Novel mechanism of chronic exposure of oleic acid-induced insulin release impairment in rat pancreatic β-cells

Takanori Kudo, Jie Wu, Yoshiji Ogawa, Sechiko Suga, Noriyuki Hasegawa, Toshihiro Suda, Hiroki Mizukami, Soroku Yagihashi, Makoto Wakui

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


A sustained, high circulating level of free fatty acids (FFAs) is an important risk factor for the development of insulin resistance, islet β-cell dysfunction, and pathogenesis of type 2 diabetes. Here, we report a novel mechanism of chronic exposure of oleic acid (OA)-induced rat insulin release impairment. Following a 4-day exposure to 0.1 mM OA, there was no significant difference in basal insulin release when comparing OA-treated and untreated islets in the presence of 2.8 mM glucose, whereas 16.7 mM glucose-stimulated insulin release increased 2-fold in control, but not in OA-treated, islets. Perforated patch-clamp recordings showed that untreated β-cells exhibited a resting potential of -62.1 ± 0.9 mV and were electrically silent, whereas OA-treated β-cells showed more positive resting potentials and spontaneous action potential firing. Cell-attached single-channel recordings revealed spontaneous opening of ATP-sensitive potassium (KATP) channels in control, but not in OA-treated, β-cells. Inside-out excised patch recordings showed similar activity in both OA-treated and untreated β-cells in the absence of ATP on the inside of the cellular membrane, whereas in the presence of ATP, KATP channel activity was significantly reduced in OA-treated β-cells. Electron microscopy demonstrated that chronic exposure to OA resulted in the accumulation of triglycerides in β-cell cytoplasm and reduced both the number of insulin-containing granules and insulin content. Collectively, chronic exposure to OA closed KATP channels by increasing the sensitivity of K ATP channels to ATP, which in turn led to the continuous excitation of β-cells, depletion of insulin storage, and impairment of glucose-stimulated insulin release.

Original languageEnglish (US)
Pages (from-to)1203-1210
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number3
StatePublished - 2006
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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