Cell Biology Program, Research Institute
Hospital for Sick Children
Research Divisions: Endocrine and Diabetes Platform
Research Interests: Regulation of glucose transport in skeletal muscle by insulin, and defects in diabetes.
Keywords: Cell Biology, Diabetes, Exocytosis, Insulin, Insulin resistance, Signal transduction.
Our research explores how insulin stimulates glucose entry into muscle cells and how this fails in insulin resistance leading to type 2 diabetes. We explore intracellular insulin signals, movement of vesicles containing glucose transporter 4 (GLUT4) and strategies to render muscle cells insulin resistant. Regarding insulin signals, we found that downstream of Akt lies the proteinAS160 that regulates the small G proteins Rab8A and Rab13, to control GLUT4 vesicle arrival near the membrane. Rab8A appears to signal through the processive motor protein Myosin Va. In addition, GLUT4 binds another myosin, Myo1c, which links the vesicles to actin filaments beneath the plasma membrane, as preamble for their docking to the membrane via SNARE proteins. Rab13 appears to work at this stage by engaging the linker protein Mical-L2. How this leads to docking and fusion is subject of our investigation. From the membrane, GLUT4 returns to its storage site and this process requires the protein syntaxin 6. Regarding insulin resistance, we found that the saturated fatty acid palmitate makes muscle cells produce factors that increase the mobility/migration of monocytes. Conversely, palmitate added to macrophages (the product of monocyte differentiation) causes production of factors that render muscle cells resistant to insulin. The macrophage products activate the novel PKC epsilon and theta, which in turn inhibit signal relay at the level of the Insulin Receptor Substrate-1 (IRS-1). The contribution of innate immunity signals to insulin resistance also occurs without innate immune cells participation, as direct activation of an innate immunity recognition receptor in the muscle cells, NOD2, causes insulin resistance. Collectively, these findings will help discover the underlying mechanism of insulin resistance during obesity and its related inflammation.
Cell and tissue culture: Muscle cells, macrophages.
Procedures: Elisa, gene expression analysis, glucose uptake, immunofluorescence and TIRF microscopy, protein-protein interactions, signal transduction, immunocytochemistry.
Tokarz, Victoria (PSL)
Within the Department of Physiology
Outside the Department:
Dana Philpott, Immunology
Erik Richter, University of Copenhagen
Katrien DeBoeck, ETH, Zurich
Committee member/officer of national/international scientific organizations
Steering Committee Member and Session Chair, Inflammation in Chronic Disease Consensus Conference, organized by CIHR
Member, Cell Biology and Mechanisms of Disease panel, Canadian Institutes of Health Research