Genetics of Noninsulin-Dependent Diabetes Mellitus (NIDDM)

  • Henning Beck-Nielsen
  • Allan Vaag
  • Kirsten Ohm Kyvik
Part of the Contemporary Biomedicine book series (CB, volume 15)


Noninsulin-dependent diabetes mellitus (NIDDM) or type II diabetes is a serious and fast-growing disease affecting about 5–10% of the adults in the Western world (1). NIDDM is preceded by impaired glucose tolerance (IGT), which affects about 25% of the population over 50 yr of age—a disease with nearly as high morbidity and mortality rate as NIDDM—despite “normal” fasting plasma glucose values (2). Both IGT and NIDDM result in 200–300% increased mortality rates, mainly from myocardial infarction (1). Therefore, the NIDDM syndrome—from the early stages to the fulminant hyperglycemic state—is a challenge for all clinicians.


Insulin Resistance Insulin Secretion Impaired Glucose Tolerance Normal Glucose Tolerance Hepatic Glucose Production 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Harris MI, Hadden WC, Knowler WC, Bennet PH. Prevelance of diabetes and impaired glucose tolerance and plasma glucose levels in U.S. populations aged 20–74 yr. Diabetes 1987; 36: 523–534.PubMedCrossRefGoogle Scholar
  2. 2.
    Beck-Nielsen H, Groop LC. Metabolic and genetic characterization of prediabetic states. J Clin Invest 1994: 1714–1721.Google Scholar
  3. 3.
    Zimmet P. Pathogenesis and prevention of diabetes in adults: genes, autoimmunity and demography. Diabetes 1994: 72–82.Google Scholar
  4. 4.
    Froguel P, Vaxillaire M, Sun F. Close linkage of glucosekinase locus on chromosome 7p to early-onset noninsulin dependent diabetes mellitus. Nature (Lond) 1992; 36: 162–164.Google Scholar
  5. 5.
    Reaven GM. Role of insulin resistance in human disease. Diabetes 1988; 37: 1595–1607.PubMedCrossRefGoogle Scholar
  6. 6.
    Martin BC, Warram JH, Krolewski AS, Bergman RN, Soeldner JS, Kahn CR. Role of glucose and insulin resistance in development of type 2 diabetes mellitus: results of a 25–year follow-up study. Lancet 1992; 340: 925–929.PubMedCrossRefGoogle Scholar
  7. 7.
    Vaag A, Henriksen JE, Madsbad S, Holm N, Beck-Nielsen H. Insulin secretion, insulin action, and hepatic glucose production in identical twins discordant for NIDDM. J Clin Invest 1995; 95: 690–698.PubMedCrossRefGoogle Scholar
  8. 8.
    Hales CN, Barker DJP. Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia 1992; 35: 595–601.PubMedCrossRefGoogle Scholar
  9. 9.
    Beck-Nielsen H, Henriksen JE, Vaag A, Hother-Nielsen O. Pathophysiology of non-insulindependent diabetes mellitus (NIDDM). Diabetes Res Clin Prac 1995; 28 (Suppl): S13–S25.CrossRefGoogle Scholar
  10. 10.
    Helmrich SP, Ragland DR, Leung RW, Paffenbarger R. Physical activity and reduced occurrence of non-insulin-dependent diabetes mellitus. New Engl J Med 1991; 325: 147–152.PubMedCrossRefGoogle Scholar
  11. 11.
    Rothman KJ. Modern Epidemiology. Boston/Toronto: Little, Brown and Company, 1986.Google Scholar
  12. 12.
    Hamman RF. Genetic and environmental determinants of non-insulin-dependent diabetes mellitus (NIDDM). Diabetes Metab Rev 1992; 8 (4): 287–338.PubMedCrossRefGoogle Scholar
  13. 13.
    Young TK, Schraer CD, Shubnikoff EV, Szathmary EJE, Nikitin YR. Prevalence of diagnosed diabetes in circumpolar indigenous populations. Int J Epidemiol 1992; 21 (4): 730–736.PubMedCrossRefGoogle Scholar
  14. 14.
    King H, Rewers M. Global estimates for prevalence of diabetes mellitus and impaired glucose tolerance in adults. Diabetes Care 1993; 16 (1): 157–177.PubMedCrossRefGoogle Scholar
  15. 15.
