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

OBJECTIVE - To evaluate the effects of intensive insulin therapy and subsequent 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 diabetes. RESEARCH DESIGN AND METHODS - Ten (five men and five postmenopausal women) nonobese, normolipidemic (total cholesterol <6.2 mmol/l, triglycerides <2.82 mmol/l), type II diabetic patients in poor metabolic control (HbA(1c) >10%, fasting plasma glucose >11 mmol/l) and receiving sulfonylurea treatment were selected. The 24-h urinary MVA excretion and plasma lipid values were determined before and after intensive insulin therapy. The acute effects of insulin on plasma MVA concentrations 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 subjects) and 1.78 +/- 0.28 in patients before and after intensive insulin therapy, respectively. Total cholesterol, low-density-lipoprotein (LDL) cholesterol, and triglycerides decreased by 9, 8, and 12%, respectively, after blood glucose optimization. Acute insulin infusion during 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, normolipidemic, type II diabetic patients under poor metabolic control, an increased cholesterol synthesis is normalized by insulin therapy. Hyperinsulinemia in the presence of euglycemia acutely decreases the circulating levels of MVA, the immediate product of hydroxymethylglutaryl-CoA reductase activity and an index of whole-body cholesterol synthesis.