Discovery of Novel Mechanisms in Skeletal Muscle and Liver Underlying the Regulation of Blood Glucose Homeostasis

Maintaining blood glucose levels is a fundamental process for sustaining life. During fasting, the liver constantly replenishes the circulating glucose supply through hepatic glucose production (HGP). After consuming a meal, insulin shuts down HGP and stimulates peripheral uptake and utilization of glucose by skeletal muscle. These processes go awry in insulin resistant individuals, resulting in lower insulin-stimulated glucose uptake, exacerbated HGP and eventually type 2 diabetes. Despite considerable attention, the mechanism of insulin resistance in muscle and liver remains unclear.
HGP and skeletal muscle glucose uptake /utilization rely on mitochondrial function. Abnormal mitochondrial function can contribute to insulin resistance. Yet, the mechanisms linking altered mitochondrial function to defects in whole-body glucose metabolism are not well understood. The primary objective of my thesis project was to investigate the role of mitochondria in skeletal muscle glucose uptake and HGP in the context of insulin resistance. Herein, I report the discovery of the mitochondrial permeability transition pore (mPTP) as a link between mitochondrial dysfunction and insulin resistance in skeletal muscle. Tissue-specific mPTP inhibition also elucidated a critical role for mitochondrial function in liver glucose utilization. Finally, I demonstrate a new role for the bioactive lipid-hydrolyzing enzyme lipid phosphate phosphatase 1 (LPP1) in HGP and liver mitochondria homeostasis during fasting. In sum, we conclude that the mitochondrion serves as a vital energy stress sensor, promoting mPTP-dependent insulin resistance in muscle and adjusting HGP in response to the liver lipid environment. This work uncovers new pathways connecting mitochondria to glucose homeostasis that may be probed in the future for potential therapeutic targets to treat diabetes.