Portha B, Lacraz G, Kergoat M, Homo-Delarche F, Giroix M-H, Bailbé D, Gangnerau M-N, Dolz M, Tourrel-Cuzin C, Movassat J
Groupe Biologie et Pathologie du Pancréas Endocrine, Laboratoire de Physiopathologie de la Nutrition, UMR CNRS 7059, Université Paris-Diderot/UP7, Paris, France.
Mol Cell Endocrinol. 2009 Jan 15;297(1-2):73-85. doi: 10.1016/j.mce.2008.06.013. Epub 2008 Jul 1.
Increasing evidence indicates that decreased functional beta-cell mass is the hallmark of type 2 diabetes (T2D) mellitus. Nowadays, the debate focuses on the possible mechanisms responsible for abnormal islet microenvironment, decreased beta-cell number, impaired beta-cell function, and their multifactorial aetiologies. This review is aimed to illustrate to what extend the Goto-Kakizaki rat, one of the best characterized animal models of spontaneous T2D, has proved be a valuable tool offering sufficient commonalities to study these aspects. We propose that the defective beta-cell mass and function in the GK model reflect the complex interactions of multiple pathogenic players: (i) several independent loci containing genes responsible for some diabetic traits (but not decreased beta-cell mass); (ii) gestational metabolic impairment inducing an epigenetic programming of the pancreas (decreased beta-cell neogenesis and/or proliferation) which is transmitted to the next generation; and (iii) loss of beta-cell differentiation due to chronic exposure to hyperglycemia/hyperlipidemia, inflammatory mediators, oxidative stress and to perturbed islet microarchitecture.
越来越多的证据表明，功能性β细胞量减少是2型糖尿病（T2D）的标志。如今，争论焦点在于导致胰岛微环境异常、β细胞数量减少、β细胞功能受损及其多因素病因的可能机制。本综述旨在说明，作为最具特征的自发性T2D动物模型之一的Goto-Kakizaki大鼠，在何种程度上已被证明是一种有价值的工具，它具有足够的共性来研究这些方面。我们提出，GK模型中β细胞量和功能的缺陷反映了多种致病因素的复杂相互作用：（i）几个独立的基因座，包含负责某些糖尿病特征（但不包括β细胞量减少）的基因；（ii）妊娠代谢损伤诱导胰腺的表观遗传编程（β细胞新生和/或增殖减少），并传递给下一代；以及（iii）由于长期暴露于高血糖/高血脂、炎症介质、氧化应激和胰岛微结构紊乱而导致的β细胞分化丧失。
