoogle Scholar
  39. 39.
    Inoue H, Ferrer J, Welling CM, Elbein SC, Hoffman M, Mayorga R, Warren-Perry M, Zhang Y, Millns H, Turner R and others. 1996. Sequence variants in the sulfonylurea receptor (SUR) gene are associated with NIDDM in Caucasians. Diabetes 45:825–31.PubMedGoogle Scholar
  40. 40.
    Stirling B, Cox NJ, Bell GI, Hanis CL, Spielman RS, Concannon P. 1995. Linkage studies in NIDDM with markers near the sulphonylurea receptor gene. Diabetologia 38:1479–81.PubMedGoogle Scholar
  41. 41.
    Iwasaki N, Kawamura M, Yamagata K, Cox NJ, Karibe S, Ohgawara H, Inagaki N, Seino S, Bell GI, Omori Y. 1996. Identification of microsatellite markers near the human genes encoding the beta-cell ATP-sensitive K+ channel and linkage studies with NIDDM in Japanese. Diabetes 45:267–9.PubMedGoogle Scholar
  42. 42.
    Rissanen J, Markkanen A, Karkkainen P, Kekalainen J, Mykkanen L, Kuusisto J,Karhapaa P, Niskanen L, Laakso M. 2000. Sulfonylurea receptor 1 gene variants are associated with gestational diabetes and type 2 diabetes but not with altered secretion of insulin. Diabetes Care 23:70–73PubMedGoogle Scholar
  43. 43.
    Hart LM, de Knijff P, Dekker JM, Stolk RP, Nijpels G, van der Does FE, Ruige JB, Grobbee DE, Heine RJ, Maassen JA. 1999. Variants in the sulphonylurea receptor gene: association of the exon 16–3t variant with Type II diabetes mellitus in Dutch Caucasians. Diabetologia 42:617–20.PubMedGoogle Scholar
  44. 44.
    Goksel DL, Fischbach K, Duggirala R, Mitchell BD, Aguilar-Bryan L, Blangero J, Stem MP, O’Connell P. 1998. Variant in sulfonylurea receptor-1 gene is associated with high insulin concentrations in non-diabetic Mexican Americans: SUR-1 gene variant and hyperinsulinemia. Hum Genet 103:280–5.PubMedGoogle Scholar
  45. 45.
    Hansen T, Echwald SM, Hansen L, Moller AM, Almind K, Clausen JO, Urhammer SA, Inoue H, Ferrer J, Bryan J and others. 1998. Decreased tolbutamide-stimulated insulin secretion in healthy subjects with sequence variants in the high-affinity sulfonylurea receptor gene. Diabetes 47:598–605.PubMedGoogle Scholar
  46. 46.
    Ishiyama-Shigemoto S, Yamada K, Yuan X, Koyama W, Nonaka K. 1998. Clinical characterization of polymorphisms in the sulphonylurea receptor 1 gene in Japanese subjects with Type 2 diabetes mellitus. Diabet Med 15:826–9.PubMedGoogle Scholar
  47. 47.
    Ohta Y, Tanizawa Y, Inoue H, Hosaka T, Ueda K, Matsutani A, Repunte VP, Yamada M, Kurachi Y, Bryan J and others. 1998. Identification and functional analysis of sulfonylurea receptor 1 variants in Japanese patients with NIDDM. Diabetes 47:476–81.PubMedGoogle Scholar
  48. 48.
    Hart LM, Dekker JM, van Haeften TW, Ruige JB, Stehouwer CD, Erkelens DW, Heine RJ, Maassen JA. 2000. Reduced second phase insulin secretion in carriers of a sulphonylurea receptor gene variant associating with Type II diabetes mellitus [In Process Citation]. Diabetologia 43:515–9.PubMedGoogle Scholar
  49. 49.
    Sakura H, Wat N, Horton V, Millns H, Turner RC, Ashcroft FM. 1996. Sequence variations in the human Kir6.2 gene, a subunit of the beta-cell ATP-sensitive K-channel: no association with NIDDM in while Caucasian subjects or evidence of abnormal function when expressed in vitro. Diabetologia 39:1233–6.PubMedGoogle Scholar
  50. 50.
    Hani EH, Boutin P, Durand E, Inoue H, Permutt MA, Velho G, Froguel P. 1998. Missense mutations in the pancreatic islet beta cell inwardly rectifying K+ channel gene (KIR6.2/BIR): a meta-analysis suggests a role in the polygenic basis of Type II diabetes mellitus in Caucasians. Diabetologia 41:1511–5.PubMedGoogle Scholar
  51. 51.
    Hansen L, Echwald SM, Hansen T, Urhammer SA, Clausen JO, Pedersen O. 1997. Amino acid polymorphisms in the ATP-regulatable inward rectifier Kir6.2 and their relationships to glucose-and tolbutamide-induced insulin secretion, the insulin sensitivity index, and NIDDM. Diabetes 46:508–12.PubMedGoogle Scholar
  52. 52.
