Novel Mechanism Of Chronic Exposure Of Oleic Acid-Induced Insulin Release Impairment In Rat Pancreatic Î²-Cells
A sustained, high circulating level of free fatty acids (FFAs) is an important risk factor for the development of insulin resistance, islet Î²-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 Î²-cells exhibited a resting potential of -62.1 Â± 0.9 mV and were electrically silent, whereas OA-treated Î²-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, Î²-cells. Inside-out excised patch recordings showed similar activity in both OA-treated and untreated Î²-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 Î²-cells. Electron microscopy demonstrated that chronic exposure to OA resulted in the accumulation of triglycerides in Î²-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 Î²-cells, depletion of insulin storage, and impairment of glucose-stimulated insulin release. Copyright Â© 2006 by The American Society for Pharmacology and Experimental Therapeutics.
Journal of Pharmacology and Experimental Therapeutics
Digital Object Identifier (DOI)
Kudo, Takanori; Wu, Jie; Ogawa, Yoshiji; Suga, Sechiko; Hasegawa, Noriyuki; Suda, Toshihiro; Mizukami, Hiroki; Yagihashi, Soroku; and Wakui, Makoto, "Novel Mechanism Of Chronic Exposure Of Oleic Acid-Induced Insulin Release Impairment In Rat Pancreatic Î²-Cells" (2006). Neurobiology. 459.