Genetic and biochemical pathways of β-cell failure in type 2 diabetes
Genetic and biochemical pathways of β-cell failure in type 2 diabetes
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DOI：
10.1111/j.1463-1326.2009.01115.x
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发表时间：
2009-11-01
影响因子：
5.8
通讯作者：
Accili, D.
中科院分区：
文献类型：
--
作者：
Talchai, C.;Lin, H. V.;Accili, D.
我们综述了2型糖尿病β细胞衰竭的机制。大量信息表明，它是由胰岛素分泌受损和β细胞质量减少引起的。有趣的是，这两种机制之间似乎存在联系。外周胰岛素抵抗的最早反应是胰岛素产生增加，主要是由于分泌增加，其次是清除率降低。实验动物模型表明，高胰岛素血症主要通过增加β细胞复制促进β细胞质量增加。相比之下，在明显的糖尿病发作后，在动物模型和糖尿病患者中，β细胞功能和质量都有缓慢的进行性损失。令人非常感兴趣的是，在全基因组关联研究中鉴定的大多数糖尿病相关基因似乎在β细胞中富集，并且具有调节质量和/或功能的潜力。在这里，我们回顾了来自实验动物模型的证据，以揭示β细胞功能障碍的机制。我们主要关注信号通路，而不是营养传感，特别是胰岛素和生长因子信号通过Foxo1在胰腺β细胞中将胰岛素分泌与细胞增殖和存活联系起来。
We review mechanisms of beta-cell failure in type 2 diabetes. A wealth of information indicates that it is caused by impaired insulin secretion and decreased beta-cell mass. Interestingly, there appears to be a link between these two mechanisms. The earliest reaction to peripheral insulin resistance is an increase in insulin production, owing primarily to increased secretion, and to a lesser extent to decreased clearance. Experimental animal models indicate that hyperinsulinaemia promotes an increase in beta-cell mass, largely via increased beta-cell replication. In contrast, following the onset of overt diabetes, there is a slowly progressive loss of beta-cell function and mass, both in animal models and in diabetic humans. It is of great interest that most diabetes-associated genes identified in genome-wide association studies appear to be enriched in the beta-cell and to have the potential to regulate mass and/or function. Here, we review evidence derived from experimental animal models to unravel the mechanisms underlying beta-cell dysfunction. We focus primarily on signalling pathways, as opposed to nutrient sensing, and specifically on the notion that insulin and growth factor signalling via Foxo1 in pancreatic beta-cells links insulin secretion with cellular proliferation and survival.