Current Atherosclerosis Reports

, Volume 4, Issue 3, pp 193–198 | Cite as

Genetic determinants of diabetes and atherosclerosis

  • Braxton D. Mitchell
  • Ikhide G. Imumorin


Common risk factors for type 2 diabetes and cardiovascular disease are suspected because of the higher than expected prevalence of cardiovascular disease in individuals with newly diagnosed type 2 diabetes and in nondiabetic individuals with impaired glucose tolerance. Some of these risk factors may be genetic in origin. The risk of diabetes and cardiovascular disease may be linked through common pathways, including insulin resistance and/or inflammation. In this review, we describe the rationale for proposing these as common mechanisms affecting both diabetes and cardiovascular risk, and we then summarize the available evidence suggesting that common genes within these pathways have pleiotropic effects influencing susceptibility to both diseases.


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  1. 1.
    Mitchell BD: Macrovascular disease in diabetes. In Diabetes: Clinical Science in Practice. Edited by Leslie RDG, Robbins DC. Cambridge, UK: Cambridge University Press; 1995:222–236.Google Scholar
  2. 2.
    Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M: Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998, 339:229–234.PubMedCrossRefGoogle Scholar
  3. 3.
    Jarrett RJ: Type 2 (non-insulin-dependent) diabetes mellitus and coronary heart disease-chicken, egg or neither? Diabetologia 1984, 26:99–102.PubMedCrossRefGoogle Scholar
  4. 4.
    Marenberg ME, Risch N, Berkman LF, Floderus B, de Faire U: Genetic susceptibility to death from coronary heart disease in a study of twins. N Engl J Med 1994, 330:1041–1046.PubMedCrossRefGoogle Scholar
  5. 5.
    Peyser PA: Genetic epidemiology of coronary artery disease. Epidemiol Rev 1997, 19:80–90.PubMedGoogle Scholar
  6. 6.
    Ceriello A: Acute hyperglycaemia and oxidative stress generation. Diabet.Med 1997, 14(suppl 3):S45-S49.PubMedCrossRefGoogle Scholar
  7. 7.
    Reaven GM: Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988, 37:1595–1607.PubMedCrossRefGoogle Scholar
  8. 8.
    Stern MP: Diabetes and cardiovascular disease. The “common soil” hypothesis. Diabetes 1995, 44:369–374.PubMedCrossRefGoogle Scholar
  9. 9.
    Haffner SM, Stern MP, Hazuda HP, Mitchell BD, Patterson JK: Cardiovascular risk factors in confirmed prediabetic individuals. Does the clock for coronary heart disease start ticking before the onset of clinical diabetes? JAMA 1990, 263:2893–2898.PubMedCrossRefGoogle Scholar
  10. 10.
    McPhillips JB, Barrett-Connor E, Wingard DL: Cardiovascular disease risk factors prior to the diagnosis of impaired glucose tolerance and non-insulin-dependent diabetes mellitus in a community of older adults. Am J Epidemiol 1990, 131:443–453.PubMedGoogle Scholar
  11. 11.
    Haffner SM, Valdez RA, Hazuda HP, et al.: Prospective analysis of the insulin-resistance syndrome (syndrome X). Diabetes 1992, 41:715–722.PubMedCrossRefGoogle Scholar
  12. 12.
    Liese AD, Mayer-Davis EJ, Tyroler HA, et al.: Development of the multiple metabolic syndrome in the ARIC cohort: joint contribution of insulin, BMI, and WHR. Atherosclerosis risk in communities. Ann Epidemiol 1997, 7:407–416.PubMedCrossRefGoogle Scholar
  13. 13.
    Hegele RA: Premature atherosclerosis associated with monogenic insulin resistance. Circulation 2001, 103:2225–2229.PubMedGoogle Scholar
  14. 14.
    Howard G, O’Leary DH, Zaccaro D, et al.: Insulin sensitivity and atherosclerosis. The Insulin Resistance Atherosclerosis Study (IRAS) Investigators. Circulation 1996, 93:1809–1817.PubMedGoogle Scholar
  15. 15.
    Despres JP, Lamarche B, Mauriege P, et al.: Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med 1996, 334:952–957.PubMedCrossRefGoogle Scholar
  16. 16.
    Folsom AR, Szklo M, Stevens J, et al.: A prospective study of coronary heart disease in relation to fasting insulin, glucose, and diabetes. The Atherosclerosis Risk in Communities (ARIC) Study. Diabetes Care 1997, 20:935–942.PubMedCrossRefGoogle Scholar
  17. 17.
    Pyorala M, Miettinen H, Laakso M, Pyorala K: Hyperinsulinemia predicts coronary heart disease risk in healthy middle-aged men: the 22-year follow-up results of the Helsinki Policemen Study. Circulation 1998, 98:398–404.PubMedGoogle Scholar
  18. 18.
