Reversal of Nonalcoholic Hepatic Steatosis, Hepatic Insulin Resistance, and Hyperglycemia by Moderate Weight Reduction in Patients With Type 2 Diabetes

  1. Kitt Falk Petersen1,
  2. Sylvie Dufour12,
  3. Douglas Befroy1,
  4. Michael Lehrke3,
  5. Rosa E. Hendler1 and
  6. Gerald I. Shulman124
  1. 1Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
  2. 2Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut
  3. 3Department of Internal Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
  4. 4Department of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut
  1. Address correspondence and reprint requests to Kitt Falk Petersen, MD, Yale University School of Medicine, Department of Internal Medicine, 300 Cedar St., S263 TAC, P.O. Box 9812, New Haven, CT 06520-8020. E-mail: kitt.petersen{at}yale.edu

Abstract

To examine the mechanism by which moderate weight reduction improves basal and insulin-stimulated rates of glucose metabolism in patients with type 2 diabetes, we used 1H magnetic resonance spectroscopy to assess intrahepatic lipid (IHL) and intramyocellular lipid (IMCL) content in conjunction with hyperinsulinemic-euglycemic clamps using [6,6-2H2]glucose to assess rates of glucose production and insulin-stimulated peripheral glucose uptake. Eight obese patients with type 2 diabetes were studied before and after weight stabilization on a moderately hypocaloric very-low-fat diet (3%). The diabetic patients were markedly insulin resistant in both liver and muscle compared with the lean control subjects. These changes were associated with marked increases in IHL (12.2 ± 3.4 vs. 0.6 ± 0.1%; P = 0.02) and IMCL (2.0 ± 0.3 vs. 1.2 ± 0.1%; P = 0.02) compared with the control subjects. A weight loss of only ∼8 kg resulted in normalization of fasting plasma glucose concentrations (8.8 ± 0.5 vs. 6.4 ± 0.3 mmol/l; P < 0.0005), rates of basal glucose production (193 ± 7 vs. 153 ± 10 mg/min; P < 0.0005), and the percentage suppression of hepatic glucose production during the clamp (29 ± 22 vs. 99 ± 3%; P = 0.003). These improvements in basal and insulin-stimulated hepatic glucose metabolism were associated with an 81 ± 4% reduction in IHL (P = 0.0009) but no significant change in insulin-stimulated peripheral glucose uptake or IMCL (2.0 ± 0.3 vs. 1.9 ± 0.3%; P = 0.21). In conclusion, these data support the hypothesis that moderate weight loss normalizes fasting hyperglycemia in patients with poorly controlled type 2 diabetes by mobilizing a relatively small pool of IHL, which reverses hepatic insulin resistance and normalizes rates of basal glucose production, independent of any changes in insulin-stimulated peripheral glucose metabolism.

Footnotes

    • Accepted November 29, 2004.
    • Received August 2, 2004.
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