Klip
Amira KlipPhD
Professor

Contact Info

T. (416) 813-6392
F. (416) 813-5028

Location

Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay Street, Rm 19.9-709
Toronto
ON, M5G 0A4

Research Interests

Regulation of glucose transport in skeletal muscle by insulin, and defects in diabetes.

Accepting

None

Appointments

Primary: Paediatrics.

Senior Scientist
Cell Biology Program, Research Institute
Hospital for Sick Children
 

Research/Teaching

Research Synopsis:

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.

Detailed Description:
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.

METHODS USED

Cell and tissue culture: Muscle cells, macrophages.

Procedures: Elisa, gene expression analysis, glucose uptake, immunofluorescence and TIRF microscopy, protein-protein interactions, signal transduction, immunocytochemistry.

PRESENT TRAINEES

CHAN, Kenny (Physiology)
CHIU, Tim (Biochemistry)
FOLEY, Kevin (Biochemistry)
AZIZI, Paymon (IMS)

PRESENT COLLABORATIONS

Within the Department of Physiology Adria Giacca
Denise Belsham

Outside the Department of Physiology Dana Philpott, Immunology, U of T
Warren Lee, IMS, U of T
Minna Woo, Medicine, U of T
Costin Antonescu, Cell Biology, Ryerson University
Erik Richter, Kroog Institut, Copenhagen
Enrique Jaimovich, University of Chile

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

Publications and Awards

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