beta-cell function in normal rats made chronically hyperleptinemic by adenovirus-leptin gene therapy.
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.
Koyama
K
K
Department of Internal Medicine, Gifford Laboratories for Diabetes Research, University of Texas Southeastern Medical Center, Dallas 75235-8854, USA.
Chen
G
G
Wang
M Y
MY
Lee
Y
Y
Shimabukuro
M
M
Newgard
C B
CB
Unger
R H
RH
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001786:Blood Glucose / Q000032:analysis / Q000378:metabolism; D001835:Body Weight / Q000502:physiology; D002352:Carrier Proteins / Q000032:analysis / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D004435:Eating / Q000502:physiology; D015316:Genetic Therapy; D005947:Glucose / Q000494:pharmacology; D015151:Immunoblotting; D066298:In Vitro Techniques; D007261:Infusions, Intra-Arterial; D007328:Insulin / Q000097:blood / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism*; D020738:Leptin; D008297:Male; D010179:Pancreas / Q000166:cytology / Q000378:metabolism*; D010477:Perfusion; D011506:Proteins / Q000032:analysis* / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D013997:Time Factors; D001616:beta-Galactosidase / Q000235:genetics
D001786:Blood Glucose; D002352:Carrier Proteins; D007328:Insulin; D020738:Leptin; D011506:Proteins; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D001120:Arginine; D001616:beta-Galactosidase; D005947:Glucose