    Pyorala M, Miettinen H, Halonen P, Laakso M, Pyorala K: Insulin resistance syndrome predicts the risk of coronary heart disease and stroke in healthy middle-aged men: the 22-year follow-up results of the Helsinki Policemen Study. Arterioscler Thromb Vasc Biol 2000, 20:538–544.PubMedGoogle Scholar
  19. 19.
    Kuusisto J, Lempiainen P, Mykkanen L, Laakso M: Insulin resistance syndrome predicts coronary heart disease events in elderly type 2 diabetic men. Diabetes Care 2001, 24:1629–1633.PubMedCrossRefGoogle Scholar
  20. 20.
    Mitchell BD, Kammerer CM, Blangero J, et al.: Genetic and environmental contributions to cardiovascular risk factors in Mexican Americans. The San Antonio Family Heart Study. Circulation 1996, 94:2159–2170.PubMedGoogle Scholar
  21. 21.
    Mitchell BD, Kammerer CM, Mahaney MC, et al.: Genetic analysis of the IRS. Pleiotropic effects of genes influencing insulin levels on lipoprotein and obesity measures. Arterioscler Thromb Vasc Biol 1996, 16:281–288.PubMedGoogle Scholar
  22. 22.
    Watanabe RM, Valle T, Hauser ER, et al.: 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 Heredity 1999, 49:159–168.PubMedCrossRefGoogle Scholar
  23. 23.
    Eriksson J, Franssila-Kallunki A, Ekstrand A, et al.: Early metabolic defects in persons at increased risk for non-insulin- dependent diabetes mellitus. N Engl J Med 1989, 321:337–343.PubMedCrossRefGoogle Scholar
  24. 24.
    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
  25. 25.
    Mitchell BD, Almasy LA, Rainwater DL, et al.: Diabetes and hypertension in Mexican American families: relation to cardiovascular risk. Am J Epidemiol 1999, 149:1047–1056.PubMedGoogle Scholar
  26. 26.
    Haffner SM, Stern MP, Hazuda HP, Mitchell BD, Patterson JK: Increased insulin concentrations in nondiabetic offspring of diabetic parents. N Engl J Med 1988, 319:1297–1301.PubMedCrossRefGoogle Scholar
  27. 27.
    Liese AD, Mayer-Davis EJ, Tyroler HA, et al.: Familial components of the multiple metabolic syndrome: the ARIC study. Diabetologia 1997, 40:963–970.PubMedCrossRefGoogle Scholar
  28. 28.
    Edwards KL, Austin MA, Newman B, et al.: Multivariate analysis of the insulin resistance syndrome in women. Arterioscler Thromb 1994, 14:1940–1945.PubMedGoogle Scholar
  29. 29.
    Meigs JB, D’Agostino RB Sr, Wilson PW, et al.: Risk variable clustering in the insulin resistance syndrome. The Framingham Offspring Study. Diabetes 1997, 46:1594–1600.PubMedCrossRefGoogle Scholar
  30. 30.
    Gray RS, Fabsitz RR, Cowan LD, et al.: Risk factor clustering in the insulin resistance syndrome. The Strong Heart Study. Am J Epidemiol 1998, 148:869–878.PubMedGoogle Scholar
  31. 31.
    Edwards KL, Newman B, Mayer E, et al.: Heritability of factors of the insulin resistance syndrome in women twins. Genet Epidemiol 1997, 14:241–253.PubMedCrossRefGoogle Scholar
  32. 32.
    Hong Y, Pedersen NL, Brismar K, de Faire U: Genetic and environmental architecture of the features of the insulin-resistance syndrome. Am J Hum Genet 1997, 60:143–152.PubMedGoogle Scholar
  33. 33.
    Schumacher MC, Hasstedt SJ, Hunt SC, Williams RR, Elbein SC: Major gene effect for insulin levels in familial NIDDM pedigrees. Diabetes 1992, 41:416–423.PubMedCrossRefGoogle Scholar
  34. 34.
    Mitchell BD, Kammerer CM, Hixson JE, et al.: Evidence for a major gene affecting postchallenge insulin levels in Mexican-Americans. Diabetes 1995, 44:284–289.PubMedCrossRefGoogle Scholar
  35. 35.
    Kao W, Hsueh WC, Blangero J, O’Leary DH, Mitchell BD: Family history of diabetes is associated with carotid artery intimal-medial thickness in Mexican Americans [abstract]. Diabetes 2001, 49:A79.Google Scholar
  36. 36.
    Duggirala R, Gonzalez VC, O’Leary DH, Stern MP, Blangero J: Genetic basis of variation in carotid artery wall thickness. Stroke 1996, 27:833–837.PubMedGoogle Scholar
  37. 37.
    Wagenknecht LE, Bowden DW, Carr JJ, et al.: Familial aggregation of coronary artery calcium in families with type 2 diabetes. Diabetes 2001, 50:861–866.PubMedCrossRefGoogle Scholar
  38. 38.
    Barakat K, Hitman GA: Genetic susceptibility to macro-vascular complications of type 2 diabetes mellitus. Best Pract Res Clin Endocrinol Metab 2001, 15:359–370.PubMedCrossRefGoogle Scholar
  39. 39.
    Moller DE, Bjorbaek C, Vidal-Puig A: Candidate genes for insulin resistance. Diabetes Care 1996, 19:396–400.PubMedCrossRefGoogle Scholar
