Effects of High-Dose Simvastatin Therapy on Glucose Metabolism and Ectopic Lipid Deposition in Nonobese Type 2 Diabetic Patients

OBJECTIVE—Statins may exert pleiotropic effects on insulin action that are still controversial. We assessed effects of high-dose simvastatin therapy on peripheral and hepatic insulin sensitivity, as well as on ectopic lipid deposition in patients with hypercholesterolemia and type 2 diabetes. RESEARCH DESIGN AND METHODS—We performed a randomized, double-blind, placebo-controlled, single-center study. Twenty patients with type 2 diabetes received 80 mg simvastatin (BMI 29 ± 4 kg/m(2), age 55 ± 6 years) or placebo (BMI 27 ± 4 kg/m(2), age 58 ± 8 years) daily for 8 weeks and were compared with 10 healthy humans (control subjects; BMI 27 ± 4 kg/m(2), age 55 ± 7 years). Euglycemic-hyperinsulinemic clamp tests combined with d-[6,6-d2]glucose infusion were used to assess insulin sensitivity (M) and endogenous glucose production (EGP). (1)H magnetic resonance spectroscopy was used to quantify intramyocellular and hepatocellular lipids. RESULTS—High-dose simvastatin treatment lowered plasma total and LDL cholesterol levels by ∼33 and ∼48% (P < 0.005) but did not affect M, intracellular lipid deposition in soleus and tibialis anterior muscles and liver, or basal and insulin-suppressed EGP. In simvastatin-treated patients, changes in LDL cholesterol related negatively to changes in M (r = −0.796, P < 0.01). Changes in fasting free fatty acids (FFAs) related negatively to changes in M (r = −0.840, P < 0.01) and positively to plasma retinol-binding protein-4 (r = 0.782, P = 0.008). CONCLUSIONS—High-dose simvastatin treatment has no direct effects on whole-body or tissue-specific insulin action and ectopic lipid deposition. A reduction in plasma FFAs probably mediates alterations in insulin sensitivity in vivo.