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

  1. Julia Szendroedi, MD, PHD123,
  2. Christian Anderwald, MAG, MD1,
  3. Martin Krssak, PHD4,
  4. Michaela Bayerle-Eder, MD1,
  5. Harald Esterbauer, MD, PHD5,
  6. Georg Pfeiler, MD6,
  7. Attila Brehm, MD1,
  8. Peter Nowotny1,
  9. Astrid Hofer1,
  10. Werner Waldhäusl, MD1 and
  11. Michael Roden, MD23
  1. 1Department of Internal Medicine 3, Medical University of Vienna, Vienna, Austria
  2. 2Karl-Landsteiner Institute of Endocrinology and Metabolism, Vienna, Austria
  3. 3Department of Medicine/Metabolic Diseases, Institute for Clinical Diabetology, German Diabetes Center, Heinrich Heine University, Düsseldorf, Germany
  4. 4Department of Radiology, Medical University of Vienna, Vienna, Austria
  5. 5Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Vienna, Austria
  6. 6Division of Special Gynecology, Medical University of Vienna, Vienna, Austria
  1. Corresponding author: Michael Roden, michael.roden{at}ddz.uni-duesseldorf.de

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 ∼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.

Footnotes

  • Published ahead of print at http://care.diabetesjournals.org on 28 October 2008.

    Clinical trial reg. no. NCT00704314, clinicaltrials.gov.

    The funding bodies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

    Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C Section 1734 solely to indicate this fact.

    • Accepted October 16, 2008.
    • Received June 25, 2008.
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  1. Diabetes Care vol. 32 no. 2 209-214
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