Dr. Marette is an international expert on the pathogenesis of insulin resistance in altered metabolic states and on the mechanisms by which exercise improves muscle metabolism. His research in the areas of insulin action and insulin resistance has advanced the understanding of the cellular/molecular defects leading to diabetes and opened new possibilities for pharmacological intervention. Some of his most important scientific contributions are:

1. Identification of NO as a novel modulator of insulin action in insulin target cells.
A major contribution of my group was to show the novel role of nitric oxide (NO) in modulating glucose transport and insulin action in skeletal muscle. We were among the first to show that muscle expresses NOS enzymes and that NO directly modulates insulin-mediated glucose transport in skeletal muscle cells. We also found that obesity and other inflammatory conditions induce the expression of an inducible NO synthase form (iNOS). We reported that cytokines reduce insulin's ability to enhance glucose transport in myocytes by inducing iNOS. We published in Nature Medicine that iNOS is overexpressed in several models of obesity and obese mice lacking iNOS are protected from developing whole-body and skeletal muscle insulin resistance. More recently, we have made the novel observation that activation of AMP-activated protein kinase by anti-diabetic drugs inhibits iNOS in myocytes, adipocytes and macrophages, which may provide a new mechanism by which AMPK improves insulin action and glucose metabolism in obesity. Finally we found that iNOS-mediated NO counteracts cytokine/LPS-mediated lipolysis in adipocytes and that this feedback mechanism involves an oxidative process. (Biochemical Journal, 325: 487-493, 1997; Diabetes, 46: 1691-1700, 1997; Amer J Physiol 274: E692-E699, 1998; Diabetologia 41: 1523-1527, 1998; Am. J. Physiol. 276: E635-E641, 1999; Diabetologia 43: 427-437, 2000; Int. J. Obesity 24 : S36-S40, 2000; Horm Metab Res 32 : 1-5, 2000; Nature Medicine 7(10):1138-43, 2001; Curr Opin Clin Nutr Metab Care 5(4):377-83, 2002 ; Int J Obes Relat Metab Disord. 27 Suppl 3:S46-8, 2003; J Biol Chem. 14;279(20):20767-74, 2004 ; Nestle Nutr Workshop Ser Clin Perform Programme. 2004;(9):141-50 ; J Lipid Res. 46(1):135-42, 2005).

2. Discovery that dietary proteins modulate obesity-linked insulin resistance and of a nutrient-sensing negative feedback loop regulating insulin signaling to glucose metabolism.
We were the first to show that dietary proteins modulate insulin sensitivity for glucose metabolism. We found that dietary cod protein is a natural insulin-sensitizing agent that appears to prevent obesity-linked muscle insulin resistance by normalizing insulin activation of the PI 3-kinase/Akt pathway and by improving GLUT4 translocation to the muscle cell surface. We next identified the serine/threonine kinases mTOR and S6K1 as part of novel feedback regulatory mechanism to control insulin action on glucose transport in skeletal muscle, adipose and liver cells. We found that activation of the mTOR/S6K1 pathway by amino acids and prolong insulin treatment inhibits insulin-stimulated glucose transport through increased serine phosphorylation of IRS-1 (Ser pIRS-1) and accelerated deactivation of IRS-1-associated PI 3-kinase. Very recently, we have shown that the mTOR/S6K1 pathway is overactivated in liver and muscle of obese rats and that this feedback regulatory loop also operates in human skeletal muscle and adipocytes (Am J Physiol Endocrinol Metab. 278(3):E491-500, 2000; Am J Physiol Endocrinol Metab. 281(1):E62-71, 2001; ; J Biol Chem.276:38052-60, 2001 ; Diabetes 52(1):29-37, 2003 ; Endocrinology 146(3):1328-37, 2005 ; Endocrinology 146(3):1473-81, 2005; Diabetes 54(9):2674-84, 2005).

3. Novel mechanisms of regulation of muscle glucose transport by insulin and contraction.
Using a new subcellular membrane fractionation procedure we were the first to demonstrate that both insulin and exercise mobilize GLUT4 glucose transporters not only to the plasma membrane but also to the T-tubules that run deep inside muscle fibers. We next showed that the impaired muscle glucose uptake in both type 1 and obese type 2 diabetic rats is linked to a defective translocation of GLUT4 to the T-tubules. More recently, we have challenged the current view of GLUT4 vesicle trafficking in both insulin -stimulated and contracted muscle by showing 1) that contraction, but not insulin, induces GLUT4 translocation from two distinct vesicle populations including recycling endosomes, and 2) that insulin induces a sustained activation of internalized insulin receptors that associates with GLUT4 vesicles prior to their departure to the cell surface, 3) that insulin and contraction activate p38 MAPK signaling in muscle leading to activation of cell surface GLUT4 and glucose transport stimulation, 4) that AMP-activated protein kinase stimulates glucose transport in muscle by promoting a selective translocation of GLUT4 to the plasma membrane and not to the T-tubules, and by activating p38 MAPK which may contribute to increase the activity of cell surface GLUT4 (Am. J. Physiol. 273 :E688-E694, 1997; Diabetes 47: 5-12, 1998; Diabetes 49 : 183-189, 2000; Diabetes 49:1772-82, 2000; Diabetes 49:1794-1800, 2000; Diabetes 50:1901-10, 2001; FASEB J 17(12):1658-65, 2003 ; Front Biosci. Sep 01;8:d1072-84, 2003).

4. Finding a novel role for the protein tyrosine phosphatase SHP-1 as a negative modulator of insulin-mediated glucose metabolism and hepatic insulin clearance.
The protein tyrosine phosphatases (PTPs) PTP1B and LAR modulate the metabolic actions of insulin in liver, skeletal muscle and fat. The PTP SHP-1 is a well known inhibitor of activation-promoting signaling cascades in hematopoietic cells but its potential role in insulin target tissues is unknown. We have recently showed that SHP-1 is expressed in mouse liver and skeletal muscle. Viable motheaten mice (mev) bearing a functionally-deficient SHP-1 protein have a lower fasting glycemia and are remarkably glucose tolerant as compared to wild-type littermates. Results of insulin tolerance tests, hyperinsulinemic-euglycemic clamps, and in vitro glucose uptake studies further revealed that mev mice are markedly insulin sensitive for glucose metabolism in liver and muscle and show increased tyrosine phosphorylation of the insulin receptor and enhanced induction of the IRS/PI3K/Akt pathway in both tissues. Adenoviral overexpression of a catalytically inert mutant of SHP-1 (C453S) in liver of normal mice was also associated with increased insulin receptor signaling to IRS/PI3K/Akt and improved glucose tolerance. Tyrosine phosphorylation of CEACAM1, a recently identified modulator of hepatic insulin clearance, was also markedly increased in liver of mev mice and following hepatic adenoviral expression of the SHP-1(C453S) mutant. Accordingly, [125I]insulin clearance was augmented in mice expressing the SHP-1(C453S) mutant in liver. In vitro dephosphorylation assays confirmed that both the IR and CEACAM1 proteins are direct substrates of SHP-1. These findings demonstrate an important role for SHP-1 in the regulation of glucose homeostasis and indicate that SHP-1 subserves this role by modulating insulin signaling in liver and muscle as well as hepatic insulin clearance. This work has recently been accepted for publicarion in Nature Medicine.

Note : All these projects are still on-going in my laboratory.