Defective fatty acid-mediated β-cell compensation in Zucker diabetic fatty rats: Pathogenic implications for obesity-dependent diabetes

Hiroshi Hirose, Young H. Lee, Lindsey R. Inman, Yoshitaka Nagasawa, John H. Johnson, Roger H. Unger

Research output: Contribution to journalArticle

116 Citations (Scopus)

Abstract

Although obesity is associated with insulin resistance, most obese humans and rodents remain nonnoglycemic because of compensatory hyperinsulinemia. This has been attributed to β-cell hyperplasia and increased low Km glucose metabolism of islets. Since free fatty acids (FFA) can induce these same β-cell changes in normal islets of Wistar rats and since plasma FFA are increased in obesity, FFA could be the signal from adipocytes that elicits β-cell compensation sufficient to prevent diabetes. To determine if FFA-induced compensation is impaired in islets of rats with a diabetogenic mutation, the Zucker diabetic fatty (ZDF) rat, we cultured islets from 6-week-old obese (fa/fa) rats that had compensated for obesity and apparently normal islets from lean ZDF rats (fα/+) in 0, 1, or 2 mM FFA. Low Km glucose usage rose 2.5-fold in FFA-cultured control islets from age-matched Wistar rats, but failed to rise in either the precompensated islets of ZDF rats or in islets of lean ZDF rats. Bromodeoxyuridine incorporation increased 3.2-fold in Wistar islets but not in islets from obese or lean ZDF rats. Insulin secretion doubled in normal islets cultured in 2 mM FFA (p < 0.01) but increased only slightly in islets from lean ZDF rats (not significant) and declined in islets from obese ZDF rats (p < 0.05). We conclude that, unlike the islets of age-matched Wistar rats, islets of 6-week-old heterozygous and homozygous ZDF rats lack the capacity for FFA-induced enhancement of β-cell function.

Original languageEnglish
Pages (from-to)5633-5637
Number of pages5
JournalJournal of Biological Chemistry
Volume271
Issue number10
DOIs
Publication statusPublished - 1996 Mar 8
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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