Genetic and Molecular Insights Into the Role of PROX1 in Glucose Metabolism

Abstract

Genome-wide association studies have shown that the rs340874 single nucleotide polymorphism (SNP) in PROX1 is a genetic susceptibility factor for type 2 diabetes. We conducted genetic and molecular studies to better understand the role of PROX1 in type 2 diabetes. We assessed the impact of the whole common genetic variability of PROX1 (80 SNPs) on type 2 diabetes–related biochemical traits in the HELENA (Healthy Lifestyle in Europe by Nutrition in Adolescence) study (n = 1,155). Three SNPs (rs340838, rs340837, and rs340836) were significantly associated with fasting plasma insulin levels (P ≤ 0.00295). We evaluated the impact of nine PROX1 SNPs (the three insulin-associated SNPs plus six SNPs in strong linkage disequilibrium) on luciferase reporter gene expression. The insulin-lowering alleles of rs340874, rs340873, and rs340835 were associated with lower luciferase activity in MIN6 and HepG2 cells (except for rs340874, which was in HepG2 cells only). Electrophoretic mobility shift assays indicated that specific nuclear protein bindings occur at the three SNPs in HepG2 cells, with allele-binding differences for rs340874. We also showed that the knockdown of Prox1 expression by small interfering RNAs in INS-1E cells resulted in a 1.7-fold reduction in glucose-stimulated insulin secretion. All together, we propose that reduced expression of PROX1 by cis-regulatory variants results in altered β-cell insulin secretion and thereby confers susceptibility to type 2 diabetes.

Restoration of lymphatic function rescues obesity in Prox1-haploinsufficient mice

“…Additionally, a recent clinical study hinted that the phenotype described in Prox1 +/ − mice could have counterparts in humans. In fact, individuals of Polish origin with obesity features have a SNP (rs340874) in the 5′-UTR region of PROX1 (54), and this SNP is mutated in some obese patients. The BMI did not differ among the obese subjects; however, individuals carrying the mutation in the PROX1 SNP had higher levels of nonesterified fatty acids after a high-fat meal, lower glucose oxidation after high-carbohydrate meal, and higher accumulation of visceral fat but, surprisingly, lower daily food consumption.…”

PROX1 gene CC genotype as a major determinant of early onset of type 2 diabetes in slavic study participants from Action in Diabetes and Vascular Disease

“…It is of interest that several polymorphisms at this locus are associated with insulin levels and its control in adolescence, selected for a lesser impact of environmental determinants at this age by Lecompte et al . [40]. As we have mentioned, the ADVANCE trial demonstrated that earlier onset of diabetes has more impact on micro than macrovascular complications [46].…”

The Lymphatic Vasculature: Its Role in Adipose Metabolism and Obesity

“…Additional large meta-analyses of GWAS confirmed a SNP (rs340874) in the 5’UTR region of PROX1 that is associated with fasting glycemia and type 2 diabetes mellitus (Dupuis et al, 2010; Lecompte et al, 2013). More recently, a new study with subjects of Polish origin evaluated the functional/phenotypic differences related to rs340874 PROX1 variants (different allelic variants, C or T allele) analyzing behavioral patterns, body fat distribution and glucose/fat metabolism after standardized meals and during the oral glucose tolerance test (Kretowski et al, 2015).…”