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ENDOCRINE AND DIABETES

Novel Mechanism of Chronic Exposure of Oleic Acid-Induced Insulin Release Impairment in Rat Pancreatic -Cells

Third Department of Internal Medicine (T.K., Y.O., N.H., T.S.) and Departments of Physiology (S.S., M.W.) and Pathology (H.M., S.Y.), Hirosaki University School of Medicine, Hirosaki, Japan; and Division of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona (J.W.)

A sustained, high circulating level of free fatty acids (FFAs) is an important risk factor for the development of insulin resistance, islet -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 -cells exhibited a resting potential of -62.1 ± 0.9 mV and were electrically silent, whereas OA-treated -cells showed more positive resting potentials and spontaneous action potential firing. Cell-attached single-channel recordings revealed spontaneous opening of ATP-sensitive potassium (K_ATP) channels in control, but not in OA-treated, -cells. Inside-out excised patch recordings showed similar activity in both OA-treated and untreated -cells in the absence of ATP on the inside of the cellular membrane, whereas in the presence of ATP, K_ATP channel activity was significantly reduced in OA-treated -cells. Electron microscopy demonstrated that chronic exposure to OA resulted in the accumulation of triglycerides in -cell cytoplasm and reduced both the number of insulin-containing granules and insulin content. Collectively, chronic exposure to OA closed K_ATP channels by increasing the sensitivity of K_ATP channels to ATP, which in turn led to the continuous excitation of -cells, depletion of insulin storage, and impairment of glucose-stimulated insulin release.

Address correspondence to: Dr. Jie Wu, Neural Physiology Laboratory, Neurology Research, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013-4496. E-mail: jie.wu{at}chw.edu