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Research of Novel Mechanism in the Genesis of Diabetes Mellitus: The Dysfunction of pancreatic beta cell by the Increase of Blood Lipid Peroxides

糖尿病发病新机制研究：血脂过氧化物升高导致胰岛β细胞功能障碍

基本信息

批准号：
13671202
负责人：
OIKAWA Shinichi
金额：
$ 2.24万
依托单位：
Nippon Medical School
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671202/
关键词：
pancreatic β-cell oxidized stress insulin secretion lipid peroxide Hit-Y15 cell oxLDL 糖尿病酸化LDL β細胞

项目摘要

It is believed that lipid peroxidation is a main mechanism in atherogenesis from the various studies on the relationships between lipid peroxides and vascular cells. However, its effect on the other cell types has not been studied. It has been suggested that insulin secretary cell of pancreas (β-cell) was weak for oxidized stress. Therefore we challenged Hit-T15 cell, which is a β-cell derived from hamster pancreatic tumor cell, to clarify the effect of phospholipid peroxides on insulin secretion. We added native phosphatidylcholine (PC), phosphatidylcholine hydroperoxide (PCOOH) and lysophosphatidylcholine (LysoPC) in the culture of HIT-T15 cell. LysoPC significantly decreased the expression of preproinsulin mRNA, intracellular insulin content, and insulin secretion. PCOOH effect did not affect on the preproinsulin mRNA expression, but decreased intracellular insulin level and insulin secretion. These oxidized phospholipids would be the components of oxidized LDL (oxLDL). Therefore we studied the effect of oxLDL in the similar experiments as Hit-T15cell culture with LysoPC as comparison with native LDL (nLDL) and acerylated LDL (AcLDL). OxLDL significantly decreased the expression of preproinsulin mRNA, intracellular insulin content, and insulin secretion as same as LysoPC. On the other hand nLDL or AcLDL had no effects. LysoPC and oxLDL did not affect MTT assay as evaluation of cell viability. These results suggested that oxLDL disturbed insulin metabolism of β-cell to decrease insulin secretion via PCOOH and PC. We proposed that oxidized stress would be diabetogenic by the effect of oxLDL.

从脂质过氧化物与血管细胞关系的研究来看，脂质过氧化作用是动脉粥样硬化形成的主要机制。然而，其对其他细胞类型的影响尚未研究。提示胰腺的胰岛素分泌细胞（β细胞）对氧化应激反应较弱。因此，我们挑战Hit-T15细胞，这是一种源自仓鼠胰腺肿瘤细胞的β细胞，以阐明磷脂过氧化物对胰岛素分泌的影响。本实验在体外培养的HIT-T15细胞中加入天然磷脂酰胆碱（PC）、磷脂酰胆碱氢过氧化物（PCOH）和溶血磷脂酰胆碱（LysoPC）。LysoPC显著降低前胰岛素原mRNA的表达、细胞内胰岛素含量和胰岛素分泌。PCOOH效应不影响前胰岛素原mRNA的表达，但降低细胞内胰岛素水平和胰岛素分泌。这些氧化磷脂是氧化LDL（oxLDL）的组成部分。因此，我们在与Hit-T15细胞培养类似的实验中研究了oxLDL与天然LDL（nLDL）和乙酰化LDL（AcLDL）的作用。OxLDL与LysoPC一样，显著降低前胰岛素原mRNA的表达、细胞内胰岛素含量和胰岛素分泌。另一方面，nLDL或AcLDL没有影响。LysoPC和oxLDL不影响MTT法评价细胞活力。提示oxLDL通过PCOOH和PC干扰胰岛β细胞的胰岛素代谢，降低胰岛素分泌。我们认为氧化应激可能通过oxLDL的作用而致糖尿病。