    Inoue H, Ferrer J, Warren-Perry M, Zhang Y, Millns H, Turner RC, Elbein SC, Hampe CL, Suarez BK, Inagaki N and others. 1997. Sequence variants in the pancreatic islet beta-cell inwardly rectifying K+ channel Kir6.2 (Bir) gene: identification and lack of role in Caucasian patients with NIDDM. Diabetes 46:5027.Google Scholar
  53. 53.
    Taylor SI. 1992. Lilly Lecture: molecular mechanisms of insulin resistance. Lessons from patients with mutations in the insulin-receptor gene. Diabetes 41:1473–90.PubMedGoogle Scholar
  54. 54.
    Hart LM, Stolk RP, Heine RJ, Grobbee DE, van der Does FE, Maassen JA. 1996. Association of the insulin-receptor variant Met-985 with hyperglycemia and noninsulin-dependent diabetes mellitus in the Netherlands: a population-based study. Am J Hum Genet 59:1119–25.PubMedGoogle Scholar
  55. 55.
    Hart LM, Stolk RP, Dekker JM, Nijpels G, Grobbee DE, Heine RJ, Maassen JA. 1999. Prevalence of variants in candidate genes for type 2 diabetes mellitus in The Netherlands: the Rotterdam study and the Hoorn study. J Clin Endocrino! Metab 84:1002–6.Google Scholar
  56. 56.
    Lepretre F, Vionnet N, Budhan S, Dina C, Powell KL, Genin E, Das AK, Nallam V, Passa P, Froguel P. 1998. Genetic studies of polymorphisms in ten non-insulindependent diabetes mellitus candidate genes in Tamil Indians from Pondichery. Diabetes Metab 24:244–50.PubMedGoogle Scholar
  57. 57.
    Hansen L, Hansen T, Clausen JO, Echwald SM, Urhammer SA, Rasmussen SK, Pedersen O. 1997. The Va1985Met insulin-receptor variant in the Danish Caucasian population: lack of associations with non-insulin-dependent diabetes mellitus or insulin resistance. Am J Hum Genet 60:1532–5.PubMedGoogle Scholar
  58. 58.
    Strack V, Bossenmaier B, Stoyanov B, Mushack J, Haring HU. 1997. A 973 valine to methionine mutation of the human insulin receptor: interaction with insulin-receptor substrate-1 and Shc in HEK 293 cells. Diabetologia 40:1135–40.PubMedGoogle Scholar
  59. 59.
    Rondinone CM, Wang LM, Lonnroth P, Wesslau C, Pierce JH, Smith U. 1997. Insulin receptor substrate (IRS) 1 is reduced and IRS-2 is the main docking protein for phosphatidylinositol 3-kinase in adipocytes from subjects with non-insulindependent diabetes mellitus. Proc Natl Acad Sci U S A 94:4171–5.PubMedGoogle Scholar
  60. 60.
    Carvalho E, Jansson PA, Axelsen M, Eriksson JW, Huang X, Groop L, Rondinone C, Sjostrom L, Smith U. 1999. Low cellular IRS 1 gene and protein expression predict insulin resistance and NIDDM. FASEB J 13:2173–8.PubMedGoogle Scholar
  61. 61.
    Imai Y, Philippe N, Sesti G, Accili D, Taylor SI. 1997. Expression of variant forms of insulin receptor substrate-1 identified in patients with noninsulin-dependent diabetes mellitus. J Clin Endocrino! Metab 82:4201–7Google Scholar
  62. 62.
    Almind K, Inoue G, Pedersen O, Kahn CR. 1996. A common amino acid polymorphism in insulin receptor substrate-1 causes impaired insulin signaling. Evidence from transfection studies. J Clin Invest 97:2569–75.PubMedGoogle Scholar
  63. 63.
    Porzio O, Federici M, Hribal ML, Lauro D, Accili D, Lauro R, Borboni P, Sesti G. 1999. The G1y972-->Arg amino acid polymorphism in IRS-1 impairs insulin secretion in pancreatic beta cells. J Clin Invest 104:357–64.PubMedGoogle Scholar
  64. 64.
    Kulkarni RN, Winnay JN, Daniels M, Bruning JC, Flier SN, Hanahan D, Kahn CR. 1999. Altered function of insulin receptor substrate- 1-deficient mouse islets and cultured beta-cell lines. J Clin Invest 104:R69–75.PubMedGoogle Scholar
  65. 65.
    Armstrong M, Haldane F, Avery PJ, Mitcheson J, Stewart MW, Turnbull DM, Walker M. 1996. Relationship between insulin sensitivity and insulin receptor substrate-1 mutations in non-diabetic relatives of NIDDM families Diabet Med 13:341–5.PubMedGoogle Scholar
  66. 66.
