1944-P: Muscle a-Parvin Is Not Necessary for Integrin-Linked Kinase Related Insulin Resistance in Diet-Induced Obese Mice

Abstract

High fat diet (HFD) causes obesity and expansion of extracellular matrix (ECM) components and causes insulin resistance. Integrins provide for adhesion between cells and the ECM and signal cells information about the local environment. A major component of signaling through the integrin β1 subunit is the integrin-linked kinase (ILK). Previous studies demonstrated mice that do not express ILK in skeletal muscle (SkM) are resistant to HFD-induced muscle insulin resistance. ILK has no catalytic activity but is the scaffold for signaling molecules, including α-parvin which regulates Rho-GTPases which are involved in actin cytoskeleton and vesicular trafficking. To test the hypothesis that ILK-related insulin resistance is mediated through α-parvin in SkM, we generated a mouse model which lacks α-parvin in SkM (mParKO) using a cre-lox system under control of HSA promoter. mParKO mice and non-transgenic littermates (WT) were fed either chow or HFD for 12 weeks after which insulin sensitivity was assessed in vivo using the hyperinsulinemic-euglycemic clamp combined with 3-[3H]glucose and 2-[14C]deoxyglucose tracers to measure glucose fluxes. Body weight was not different between mParKO and WT mice on either diet, nor was fasting blood glucose. In contrast to previous clamp studies of HFD-fed muscle ILK knockout mice, clamp glucose infusion rate, tracer-determined glucose rates of appearance and disappearance, and an index of SkM glucose uptake were not different between mParKO and WT mice on either diet. These results suggest that the α-parvin unit does not mediate the profound ILK-related susceptibility to insulin resistance in HFD fed mice. Disclosure D.A. Cappel: None. A. Pozzi: None. R. Zent: None. D. Wasserman: None. Funding National Institutes of Health (DK59637, DK50277, DK54902); American Heart Association