Increased insulin resistance, which is present in the majority of type 2 diabetics patients, is associated with other metabolic and pro-coagulant cardiovascular risk factors and may account for the accelerated atherosclerosis and increased thrombotic potential observed in these patients. In individuals with normoglycaemia or impaired glucose tolerance (IGT), hyperinsulinaemia (a marker of insulin resistance) is associated with a similar clustering of risk factors and is predictive of cardiovascular events. The origins of insulin resistance are not well understood but data from families, twins and extended pedigrees suggest significant genetic and environmental contributions. The clustering of atherogenic traits begins in childhood, carries through to adult life and may result from the multiple effects of individual genes (pleiotropy) and environmental influences. Important environmental determinants of insulin resistance may occur before birth and, in conjunction with subsequent diet and exercise habits which result in obesity, lead to increased insulin resistance and cardiovascular risk. Therefore, primary prevention should centre around lifestyle changes which increase insulin sensitivity, maintain normoglycaemia and ameliorate atherothrombotic risk factor clustering.
Haffner SM, Lehto S., Ronnemaa T. et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction . N Engl J Med1998;339:229-34.
2.
Petersen S., Rayner M., Press V.Coronary Heart DiseaseStatistics: British Heart Foundation Statistics Database2000 . British Heart Foundation; 2000 .
3.
Reaven GMRole of insulin resistance in human disease. Diabetes1988;37:1595-607.
4.
Ukkola O., Bouchard C.Clustering of metabolic abnormalities in obese individuals: the role of genetic factors. Ann Med2001;33:79-90.
5.
Yudkin JS, Kumari M., Humphries SE et al. Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link?Atherosclerosis2000 ;148:209-14.
6.
Hollenbeck C. , Reaven GMVariations in insulin-stimulated glucose uptake in healthy individuals with normal glucose tolerance. J Clin Endocrinol Metab1987;64:1169-73.
7.
Zavaroni I., Bonora E., Pagliara M. et al. Risk factors for coronary artery disease in healthy persons with hyperinsulinemia and normal glucose tolerance. N Engl J Med1989;320:702-6.
8.
Laakso M.How good a marker is insulin level for insulin resistance?Am J Epidemiol1993;137:959-65.
9.
Ducimetière P., Eschwege E., Papoz L. et al. Relationship of plasma insulin levels to the incidence of myocardial infarction and coronary heart disease mortality in a middle-aged population. Diabetologia1989;19:205-10.
10.
Despres JP, Lamarche B., Mauriege P. et al. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med1996;334: 952-7.
11.
Pyorala M., Miettinen H., Laakso M. et al. Hyperinsulinemia predicts coronary heart disease risk in healthy middle-aged men: the 22-year follow-up results of the Helsinki Policemen Study . Circulation1998;98:398-404.
12.
Lempiainen P., Mykkanen L., Pyorala K. et al. Insulin resistance syndrome predicts coronary heart disease events in elderly nondiabetic men . Circulation1999;100:123-8.
13.
Uusitupa MI , Niskanen LK, Siitonen O. et al. 5-year incidence of atherosclerotic vascular disease in relation to general risk factors, insulin level, and abnormalities in lipoprotein composition in non-insulin-dependent diabetic and nondiabetic subjects. Circulation1990;82:27-36.
14.
Pyorala M., Miettinen H., Laakso M. et al. Hyperinsulinemia and the risk of stroke in healthy middle-aged men: the 22-year follow-up results of the Helsinki Policemen Study. Stroke1998;29:1860-6.
15.
Ferrara A., Barrett-Connor EL, Edelstein SLHyperinsulinemia does not increase the risk of fatal cardiovascular disease in elderly men or women without diabetes: the Rancho Bernardo Study, 1984-1991 . Am J Epidemiol1994;140:857-69.
16.
Orchard TJ, Eichner J., Kuller LH et al. Insulin as a predictor of coronary heart disease: interaction with apolipoprotein E phenotype. A report from the Multiple Risk Factor Intervention Trial. Ann Epidemiol1994;4:40-5.
