193-OR: Muscle α-Parvin Deletion Results in Insulin Resistance by Impairing GLUT4 Translocation and Hexokinase II Association with Mitochondria in Mice
Diabetes(2023)
Abstract
Genetic deletions of specific integrin receptor a-subunits and the integrin-like kinase (ILK) have no effect on insulin action in lean C57Bl/6J mice but are required for insulin resistance in diet-induced obese (DIO) mice. ILK binds to a-parvin through which it controls the rho kinase pathway and cytoskeleton thereby altering cellular compartmentation and dynamics. The hypothesis tested was that integrin signaling is required for insulin resistance in DIO mice due to disruption of the critical interaction between ILK and a-parvin. We predicted that preventing this interaction in lean mice would recapitulate the insulin resistance observed in DIO mice. Lean and DIO mice with muscle-specific a-parvin (mPar) knockout (KO) and wild type littermates (WT) were studied. Insulin clamps were performed in mPar KO and WT mice. A muscle-specific index of glucose uptake (Rg) was measured isotopically during insulin clamps. Lean mPar KO had a 50% reduction in muscle Rg that was associated with a similar deficit in GLUT4 translocation to the cell membrane and a decrease in hexokinase II-associated with mitochondria. Mitochondria oxidative capacity was reduced by 50% in lean mPar KO mice compared to lean WT mice. The insulin resistance in DIO WT mice was no worse in DIO mPar KO mice. Insulin signaling was not impaired by mPar KO in lean mice. However, lean mPar KO had impaired a-actinin, Rac1, p-cofilin/cofilin, and p-MLC/MLC compared to lean WT mice during insulin stimulation. These changes affect cytoskeletal dynamics and provide a basis for the reduction in GLUT4 translocation, hexokinase II localization to mitochondria, and impaired mitochondria oxidation. In conclusion, a-parvin is a key node in coupling integrin signaling as it causes muscle insulin resistance in otherwise healthy lean mice. Deletion of muscle a-parvin does not affect insulin signaling but rather attenuates insulin-stimulated glucose uptake by impairing cytoskeletal dynamics. Disclosure D.A.Cappel: None. D.H.Wasserman: None. J.W.Deaver: None. L.Cozzani: None. D.Bracy: None. L.Lantier: None. X.Dong: None. R.Printz: None. R.Zent: None. A.Pozzi: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (R01DK050277, R01DK054902, R24DK059637)
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Key words
mitochondria,insulin resistance,impairing glut4 translocation,hexokinase ii association
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