TY - JOUR
T1 - β-Cell function in normal rats made chronically hyperleptinemic by adenovirus-leptin gene therapy
AU - Koyama, Kazunori
AU - Chen, Guoxun
AU - Wang, May-Yun
AU - Lee, Young H
AU - Shimabukuro, Michio
AU - Newgard, Christopher B.
AU - Unger, Roger H
N1 - Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 1997
Y1 - 1997
N2 - 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.
AB - 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.
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U2 - 10.2337/diab.46.8.1276
DO - 10.2337/diab.46.8.1276
M3 - Article
C2 - 9231651
AN - SCOPUS:0030871847
SN - 0012-1797
VL - 46
SP - 1276
EP - 1280
JO - Diabetes
JF - Diabetes
IS - 8
ER -