17.
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 Care1997;20:935-42.
18.
Ruige JB, Assendelft WJ, Dekker JM et al. Insulin and risk of cardiovascular disease: a meta-analysis . Circulation1998;97:996-1001.
19.
Haffner SM, Stern MP, Hazuda HP et al. Cardiovascular risk factors in confirmed prediabetic individuals. Does the clock for coronary heart disease start ticking before the onset of clinical diabetes?JAMA1990;263:2893-8.
20.
U.K. prospective diabetes study 16.Overview of 6 years' therapy of type II diabetes: a progressive disease. U.K. Prospective Diabetes Study Group. Diabetes1995;44:1249-58.
21.
Haffner SM, Mykkanen L., Festa A. et al. Insulin-resistant prediabetic subjects have more atherogenic risk factors than insulin-sensitive prediabetic subjects: implications for preventing coronary heart disease during the prediabetic state. Circulation2000;101:975-80.
22.
Edelstein SL , Knowler WC, Bain RP et al. Predictors of progression from impaired glucose tolerance to NIDDM: an analysis of six prospective studies. Diabetes1997;46:701-10.
23.
Zavaroni I. , Dall'Aglio E., Bonora E. et al. Evidence that multiple risk factors for coronary artery disease exist in persons with abnormal glucose tolerance . Am J Med1987;83:609-12.
24.
Fontbonne A. , Charles MA, Thibult N. et al. Hyperinsulinaemia as a predictor of coronary heart disease mortality in a healthy population: the Paris Prospective Study, 15-year follow-up. Diabetologia1991 ;34:356-61.
25.
Fuller JH, Shipley MJ, Rose G. et al. Mortality from coronary heart disease and stroke in relation to degree of glycaemia: the Whitehall study. Br Med J (Clin Res Ed)1983;287:867-70.
26.
Donahue RP, Abbott RD, Reed DM et al. Postchallenge glucose concentration and coronary heart disease in men of Japanese ancestry. Honolulu Heart Program. Diabetes1987;36:689-92.
27.
Jarrett RJ, McCartney P., Keen H.The Bedford survey: ten year mortality rates in newly diagnosed diabetics, borderline diabetics and normoglycaemic controls and risk indices for coronary heart disease in borderline diabetics. Diabetologia1982;22:79-84.
28.
Fujishima M. , Kiyohara Y., Kato I. et al. Diabetes and cardiovascular disease in a prospective population survey in Japan: The Hisayama Study. Diabetes1996;45(suppl 3):S14-S16.
29.
Temelkova-Kurktschiev T., Koehler C., Schaper F. et al. Relationship between fasting plasma glucose, atherosclerosis risk factors and carotid intima media thickness in non-diabetic individuals. Diabetologia1998 ;41:706-12.
30.
Balkau B., Shipley M., Jarrett RJ et al. High blood glucose concentration is a risk factor for mortality in middle-aged nondiabetic men. 20-year follow-up in the Whitehall Study, the Paris Prospective Study, and the Helsinki Policemen Study. Diabetes Care1998;21:360-7.
31.
Gerstein HC , Yusuf S.Dysglycaemia and risk of cardiovascular disease . Lancet1996;347:949-50.
32.
Potter van Loon BJ, Kluft C., Radder JK et al. The cardiovascular risk factor plasminogen activator inhibitor type 1 is related to insulin resistance . Metabolism1993;42:945-9.
33.
Nilsson TK, Boman K., Bjerle P. et al. von Willebrand factor and fibrinolytic variables are differently affected in the insulin resistance syndrome. J Intern Med1994;235:419-23.
34.
Carter AM, Catto AJ, Grant PJDeterminants of tPA antigen and associations with coronary artery disease and acute cerebrovascular disease. Thromb Haemost1998;80:632-6.
35.
Meigs JB, Mittleman MA, Nathan DM et al. Hyperinsulinemia, hyperglycemia, and impaired hemostasis: the Framingham Offspring Study. JAMA2000;283:221-8.
36.