    Koch M, Rett K, Volk A, Maerker E, Haist K, Deninger M, Renn W, Haring HU. 1999. Amino acid polymorphism Gly 972 Arg in IRS-1 is not associated to lower clamp-derived insulin sensitivity in young healthy first degree relatives of patients with type 2 diabetes. Exp. Clin Endocrinol Diabetes 107:318–22.Google Scholar
  67. 67.
    Laakso M, Malkki M, Kekalainen P, Kuusisto J, Deeb SS. 1994. Insulin receptor substrate-1 variants in non-insulin-dependent diabetes. J Clin Invest 94:1141–6.PubMedGoogle Scholar
  68. 68.
    Yamada K, Yuan X, Ishiyama S, Shoji S, Kohno S, Koyama K, Koyanagi A, Koyama W, Nonaka K. 1998. Codon 972 polymorphism of the insulin receptor substrate-1 gene in impaired glucose tolerance and late-onset NIDDM. Diabetes Care 21:753–6.PubMedGoogle Scholar
  69. 69.
    Zhang Y, Wat N, Stratton IM, Warren-Perry MG, Orho M, Groop L, Turner RC. 1996. UKPDS 19: heterogeneity in NIDDM: separate contributions of IRS-1 and beta 3-adrenergic-receptor mutations to insulin resistance and obesity respectively with no evidence for glycogen synthase gene mutations. UK Prospective Diabetes Study. Diabetologia 39:1505–11.PubMedGoogle Scholar
  70. 70.
    Sigal RJ, Doria A, Warram JH, Krolewski AS. 1996. Codon 972 polymorphism in the insulin receptor substrate-1 gene, obesity, and risk of noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 81:1657–9.PubMedGoogle Scholar
  71. 71.
    Baroni MG, D’Andrea MP, Montali A, Pannitteri G, Barilla F, Campagna F, Mazzei E, Lovari S, Seccareccia F, Campa PP and others. 1999. A common mutation of the insulin receptor substrate-1 gene is a risk factor for coronary artery disease. Arterioscler Thromb Vasc Biol 19:2975–80.PubMedGoogle Scholar
  72. 72.
    Mori H, Hashiramoto M, Kishimoto M, Kasuga M. 1995. Amino acid polymorphisms of the insulin receptor substrate-1 in Japanese noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 80:2822–6.PubMedGoogle Scholar
  73. 73.
    Celi FS, Silver K, Walston J, Knowler WC, Bogardus C, Shuldiner AR. 1995. Lack of IRS-1 codon 513 and 972 polymorphism in Pima Indians. J Clin Endocrinol Metab 80:2827–9.PubMedGoogle Scholar
  74. 74.
    Chuang LM, Lai CS, Yeh JI, Wu HP, Tai TY, Lin BJ. 1996. No association between the GIy971Arg variant of the insulin receptor substrate 1 gene and NIDDM in the Taiwanese population. Diabetes Care 19:446–9.PubMedGoogle Scholar
  75. 75.
    Shimokawa K, Kadowaki H, Sakura H, Otabe S, Hagura R, Kosaka K, Yazaki Y, Akanuma Y, Kadowaki T. 1994. Molecular scanning of the glycogen synthase and insulin receptor substrate-1 genes in Japanese subjects with non-insulin-dependent diabetes mellitus. Biochem Biophys Res Commun 202:463–9.PubMedGoogle Scholar
  76. 76.
    Ura S, Araki E, Kishikawa H, Shirotani T, Todaka M, Isami S, Shimoda S, Yoshimura R, Matsuda K, Motoyoshi S and others. 1996. Molecular scanning of the insulin receptor substrate-1 (IRS-l) gene in Japanese patients with NIDDM: identification of five novel polymorphisms. Diabetologia 39:600–8.PubMedGoogle Scholar
  77. 77.
    Lei HH, Coresh J, Shuldiner AR, Boerwinkle E, Brancati FL. 1999. Variants of the insulin receptor substrate-1 and fatty acid binding protein 2 genes and the risk of type 2 diabetes, obesity, and hyperinsulinemia in African-Americans: the Atherosclerosis Risk in Communities Study. Diabetes 48:1868–72.PubMedGoogle Scholar
  78. 78.
    Elbein SC, Chiu KC, Hoffman MD, Mayorga RA, Bragg KL, Leppert MF. 1995. Linkage analysis of 19 candidate regions for insulin resistance in familial NIDDM. Diabetes 44:1259–65.PubMedGoogle Scholar
  79. 79.
    Kalidas K, Wasson J, Glaser B, Meyer JM, Duprat U, White MF, Permutt MA. 1998. Mapping of the human insulin receptor substrate-2 gene, identification of a linked polymorphic marker and linkage analysis in families with Type II diabetes: no evidence for a major susceptibility role. Diabetologia 41:1389–91.PubMedGoogle Scholar
  80. 80.
    Bektas A, Warram JH, White MF, Krolewski AS, Doria A. 1999. Exclusion of insulin receptor substrate 2 (IRS-2) as a major locus for early-onset autosomal dominant type 2 diabetes. Diabetes 48:640–2.PubMedGoogle Scholar
  81. 81.
