Muscle Insulin Resistance: Novel Mechanisms and New Treatment Targets

Abstract

This project investigated the significance of extramyocellular barriers to the pathogenesis of skeletal muscle insulin resistance and their potential as therapeutic targets. The goals of this dissertation were to determine the impact of capillary rarefaction to muscle insulin resistance, the efficacy of the vasoactive and extracellular matrix degrading hormone relaxin to rescue muscle insulin resistance, and the effects of high fat-feeding on caveolae microstructures within skeletal muscle capillaries. Data from obese patients and animal experiments describe a strong association between peripheral insulin resistance and attenuation of skeletal muscle capillary density. Whether the relationship of capillary density and the development of skeletal muscle insulin resistance are casual remains to be elucidated. We utilized a genetic mouse model with muscle-specific deletion of vascular endothelial growth factor-A (VEGF) to induce capillary rarefaction in otherwise lean, healthy mice. VEGF deficient mice had 60% fewer muscle capillaries inducing impairment in muscle insulin action. Furthermore, we investigated the therapeutic potential of targeting the vascular dysfunction and extracellular matrix remodeling associated with a high fat diet with a pharmacological dose of the endogenous hormone relaxin. A 3 week relaxin intervention in high fat-fed C57BL/6J mice rescued the metabolic and vascular dysfunction caused by the diet. The interplay between vascular and metabolic disease are significant mortality risk factors and the extramyocellular adaptations to an obesogenic diet are viable pharmacological targets. The transport of insulin across the capillary wall is rate-limiting to the onset of skeletal muscle insulin action. Transendothelial insulin transport is dependent on caveolae structures of the endothelial layer of muscle capillaries. Employing transmission electron microscopy, we show for the first time that caveolae number in muscle capillaries of 16 week high-fat fed mice are diminished compared to low fat-fed controls. These data suggest a contribution of diminished caveolae density in transendothelial insulin transport, thus augmenting the barrier for insulin delivery. In conclusion, the experiments performed in this dissertation support the paradigm that extramyocellular barriers to insulin-stimulated muscle glucose uptake are significant to the etiology of insulin resistance and these barriers provide novel targets for the treatment of vascular and metabolic disorders associated with obesity.