β-Cell Function in Normal Rats Made Chronically Hyperleptinemic by Adenovirus-Leptin Gene Therapy

  1. Roger H Unger
  1. Departments of Internal Medicine and Biochemistry, Gifford Laboratories for Diabetes Research, University of Texas Southeastern Medical Center Dallas, Texas.
  2. Department of Veterans Affairs Medical Center Dallas, Texas.
  1. Address correspondence to Roger H. Unger, MD, Center for Diabetes Research, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75235–8854.

Abstract

Leptin was overexpressed in the liver of normal Wistar rats by infusing recombinant adenovirus containing the cDNA encoding leptin. Plasma leptin levels rose to 12–24 ng/ml (vs. <2 ng/ml in control rats), and food intake and body weight fell. Visible fat disappeared within 7 days. Plasma insulin fell to <50% of normal in association with hypoglycemia, suggesting enhanced insulin sensitivity. Although β-cells appeared histologically normal, the pancreases were unresponsive to perfusion with stimulatory levels of glucose and arginine. Since islet triglyceride content was 0, compared with 14 ng/islet in pair-fed control rats, we coperfused a 2:1 oleate:palmitate mixture (0.5 mmol/l). This restored insulin responses to supranormal levels. When normal islets were cultured with 20 ng/ml of leptin, they too became triglyceride-depleted and failed to respond when perifused with glucose or arginine. Perifusion of fatty acids restored both responses. We conclude that in normal rats, hyperleptinemia for 2 weeks causes reversible β-cell dysfunction by depleting tissue lipids, thereby depriving β-cells of a lipid-derived signal required for the insulin response to other fuels.

  • Received February 14, 1997.
  • Revision received April 8, 1997.
  • Accepted April 8, 1997.
No Related Web Pages
| Table of Contents