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

Journal Article (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

Digital Object Identifier (DOI)

  • 10.2337/diab.46.8.1276


  • eng

Conference Location

  • United States