Portha Bernard, Giroix Marie-Hélène, Tourrel-Cuzin Cecile, Le-Stunff Hervé, Movassat Jamileh
Laboratoire B2PE (Biologie et Pathologie du Pancréas Endocrine), Unité BFA (Biologie Fonctionnelle et Adaptive), Université Paris-Diderot, CNRS EAC 4413, Paris, France.
Methods Mol Biol. 2012;933:125-59. doi: 10.1007/978-1-62703-068-7_9.
Type 2 diabetes mellitus (T2D) arises when the endocrine pancreas fails to secrete sufficient insulin to cope with the metabolic demand because of β-cell secretory dysfunction and/or decreased β-cell mass. Defining the nature of the pancreatic islet defects present in T2D has been difficult, in part because human islets are inaccessible for direct study. This review is aimed to illustrate to what extent the Goto Kakizaki rat, one of the best characterized animal models of spontaneous T2D, has proved to be a valuable tool offering sufficient commonalities to study this aspect. A comprehensive compendium of the multiple functional GK abnormalities so far identified is proposed in this perspective, together with their time-course and interactions. A special focus is given toward the pathogenesis of defective β-cell number and function in the GK model. It is proposed that the development of T2D in the GK model results from the complex interaction of multiple events: (1) several susceptibility loci containing genes responsible for some diabetic traits; (2) gestational metabolic impairment inducing an epigenetic programming of the offspring pancreas and the major insulin target tissues; and (3) environmentally induced loss of β-cell differentiation due to chronic exposure to hyperglycemia/hyperlipidemia, inflammation, and oxidative stress.
2型糖尿病（T2D）是由于β细胞分泌功能障碍和/或β细胞数量减少，导致内分泌胰腺无法分泌足够的胰岛素来满足代谢需求时发生的。确定T2D中胰岛缺陷的本质一直很困难，部分原因是无法直接获取人类胰岛进行研究。本综述旨在说明，自发性T2D特征最明确的动物模型之一——Goto Kakizaki大鼠，在多大程度上已被证明是一个有价值的工具，能为研究这方面提供足够多的共性。从这个角度出发，本文提出了一个迄今为止已确定的多种功能性GK异常的综合纲要，以及它们的时间进程和相互作用。特别关注GK模型中β细胞数量和功能缺陷的发病机制。本文提出，GK模型中T2D的发生是多种事件复杂相互作用的结果：（1）几个含有负责某些糖尿病性状基因的易感位点；（2）孕期代谢损伤诱导后代胰腺以及主要胰岛素靶组织的表观遗传编程；（3）长期暴露于高血糖/高血脂、炎症和氧化应激导致环境诱导的β细胞分化丧失。
