Integrin regulation of insulin sensitivity

摘要 胰岛素抵抗是心血管疾病的主要危险因素，而心血管疾病又是发病率的主要原因。 以及糖尿病的死亡率。在全球肥胖的背景下，胰岛素抵抗的患病率正在增加 流行病。长期的目标是了解细胞表面基质受体的整合素家族在 调节肥胖和胰岛素抵抗。本应用程序的总体目标是阐明 αvβ5整合素及其配体乳脂球样表皮生长因子8在骨骼调节中的作用 肌肉胰岛素抵抗。中心假设是胰岛素通过促进MFGE8的运动 内质网/高尔基体网络，随后到达外质膜，在那里它结合αvβ5； αvβ5随后与含有胰岛素受体的复合体相互作用，从而抑制胰岛素 受体信号和MFGE8-整合素途径的破坏将改善胰岛素抵抗。这些 假设基于的数据表明，MFGE8/αvβ5途径的急性破坏调节骨骼 肌肉胰岛素介导的葡萄糖摄取和胰岛素受体β酪氨酸磷酸化/激活 亚基(IRβ)和胰岛素受体底物-1(IRS1)结合的证据表明，胰岛素受体 直接与αvβ5整合素相互作用，这种相互作用被胰岛素和MFGE8加强 (1)。这些假说将通过三个具体的目标来检验：1)确定细胞机制，通过 2)研究MFGE_8-αvβ_5途径是否诱导 通过调节IR、β和IRS1的去磷酸化来调节胰岛素抵抗；3)研究骨骼对胰岛素抵抗的贡献 肌肉MFGE8/β5信号在调节基础胰岛素抵抗和肥胖诱导的胰岛素抵抗中的作用。目标一号将决定 胰岛素如何促进骨骼肌质膜Mfge8定位并与αvβ5结合，从而 激活下游信号导致胰岛素敏感性降低。目标2将研究如何激活 Mfge8-整合素轴导致磷酸酶Ptp1β活性增加，从而使其去磷酸化 并使骨骼肌中的胰岛素受体失活，导致血浆膜转位减少 葡萄糖转运蛋白4和葡萄糖摄取减少。目标3将检查系统的治疗潜力 阻断β-5整合素或MFGE-8改善饮食诱导的小鼠胰岛素抵抗 肥胖和胰岛素抵抗以及骨骼肌在这一过程中的相对贡献。建议数 这项研究具有创新性，因为它确定了胰岛素激活整合素途径的机制， 随后反馈终止胰岛素信号。这项拟议的研究具有重要意义，因为它具有 有可能为治疗胰岛素抵抗的新疗法的开发提供信息。

SUMMARY Insulin resistance is a major risk factor for cardiovascular disease which in turn is the major cause of morbidity and mortality in diabetes. The prevalence of insulin resistance is increasing in the setting of a global obesity epidemic. The long-term goal is to understand the role of the integrin family of cell surface matrix receptors in regulating obesity and insulin resistance. The overall objective of this application is to elucidate the role of the αvβ5 integrin and its ligand, Milk Fat Globule Epidermal Growth Factor like 8 (Mfge8), in regulating skeletal muscle insulin resistance. The central hypothesis is that insulin accelerates movement of MFGE8 through the endoplasmic reticulum/Golgi network and subsequently to the outer plasma membrane where it binds αvβ5; αvβ5 subsequently interacts with a complex containing the insulin receptor leading to dampening of insulin receptor signaling and that disruption of the MFGE8-integrin pathway will ameliorate insulin resistance. These hypotheses are based on data showing that acute disruption of the MFGE8/αvβ5 pathway modulates skeletal muscle insulin-mediated glucose uptake and tyrosine phosphorylation/activation of the Insulin Receptor β subunit (IRβ) and the Insulin Receptor Substrate-1 (IRS1) coupled with evidence that the insulin receptor interacts directly with the αvβ5 integrin and that this interaction is strengthened by insulin as well as by MFGE8 (1). These hypotheses will be tested through 3 specific aims: 1) determining the cellular mechanism by which insulin induces cell surface enrichment of MFGE8; 2) investigating whether the MFGE8-αvβ5 pathway induces insulin resistance by regulating dephosphorylation of IRβ and IRS1; 3) investigating the contribution of skeletal muscle MFGE8/β5 signaling in regulating basal and obesity-induced insulin resistance. Aim 1 will determine how insulin promotes skeletal muscle plasma membrane Mfge8 localization and binding to αvβ5 which then activates downstream signaling leading to reduced insulin sensitivity. Aim 2 will examine how activation of the Mfge8-integrin axis leads to increase activity of the phosphatase PTP1β which subsequently dephosphorylates and inactivates the insulin receptor in skeletal muscle leading to reduced plasma membrane translocation of Glucose Transporter 4 and reduced glucose uptake. Aim 3 will examine the therapeutic potential of systemic blockade of the β5 integrin or MFGE8 in ameliorating insulin resistance in a mouse model of diet-induced obesity and insulin resistance and the relative contribution of skeletal muscle to this process. The proposed research is innovative, because it identifies a mechanism by which insulin activates an integrin pathway that subsequently feeds back to terminate insulin signaling. The proposed research is significant because it has the potential to inform the development of novel therapeutics that treat insulin resistance.