EFFECTS OF INSULIN ON CHOLESTEROL-SYNTHESIS IN TYPE-II DIABETES PATIENTS

OBJECTIVE - To evaluate the effects of intensive insulin therapy and s ubsequent optimized metabolic control on daily urinary mevalonic acid (MVA) excretion, an index of whole-body cholesterol synthesis, and the acute effects of insulin on plasma MVA concentrations in type II diab etes. RESEARCH DESIGN AND METHODS - Ten (five men and five postmenopau sal women) nonobese, normolipidemic (total cholesterol <6.2 mmol/l, tr iglycerides <2.82 mmol/l), type II diabetic patients in poor metabolic control (HbA(1c) >10%, fasting plasma glucose >11 mmol/l) and receivi ng sulfonylurea treatment were selected. The 24-h urinary MVA excretio n and plasma lipid values were determined before and after intensive i nsulin therapy. The acute effects of insulin on plasma MVA concentrati ons were also evaluated during a 3-h euglycemic hyperinsulinemic clamp study. RESULTS - Urinary MVA excretion rates (mu mol/24 h) were 1.82 +/- 0.21 in control subjects and 2.49 +/- 0.35 (P < 0.01 vs. control s ubjects) and 1.78 +/- 0.28 in patients before and after intensive insu lin therapy, respectively. Total cholesterol, low-density-lipoprotein (LDL) cholesterol, and triglycerides decreased by 9, 8, and 12%, respe ctively, after blood glucose optimization. Acute insulin infusion duri ng the euglycemic clamp studies reduced mean plasma MVA concentrations al 120 and 180 min by 29 and 38%, respectively (P < 0.01 for both vs. baseline). CONCLUSIONS - Our study demonstrates that in nonobese, nor molipidemic, type II diabetic patients under poor metabolic control, a n increased cholesterol synthesis is normalized by insulin therapy. Hy perinsulinemia in the presence of euglycemia acutely decreases the cir culating levels of MVA, the immediate product of hydroxymethylglutaryl -CoA reductase activity and an index of whole-body cholesterol synthes is.