    Almind K, Frederiksen SK, Bernal D, Hansen T, Ambye L, Urhammer S, Ekstrom CT, Berglund L, Reneland R, Lithell H and others. 1999. Search for variants of the gene-promoter and the potential phosphotyrosine encoding sequence of the insulin receptor substrate-2 gene: evaluation of their relation with alterations in insulin secretion and insulin sensitivity. Diabetologia 42:1244–9.PubMedGoogle Scholar
  82. 82.
    Bernal D, Almind K, Yenush L, Ayoub M, Zhang Y, Rosshani L, Larsson C, Pedersen O, White MF. 1998. Insulin receptor substrate-2 amino acid polymorphisms are not associated with random type 2 diabetes among Caucasians. Diabetes 47:9769.Google Scholar
  83. 83.
    Almind K, Frederiksen SK, Ahlgren MG, Urhammer S, Hansen T, Clausen JO, Pedersen O. 1998. Common amino acid substitutions in insulin receptor substrate-4 are not associated with Type H diabetes mellitus or insulin resistance. Diabetologia 41:969–74.PubMedGoogle Scholar
  84. 84.
    Baier LJ, Wiedrich C, Hanson RL, Bogardus C. 1998. Variant in the regulatory subunit of phosphatidylinositol 3-kinase (p85alpha): preliminary evidence indicates a potential role of this variant in the acute insulin response and type 2 diabetes in Pima women. Diabetes 47:973–5.PubMedGoogle Scholar
  85. 85.
    Hansen T, Andersen CB, Echwald SM, Urhammer SA, Clausen JO, Vestergaard H, Owens D, Hansen L, Pedersen O. 1997. Identification of a common amino acid polymorphism in the p85alpha regulatory subunit of phosphatidylinositol 3-kinase: effects on glucose disappearance constant, glucose effectiveness, and the insulin sensitivity index. Diabetes 46:494–501.PubMedGoogle Scholar
  86. 86.
    Kawanishi M, Tamori Y, Masugi J, Mori H, Ito C, Hansen T, Andersen CB, Pedersen O, Kasuga M. 1997. Prevalence of a polymorphism of the phosphatidylinositol 3-kinase p85 alpha regulatory subunit (codon 326 Met-->Ile) in Japanese NIDDM patients [letter]. Diabetes Care 20:1043.PubMedGoogle Scholar
  87. 87.
    Baynes KCR, Beeton CA, Panayotou G, Stein R, Soos M, Hansen T, Simpson H, O’Rahilly S, Shepherd PR, Whitehead JP. 2000. Natural variants of human p85ct phosphoinositide 3-kinase in severe insulin resistance: a novel variant with impaired insulin-stimulated lipid kinase activity. Diabetologia 43:321–331.PubMedGoogle Scholar
  88. 88.
    Lehtovirta M, Kaprio J, Forsblom C, Eriksson J, Tuomilehto J, Groop L. 2000. Insulin sensitivity and insulin secretion in monozygotic and dizygotic twins [In Process Citation]. Diabetologia 43:285–93.PubMedGoogle Scholar
  89. 89.
    Gulli G, Ferrannini E, Stem M, Haffner S, DeFronzo RA. 1992. The metabolic profile of NIDDM is fully established in glucose-tolerant offspring of two Mexican-American NIDDM parents. Diabetes 41:1575–86.PubMedGoogle Scholar
  90. 90.
    Eriksson J, Franssila-Kallunki A, Ekstrand A, Saloranta C, Widen E, Schalin C, Groop L. 1989. Early metabolic defects in persons at increased risk for non-insulindependent diabetes mellitus. N Engl J Med 321:337–43.PubMedGoogle Scholar
  91. 91.
    Vauhkonen I, Niskanen L, Vanninen E, Kainulainen S, Uusitupa M, Laakso M. 1998. Defects in insulin secretion and insulin action in non-insulin-dependent diabetes mellitus are inherited. Metabolic studies on offspring of diabetic probands. J Clin Invest 101:86–96.PubMedGoogle Scholar
  92. 92.
    Cline GW, Petersen KF, Krssak M, Shen J, Hundal RS, Trajanoski Z, Inzucchi S, Dresner A, Rothman DL, Shulman GI. 1999. Impaired glucose transport as a cause of decreased insulin-stimulated muscle glycogen synthesis in type 2 diabetes. N Engl J Med 341:240–6.PubMedGoogle Scholar
  93. 93.
    Roden M, Shulman GI. 1999. Applications of NMR spectroscopy to study muscle glycogen metabolism in man. Annu Rev Med 50:277–90.PubMedGoogle Scholar
  94. 94.
    Shepherd PR, Kahn BB. 1999. Glucose transporters and insulin action--implications for insulin resistance and diabetes mellitus. N Engl J Med 341:248–57.PubMedGoogle Scholar
  95. 95.
