Contribution de l'intestin dans le syndrome de resistance a l'insuline chez l'enfant

It is very well established that obesity in youth reached alarming proportions in Canada and worldwide. This form of obesity represents a great risk for type 2 diabetes, hyperlipidemia and atherosclerosis. Furthermore, it is closely associated to insulin resistance and can be found in the center of insulin resistance syndrome (IRS), defined as a cluster of several cardiovascular risk factors such as hypertension, dyslipidemia, obesity, glucose intolerance, hyperinsulinemia as well as fibrinolysis and coagulation abnormalities. Numerous studies showed the simultaneous presence of these risk factors in adults, but very little data emerged from pediatric populations. In this context, this project aims specifically to study the contribution of the intestine in IRS in youth, more exactly through lipid metabolism. The studied population consists of three groups of Quebec children and adolescents, aged 9, 13 and 16 years respectively, for a total of 2249 participants. Among instruments used during data collection, there were questionnaires, anthropometric measures such as weight, height and skinfolds, blood pressure and blood samples. Fasting plasma insulin, glyceamia and a complete lipid profile were available. Residual plasma and DNA were also available for complementary measurements. We determined an important cardiovascular risk factor for the precise evaluation of the atherosclerotic risk: LDL particle size. Considering this objective, a part of our study consists in analyzing the role of FABP2 Ala54Thr and MTP -493G/T gene polymorphisms in IRS pathogenesis and a parallel was made between epidemiological and fundamental studies performed in human intestinal explants. This study allowed to demonstrate, in youth presenting IRS, a variability in the dyslipidemia expression (↑ total cholesterol, ↑LDL-C, ↑apo B) according to I-FABP genotype, an effect modulated by triglyceridemia. An increase of lipid secretion in the presence of the FABP2 Thr allele was observed in-vitro, while no impact of the MTP genotype was recorded. We previously proceeded to the characterization of the MTP, by examining its ontogenetic profile and its intracellular distribution. This study also described the LDL particle size distribution, since little information is available in pediatric population and allowed the identification of several biochemical variables associated with LDL particle size. Another factor having held our attention is leptin. The study of the effect of this adipocyte hormone on lipid metabolism in Caco-2 cells brought new lighting as to its implication in the intestinal contribution to post-prandial hyperlipidemia, namely a reduction in lipid transport. This study is unique, because the variety of elements available in this pediatric population lead towards a complete characterization of IRS, which will allow to establish evaluation or diagnostic criterias as well as therapeutic measures to prevent potential complications.