    Knowler WC, Pettitt DJ, Lillioja S, Nelson RG. Genetic and environmental factors in the development of diabetes mellitus in the Pima (American) Indians. In: Proceedings of the 1st Ernhold Lundstrom Symposium on Genetic Susceptibility to Environmental Factors-a Challenge for Public Intervention. Smith U, et al., eds. Malmo: Almqvist & Wiksell, pp. 67–74, 1987.Google Scholar
  16. 16.
    Rushfort NB, Bennet PH, Steinberg AG, Burch TA, Miller M. Diabetes in Pima Indians: evidence of bimodality in glucose tolerance distributions. Diabetes 1971; 20: 756–765.Google Scholar
  17. 17.
    Zimmet P, Whitehouse S. Bimodality of fasting and two-hour glucose tolerance distributions in a Micronesian population. Diabetes 1978; 27: 793–800.PubMedCrossRefGoogle Scholar
  18. 18.
    Rosenthal M, McMahan CS, Stern MP, Eifler CW, Haffner SM, Hazuda HP, Franco U. Evidence of bimodality of two-hour plasma-glucose concentrations in Mexican Americans: results from the San Antonio Heart Study. J Chron Dis 1985; 38: 5–16.PubMedCrossRefGoogle Scholar
  19. 19.
    Haas T, Svacina S, Pay J, Hovorka R, Sucharda P, Sonka J. Risk calculation of Type 2 diabetes. Comput Methods Program Biomed 1994; 41: 297–303.CrossRefGoogle Scholar
  20. 20.
    Gottlieb MS, Root HF. Diabetes mellitus in twins. Diabetes 1968; 17: 693–704.PubMedGoogle Scholar
  21. 21.
    Harvald B, Hauge M. Hereditary Factors Elucidated by Twin Studies. In: Genetics and the Epidemiology of Chronic Diseases. Neel JV, Shaw MW, Schull WJ, eds. Washington DC: US Department of Health, Education and Welfare. Public Health Service Publication no. 1163., pp. 61–76, 1965.Google Scholar
  22. 22.
    Then Bergh H. Zur frage der psychischen and neurologischen Erscheinungen bei Diabetes-kranken and deren Verwandten. Z Ges Neurol Psychiatr 1939; 165: 278–283.CrossRefGoogle Scholar
  23. 23.
    Newman B, Selby TV, King MC, Slemenda C, Fabsitz R, Friedman GD. Concordance for Type 2 (non-insulin-dependent) diabetes in male twins. Diabetologia 1987; 30 (10): 763–768.PubMedCrossRefGoogle Scholar
  24. 24.
    Kaprio J, Tuomilehto J, Koskenvou M, Romanov K, Reunanen A, Eriksson J et al. Concordance for type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus in a population-based cohort of twins in Finland. Diabetologia 1992; 35: 1060–1067.PubMedCrossRefGoogle Scholar
  25. 25.
    Alcolado JC, Alcolado R. Importance of maternal history of non-insulin dependent diabetic patients. Brit Med J 1991; 302: 1178–1180.PubMedCrossRefGoogle Scholar
  26. 26.
    Pettitt DJ, Knowler WC, Bennet PH, Aleck KA, Baird HR. Obesity in offspring of diabetic Pima Indian women despite normal birth weight. Diabetes Care 1987; 10 (1): 76–80.PubMedCrossRefGoogle Scholar
  27. 27.
    Matsuda A, Kuzuya T. Relationship between obesity and concordance rate for type 2 (noninsulin-dependent) diabetes mellitus among twins. Diabetes Res. Clin. Pract. 1994; 26 (2): 137–143.PubMedCrossRefGoogle Scholar
  28. 28.
    Sorensen TI, Stunkard AJ. Does obesity run in families because of genes? An adoption study using silhouettes as a measure of obesity. Acta Psychiatr Scand Suppl 1993; 370: 67–72.PubMedCrossRefGoogle Scholar
  29. 29.
    Barnett AH, Eff C, Leslie RDG, Pyke DA. Diabetes in identical twins. Diabetologia 1981; 20: 87–93.PubMedCrossRefGoogle Scholar
  30. 30.
    Skarfors ET, Wegener TA, Lithell H, Selinus I. Physical training as treatment for type 2 (noninsulin-dependent) diabetes in elderly men. A feasibility study over 2 years. Diabetologia 1987; 30: 930–933.PubMedCrossRefGoogle Scholar
  31. 31.
