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

Julia Szendroedi, Christian Anderwald, Martin Krssak, Michaela Bayerle-Eder, Harald Esterbauer, Georg Pfeiler, Attila Brehm, Peter Nowotny, Astrid Hofer, Werner Waldhäusl, Michael Roden, Julia Szendroedi, Christian Anderwald, Martin Krssak, Michaela Bayerle-Eder, Harald Esterbauer, Georg Pfeiler, Attila Brehm, Peter Nowotny, Astrid Hofer, Werner Waldhäusl, Michael Roden

Abstract

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/m2, age 55 +/- 6 years) or placebo (BMI 27 +/- 4 kg/m2, age 58 +/- 8 years) daily for 8 weeks and were compared with 10 healthy humans (control subjects; BMI 27 +/- 4 kg/m2, 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). 1H magnetic resonance spectroscopy was used to quantify intramyocellular and hepatocellular lipids.

Results: High-dose simvastatin treatment lowered plasma total and LDL cholesterol levels by approximately 33 and approximately 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.

Trial registration: ClinicalTrials.gov NCT00704314.

Figures

Figure 1
Figure 1
Whole-body insulin sensitivity (M value) (A), ectopic lipid deposition in liver (B) soleus muscle (C), and anterior tibialis muscle (D) in patients with type 2 diabetes before and after treatment with 80 mg/day simvastatin (S, n = 10, ▪) or placebo (P, n = 10, ), and healthy humans (CON, n = 10, □, P < 0.005 versus simvastatin and placebo groups).
Figure 2
Figure 2
Correlation of changes in fasting FFAs with the changes in whole-body insulin sensitivity (M value) (A) and RBP-4 (B) in patients with type 2 diabetes before and after treatment with 80 mg/day simvastatin (S, n = 10).

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Source: PubMed

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