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细胞的功能，使用分离的大鼠胰岛研究了棕榈酸对proinsulin生物合成和胰岛素分泌的影响。将胰岛暴露于棕榈酸中1小时减少了葡萄糖刺激的胰岛素生物合成，而胰岛素分泌没有变化。那就是棕榈酸初级抑制葡萄糖诱导的促蛋白，然后改变胰岛素释放。众所周知，长期暴露的游离脂肪酸导致胰岛中过氧化物组增殖物激活的受体γ（PPARγ）的过表达。然后，在体外研究了PPARγ超压力对胰岛素和谷歌分泌的影响。通过PPARγ的过表达，葡萄糖刺激和高钾诱导的胰岛素分泌显着降低。但是，高钾沉积的胰高血糖素释放并未改变。因此，变质效应似乎是β细胞的特异性。最近，许多研究小组试图通过基因工程技术扩展或再生胰腺β细胞，但是，尚未建立一种定义的调节胰岛素分泌的方法。我们提出了事实，即同采用的许多细胞因子（例如TNF-α和脂联素）特征是秘密的，并且可以通过胰岛素刺激触发了受调节的GLUT4的胞吐途径。有趣的是，当将腺病毒介导的前胰岛素基因转移到3T31_L脂肪细胞中时，用Glut4囊泡共定位了表达的Proinsulin，并被发现已加工成胰岛素。转移到脂肪组织中的基因可改善肥胖的糖尿病KKAY小鼠的高血糖症至少2周。随后的葡萄糖毒性紧急情况有望恢复糖尿病中的胰腺β细胞功能。