    Hales CN, Barker DJ, Clark PM, Cox LJ, Fall C, Osmond C, and Winter PD. Fetal and infant growth and impaired glucose tolerance at age 64 [see comments]. Brit Med J 1991; 303: 1019–1022.PubMedCrossRefGoogle Scholar
  32. 32.
    Phipps K, Barker DJ, Hales CN, Fall C, and Clark PM. Fetal growth and impaired glucose tolerance in men and women. Diabetologia 1993; 36: 225–228.PubMedCrossRefGoogle Scholar
  33. 33.
    McCance DR, Pettitt DJ, Hanson RL, Jacobsson LTH, Knowler WC, Bennett PH. Birth weight and non-insulin dependent diabetes: thrifty genotype, thrifty phenotype, or surviving small baby genotype? Brit Med 11994; 308: 942–945.Google Scholar
  34. 34.
    Phillips DIW, Barker DIP, Hales CN, Hirst S, Osmond C. Thinness at birth and insulin resistance in adult life. Diabetologia 1994; 37: 150–154.PubMedCrossRefGoogle Scholar
  35. 35.
    Cook JTE, Levy JC, Page RCL, Shaw JAG, Hattersley AT, Turner RC. Association of low birth weight with beta-cell function in the adult first degree relatives of non-insulin-dependent subject. Brit Med J 1993; 306: 302–306.PubMedCrossRefGoogle Scholar
  36. 36.
    Zimmet P. Type 2 (non-insulin-dependent) diabetes-an epidemiological overview. Diabetologia 1982; 22: 399–411.PubMedCrossRefGoogle Scholar
  37. 37.
    Hansen BC, Bodkin NL. Primary prevention of diabetes mellitus by prevention of obesity in monkeys. Diabetes 1993; 42: 1809–1814.PubMedCrossRefGoogle Scholar
  38. 38.
    Eriksson KF, Lindgarde F. Prevention of type 2 (non-insulin-dependent) diabetes mellitus by diet and physical exercise. The 6-year Malmo feasibility study. Diabetologia 1991; 34: 891–898.PubMedCrossRefGoogle Scholar
  39. 39.
    Olefsky JM, Nolan JJ. Insulin resistance and non-insulin-dependent diabetes mellitus: cellular and molecular mechanisms 1-3. Am J Clin Nutr 1995; 61 (Suppl): 980S–986S.PubMedGoogle Scholar
  40. 40.
    Rossetti L, Giaccari A, DeFronzo RA. Glucose toxicity. Diabetes Care 1990; 13: 610–630.PubMedCrossRefGoogle Scholar
  41. 41.
    Randle PI, Garland PB, Hales CN, Newsholme EA. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1963; 1: 785–789.PubMedCrossRefGoogle Scholar
  42. 42.
    Felber JR Significance of the Randle-mechanism in the etiology of diabetes type II. Horm Metab Res Suppl 1990; 22: 11–17.Google Scholar
  43. 43.
    Vaag AA, Handberg A, Skott P, Richter EA, Beck Nielsen H. Glucose-fatty acid cycle operates in humans at the levels of both whole body and skeletal muscle during low and high physiological plasma insulin concentrations. Eur J Endocrinol 1994; 130: 70–79.PubMedCrossRefGoogle Scholar
  44. 44.
    Saloranta C, Franssila-Kallunki A, Ekstrand A, Taskinen MR, Groop L. Modulation of hepatic glucose production by non-esterified fatty acids in Type 2 (non-insulin dependent) diabetes mellitus. Diabetologia 1991; 34: 409–415.PubMedCrossRefGoogle Scholar
  45. 45.
    Leslie RDG, Ganash A, Volkmann HP, Harming I, Alberti KGMM. Insensitivity to insulin in offspring of non-insulin dependent diabetic patients. Diabetes Nutr Metab 1988; 3: 235–237.Google Scholar
  46. 46.
    Warram JH, Martin BC, Krolewski AS, Soeldner JS, Kahn CR. Slow glucose removal rate and hyperinsulinemia precede the development of type II diabetes in the offspring of diabetic parents. Ann Intern Med 1990; 113: 909–915.PubMedGoogle Scholar
  47. 47.
