Liver and skeletal muscle insulin resistance represent two core defects in individuals with Type 2 Diabetes. Although dysregulated glycogen metabolism is linked to insulin sensitivity, it is not entirely understood how glycogen metabolism modifies insulin sensitivity. New preliminary data generated by the applicant suggests that the autophagic degradation of glycogen (i.e. glycophagy) by the lysosomal enzyme alpha acid glucosidase (GAA) plays a previously unrecognized role in modulating liver and skeletal insulin sensitivity and energy metabolism. In mice, high-fat diet feeding reduced insulin sensitivity, an effect associated with an increase in liver GAA levels, whereas exercise or muscle contraction increased insulin sensitivity, an effect associated with reduced muscle GAA levels. Follow-up mechanistic studies in liver or skeletal muscle cells showed that acute inhibition of glycophagy reduced glycolytic capacity while increasing insulin sensitivity, mitochondrial biogenesis, and fatty acid oxidation, effects that were associated with an induction of SIRT1 signaling and reduced oxidative stress. To better define the link between glycophagy, insulin sensitivity, and energy metabolism in mice, the applicant used CRISPR/Cas 9 technology to generate a novel mouse model with inducible liver or skeletal muscle specific knockout of GAA. The overarching objective of this K01 proposal is to define the role of glycophagy in liver and skeletal muscle insulin sensitivity and energy metabolism in mice. Additionally, the applicant has assembled an interdisciplinary grant advisory panel to provide mentorship and guidance for the proposed research. The training plan was designed to build upon the applicant?s prior expertise in metabolism by providing additional training in analytical techniques, research concepts, data analysis, grant and manuscript writing, didactic training in tracer methodology, establishing productive collaborations, and leadership skills. This proposal will help the applicant initiate his own investigative niche in the field of glycophagy and serve as a springboard to his independent research career.
Insulin resistance and dysregulated energy metabolism are major underlying pathologies in the development of Type 2 Diabetes. The experiments proposed in this application are relevant to public health in that they will advance our understanding of how glycophagy modifies insulin sensitivity and energy metabolism in liver and skeletal muscle tissue. Ultimately, the data generated will have the potential to inspire new therapeutic approaches that improve insulin sensitivity and energy metabolism, which have great potential to improve health and help prevent or treat Type 2 Diabetes.