β-Cell function in normal rats made chronically hyperleptinemic by adenovirus-leptin gene therapy

Kazunori Koyama, Guoxun Chen, May-Yun Wang, Young H Lee, Michio Shimabukuro, Christopher B. Newgard, Roger H Unger

Research output: Contribution to journalArticle

122 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1276-1280
Number of pages5
JournalDiabetes
Volume46
Issue number8
StatePublished - 1997

Fingerprint

Leptin
Adenoviridae
Genetic Therapy
Insulin
Arginine
Triglycerides
Lipids
Glucose
Palmitates
Oleic Acid
Hypoglycemia
Insulin Resistance
Wistar Rats
Pancreas
Fatty Acids
Complementary DNA
Perfusion
Eating
Fats
Body Weight

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

β-Cell function in normal rats made chronically hyperleptinemic by adenovirus-leptin gene therapy. / Koyama, Kazunori; Chen, Guoxun; Wang, May-Yun; Lee, Young H; Shimabukuro, Michio; Newgard, Christopher B.; Unger, Roger H.

In: Diabetes, Vol. 46, No. 8, 1997, p. 1276-1280.

Research output: Contribution to journalArticle

Koyama, Kazunori ; Chen, Guoxun ; Wang, May-Yun ; Lee, Young H ; Shimabukuro, Michio ; Newgard, Christopher B. ; Unger, Roger H. / β-Cell function in normal rats made chronically hyperleptinemic by adenovirus-leptin gene therapy. In: Diabetes. 1997 ; Vol. 46, No. 8. pp. 1276-1280.
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