We tested the hypothesis that Insulin resistance, rather than high Insulin level, is associated with lipid and lipoprotein changes favoring atherosclerosis Independently of the glucose tolerance status. To this aim, 50 subjects with normal glucose tolerance, 28 subjects with Impaired glucose tolerance, and 54 subjects with nonlnsulln-dependent diabetes (NIDDM) were studied. Subjects wtth low glucose disposal rate (GDR) or a high degree of Insulin resistance as measured by the euglycemlc hyperinsullnemlc damp technique had lower high density lipoprotein (HDL) cholesterol and higher total and very low density lipoprotein (VLDL) triglycerldea than did subjects wtth high GDR (highest GDR fertile). These associations were Independent of fasting insulin level and other confounding factors. In stepwlse multiple linear regression analysis, GDR was the most important single variable associated with HDL cholesterol and VLDL trigh/ceride level Independently of age, obesity, distribution of obesity (waist/hip ratio), 2-hour glucose level, and free fatty acid concentration. 12 Three prospective population studies, the Helsinki Policemen Study, the Paris Prospective Study, and the Busselton Study, have independently shown that high plasma insulin level is associated with an increased risk of coronary heart disease in nondiabetic male subjects.345 Information on the relationship of plasma insulin to atherosclerosis in noninsulin-dependent diabetes (NIDDM) is scanty. 6 The mechanisms by which hyperinsulinemia promotes atherosclerosis are, however, unknown. Several studies indicate that high insulin concentration is associated with adverse changes in serum lipid and lipoprotein levels, characterized by elevated total and very low density lipoprotein (VLDL) triglyceride and decreased high density lipoprotein (HDL) cholesterol levels in subjects with normal glucose tolerance (NGT) concentration Is only an indirect indicator of the link between insulin resistance and adverse changes in lipid and lipoprotein levels. Indeed, two recent studies in subjects with NGT have demonstrated that low insulinmediated glucose uptake is associated with lipid and lipoprotein changes favoring atherosclerosis.1314 Subjects with impaired glucose tolerance (IGT) and NIDDM are more insulin-resistant than are subjects with NGT,16 and in both there is an increased risk of atherosclerosis.2 Therefore, if insulin resistance is a general risk factor for atherosclerosis, low insulin-mediated glucose uptake should be associated with adverse lipid and lipoprotein changes irrespective of the glucose tolerance status. To test this hypothesis, we studied lipid and lipoprotein levels and their association with insulin-mediated glucose uptake in a total of 132 subjects with varying degrees of glucose tolerance. Methods SubjectsThe subjects for this study, ages 50 years and older, were recruited from the previous population studies done by our department. 1617 Random samples of 50 subjects with NGT, 28 subjects with IGT, and 54 patients with NIDDM (duration of diab...

High plasma insulin has been shown to be associated with the risk of coronary heart disease in nondiabetic subjects in prospective population studies. Furthermore, insulin resistance measured by the euglycemic glucose clamp technique has been shown to be related to lipid and lipoprotein changes favoring atherosclerosis and to high blood pressure. No study, however, has demonstrated that insulin resistance per se is directly associated with atherosclerosis. With this aim, we studied 30 middle-aged nonobese subjects with asymptomatic atherosclerosis in the femoral or carotid arteries and 13 corresponding control subjects. Fasting blood glucose, insulin, and C-peptide levels were only slightly and nonsignificantly higher in subjects with atherosclerosis than in controls, and during the oral glucose tolerance test 1-and 2-hour glucose, insulin, and C-peptide levels were similar in both groups. During the euglycemic hyperinsulinemic (1,200 pmol/1) clamp studies, subjects with atherosclerosis had a 20% reduced whole-body glucose uptake (58 ±2 versus 71±4 /tmol/kg/min, /?=0.004). Glucose oxidation, lipid oxidation, suppression of free fatty acid levels, and potassium disposal were similar in both groups. In contrast, nonoxidative glucose disposal was significantly reduced in patients compared with that in controls (37±2 versus 50±4 jumol/kg/min, p=0.004). When glucose uptakes were matched during the hyperglycemic clamp studies, the rate of nonoxidative glucose uptake was normalized in the patients. These results provide the first direct evidence that asymptomatic atherosclerosis is associated with insulin resistance. This insulin resistance is characterized by reduced whole-body and nonoxidative glucose uptake. In contrast, glucose and lipid oxidation, potassium disposal, and suppression of free fatty acid levels during hyperinsulinemia did not differ between the subjects with and without atherosclerosis. insulin levels are independent predictors of coronary heart disease risk in nondiabetic subjects. Mechanisms of the association of atherosclerosis with hyperinsulinemia are, however, incompletely understood. Several possibilities have been proposed as explanations for this relation. First, a high insulin level may directly promote the formation of the atheroma in the arterial wall through its effects on

