β-Cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats: Impairment in adipocyte-β-cell relationships

Y. Lee, H. Hirose, M. Ohneda, J. H. Johnson, J. D. McGarry, R. H. Unger

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Abstract

Hyperinsulinemia, loss of glucose-stimulated insulin secretion (GSIS), and peripheral insulin resistance coexist in non-insulin-dependent diabetes mellitus (NIDDM). Because free fatty acids (FFA) can induce these same abnormalities, we studied their role in the pathogenesis of the NIDDM of obese Zucker diabetic fatty (ZDF-drt) rats from 5 weeks of age (before the onset of hyperglycemia) until 14 weeks. Two weeks prior to hyperglycemia, plasma FFA began to rise progressively, averaging 1.9 ± 0.06 mM at the onset of hyperglycemia (P < 0.001 vs. controls). At this time GSIS was absent and β-cell GLUT-2 glucose transporter was decreased. The triacylglycerol content of prediabetic islets rose to 10 times that of controls and was correlated with plasma FFA (r = 0.825; P < 0.001), which, in turn, was correlated with the plasma glucose concentration (r = 0.873; P < 0.001). Reduction of hyperlipacidemia to 1.3 ± 0.07 mM by pair feeding with lean littermates reduced all β-cell abnormalities and prevented hyperglycemia. Normal rat islets that had been cultured for 7 days in medium containing 2 mM FFA exhibited increased basal insulin secretion at 3 mM glucose, and first-phase GSIS was reduced by 68%; in prediabetic islets, first-phase GSIS was reduced by 69% by FFA. The results suggest a role for hyperlipacidemia in the pathogenesis of NIDDM; resistance to insulin-mediated antilipolysis is invoked to explain the high FFA despite hyperinsulinemia, and sensitivity of β cells to hyperlipacedemia is invoked to explain the FFA-induced loss of GSIS.

Original languageEnglish
Pages (from-to)10878-10882
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume91
Issue number23
DOIs
Publication statusPublished - 1994 Nov 19
Externally publishedYes

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