Department of BioSciences
INSA-Lyon, 20 Av. Albert Einstein,
F-69621 Villeurbanne, France
Cardiovascular, Metabolism, diabetology and Nutrition
CARMEN Institute INSERM UMR1060
Bldg IMBL, INSA-Lyon, 20 Av. Albert Einstein,
F-69621 Villeurbanne, France
Team 1: Nutritional adaptations, environment and diabetes
Insulin resistance is a primary risk factor for several common diseases, including diabetes, cardiovascular diseases and hypertension. The mechanisms underlying insulin resistance are to date not completely understood. My research focuses on the pathophysiological mechanisms underlying the devlopment of insulin resistance and metabolic syndrom. I am especially interested in the role of oxidative stress and uraemic toxins in the pathophysiology of insulin resistance using animal as well as in vitro models.
1) Role of oxidative stress and lipid peroxidation byproducts in the pathophysiology of insulin resistance and diabetes
I am interested in the role of hydroxyalkenals derived from lipid peroxidation in the pathogenesis of insulin resistance and type 2 diabetes. Diabetes is associated with the presence of oxidative stress resulting from excessive production of pro-oxidant elements and / or a deficit of antioxidant defenses of the body. Peroxidation of polyunsaturated fatty acids, targets of radical attack, leads to the formation of toxic aldehydes. Peroxidation of fatty acids omega-3 series and omega-6, respectively, led to the formation of 4-hydroxy-2-hexenal (4-HHE) and 4-hydroxy-2-nonenal (4-HNE), secondary products can transmit the detrimental effects of oxidative stress. We demonstrated that 4-HHE plasma is increased in patients with type 2 diabetes and in a model of experimental diabetes in rats. On muscle cells or adipocytes cell lines, 4-HHE and 4-HNE cause massive carbonylation of cellular proteins (carbonyl stress) and induce insulin resistance by disrupting glucose transport and insulin signaling pathways. We demonstrated that their harmful effects can be counteracted by an increase of reduced glutathione or by supplementation with antioxidants. We also demonstrated that 4-HHE and 4-HNE can induce functional and structural changes in the insulin molecule, which may in turn be pivotal in the development of insulin resistance and diabetes.
2) Molecular determinants of metabolic syndrome and insulin resistance associated with chronic renal failure. Putative role of uremic toxins.
Chronic kidney disease (CKD) is characterized by profound alterations in metabolism, among which dyslipidemia and insulin resistance. The causes of insulin resistance in CKD remains to date poorly understood. The p-cresol, produced in the gut from the degradation of tyrosine by bacterial fermentation, has been identified as a major uremic toxins involved in vascular damage associated with CKD and it is now well established that free concentrations of its metabolite p-cresyl sulfate is an independent predictor of mortality. However no studies to date explored the role of uremic toxins in the development of insulin resistance and other metabolic complications associated with CKD. We demonstrated on cultured cells (C2C12 muscle cells, 3T3-L1 adipocytes) as well as on rodent models that p-cresol and p-cresyl sulfate at concentrations found in end stage CKD patient can induce insulin resistance and dyslipidemia. We are looking for therapeutic strategies to prevent p-cresyl-sulfate accumulation in body fluids amongst which the use of prebiotics, protein restriction and chemical absorbants.