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.
β-Cell Function in Normal Rats Made Chronically Hyperleptinemic by Adenovirus-Leptin Gene Therapy
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Kazunori Koyama, Guoxun Chen, May-Yun Wang, Young Lee, Michio Shimabukuro, Christopher B Newgard, Roger H Unger; β-Cell Function in Normal Rats Made Chronically Hyperleptinemic by Adenovirus-Leptin Gene Therapy. Diabetes 1 August 1997; 46 (8): 1276–1280. https://doi.org/10.2337/diab.46.8.1276
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