Do increased proinsulin concentrations explain the excess risk of coronary heart disease in diabetic and prediabetic subjects?

Type 2 diabetes is associated with a marked increase in the risk of coronary heart disease (CHD).1 In addition, small increases in glucose concentrations in the nondiabetic range also may be associated with an increased risk of CHD (see the Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe [DECODE] study2). However, the increase in CHD in diabetic subjects may not be entirely due to increases in glucose levels per se, because in many studies, including the United Kingdom Prospective Diabetes Study (UKPDS),3 although glucose levels were significantly related to CHD, the magnitude of the association is only modest. One explanation for the increased risk of CHD in diabetics may be the insulin resistance syndrome.4 A related possibility may be the atherogenicity of the prediabetic state.4 Indeed, insulin resistance, rather than decreased insulin secretion, seems to be most responsible for the increased cardiovascular risk factors in the prediabetic state (ie, increased triglyceride and blood pressure and decreased high-density lipoprotein cholesterol [HDL-C] even before the onset of diabetes).5 In some studies, insulin concentrations (as a surrogate for insulin resistance) have been strongly related to CHD6; however, in other studies that include meta-analysis, insulin concentrations have been only modestly associated with CHD.7