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

为了确定游离脂肪酸是否影响胰腺β细胞功能，使用分离的大鼠胰岛研究了棕榈酸对胰岛素原生物合成和胰岛素分泌的影响。将胰岛暴露于棕榈酸1小时减少葡萄糖刺激的胰岛素生物合成，而未观察到胰岛素分泌的变化。因此，棕榈酸在胰岛素释放改变之前主要抑制葡萄糖诱导的胰岛素原。长期暴露于游离脂肪酸可导致胰岛过氧化物酶体增殖物激活受体γ（peroxisome proliferator-activated receptor γ，PPAR γ）过度表达。然后，在体外研究了抑制PPAR γ β对胰岛素和胰高血糖素分泌的影响。通过过表达PPAR γ，葡萄糖刺激和高钾诱导的胰岛素分泌显著减少。然而，高钾去极化的胰高血糖素释放没有改变。因此，恶化效应似乎是β细胞特异性的。近年来，许多研究小组尝试利用基因工程技术扩增或再生胰岛β细胞，但对胰岛β细胞胰岛素分泌的调控机制尚未建立。我们进一步认识到，Adopocytes特征性地分泌许多细胞因子，如TNF-α和脂联素，并且胰岛素刺激可以触发GLUT 4的调节胞吐途径。有趣的是，当腺病毒介导的前胰岛素原基因转移到3T31_1脂肪细胞中时，表达的胰岛素原与GLUT 4囊泡共定位，并被发现被加工成胰岛素。将基因转移到脂肪组织中改善肥胖糖尿病KKAy小鼠的高血糖症至少2周。预期随后葡萄糖毒性的消除可恢复糖尿病中的胰腺β细胞功能。

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.