Insulin signaling, GSK-3, heat shock proteins and the natural history of type 2 diabetes mellitus: A hypothesis
Insulin signaling, GSK-3, heat shock proteins and the natural history of type 2 diabetes mellitus: A hypothesis
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DOI：
10.1089/met.2007.0005
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发表时间：
2007-09-01
影响因子：
2.1
通讯作者：
Hooper, Philip L.
中科院分区：
文献类型：
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作者：
Hooper, Philip L.
代谢综合征和2型糖尿病是进行性、惰性、多器官疾病。了解这些疾病中热休克蛋白（HSPs）的异常对于了解其发病机制至关重要。在胰岛素抵抗状态和糖尿病中，热休克因子1（HSF-1）在胰岛素敏感组织中低，导致低Hsp 60、70和90水平。我们认为低Hsps水平是胰岛素作用降低导致PI 3 K、PKB和糖原合成酶激酶-3（GSK-3）磷酸化减少的结果。更重要的是，GSK-3磷酸化程度越低（GSK-3活性越高），HSF-1的水平就越低。低Hsps使器官易受损伤，损害应激反应，加速全身炎症，增加胰岛淀粉样多肽，并增加胰岛素抵抗。这个循环的营养是过量的饱和脂肪和卡路里消耗、高血压、不活动、衰老和遗传易感性-所有这些都与高GSK-3活性和低Hsps有关。对所提出的“恶性”循环的支持是基于这样的观察：GSK-3抑制和Hsp刺激会增加胰岛素敏感性、减少细胞内变性蛋白的积累、改善伤口愈合、减少器官损伤并改善血管缺血的恢复。认识到GSK-3和Hsps在胰岛素抵抗的发病机制中的作用，代谢综合征和2型糖尿病的中心共同特征将扩大我们对该疾病的理解，提供新的治疗选择。
Metabolic syndrome and type 2 diabetes are progressive, indolent, multi-organ diseases. Understanding the abnormalities of heat shock proteins (HSPs) in these diseases is paramount to understanding their pathogenesis. In insulin resistant states and diabetes, heat shock factor 1(HSF-1) is low in insulin sensitive tissues, resulting in low Hsp 60, 70, and 90 levels. We propose that low Hsps levels are the result of decreased insulin action leading to less phosphorylation of PI3K, PKB, and glycogen synthase kinase-3 (GSK-3). Importantly, less GSK-3 phosphorylation (and thus more GSK-3 activity) will lower HSF-1. Low Hsps make organs vulnerable to injury, impair the stress response, accelerate systemic inflammation, raise islet amyloid polypeptide, and increase insulin resistance. Feeding this cycle is excess saturated fat and calorie consumption, hypertension, inactivity, aging, and genetic predisposition- all of which are a associated with high GSK-3 activity and low Hsps. Support for the proposed "vicious" cycle is based on the observation that GSK-3 inhibition and Hsp stimulation result in increased insulin sensitivity, reduced accumulation of degenerative proteins with in the cell, improved wound healing, decreased organ damage and improved recovery from vascular ischemia. Recognizing GSK-3 and Hsps in the pathogenesis of insulin resistance, the central common feature of the metabolic syndrome, and type 2 diabetes will expand our understanding of the disease, offering new therapeutic options.