In lean individuals, skeletal muscle is responsible for up to 80% of uptake and utilization of glucose after a meal. In patients with type 2 diabetes, skeletal muscle glucose uptake and utilization are compromised. Although muscle glucose uptake is largely regulated by insulin-dependent translocation of glucose transporters to the plasma membrane, evidence is accumulating that skeletal muscle mitochondrial dynamics and bioenergetics also play important roles in regulation of glycemia. In obesity, mitochondria become highly fragmented and the mitochondrial membrane potential is dissipated. Genetic or pharmacologic means of stimulating mitochondrial fusion and removal of damaged regions has been shown to improve glucose tolerance in mice. However, little is known about the intracellular signaling pathways that regulate mitochondrial fission and turnover in skeletal muscles of obese animals. The premise of this proposal is that altered mitochondrial dynamics have functional consequences for skeletal muscle glucose oxidation in obesity. We found that expression of the AMPK-related kinase salt inducible kinase 1 (SIK1) is increased in skeletal muscles of obese mice. Genetic knockout of the catalytic domain of this enzyme in skeletal muscle enhanced glucose uptake in muscles of diabetic mice. In this proposal, we will test how SIK1 regulates mitochondrial structure and function, and ultimately glucose metabolism, by comparing metabolism in SIK1-deficient and SIK1 over-expressing skeletal muscles. We will test how SIK1 regulates muscle metabolism by focusing on two SIK1 interacting proteins. As mitochondrial activity and structural organization are negatively impacted by obesity, this project has the potential to uncover a novel regulatory pathway to improve mitochondrial health and function in obesity that could be targeted independently of the canonical insulin signaling pathway.
The proposed studies will investigate the contributions of salt inducible kinase 1 (SIK1) to regulation of skeletal muscle glucose utilization in the context of obesity. Loss of skeletal muscle glucose uptake and disposal is an underlying cause of hyperglycemia in type 2 diabetes. In this project, we will test how this enzyme (SIK1) impacts muscle glucose utilization independent of insulin action. Identification of a new regulatory pathway that contributes to muscle glucose uptake and utilization could reveal new ways to help alleviate hyperglycemia in patients with insulin resistance and type 2 diabetes.
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