etabolic mechanisms of failure of intraportally transplanted pancreatic β-cells in rats -: Role of lipotoxicity and prevention by leptin
etabolic mechanisms of failure of intraportally transplanted pancreatic β-cells in rats -: Role of lipotoxicity and prevention by leptin
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DOI：
10.2337/db07-0460
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发表时间：
2007-09-01
期刊：
影响因子：
7.7
通讯作者：
Unger, Roger H.
中科院分区：
文献类型：
--
作者：
Lee, Young;Ravazzola, Mariella;Unger, Roger H.
本研究的目的是确定通过门静脉移植的胰岛中β细胞的晚期衰竭是否由过量胰岛素刺激的脂肪生成和脂毒性引起，如果是，是否可以通过减少胰岛周围的脂肪生成来预防损伤。基于门静脉高水平的营养素和肠促胰岛素会刺激高胰岛素血症，从而诱导附近肝细胞中强烈的脂肪生成的前提，将正常胰岛移植到同基因链脲佐菌素诱导的糖尿病受者的肝脏中。周围脂肪的水解会使胰岛移植物充满脂肪酸，这可能会损害和破坏β细胞。通过瘦素或热量限制来减少脂肪生成应该可以防止或减少这种破坏。移植后胰岛素水平升高后，逐渐下降，高血糖增加。移植4周后，这些受体的肝脏中脂肪生成转录因子、固醇调节元件结合蛋白-1c（SREBP-1c）及其脂肪生成靶酶的mRNA升高，三酰甘油含量也升高。在β细胞受损的胰岛周围肝细胞中观察到脂质油红0染色阳性和SREBP-1免疫染色阳性。瘦素诱导的脂质过氧化预防和热量限制减少脂肪变性，高血糖症和凋亡β细胞破坏。在肝细胞中由胰岛素分泌过多诱导的过量SREBP-lc介导的脂肪生成之后是移植物中的β细胞破坏和糖尿病的再现。通过阻断脂肪生成可以防止移植失败。结果表明，严格的抗脂肪生成干预可能会改善人类胰岛移植后的结果。
The objective of this study was to determine whether the late failure of beta-cells in islets transplanted via the portal vein is caused by excess insulin-stimulated lipogenesis and lipotoxicity and, if so, whether the damage can be prevented by reducing lipogenesis surrounding the islets. Based on the premise that high portal vein levels of nutrients and incretins would stimulate hyperinsulinemia, thereby inducing intense lipogenesis in nearby hepatocytes, normal islets were transplanted into livers of syngeneic streptozotocin-induced diabetic recipients. Hydrolysis of the surrounding fat would flood the islet grafts with fatty acids that could damage and destroy the beta-cells. Reducing lipogenesis by leptin or caloric restriction should prevent or reduce the destruction. After a rise after transplantation, insulin levels gradually declined and hyperglycemia increased. Four weeks after transplantation mRNA of the lipogenic transcription factor, sterol regulatory element-binding protein-1c (SREBP-1c) and its lipogenic target enzymes were elevated in livers of these recipients, as was triacylglycerol content. Positive oil red 0 staining for lipids and immunostaining for SREBP-1 were observed in hepatocytes surrounding islets with damaged beta-cells. Leptin-induced lipopenia prevented and caloric restriction reduced steatosis, hyperglycemia, and apoptotic beta-cell destruction. Excessive SREBP-lc-mediated lipogenesis, induced in hepatocytes by insulin hypersecretion, is followed by beta-cell destruction in the grafts and reappearance of diabetes. Graft failure is prevented by blocking lipogenesis. The results suggest that strict antilipogenic intervention might improve outcomes after human islet transplantation.