  40. 40.
    Burks DJ, White MF: IRS proteins and beta-cell function. Diabetes 2001, 50(suppl 1):S140-S145.PubMedCrossRefGoogle Scholar
  41. 41.
    Tracy RP: Inflammation in cardiovascular disease: cart, horse, or both? Circulation 1998, 97:2000–2002.PubMedGoogle Scholar
  42. 42.
    Ross R: Atherosclerosis—an inflammatory disease. N Engl J Med 1999, 340:115–126.PubMedCrossRefGoogle Scholar
  43. 43.
    Duncan BB, Schmidt MI, Offenbacher S, et al.: Factor VIII and other hemostasis variables are related to incident diabetes in adults. The Atherosclerosis Risk in Communities (ARIC) Study. Diabetes Care 1999, 22:767–772.PubMedCrossRefGoogle Scholar
  44. 44.
    Schmidt MI, Duncan BB, Sharrett AR, et al.: Markers of inflammation and prediction of diabetes mellitus in adults (Atherosclerosis Risk in Communities study): a cohort study. Lancet 1999, 353:1649–1652.PubMedCrossRefGoogle Scholar
  45. 45.
    Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM: C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 2001, 286:327–334.PubMedCrossRefGoogle Scholar
  46. 46.
    Barzilay JI, Abraham L, Heckbert SR, et al.: The relation of markers of inflammation to the development of glucose disorders in the elderly: the Cardiovascular Health Study. Diabetes 2001, 50:2384–2389.PubMedCrossRefGoogle Scholar
  47. 47.
    Kuller LH, Tracy RP, Shaten J, Meilahn EN: Relation of C-reactive protein and coronary heart disease in the MRFIT nested case-control study. Multiple Risk Factor Intervention Trial. Am J Epidemiol 1996, 144:537–547.PubMedGoogle Scholar
  48. 48.
    Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH: Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997, 336:973–979.PubMedCrossRefGoogle Scholar
  49. 49.
    Tracy RP, Lemaitre RN, Psaty BM, et al.: Relationship of C-reactive protein to risk of cardiovascular disease in the elderly. Results from the Cardiovascular Health Study and the Rural Health Promotion Project. Arterioscler Thromb Vasc Biol 1997, 17:1121–1127.PubMedGoogle Scholar
  50. 50.
    Hansson GK: Immune mechanisms in atherosclerosis. Arterioscler Thromb Vasc Biol 2001, 21:1876–1890.PubMedGoogle Scholar
  51. 51.
    Pankow JS, Folsom AR, Cushman M, et al.: Familial and genetic determinants of systemic markers of inflammation: the NHLBI family heart study. Atherosclerosis 2001, 154:681–689.PubMedCrossRefGoogle Scholar
  52. 52.
    Frohlich M, Imhof A, Berg G, et al.: Association between C-reactive protein and features of the metabolic syndrome: a population-based study. Diabetes Care 2000, 23:1835–1839.PubMedCrossRefGoogle Scholar
  53. 53.
    Pannacciulli N, Cantatore FP, Minenna A, et al.: C-reactive protein is independently associated with total body fat, central fat, and insulin resistance in adult women. Int J Obes Relat Metab Disord 2001, 25:1416–1420.PubMedCrossRefGoogle Scholar
  54. 54.
    Hak AE, Pols HA, Stehouwer CD, et al.: Markers of inflammation and cellular adhesion molecules in relation to insulin resistance in nondiabetic elderly: the Rotterdam study. J Clin Endocrinol Metab 2001, 86:4398–4405.PubMedCrossRefGoogle Scholar
  55. 55.
    Meigs JB: Invited commentary: insulin resistance syndrome? Syndrome X? Multiple metabolic syndrome? A syndrome at all? Factor analysis reveals patterns in the fabric of correlated metabolic risk factors. Am J Epidemiol 2000, 152:908–911.PubMedCrossRefGoogle Scholar
  56. 56.
    Camacho-Hubner C, Savage M: Insulin-like growth factor -I deficiency. Horm Res 2001, 55(suppl 1):17–20.PubMedCrossRefGoogle Scholar
  57. 57.
    Vaessen N, Heutink P, Janssen JA, et al.: A polymorphism in the gene for IGF-I: functional properties and risk for type 2 diabetes and myocardial infarction. Diabetes 2001, 50:637–642.PubMedCrossRefGoogle Scholar
  58. 58.
    Ortlepp JR, Lauscher J, Hoffmann R, Hanrath P, Joost HG: The vitamin D receptor gene variant is associated with the prevalence of Type 2 diabetes mellitus and coronary artery disease. Diabet Med 2001, 18:842–845.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc 2002

Authors and Affiliations

  • Braxton D. Mitchell
    • 1
  • Ikhide G. Imumorin
    • 1
  1. 1.Division of Endocrinology, Diabetes, and NutritionUniversity of Maryland School of MedicineBaltimoreUSA

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