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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^sup 2^, age 55 ± 6 years) or placebo (BMI 27 ± 4 kg/m^sup 2^, age 58 ± 8 years) daily for 8 weeks and were compared with 10 healthy humans (control subjects; BMI 27 ± 4 kg/m^sup 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). ^sup 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.
Diabetes Care 32:209-214, 2009
Type 2 diabetes is commonly associ- ated with dyslipidemia, which rep- resents a synergistic risk factor for cardiovascular disease (1). High- circulating lipids (free fatty acids [FFAs]) induce insulin resistance because of im- paired muscle glucose transport/ phosphorylation, and intracellular lipids in muscle (IMCLs) and liver (HCLs) predict insulin resistance (2).
Interventional studies emphasized that statin treatment leads to a reduction in cardiovascular events with benefits for patients with type 2 diabetes (3). Statins could also contribute to diabetes prevention owing to lipid-lowering and so-called pleiotropic action. Statin therapy was shown to improve endothelial function, inhibit smooth muscle cell proliferation, and reduce oxidative...