We studied the relationship of slight albuminuria (microalbuminuria) to serum lipid and lipoproteins in a representative group of middle-aged Type 2 (non-insulin-dependent) diabetic patients. A random sample of non-diabetic control subjects was also examined. Diabetic patients had both at diagnosis and after five years higher total, LDL- and VLDL-triglyceride levels and higher VLDL-cholesterol, but lower HDL-cholesterol levels than non-diabetic subjects. No consistent difference was found in LDL-cholesterol levels between diabetic and non-diabetic subjects. The prevalence of microalbuminuria (greater than 35 mg/24h) remained about the same in diabetic patients at both examinations (19-20%). The diabetic patients with persistent microalbuminuria were slightly hyperglycaemic and they tended to have lower creatinine clearance at the 5-year examination than those without persistent microalbuminuria. There were no differences in the blood pressure levels or the occurrence of hypertension between the diabetic groups with and without microalbuminuria. At the baseline examination, no differences were seen in serum lipids and lipoproteins between diabetic patients with and without microalbuminuria. In patients with persistent microalbuminuria, a statistically significant increase in VLDL-cholesterol (p less than 0.05) and VLDL- and LDL-triglyceride levels (p less than 0.05) and a decrease in HDL-cholesterol level (p less than 0.05) was seen at the 5-year follow-up. These changes could not be explained by age, sex, body mass index or HbA1. In conclusion, persistent microalbuminuria predicts and aggravates abnormalities in lipoprotein composition and a decrease in HDL-cholesterol in patients with Type 2 diabetes mellitus.(ABSTRACT TRUNCATED AT 250 WORDS)

A recent study has shown that young, lean, hypertensive subjects are more insulin resistant than corresponding normotensive subjects. Whether this finding can also be demonstrated in the presence of non-insulin-dependent diabetes mellitus (NIDDM) is not known. Therefore, the degree of insulin resistance was studied in 26 middle-aged hypertensive patients with NIDDM (11 men, 15 women) and 14 normotensive patients with NIDDM (eight men, six women) matched for age, metabolic control and the duration of diabetes, utilizing the glucose clamp technique. Non-obese NIDD patients (body mass index less than 27.0 kg m-2) with hypertension (n = 11) had significantly lower glucose disposal rates (GDRs) during the last 60 min of euglycaemic (5.5 mmol l-1) and hyperinsulinaemic (approximately 600 pmol l-1) clamp studies than NIDD patients without hypertension (n = 6) (782 +/- 94 vs. 1418 +/- 97 mumol m-2 min-1, P less than 0.05). In contrast, GDRs were similar in obese NIDD patients with (n = 15) and without (n = 8) hypertension (802 +/- 90 vs. 849 +/- 90 mumol m-2/min-1, respectively, P = NS). Basal hepatic glucose output, suppression of hepatic glucose production during hyperinsulinaemia and insulin secretion capacity did not differ between hypertensive and normotensive subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Our results indicate that a cluster of cardiovascular risk factors around hyperinsulinemia is an important predictor of diabetes in 8-year follow-up independent of family history of diabetes.