    Lesage S, Zouali H, Vionnet N, Philippi A, Velho G, Serradas P, Passa P, Demenais F, Froguel P. 1997. Genetic analyses of glucose transporter genes in French noninsulin-dependent diabetic families. Diabetes Metab 23:137–42.PubMedGoogle Scholar
  96. 96.
    Bjorbaek C, Echwald SM, Hubricht P, Vestergaard H, Hansen T, Zierath J, Pedersen O. 1994. Genetic variants in promoters and coding regions of the muscle glycogen synthase and the insulin-responsive GLUT4 genes in NIDDM. Diabetes 43:976–83.PubMedGoogle Scholar
  97. 97.
    Buse JB, Yasuda K, Lay TP, Seo TS, Olson AL, Pessin JE, Karam JH, Seino S, Bell GI. 1992. Human GLUT4/muscle-fat glucose-transporter gene. Characterization and genetic variation. Diabetes 41:1436–45.PubMedGoogle Scholar
  98. 98.
    Crook A, Stratton IM, O’Rahilly S. 1992. Rapid and simultaneous detection of multiple mutations by pooled and multiplex single nucleotide primer extension: application to the study of insulin-responsive glucose transporter and insulin receptor mutations in non-insulin-dependent diabetes. Hum Mol Genet 1:391–5.Google Scholar
  99. 99.
    Lawrence JC, Jr., Roach Pi. 1997. New insights into the role and mechanism of glycogen synthase activation by insulin. Diabetes 46:541–7.PubMedGoogle Scholar
  100. 100.
    Lehto M, Huang X, Davis EM, Le Beau MM, Laurila E, Eriksson KF, Bell GI, Groop L. 1995. Human hexokinase II gene: exon-intron organization, mutation screening in NIDDM, and its relationship to muscle hexokinase activity. Diabetologia 38:146674.Google Scholar
  101. 101.
    Vestergaard H, Bjorbaek C, Hansen T, Larsen FS, Granner DK, Pedersen O. 1995. Impaired activity and gene expression of hexokinase II in muscle from non-insulindependent diabetes mellitus patients. J Clin Invest 96:2639–45.PubMedGoogle Scholar
  102. 102.
    Vionnet N, Hani EH, Lesage S, Philippi A, Hager J, Varret M, Stoffel M, Tanizawa Y, Chiu KC, Glaser B and others. 1997. Genetics of NIDDM in France: studies with 19 candidate genes in affected sib pairs. Diabetes 46:1062–8.PubMedGoogle Scholar
  103. 103.
    Ardehali H, Tiller GE, Printz RL, Mochizuki H, Prochazka M, Granner DK. 1996. A novel (TA)n polymorphism in the hexokinase Il gene: application to noninsulindependent diabetes mellitus in the Pima Indians. Hum Genet 97:482–5.PubMedGoogle Scholar
  104. 104.
    Echwald SM, Bjorbaek C, Hansen T, Clausen JO, Vestergaard H, Zierath JR, Printz RL, Granner DK, Pedersen O. 1995. Identification of four amino acid substitutions in hexokinase II and studies of relationships to NIDDM, glucose effectiveness, and insulin sensitivity. Diabetes 44:347–53.PubMedGoogle Scholar
  105. 105.
    Laakso M, Malkki M, Kekalainen P, Kuusisto J, Deeb SS. 1995. Polymorphisms of the human hexokinase II gene: lack of association with NIDDM and insulin resistance. Diabetologia 38:617–22.PubMedGoogle Scholar
  106. 106.
    Laakso M, Malkki M, Deeb SS. 1995. Amino acid substitutions in hexokinase II among patients with NIDDM. Diabetes 44:330–4.PubMedGoogle Scholar
  107. 107.
    Malkki M, Laakso M, Deeb SS. 1997. The human hexokinase II gene promoter: functional characterization and detection of variants among patients with NIDDM. Diabetologia 40:1461–9.PubMedGoogle Scholar
  108. 108.
    Taylor RW, Printz RL, Armstrong M, Granner DK, Alberti KG, Tumbull DM, Walker M. 1996. Variant sequences of the Hexokinase II gene in familial NIDDM. Diabetologia 39:322–8.PubMedGoogle Scholar
  109. 109.
    Vidal-Puig A, Printz RL, Stratton IM, Granner DK, Moller DE. 1995. Analysis of the hexokinase II gene in subjects with insulin resistance and NIDDM and detection of a G1n142-->His substitution. Diabetes 44:340–6.PubMedGoogle Scholar
  110. 110.
    Malkki M, Laakso M, Deeb SS. 1998. Functional consequences of naturally occurring variants of human hexokinase II. Diabetologia 41:1205–9.PubMedGoogle Scholar
  111. 111.
    Elbein SC, Hoffman M, Ridinger D, Otterud B, Leppert M. 1994. Description of a second microsatellite marker and linkage analysis of the muscle glycogen synthase locus in familial NIDDM. Diabetes 43:1061–5.PubMedGoogle Scholar
  112. 112.
