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Etude du rôle du gène PROX1 dans le diabète de type 2

Abstract : As PROX1 is a susceptibility factor for type 2 diabetes (T2D), we conductedgenetic and molecular studies to better understand the role of PROX1 in the etiology of T2D. We assessed the impact of 80 PROX1 SNPs on T2D-related biochemical traits in the HELENA study (n=1155 adolescents) and showed that 3 SNPs (rs340838, rs340837 and rs340836) were significantly associated with fasting plasma insulin levels. We evaluated the functional impact of 9 SNPs (the 3 insulin-associated SNPs plus 6 SNPs in linkage disequilibrium) using a Luciferase reporter gene expression in HepG2 and MIN6 cells. The insulin-lowering alleles of the rs340874, rs340873 and rs340835 SNPs were associated with lower Luciferase gene expression, suggesting that PROX1 expression may be lower in individuals carrying the insulin-lowering alleles. We also showed that the knock-down of Prox1 expression by siRNA in INS-1E cells resulted in a 1.7 fold reduced glucose-stimulated insulin secretion and that high concentrations of glucose positively modulated Prox1 protein expression. Then, microarray analyses performed in INS-1E cells showed that some PROX1 target genes in the _cells are implicated in insulin secretion pathways. Finally, we observed that the PPARgamma agonist, the troglitazone, decreased Prox1 expression in INS-1E cells. Altogether, these results suggest that an altered expression of Prox1 bys cisregulators variants results in an altered -cell glucose-stimulated insulin secretion andthereby confers susceptibility to T2D.
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Sophie Lecompte. Etude du rôle du gène PROX1 dans le diabète de type 2. Médecine humaine et pathologie. Université du Droit et de la Santé - Lille II, 2012. Français. ⟨NNT : 2012LIL2S021⟩. ⟨tel-00790524⟩

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