    Vaag A, Henriksen JE, Beck Nielsen H. Decreased insulin activation of glycogen synthase in skeletal muscles in young nonobese Caucasian first-degree relatives of patients with noninsulin-dependent diabetes mellitus. J Clin Invest 1992; 89: 782–788.PubMedCrossRefGoogle Scholar
  48. 48.
    Eriksson J, Franssila-Kallunki A, Ekstrand A, Saloranta C, Widen E, Schalin C, Groop L. Early metabolic defects in persons at increased risk for non-insulin-dependent diabetes mellitus. New Engl J Med 1989; 321: 337–343.PubMedCrossRefGoogle Scholar
  49. 49.
    Gulli G, Ferrannini E, Stern M, Haffner S, DeFronzo RA. The metabolic profile of NIDDM is fully established in glucose-tolerant offspring of two Mexican-American NIDDM parents. Diabetes 1992; 41: 1575–1586.PubMedCrossRefGoogle Scholar
  50. 50.
    Schalin Jantti C, Harkonen M, Groop LC. Impaired activation of glycogen synthase in people at increased risk for developing NIDDM. Diabetes 1992; 41: 598–604.CrossRefGoogle Scholar
  51. 51.
    Lillioja S, Mott DM, Howard BV, Howard BV, Bennett PH, Yki-Järvinen H, Freymond D, Nyomba BI, Zurlo F, Swinburn B, Bogardus C. Impaired glucose tolerance as a disorder of insulin action. Longitudinal and cross-sectional studies in Pima Indians. New Engl J Med 1988; 318: 1217–1225.PubMedCrossRefGoogle Scholar
  52. 52.
    Bodkin NL, Metzger BL, Hansen BC. Hepatic glucose production and insulin sensitivity preceding diabetes in monkeys. Am J Physiol 1989; 256: E676–E681.PubMedGoogle Scholar
  53. 53.
    O’Rahilly S, Turner RC, Matthews DR. Impaired pulsatile secretion of insulin in relatives of patients with non-insulin-dependent diabetes. New Engl J Med 1988; 318: 1225–1230.CrossRefGoogle Scholar
  54. 54.
    Biarnés J, Camps I, Riopollés J, Soler J, Fernandez Castaner M. Decline of beta cell function with age in first degree relatives of NIDDM. Diabetologia 1995; 38 (Supp11): Al2 (40).Google Scholar
  55. 55.
    Damsbo P, Vaag A, Hother-Nielsen O, and Beck-Nielsen H. Reduced glycogen synthase activity in skeletal muscle from obese patients with and without Type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia; 1991; 34: 239–245.PubMedCrossRefGoogle Scholar
  56. 56.
    Lindpainter K. Clinical implications of basic research. Finding an obesity gene-a tale of mice and man. New Engl J Med 1995; 332: 679–680.CrossRefGoogle Scholar
  57. 57.
    Walston J, Silver K, Bogardus C, Knowler W, Celi FX, Austin S, Manning B, Strosberg D, Stern MP, Raben N, SorkinJD, Roth J, Shuldine AR. Time of onset of non-insulin-dependent diabetes mellitus and genetic variation in the 133-adrenergic-receptor gene. New Engl J Med 1995; 333: 343–347.PubMedCrossRefGoogle Scholar
  58. 58.
    Turner RC, Hattersley AT, Shaw JTE, Levy JC. Perspectives in diabetes. Type II diabetes: Clinical aspects of molecular biological studies. Diabetes 1995; 44: 1–10.PubMedCrossRefGoogle Scholar
  59. 59.
    McCarthy MI, Froguel P, Hitman GA. The genetics of non-insulin-dependent diabetes mellitus: tools and aims. Diabetologia 1994; 37: 959–968.PubMedCrossRefGoogle Scholar
  60. 60.
    Bell GI, Xiang KS, Newman MV. Gene for non-insulin dependent diabetes mellitus (maturity-onset diabetes of the young) is linked to DNA polymorphism of human chromosome 20q. Proc Natl Acad Sci USA 1991; 88: 1484–1488.PubMedCrossRefGoogle Scholar
  61. 61.
    Groop LC, Kankuri M, Schalin-Jäntti C, Kestrand A, Nikula-Ijas P, Widen E, Kuismanen E, Eriksson J, Franssisla-Kallunki A, Saloranta C, Koskimies S. Association between polymorphism of the glycogen synthase gene and non-insulin-dependent diabetes mellitus [see comments]. New Engl J Med 1993; 328: 10–14.PubMedCrossRefGoogle Scholar
  62. 62.