    Majer M, Mott DM, Mochizuki H, Rowles JC, Pedersen O, Knowler WC, Bogardus C, Prochazka M. 1996. Association of the glycogen synthase locus on 19q13 with NIDDM in Pima Indians. Diabetologia 39:314–21.PubMedGoogle Scholar
  113. 113.
    Kuroyama H, Sanke T, Ohagi S, Furuta M, Furuta H, Nanjo K. 1994. Simple tandem repeat DNA polymorphism in the human glycogen synthase gene is associated with NIDDM in Japanese subjects. Diabetologia 37:536–9.PubMedGoogle Scholar
  114. 114.
    Groop LC, Kankuri M, Schalin-Jantti C, Ekstrand A, Nikula-Ijas P, Widen E, Kuismanen E, Eriksson J, Franssila-Kallunki A, Saloranta C and others. 1993. Association between polymorphism of the glycogen synthase gene and non-insulindependent diabetes mellitus. N Engl J Med 328:10–4.PubMedGoogle Scholar
  115. 115.
    Orho-Melander M, Almgren P, Kanninen T, Forsblom C, Groop LC. 1999. A paired-sibling analysis of the Xbal polymorphism in the muscle glycogen synthase gene. Diabetologia 42:1138–45.PubMedGoogle Scholar
  116. 116.
    Kadowaki T, Kadowaki H, Yazaki Y. 1993. Polymorphism of the glycogen synthase gene and non-insulin-dependent diabetes mellitus. N Engl J Med 328:1568–9.PubMedGoogle Scholar
  117. 117.
    Babadjanova G, Allolio B, Beuschlein F, Chuchalin A, Reincke M. 1997. Polymorphism of the glycogen synthase gene and non-insulin-dependent diabetes mellitus in the Russian population. Metabolism 46:121–2.PubMedGoogle Scholar
  118. 118.
    Zouali H, Velho G, Froguel P. 1993. Polymorphism of the glycogen synthase gene and non-insulin-dependent diabetes mellitus. N Engl J Med 328:1568.PubMedGoogle Scholar
  119. 119.
    Orho-Melander M, Shimomura H, Sanke T, Rasmussen SK, Nanjo K, Pedersen O, Groop LC. 1999. Expression of naturally occurring variants in the muscle glycogen synthase gene. Diabetes 48:918–20.PubMedGoogle Scholar
  120. 120.
    Rissanen J, Pihlajamaki J, Heikkinen S, Kekalainen P, Mykkanen L, Kuusisto J, Kolle A, Laakso M. 1997. New variants in the glycogen synthase gene (G1n71His, Met416Val) in patients with NIDDM from eastern Finland. Diabetologia 40:1313–9.PubMedGoogle Scholar
  121. 121.
    Shimomura H, Sanke T, Ueda K, Hanabusa T, Sakagashira S, Nanjo K. 1997. A missense mutation of the muscle glycogen synthase gene (M416V) is associated with insulin resistance in the Japanese population. Diabetologia 40:947–52.PubMedGoogle Scholar
  122. 122.
    Chen YH, Hansen L, Chen MX, Bjorbaek C, Vestergaard H, Hansen T, Cohen PT, Pedersen O. 1994. Sequence of the human glycogen-associated regulatory subunit of type 1 protein phosphatase and analysis of its coding region and mRNA level in muscle from patients with NIDDM. Diabetes 43:1234–41.PubMedGoogle Scholar
  123. 123.
    Bjorbaek C, Vik TA, Echwald SM, Yang PY, Vestergaard H, Wang JP, Webb GC, Richmond K, Hansen T, Erikson RL and others. 1995. Cloning of a human insulin-stimulated protein kinase (ISPK-1) gene and analysis of coding regions and mRNA levels of the ISPK-1 and the protein phosphatase-1 genes in muscle from NIDDM patients. Diabetes 44:90–7.PubMedGoogle Scholar
  124. 124.
    Prochazka M, Mochizuki H, Baier LJ, Cohen PT, Bogardus C. 1995. Molecular and linkage analysis of type-1 protein phosphatase catalytic beta-subunit gene: lack of evidence for its major role in insulin resistance in Pima Indians. Diabetologia 38:461–6.PubMedGoogle Scholar
  125. 125.
    Hansen L, Hansen T, Vestergaard H, Bjorbaek C, Echwald SM, Clausen JO, Chen YH, Chen MX, Cohen PT, Pedersen O. 1995. A widespread amino acid polymorphism at codon 905 of the glycogen-associated regulatory subunit of protein phosphatase-1 is associated with insulin resistance and hypersecretion of insulin. Hum Mol Genet 4:1313–20.PubMedGoogle Scholar
  126. 126.
