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

游离脂肪酸对胰腺β细胞功能影响的分子生理学和生物学研究

基本信息

批准号：
12671126
负责人：
ISHIDA Hitoshi
金额：
$ 1.92万
依托单位：
Kyorin University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12671126/
关键词：
proinsulin free fatty acids insulin secretion intracellular calcium PPARγ glucagon secretion exocytotic system insulin biosynthesis カルシウムイオン

项目摘要

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.

为了确定游离脂肪酸是否影响胰腺β细胞功能，我们利用离体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。胰岛暴露于棕榈酸1小时后，葡萄糖刺激的胰岛素生物合成减少，而胰岛素分泌没有变化。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。众所周知，长期暴露于游离脂肪酸会导致胰岛过氧化物酶体增殖物激活受体γ (PPAR γ)的过度表达。然后，体外研究PPAR γ过表达对胰岛素和胰高血糖素分泌的影响。通过PPAR γ过表达，葡萄糖刺激和高钾诱导的胰岛素分泌明显减少。而高钾去极化对胰高血糖素的释放没有影响。因此，退化效应似乎是β细胞特异性的。近年来，许多研究小组试图通过基因工程技术扩增或再生胰腺β细胞，但尚未建立明确的调节胰岛素分泌的方法。我们提前认识到，过继细胞特征性地分泌许多细胞因子，如TNF-α和脂联素，并且胰岛素刺激可触发GLUT4的调节胞外通路。有趣的是，当腺病毒介导的胰岛素前原基因转移到3T31_l脂肪细胞时，表达的胰岛素前原与GLUT4囊泡共定位，并被发现加工成胰岛素。基因转移到脂肪组织可以改善肥胖糖尿病KKAy小鼠的高血糖至少2周。随后葡萄糖毒性的消除有望恢复糖尿病患者胰腺β细胞的功能。