The rs340874 PROX1 type 2 diabetes mellitus risk variant is associated with visceral fat accumulation and alterations in postprandial glucose and lipid metabolism

Abstract

Large-scale meta-analyses of genome-wide association studies have recently confirmed that the rs340874 single-nucleotide polymorphism in PROX1 gene is associated with fasting glycemia and type 2 diabetes mellitus; however, the mechanism of this link was not well established. The aim of our study was to evaluate the functional/phenotypic differences related to rs340874 PROX1 variants. The study group comprised 945 subjects of Polish origin (including 634 with BMI > 25) without previously known dysglycemia. We analyzed behavioral patterns (diet, physical activity), body fat distribution and glucose/fat metabolism after standardized meals and during the oral glucose tolerance test. We found that the carriers of the rs340874 PROX1 CC genotype had higher nonesterified fatty acids levels after high-fat meal (p = 0.035) and lower glucose oxidation (p = 0.014) after high-carbohydrate meal in comparison with subjects with other PROX1 genotypes. Moreover, in subjects with CC variant, we found higher accumulation of visceral fat (p < 0.02), but surprisingly lower daily food consumption (p < 0.001). We hypothesize that lipid metabolism alterations in subjects with the PROX1 CC genotype may be a primary cause of higher glucose levels after glucose load, since the fatty acids can inhibit insulin-stimulated glucose uptake by decreasing carbohydrate oxidation. Our observations suggest that the PROX1 variants have pleiotropic effect on disease pathways and it seem to be a very interesting goal of research on prevention of obesity and type 2 diabetes mellitus. The study may help to understand the mechanisms of visceral obesity and type 2 diabetes mellitus risk development.

The MC4R genetic variants are associated with lower visceral fat accumulation and higher postprandial relative increase in carbohydrate utilization in humans

“…The 597 of individuals were overweight/obese, with BMI ≥ 25 kg/m 2 (the mean age 44.20 ± 0.58 years; mean BMI 31.37 0.24 kg/ m 2 ), and 330 were healthy volunteers with normal weight, BMI < 25 kg/m 2 (mean age 33.08 ± 0.64 years, mean BMI 22.39 ± 0.11 kg/m 2 ). Participants were sent by primary care physicians as an apparently healthy people, and were recruited for a cohort study, described previously [14,29]. The clinical characteristics of the studied population, determined by investigated genotypes, are reported in Tables 1, 2, 3, and 4.…”

“…Some of the SNPs may be associated with the weight gain due to larger amounts of consumed food, due to deprivation of postprandial satiety, as well as due to deprivation of energy expenditure and/or substrate utilization [5][6][7][8][9][10]. In our previous studies, we have noticed that some of the metabolic changes may appear only in postprandial state, and that postprandial metabolism can be dependent on the meal content [11,12], as well as on the carried genetic variants [13,14]. It is beyond any doubts that genetic factors predispose to obesity, however, obesity should not be considered only as a genetic disorder.…”

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). Interestingly they found that subjects with the PROX1 CC variant, had higher non-esterified fatty acids levels after high-fat meal, higher accumulation of visceral fat, but surprisingly lower daily food consumption (Kretowski et al, 2015).…”

“…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). Interestingly they found that subjects with the PROX1 CC variant, had higher non-esterified fatty acids levels after high-fat meal, higher accumulation of visceral fat, but surprisingly lower daily food consumption (Kretowski et al, 2015). These results suggest that there is a percentage of obese individuals whose accumulation of abdominal fat is not due to an excess of caloric intake, but rather to a SNP PROX1 allelic variant that predisposes them to accumulate abdominal fat.…”

Hematopoietically expressed homeobox (HHEX) gene polymorphism (rs5015480) is associated with increased risk of gestational diabetes mellitus

“…Boesgaard et al have indicated that PROX1 variants are associated with decreased insulin secretion by glucose-stimulated pancreatic beta cells (18). A study by Kretowski et al suggests that PROX1 gene variants may alter glucose and lipid metabolism as well as visceral fat accumulation (21). Furthermore, PROX1 SNPs are significantly associated with fasting plasma insulin levels and altered insulin secretion by pancreatic beta cells and thereby are risk factors of diabetes type 2 (9,20).…”