    Shen GQ, Ikegami H, Kawaguchi Y, Fujisawa T, Hamada Y, Ueda H, Shintani M, Nojima K, Kawabata Y, Yamada K and others. 1998. Asp905Tyr polymorphism of the gene for the skeletal muscle-specific glycogen-targeting subunit of protein phosphatase 1 in NIDDM. Diabetes Care 21:1086–9.PubMedGoogle Scholar
  127. 127.
    Boullu-Sanchis S, Lepretre F, Hedelin G, Donnet JP, Schaffer P, Froguel P, Pinget M. 1999. Type 2 diabetes mellitus: association study of five candidate genes in an Indian population of Guadeloupe, genetic contribution of FABP2 polymorphism. Diabetes Metab 25:150–6.PubMedGoogle Scholar
  128. 128.
    Xia J, Scherer SW, Cohen PT, Majer M, Xi T, Norman RA, Knowler WC, Bogardus C, Prochazka M. 1998. A common variant in PPPIR3 associated with insulin resistance and type 2 diabetes. Diabetes 47:1519–24.PubMedGoogle Scholar
  129. 129.
    Ross J. 1996. Control of messenger RNA stability in higher eukaryotes. Trends Genet 12:171–5.PubMedGoogle Scholar
  130. 130.
    Xia J, Bogardus C, Prochazka M. 1999. A type 2 diabetes-associated polymorphic ARE motif affecting expression of PPPIR3 is involved in RNA-protein interactions. Mol Genet Metab 68:48–55.PubMedGoogle Scholar
  131. 131.
    Maegawa H, Shi K, Hidaka H, Iwai N, Nishio Y, Egawa K, Kojima H, Haneda M, Yasuda H, Nakamura Y and others. 1999. The 3’-untranslated region polymorphism of the gene for skeletal muscle-specific glycogen-targeting subunit of protein phosphatase 1 in the type 2 diabetic Japanese population. Diabetes 48:1469–72.PubMedGoogle Scholar
  132. 132.
    Hansen L, Reneland R, Berglund L, Rasmussen SK, Hansen T, Lithell H, Pedersen 0. 2000. Polymorphism in the glycogen-associated regulatory subunit of type 1 protein phosphatase (PP1R3) gene and insulin sensitivity. Diabetes 49:298–301.PubMedGoogle Scholar
  133. 133.
    Hegele RA, Harris SB, Zinman B, Wang J, Cao H, Hanley Ai, Tsui LC, Scherer SW. 1998. Variation in the AU(AT)-rich element within the 3’-untranslated region of PPP1R3 is associated with variation in plasma glucose in aboriginal Canadians. J Clin Endocrinol Metab 83:3980–3.PubMedGoogle Scholar
  134. 134.
    Permana PA, Luczy-Bachman G, Bogardus C. 1999. Protein targeting to glycogen/PPP1R5: screening of coding and flanking genomic regions for polymorphisms and association analysis with insulin action in Pima Indians. Biochem Biophys Res Commun 258:184–6.PubMedGoogle Scholar
  135. 135.
    Hansen L, Arden KC, Rasmussen SB, Viars CS, Vestergaard H, Hansen T, Moller AM, Woodgett JR, Pedersen 0. 1997. Chromosomal mapping and mutational analysis of the coding region of the glycogen synthase kinase-3alpha and beta isoforms in patients with NIDDM. Diabetologia 40:940–6.PubMedGoogle Scholar
  136. 136.
    Hansen L, Fjordvang H, Rasmussen SK, Vestergaard H, Echwald SM, Hansen T, Alessi D, Shenolikar S, Saltiel AR, Barbetti F and others. 1999. Mutational analysis of the coding regions of the genes encoding protein kinase B-alpha and -beta, phosphoinositide-dependent protein kinase-1, phosphatase targeting to glycogen, protein phosphatase inhibitor-1, and glycogenin: lessons from a search for genetic variability of the insulin-stimulated glycogen synthesis pathway of skeletal muscle in NIDDM patients. Diabetes 48:403–7.PubMedGoogle Scholar
  137. 137.
    Permana PA, Mott DM. 1997. Genetic analysis of human type 1 protein phosphatase inhibitor 2 in insulin-resistant Pima Indians. Genomics 41:110–4.PubMedGoogle Scholar
  138. 138.
    Auwerx J. 1999. PPARgamma, the ultimate thrifty gene. Diabetologia 42:1033–49.PubMedGoogle Scholar
  139. 139.
    Barroso I, Gurnell M, Crowley VE, Agostini M, Schwabe JW, Soos MA, Maslen GL, Williams TD, Lewis H, Schafer AJ and others. 1999. Dominant negative mutations in human PPARgamma associated with severe insulin resistance, diabetes mellitus and hypertension. Nature 402:880–3.PubMedGoogle Scholar
  140. 140.
    Deeb SS, Fajas L, Nemoto M, Pihlajamaki J, Mykkanen L, Kuusisto J, Laakso M, Fujimoto W, Auwerx J. 1998. A Prol2Ala substitution in PPARgamma2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nat Genet 20:284–7.PubMedGoogle Scholar
  141. 141.
