Gupta Deepashree, Krueger Charles B, Lastra Guido
Department of Internal Medicine, Division of Endocrinology and Metabolism, University of Missouri School of Medicine, One, Hospital Drive, Columbia, MO 65203, USA.
Curr Diabetes Rev. 2012 Mar;8(2):76-83. doi: 10.2174/157339912799424564.
The incidence of type 2 diabetes mellitus (DM2) has increased dramatically over the last several decades, largely driven by equally worrisome growing rates of obesity. Chronic diabetic complications are leading causes of morbidity and mortality worldwide. Key players in the pathophysiology of DM2 are insulin resistance and β cell dysfunction, which in turn is a result of both β cell functional abnormality as well as reduced β cell mass. The mechanisms implicated are multifactorial and include genetic and environmental factors related to obesity. Glucose homeostasis is critically dependent on a finely regulated balance between insulin sensitivity and output in the pancreas, and insulin resistance demands a corresponding rise in insulin output in order to maintain normal glycemia. However, this compensation is lost in individuals predisposed to DM2, resulting in overt hyperglycemia. Furthermore, insulin resistance related to excess adiposity is linked to several abnormalities which impact β cell function and viability. These include glucotoxicity, lipotoxicity, increased oxidative stress, and inflammation. In addition, insulin signaling in the β cell is essential to its own functionality and viability, and obesity-related abnormalities in insulin signaling are known to induce failure of insulin secretion and hyperglycemia. Insulin resistance in the β cell arises from defects in phosphorylation/activation of insulin receptor substrates (IRS) proteins, which result in impairment in glucose sensing, glucose stimulated insulin secretion, and also in increased loss of β cells. This review intends to provide an update on the main characteristics and mechanisms that link obesity and insulin resistance to β cell dysfunction in the pathogenesis of DM2.
在过去几十年中，2型糖尿病（DM2）的发病率急剧上升，这在很大程度上是由同样令人担忧的肥胖率不断上升所驱动的。慢性糖尿病并发症是全球发病和死亡的主要原因。DM2病理生理学中的关键因素是胰岛素抵抗和β细胞功能障碍，而这又是β细胞功能异常以及β细胞数量减少的结果。其中涉及的机制是多因素的，包括与肥胖相关的遗传和环境因素。葡萄糖稳态严重依赖于胰腺中胰岛素敏感性和分泌之间精确调节的平衡，胰岛素抵抗需要相应增加胰岛素分泌以维持正常血糖水平。然而，在易患DM2的个体中这种代偿作用丧失，导致明显的高血糖。此外，与肥胖过多相关的胰岛素抵抗与几种影响β细胞功能和生存能力的异常情况有关。这些包括糖毒性、脂毒性、氧化应激增加和炎症。此外，β细胞中的胰岛素信号传导对其自身的功能和生存能力至关重要，已知与肥胖相关的胰岛素信号传导异常会导致胰岛素分泌衰竭和高血糖。β细胞中的胰岛素抵抗源于胰岛素受体底物（IRS）蛋白磷酸化/激活缺陷，这会导致葡萄糖感知、葡萄糖刺激的胰岛素分泌受损，还会导致β细胞损失增加。本综述旨在提供关于肥胖和胰岛素抵抗与DM2发病机制中β细胞功能障碍相关的主要特征和机制的最新信息。