Mansfield MW , Stickland MH, Grant PJPAI-1 concentrations in first-degree relatives of patients with non-insulin-dependent diabetes: metabolic and genetic associations . Thromb Haemost1997;77:357-61.
37.
Juhan-Vague I., Pyke SDM, Alessi MC et al. Fibrinolytic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. Circulation1996;94:2057-63.
38.
Kohler HP, Grant PJPlasminogen-activator inhibitor type 1 and coronary artery disease . N Engl J Med2000;342:1792-801.
39.
Chandler WL, Alessi MC, Aillaud MF et al. Clearance of Tissue Plasminogen Activator (TPA) and TPA/Plasminogen Activator Inhibitor Type 1 (PAI-1) Complex. Circulation1997;96:761-8.
40.
Steins MB, Padro T., Li CX et al. Overexpression of tissue-type plasminogen activator in atherosclerotic human coronary arteries. Atherosclerosis1999 ;145:173-80.
41.
Haverkate F. , Thompson SG, Duckert F.Haemostasis factors in angina pectoris; relation to gender, age and acute-phase reaction. Results of the ECAT Angina Pectoris Study Group. Thromb Haemost1995;73:561-7.
42.
Meade TW, Mellows S., Brozovic M. et al. Haemostatic function and ischaemic heart disease: Principal Results of the Northwick Park Heart Study. Lancet1986;2:533-7.
43.
Heinrich J., Balleisen L., Schulte H. et al. Fibrinogen and factor VII in the prediction of coronary risk. Results from the PROCAM Study in Healthy Men. Arterioscler Thromb Vasc Biol1994;14:54-9.
44.
Folsom AR, Wu KK, Rosamond WD et al. Prospective study of hemostatic factors and incidence of coronary heart disease. The Atherosclerosis Risk in Communities (ARIC) Study. Circulation1997;96:1102-8.
45.
Meade TW, Ruddock V., Stirling Y. et al. Fibrinolytic activity, clotting factors, and long-term incidence of ischaemic heart disease in the Northwick Park Heart Study. Lancet1993;342:1076-9.
46.
Heywood DM, Mansfield MW, Grant PJFactor VII gene polymorphisms, factor VII:C levels and features of insulin resistance in non-insulin dependent diabetes mellitus. Thromb Haemost1996;75:401-6.
47.
Mansfield MW , Heywood DM, Grant PJCirculating levels of factor VII, fibrinogen, and von Willebrand factor and features of insulin resistance in first-degree relatives of patients with NIDDM. Circulation1996;94:2171-6.
48.
Zitoun D., Bara L., Basdevant A. et al. Levels of factor VIIc associated with decreased tissue factor pathway inhibitor and increased plasminogen activator inhibitor-1 in dyslipidemias . Arterioscler Thromb Vasc Biol1996;16:77-81.
49.
Humphries SE , Lane A., Green FR et al. Factor VII coagulant activity and antigen levels in healthy men are determined by interaction between factor VII genotype and plasma triglyceride concentration. Arterioscler Thromb1994;14:193-8.
50.
Ernst E., Resch KLFibrinogen as a cardiovascular risk factor: a meta-analysis and review of the literature. Ann Intern Med1993;118:956-63.
51.
Ganda OP, Arkin CFHyperfibrinogenemia. An important risk factor for vascular complications in diabetes. Diabetes Care1992;15:1245-50.
52.
Landin K., Stigendal L., Eriksson E. et al. Abdominal obesity is associated with an impaired fibrinolytic activity and elevated plasminogen activator inhibitor-1. Metabolism1990;39:1044-8.
53.
Festa A., D'Agostino R., Howard G. et al. Inflammation and microalbuminuria in nondiabetic and type 2 diabetic subjects: The Insulin Resistance Atherosclerosis Study. Kidney Int2000;58:1703-10.
54.
Yudkin JSAbnormalities of coagulation and fibrinolysis in insulin resistance. Evidence for a common antecedent?Diabetes Care1999 ;22 (suppl 3):C25-C30.
55.
