fantus
I. George FantusMD
Professor
Endocrine and Diabetes Platform

Contact Info

T. (416) 586-8665
F. (416) 361-2657

Location

Mount Sinai Hospital, Joseph & Wolfe Lebovic Building, 60 Murray Street, Rm 5028
Toronto
ON, M5T 3L9

Research Interests

Insulin Receptor, Tyrosine Kinase, Diabetic Nephropathy, Thiredoxin-interacting protein, Mesangial cells, Podocytes, Oxidative Stress, Protein Tyrosine Phosphatase, Glucose Transport, Insulin Resistance, Adipocytes

Accepting

None

Appointments

Primary: Medicine, Institute of Medical Science

Affiliations: Mount Sinai Hospital and Lunenfeld-Tanenbaum Research Institute, Baycrest Centre for Geriatric Care

Research/Teaching

Research Synopsis:

Research Interests:

  • The regulation of insulin signaling and the pathophysiology of insulin resistance as it relates to diabetes mellitus.
  • The pathogenesis of the complications of diabetes, particularly diabetic nephropathy.
  • The mechanisms of high glucose-induced alterations in cell signalling.

Detailed Description: Our research program is focused on the regulation of insulin action in particular, in understanding the cellular and molecular mechanisms which lead to insulin resistance, a metabolic abnormality associated with obesity and Type 2 diabetes mellitus.

Our previous studies of the role of Tyr phosphorylation in insulin biological effects utilizing the protein Tyr phosphatase inhibitor vanadate as a probe, has revealed the following principles:

  1. Inhibition of protein Tyr phosphatases (PTPs) mimics several acute (glucose transport, lipogenesis) and more chronic (receptor downregulation) actions of insulin.
  2. Inhibition of PTPs leads to enhanced sensitivity to insulin.
  3. Inhibition of PTPs leads to a prolonged duration of insulin biological responses. We demonstrated that the amplitude of the insulin receptor Tyr kinase signal is a determinant of response duration.
  4. Tyr phosphorylation is important in promoting IR internalization but Tyr dephosphorylation appears to be required for degradation of multiple receptors and the movement of receptors from a late endosomal to lysosomal compartment.
  5. Tyr dephosphorylation is important not only in terminating the insulin signal but also for propagation of several insulin biological effects, namely amino acid uptake and mitogenesis. This action results in PTP inhibitors, such as vanadate, enhancing the ratio of metabolic versus mitogenic insulin bioeffects.
  6. The insulin-mimetic effects of vanadium compounds on glucose transport are tyrosine-kinase dependent but in contrast to insulin, these agents can stimulate glucose uptake independent of the enzyme phosphatidylinositol-3-kinase and Akt/PKB (protein kinase B).
  7. The sensitivity to vanadate of tissues depends on the redox state of the cell. The presence of reactive oxygen species (ROS) will promote the oxidized (+5) state (vanadate) rather than the less active (+4) (vanadyl) oxidation state. A second determinant of tissue sensitivity to vanadate is the duration of exposure to the compound.

Current Projects

Our overall goals are:

  1. To understand the role of altered cell signaling in the pathogenesis of diabetic nephropathy.
  2. To determine the various mechanisms by which insulin action is inhibited in disease states and identify potential therapeutic targets to increase insulin sensitivity.

Specific Objectives

The pathogenesis of diabetic nephropathy - We are investigating the effects of high glucose on signaling by the mitogen activated protein kinase (MAPK) family of enzymes, ERKs and p38 and the EGF receptor, the role of the tyrosine kinase Src, the mechanism of action of Thioredoxin-interacting protein (TxNIP) which is highly induced by hyperglycemia. TxNIP knockout mice are protected from diabetic nephropathy.

Insulin Resistance: We are investigating the model of insulin resistance caused by exposure to high levels of glucose in combination with insulin. We are exploring a) the signaling defects responsible for the insulin resistance in adipocytes b) the possible cellular mechanisms of the defects including oxidative stress, activation of protein kinase C and degradation of the glucose transporter, GLUT4, and c) examining agents, eg bradykinin, to increase insulin sensitivity.

METHODS USED

Cardiomyocytes, Adiocytes, Mesangial Cells, Podocytes, Muscle Cells

Procedures: Adenovirus, Elisa, Gene Expression Analysis, Glucose Clamp, Immunohistochemistry, Mass Spectrometry, Microarrays, Protemics, qRT-PCR, RIA, RT-PCR, Signal Transduction Characterization, siRNA, Western Blot

EQUIPMENT USED

Analytical Balances, Benchtop Centrifuge, Blotting Apparatus, Confocal Microscope, Culture hood, Culture Incubators, Cryostat, Departmental beta and gamma counters, Digital Microscope, Fluorescence Microscope, Fresh Tissue sectioning systems, Gel Apparatus, Low- and High Speed Centrifuge, Low and Ultralow Freezers, Microwave Oven, Mini Vortexer, Plate Reader, ProBlot Hybridization Oven, Real-time/ Thermocycler, Setups for electropherosis, Stirrer/Hot Plate, Water Baths

PRESENT TRAINEES                                                                                                     

Anu Shah

PRESENT COLLABORATIONS

Adria Giacca
Peter Backx

Outside the Department of Physiology:

Tianru  Jin                    LMP/University of Toronto, Canada
Susan  Quaggin          Medicine/Northwestern University, USA
Marc  Grynpas           LMP/University of Toronto, Canada
Rohan  John                 LMP/University of Toronto, Canada

Committee member/officer of national/international scientific organizations

PRESENT GRANT COMMITTEES SERVED ON

Agency: Canadian Diabetes Association
Committee: Operating

Canadian Institutes of Health Research
Committee:  Operating (Invitation)

Courses:

PSL425H/PSL1425 - Integrative Metabolism and its endocrine regulation

Publications and Awards

Recent Publications

http://www.ncbi.nlm.nih.gov/pubmed/25974101

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