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Beta-cell Function in Normal Rats Made Chronically Hyperleptinemic by Adenovirus-leptin Gene Therapy
Diabetes (1997)
  • Guoxun Chen, University of Tennessee - Knoxville
  • K. Koyama
  • M. Y. Wang
  • Y. Lee
  • M. Shimabukuro
  • C. B. Newgard
  • R. H. Unger
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 beta-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 beta-cell dysfunction by depleting tissue lipids, thereby depriving beta-cells of a lipid-derived signal required for the insulin response to other fuels.

Publication Date
August, 1997
Citation Information
Guoxun Chen, K. Koyama, M. Y. Wang, Y. Lee, et al.. "Beta-cell Function in Normal Rats Made Chronically Hyperleptinemic by Adenovirus-leptin Gene Therapy" Diabetes Vol. 46 Iss. 8 (1997)
Available at: http://works.bepress.com/guoxun_chen/8/