beta-cell function in normal rats made chronically hyperleptinemic by adenovirus-leptin gene therapy.

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Koyama, K; Chen, G; Wang, MY; Lee, Y; Shimabukuro, M; Newgard, CB; Unger, RH

Published Date

  • August 1997

Published In

Volume / Issue

  • 46 / 8

Start / End Page

  • 1276 - 1280

PubMed ID

  • 9231651

International Standard Serial Number (ISSN)

  • 0012-1797

Language

  • eng

Conference Location

  • United States