CELLULAR
AND MOLECULAR MODES OF ACTION OF INSULIN ON GLUCOSE METABOLISM IN SKELETAL MUSCLE AND
ADIPOSE CELLS AND THEIR DEFECTS IN DIABETES
André MARETTE’s principal research goal is to unravel the molecular mechanisms of action of insulin and exercise on glucose metabolism, and to determine the molecular basis of insulin resistance in obesity and diabetes. His group is currently investigating the role of the AMPK and p38 MAPK signaling pathways in mediating insulin-and contraction-induced glucose uptake in skeletal muscle. He is also investigating the role of novel insulin resistance promoting pathways in skeletal muscle and other insulin-target tissues. He was the first to show that iNOS-mediated NO overproduction causes insulin resistance in obese diabetic mice. Recent work further showed that activation of the mTOR/S6K pathway reduces insulin action on glucose metabolism in insulin target cells cells. The mTOR pathway is activated by cytokines and hyperinsulinemia and could mediate insulin resistance in insulin target tissues of obese subjects. His lab also showed that dietary proteins modulate insulin sensitivity in rats. Of particular interest was the finding that dietary cod protein is a natural insulin-sensitizing agent that appears to prevent obesity-linked muscle insulin resistance. We are now planning to test the hypothesis that fish proteins exert beneficial effects on glucose homeostasis and insulin sensitivity in insulin-resistant obese subjects.
These projects are supported by the Medical Research Council of Canada and the Canadian Diabetes Association.
Dombrowski L, Roy D, Marcotte B, Marette A (1996) A new method for the isolation of plasma membranes, transverse tubules, and internal membranes from skeletal muscle. Amer J Physiol 270 (Endo. Metab. 33): E667-E676.
Bédard S, Marcotte B, Marette A (1997) Cytokines modulate glucose transport in skeletal muscle by inducing the expression of inducible nitric oxide synthase. Biochemical Journal 325: 487-493.
Kapur S, Bédard S, Marcotte B, Côté C, Marette A (1997) Expression of nitric oxide synthase in skeletal muscle: a novel role for nitric oxide as a modulator of insulin action. Diabetes 46: 1691-1700
Roy D, Johannson E, Bonen A, Marette A (1997) Electrical stimulation induces fiber-type specific translocation of GLUT4 to transverse tubules from an intracellular pool in rat skeletal muscle. Am J Physiol 273 (Endo. and Metab. 36): E688-E694.
Dombrowski D, Roy D, Marette A (1998) Selective impairment in GLUT4 translocation to transverse tubules in skeletal muscle of STZ-diabetic rats. Diabetes 47: 5-12.
Mylène Perreault and André MARETTE. Targeted disruption of inducible nitric oxide synthase protects against obesity-linked insulin resistance in muscle. Nature Medicine 7 :1938-1143, 2001.
Frédéric TREMBLAY and André MARETTE. Amino acids and insulin signaling via the mTOR/p70 S6 kinase pathway: a negative feedback mechanism leading to insulin resistance in skeletal muscle cells. Journal of Biological Chemistry 276 : 38052-38060, 2001.
Frédéric TREMBLAY , Charles LAVIGNE , Hélène JACQUES, and André MARETTE. Dietary cod protein restores insulin-induced activation of PI 3-kinase/Akt and GLUT4 translocation to the T-tubules in skeletal muscle of high fat-fed obese rats. Diabetes 52(1):29-37, 2003.
Kathleen LEMIEUX, Daniel KONRAD, Amira KLIP and André MARETTE. The AMP-activated protein kinase activator AICAR does not induce GLUT4 translocation to transverse tubules but stimulates glucose uptake and p38 mitogen-activated protein kinases α and β in skeletal muscle FASEB J 17 : 1658-1665, 2003.
Geneviève PILON, Patrice DALLAIRE and André MARETTE. Inhibition of inducible nitric oxide synthase by activators of AMP-activated protein kinase : Inhibition of inducible nitric oxide synthase by activators of AMP-activated protein kinase : a new mechanism of action of insulin-sensitizing drugs. J Biol Chem. 279(20):20767-74, 2004.