    Ouwenland van den JMW, Lemkes HHPJ, Ruitenbeek W. Mutation in mitochrondrial tNALeu(uuR) gene in a large pedigree with maternally transmitted type 2 diabetes mellitus and deafness. Nature Genet 1992; 1: 368–371.CrossRefGoogle Scholar
  63. 63.
    Bjorbaek C, Echwald SM, Urhammer SA, Rasmussen S, Andersen CB, Hansen L, Almind K, Winther K, Haraldsdòttir, Borch-Johnsen K, Pedersen O. Insulin resistance: interactions between obesity and a common variant of insulin receptor substrate-1. Lancet 1995; 346: 397–402.PubMedCrossRefGoogle Scholar
  64. 64.
    Taylor SI, Accili A. Molecular genetics of insulin resistant diabetes mellitus. J Clin Endocrinol Metab 1991; 73: 1158–1163.PubMedCrossRefGoogle Scholar
  65. 65.
    Hansen L, Hansen T, Vestergaard H, Bjerbæk C, Echwald SM, Calusen J, Chen YH, Chen MX, Cohen PWT, Pedersen O. A widespread amino acid polymorphism oat codon 905 of the glycogen-associated regulatory subunit of protein phosphatase-1 is associated with insulin resistance and hypersecretion of insulin. Human Mol Gene 1995; 4, no. 8: 1313–1320.CrossRefGoogle Scholar
  66. 66.
    Bjerbæk C, Vik TA, Echwald SM, Yang P-Y, Vestergaard H, Wang JP, Webb GC, Richmond K, Hansen T, Erikson RL, Miklos GLG, Cohen PTWC, Pedersen O. 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 1995; 44: 90–97.CrossRefGoogle Scholar
  67. 67.
    Vestergaard H, Lund S, Larsen S, Bjerrum O, Pedersen O. Glycogen synthase and phosphofructokinase protein and mRNA levels in skeletal muscle from insulin-resistant patients with non-insulin dependent diabetes mellitus. J Clin Invest 1993; 91: 2342–2350.PubMedCrossRefGoogle Scholar
  68. 68.
    Kuroyama H, Sanke T, Ohagi S, Furuta M, Furuta H, Nanjo K. Simple tandem repeat DNA polymorphism in the human glycogen synthase gene is associated with NIDDM in Japanese subjects. Diabetologia 1994; 37: 536–539.PubMedCrossRefGoogle Scholar
  69. 69.
    Echwald SM, Bjorbaek C, Hansen T, Pedersen O. Identification of four amino acid substitutions in hexokinase II and studies of relationships to NIDDM, glucose effectiveness, and insulin sensitivity. Diabetes 1995; 44: 347–353.PubMedCrossRefGoogle Scholar
  70. 70.
    Antonetti DA, Reynet C, Kahn CR. Increased expression of mitochondrial-encoded genes in skeletal muscle of humans with diabetes mellitus. J Clin Invest 1995; 95: 1383–1388.PubMedCrossRefGoogle Scholar
  71. 71.
    Randle PJ. Glucokinase and candidate genes for Type (non-insulin-dependent) diabetes mellitus. Diabetologia 1993; 36: 269–275.PubMedCrossRefGoogle Scholar
  72. 72.
    Reynet C, Kahn CR. Rad: A member of the Ras family overexpressed in muscle of Type II diabetic humans. Science (Wash DC) 1993; 262: 1441–1444.CrossRefGoogle Scholar
  73. 73.
    Neel V. Diabetes mellitus: a “thrifty” genotype rendered detrimental by progress? Am J Hum Genet 1962; 14: 353–362.PubMedGoogle Scholar
  74. 74.
    Coleman DL. Obesity genes: beneficial effects in heterozygous mice. Science (Wash DC) 1979; 203: 663–665.Google Scholar
  75. 75.
    Widé E, Lehto M, Kanninen T, Walston J Schuldiner AR, Groop LC. Association of a polymorphism in the 133-adrenergic-receptor gene with features of the insulin resistance syndrome in Finns. New Engl J Med 1995; 333: 348–351.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1997

Authors and Affiliations

  • Henning Beck-Nielsen
  • Allan Vaag
  • Kirsten Ohm Kyvik

There are no affiliations available

Personalised recommendations