Regulation of glucose homeostasis:investigation of novel polyphenols

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My main research program investigates how different stimuli including hormones control skeletal muscle glucose metabolism. My focus is to understand the intracellular signaling pathways that are activated and control glucose transport and metabolism and to find food components, nutraceuticals, or functional foods that modulate these signaling pathways. Insulin is a pancreatic hormone that plays an important role in skeletal muscle glucose transport and metabolism. Insulin binds to its receptor found on the plasma membrane of skeletal muscle cells and activates the phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway causing translocation of intracellularly stored glucose transporter proteins (GLUT4) to the plasma membrane resulting in increased skeletal muscle glucose uptake and metabolism. Defects or impairments in the PI3K-Akt signaling pathway lead to inability of insulin to act on skeletal muscle tissue, a condition termed insulin resistance. Activation of another signaling cascade, the AMP-activated protein kinase (AMPK) cascade in skeletal muscle cells also leads to increased muscle glucose uptake and metabolism. The AMP-activated protein kinase (AMPK) is a serine/threonine kinase that functions as a cellular energy sensor and becomes activated in response to increased AMP/ATP ratio. Importantly, skeletal muscle AMPK is activated by exercise/contraction, and various compounds including the drug metformin which is used to treat individuals with increased blood glucose levels, and insulin resistance. My work on the intracellular signaling mechanisms controlling glucose uptake and metabolism has led me to search for compounds that can modulate these intracellular pathways. Recently we found evidence that some polyphenols that are present in rosemary extract can influence these signaling pathways and alter glucose metabolism in ways that might be beneficial in conditions of insulin resistance. The long term goals of the proposed research program are to elucidate the mechanism of action of rosemary extract and rosemary extract polyphenols on skeletal muscle glucose metabolism. These goals will be addressed using muscle cells in culture (in vitro) and animal models of skeletal muscle insulin resistance. The proposed studies will help determine the active pharmaceutical ingredients (APIS) present in rosemary extract and use these APIs to investigate fundamental cellular mechanisms involved in insulin resistance. Many Canadians suffer from insulin resistance. My research focused on investigating the cellular mechanism of these conditions and finding phenolic compounds to modify them will provide huge benefit to the Canadian society.