Effects of high dose simvastatin therapy on glucose metabolism and ectopic lipid deposition in non-obese type 2 diabetic patients

Abstract

Objectives: Statins may exert pleiotropic effects on insulin action which 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 T2DM received 80 mg simvastatin (BMI: 29±4 kg.m^-2, age: 55±6 y) or placebo (27±4 kg.m^-2, 58±8 y) daily for 8 weeks and were compared to ten healthy humans (CON; 27±4 kg.m^-2; 55±7 y). Euglycemic-hyperinsulinemic clamp tests combined with D-(6,6-d2) glucose infusion were employed to assess insulin sensitivity (M) and endogenous glucose production (EGP). ¹H magnetic resonance spectroscopy was used to quantify intramyocellular and hepatocellular lipids.

Results: High-dose simvastatin treatment lowered plasma total and LDL cholesterol by ∼33% and ∼48% (p<0.005), but neither affected M nor intracellular lipid deposition in soleus, tibialis anterior muscle and liver nor basal and insulin-suppressed EGP. In simvastatin-treated patients, changes of LDL-C related negatively to changes in M (r=-0.796, p values<0.01). Changes of fasting free fatty acids (FFA) related negatively to changes in M (r=-0.840, p values<0.01) and positively to plasma retinol-binding protein 4 (RBP4, r=0.782, p=0.008).

Conclusion: High-dose simvastatin treatment has no direct effects on whole-body or tissue-specific insulin action and ectopic lipid deposition. Reduction of plasma FFA likely mediates alterations in insulin sensitivity in vivo.