    Yen CJ, Beamer BA, Negri C, Silver K, Brown KA, Yamall DP, Burns DK, Roth J, Shuldiner AR. 1997. Molecular scanning of the human peroxisome proliferator activated receptor gamma (hPPAR gamma) gene in diabetic Caucasians: identification of a Prol2Ala PPAR gamma 2 missense mutation. Biochem Biophys Res Commun 241:270–4.PubMedGoogle Scholar
  142. 142.
    Mori Y, Kim-Motoyama H, Katakura T, Yasuda K, Kadowaki H, Beamer BA, Shuldiner AR, Akanuma Y, Yazaki Y, Kadowaki T. 1998. Effect of the Prol2Ala variant of the human peroxisome proliferator-activated receptor gamma 2 gene on adiposity, fat distribution, and insulin sensitivity in Japanese men. Biochem Biophys Res Commun 251:195–8.Google Scholar
  143. 143.
    Hara K, Okada T, Tobe K, Yasuda K, Mori Y, Kadowaki H, Hagura R, Akanuma Y, Kimura S, Ito C and others. 2000. The Prol2Ala polymorphism in PPAR gamma2 may confer resistance to type 2 diabetes. Biochem Biophys Res Commun 271:212–6.PubMedGoogle Scholar
  144. 144.
    Hegele RA, Cao H, Harris SB, Zinman B, Hanley AJO, Anderson CM. 2000. Peroxisome-proliferator-activated receptor-g2 P12A and type 2 diabetes in Canadian Oji-Cree. J Clin Endocrinol Metab 85:2014–2019.PubMedGoogle Scholar
  145. 145.
    Oh EY, Min KM, Chung JH, Min Y-K, Lee M-S, Kim K-W, Lee M-K. 2000. Significance of Prol2Ala mutation in peroxisome proliferator-activated receptor-y2 in Korean diabetic and obese subjects. J Clin Endocrinol Metab 85:1801–1804.PubMedGoogle Scholar
  146. 146.
    Mancini FP, Vaccaro O, Sabatino L, Tufano A, Rivellese AA, Riccardi G, Colantuoni V. 1999. Prol2Ala substitution in the peroxisome proliferator-activated receptor-gamma2 is not associated with type 2 diabetes. Diabetes 48:1466–8.PubMedGoogle Scholar
  147. 147.
    Meirhaeghe A, Fajas L, Helbecque N, Cottel D, Auwerx J, Deeb SS, Amouyel P. 2000. Impact of the peroxisome proliferator activated receptor gamma2 Prol2Ala polymorphism on adiposity, lipids and non-insulin-dependent diabetes mellitus. Int J Obes Relat Metab Disord 24:195–9.PubMedGoogle Scholar
  148. 148.
    Ringel J, Engeli S, Distler A, Sharma AM. 1999. Prol2Ala missense mutation of the peroxisome proliferator activated receptor gamma and diabetes mellitus. Biochem Biophys Res Commun 254:450–3.PubMedGoogle Scholar
  149. 149.
    Clement K, Hercberg S, Passinge B, Galan P, Varroud-Vial M, Shuldiner AR, Bearer BA, Charpentier G, Guy-Grand B, Froguel P and others. 2000. The Prol15G1n and Prol2Ala PPAR gamma gene mutations in obesity and type 2 diabetes. Int J Obes Relat Metab Disord 24:391–3.PubMedGoogle Scholar
  150. 150.
    Altshuler D, Hirschhorn JN, Klannemark M, Lindgren CM, Vohl M-C, Nemesh J, Lane CR, Schaffner SF, Bolk S, Brewer C and others. 2000. The common PPARy Prol2Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet 26.Google Scholar
  151. 151.
    Koch M, Rett K, Maerker E, Volk A, Haist K, Deninger M, Renn W, Haring HU. 1999. The PPARgamma2 amino acid polymorphism Pro 12 Ala is prevalent in offspring of Type II diabetic patients and is associated to increased insulin sensitivity in a subgroup of obese subjects. Diabetologia 42:758–62.PubMedGoogle Scholar
  152. 152.
    Beamer BA, Yen CJ, Andersen RE, Muller D, Elahi D, Cheskin LJ, Andres R, Roth J, Shuldiner AR. 1998. Association of the Prol2Ala variant in the peroxisome proliferator-activated receptor-gamma2 gene with obesity in two Caucasian populations. Diabetes 47:1806–8.PubMedGoogle Scholar
  153. 153.
    Valve R, Sivenius K, Miettinen R, Pihlajamaki J, Rissanen A, Deeb SS, Auwerx J, Uusitupa M, Laakso M. 1999. Two polymorphisms in the peroxisome proliferatoractivated receptor-gamma gene are associated with severe overweight among obese women. J Clin Endocrinol Metab 84:3708–12.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • William L. LoweJr.
    • 1
  1. 1.Northwestern University Medical SchoolChicagoUSA

Personalised recommendations