Miller GJ, Esnouf MP, Burgess AI et al. Risk of coronary heart disease and activation of factor XII in middle-aged men. Arterioscler Thromb Vasc Biol1997;17:2103-6.
56.
Kohler HP, Carter AM, Stickland MH et al. Levels of activated FXII in survivors of myocardial infarction-- association with circulating risk factors and extent of coronary artery disease . Thromb Haemost1998;79:14-8.
57.
Haffner SM, Stern MP, Hazuda HP et al. Increased insulin concentrations in nondiabetic offspring of diabetic parents. N Engl J Med1988;319:1297-301.
58.
Chen W., Srinivasan SR, Elkasabany A. et al. The association of cardiovascular risk factor clustering related to insulin resistance syndrome (Syndrome X) between young parents and their offspring: the Bogalusa Heart Study. Atherosclerosis1999;145:197-205.
59.
Bao W., Srinivasan SR, Wattigney WA et al. Persistence of multiple cardiovascular risk clustering related to syndrome X from childhood to young adulthood. The Bogalusa Heart Study . Arch Intern Med1994;154:1842-7.
60.
Bao W., Srinivasan SR, Berenson GSPersistent elevation of plasma insulin levels is associated with increased cardiovascular risk in children and young adults. The Bogalusa Heart Study . Circulation1996;93:54-9.
61.
Mayer EJ, Newman B., Austin MA et al. Genetic and environmental influences on insulin levels and the insulin resistance syndrome: an analysis of women twins. Am J Epidemiol1996;143:323-32.
62.
Narkiewicz K., Chrostowska M., Kuchta G. et al. Genetic influences on insulinemia in normotensive twins. Am J Hypertens1997;10:467-70.
63.
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. Circulation1996 ;94:2159-70.
64.
de Lange M. , Snieder H., Ariëns RAS et al. The genetics of haemostasis: a twin study. Lancet2001;357:101-5.
65.
Souto JC, Almasy L., Borrell M. et al. Genetic determinants of hemostasis phenotypes in Spanish families . Circulation2000;101:1546-51.
66.
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 Biol1996;16:281-8.
67.
Hong Y., Pedersen NL, Brismar K. et al. Genetic and environmental architecture of the features of the insulin-resistance syndrome. Am J Hum Genet1997;60:143-52.
68.
Ravelli AC, van der Meulen JH, Michels RP et al. Glucose tolerance in adults after prenatal exposure to famine . Lancet1998;351:173-7.
69.
Mayer-Davis EJ, D'Agostino R., Jr., Karter AJ et al. Intensity and amount of physical activity in relation to insulin sensitivity: the Insulin Resistance Atherosclerosis Study. JAMA1998 ;279:669-74.
70.
Lithell HO, McKeigue PM, Berglund L. et al. Relation of size at birth to non-insulin dependent diabetes and insulin concentrations in men aged 50-60 years. BMJ1996;312:406-10.
71.
Shimokata H. , Muller DC, Andres R.Studies in the distribution of body fat. III. Effects of cigarette smoking. JAMA1989;261:1169-73.
72.
Frati AC, Iniestra F., Ariza CRAcute effect of cigarette smoking on glucose tolerance and other cardiovascular risk factors. Diabetes Care1996;19:112-8.
73.
Facchini FS , Hollenbeck CB, Jeppesen J. et al. Insulin resistance and cigarette smoking . Lancet1992;339:1128-30.
74.
Eliasson B. , Attvall S., Taskinen MR et al. Smoking cessation improves insulin sensitivity in healthy middle-aged men. Eur J Clin Invest1997;27:450-6.
75.
Dallosso HM , James WPThe role of smoking in the regulation of energy balance. Int J Obes1984;8:365-75.
76.
Grant PJThe effects of high and medium dose metformin therapy on cardiovascular risk factors in patients with type II diabetes. Diabetes Care1996;19:64-6.
77.
Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).UK Prospective Diabetes Study (UKPDS) Group . Lancet1998;352:854-65.
Tuomilehto J., Lindstrom J., Eriksson JG et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med2001;344:1343-50.
