Integrin regulation of insulin sensitivity

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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.