Molecular physiological and biological studies on the effect of free fatty acids on pancreatic β cell function

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In order to determine whether free fatty acids affect pancreatic βcell functions, the effect of palmitic acid on proinsulin biosynthesis and insulin secretion was studied using isolated rat islets. Expose of islets to palmitic acid for 1 hour reduced glucose-stimulated insulin biosynthesis, whereas no change in insulin secretion was observed. Thus, palmitic acid primarily suppress glucose-induced proinsulin prior to alteration of insulin release. It has been known that long expose of free fatty acids leads the overexpression of peroxisome proliferator-activated receptor γ (PPAR γ) in pancreatic islets. Then, the effect of PPAR γ overepression on the secretion of insulin and glucagon was investigated in vitro. The glucose-stimulated and high potassium-induced insulin secretion was markedly reduced through PPAR γ overexpression. However, the glucagon release by high-potassium depolarization was not changed. The deteriorative effect seems to be, therefore, β-cell specific. Recently, many research groups have tried to expand or regenerate pancreatic β cells by genetic engineering techniques, however, a definite way to regulate insulin secretion was not established. We took advance to facts that adopocytes characteristically secrete many cytokines such as TNF-α and adiponectin, and that the regulated exocytotic pathway to GLUT4 can be triggered by insulin stimulation. Interestingly, when adenovirus-mediated preproinsulin gene was transferred into 3T31_l adipocytes, expressed proinsulin was co-localized with GLUT4 vesicle and was found to be processed into insulin. The gene transfer into adipose tissues ameliorates hyperglycemia in obese diabetic KKAy mice for at least 2 weeks. The subsequent elimination of glucose toxicity can be expected to restore pancreatic β cell function in diabetes.