Insulin signaling, resistance, and the metabolic syndrome: insights from mouse models into disease mechanisms.
Insulin signaling, resistance, and the metabolic syndrome: insights from mouse models into disease mechanisms.
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DOI：
10.1530/joe-13-0327
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发表时间：
2014-02
期刊：
影响因子：
--
通讯作者：
Guo S
中科院分区：
文献类型：
--
作者：
Guo S
胰岛素抵抗是“代谢综合征”的主要潜在机制，代谢综合征也称为胰岛素抵抗综合征。代谢综合征正以惊人的速度增加，成为世界范围内的主要公共和临床问题。代谢综合征是一组相互关联的疾病，包括肥胖、高血糖、高脂血症和高血压。它也是心血管疾病的一个重要危险因素，增加了发病率和死亡率。动物研究表明，胰岛素及其信号级联通常通过激活促分裂原活化蛋白激酶（MAPK）和磷脂酰肌醇-3-激酶（PI 3 K）来控制细胞生长、代谢和存活，其中PI-3 K的激活与胰岛素受体底物-1和-2（IRS 1，2）随后Akt→ Foxo 1磷酸化级联反应在控制营养稳态和器官存活中起核心作用。高胰岛素血症、代谢性炎症和过度营养后，Akt的失活和Foxo 1的激活通过抑制不同器官中的IRS 1和IRS 2可能为人类代谢综合征提供潜在机制。靶向IRS→Akt→ Foxo 1信号级联反应可能为2型糖尿病及其并发症的治疗干预提供策略。本文综述了胰岛素信号转导的基础、不同小鼠模型的胰岛素抵抗以及不同器官胰岛素信号转导成分的缺乏如何导致代谢综合征的特征。重点将放在IRS 1，IRS 2的作用，以及相关的信号通路，耦合到Akt和叉头/翅螺旋转录因子Foxo 1。
Insulin resistance is a major underlying mechanism for the “metabolic syndrome”, which is also known as insulin resistance syndrome. Metabolic syndrome is increasing at an alarming rate, becoming a major public and clinical problem worldwide. Metabolic syndrome is represented by a group of interrelated disorders, including obesity, hyperglycemia, hyperlipidemia, and hypertension. It is also a significant risk factor for cardiovascular disease and increased morbidity and mortality. Animal studies demonstrate that insulin and its signaling cascade normally control cell growth, metabolism and survival through activation of mitogen-activated protein kinases (MAPKs) and phosphotidylinositide-3-kinase (PI3K), of which activation of PI-3K-associated with insulin receptor substrate-1 and -2 (IRS1, 2) and subsequent Akt→Foxo1 phosphorylation cascade has a central role in control of nutrient homeostasis and organ survival. Inactivation of Akt and activation of Foxo1, through suppression IRS1 and IRS2 in different organs following hyperinsulinemia, metabolic inflammation, and over nutrition may provide the underlying mechanisms for metabolic syndrome in humans. Targeting the IRS→Akt→Foxo1 signaling cascade will likely provide a strategy for therapeutic intervention in the treatment of type 2 diabetes and its complications. This review discusses the basis of insulin signaling, insulin resistance in different mouse models, and how a deficiency of insulin signaling components in different organs contributes to the feature of the metabolic syndrome. Emphasis will be placed on the role of IRS1, IRS2, and associated signaling pathways that couple to Akt and the forkhead/winged helix transcription factor Foxo1.