The common PPAR-γ2 Pro12Ala variant is associated with greater insulin sensitivity

Abstract

Several genetic variants of peroxisome proliferator-activated receptor-c2 (PPAR-c2) have been identified, among which Pro12Ala, a missense mutation in exon 2, is highly prevalent in Caucasian populations. Up to now, conflicting results with regard to the association between this mutation and complex traits, such as obesity, insulin sensitivity and Type 2 diabetes, have been reported. We investigated the influence of the Pro12Ala polymorphism of PPAR-c2 on insulin sensitivity in a large Italian population sample, n ¼ 1215, in whom extensive clinical and biochemical analyses were performed. To estimate the insulin sensitivity status, the homeostasis model assessment of insulin resistance (HOMA-IR) was calculated; in the obese/ overweight subjects an oral glucose tolerance test (OGTT) was also performed and the Matsuda insulin sensitivity index (ISI) calculated. The insulin secretion index (homeostasis model assessment of percent b-cell function, HOMA-b%) was utilized to evaluate b-cell function. The effect of the Pro12Ala polymorphism on quantitative variables was tested using multiple linear regression analysis. X12Ala (either Pro12Ala or Ala12Ala) genotype was associated with significantly lower fasting insulin levels compared to Pro/Pro (P ¼ 0.01 after correction for multiple comparisons) in all subjects. Consistent with this finding, significantly lower HOMA-IR was observed in X12Ala carriers (P ¼ 0.013 after correction for multiple comparisons) in all cohort. Moreover, no significant interaction effect was observed between body mass index and X12Ala polymorphism and between gender and X12Ala polymorphism in modulating insulin sensitivity. Our observations substantially extend previous findings and demonstrated that X12Ala variant is significantly associated with greater insulin sensitivity.

The in vivo effects of the Pro12Ala PPARγ2 polymorphism on adipose tissue NEFA metabolism: the first use of the Oxford Biobank

“…This occurred despite identical fasting concentrations of insulin and glucose. This can only be interpreted as a sign of increased insulin sensitivity in the Ala12 carriers, which is consistent with the findings of other groups [5][6][7][8][9]28].…”

“…Could a difference in the generation of NEFAs from dietary triglycerides account for the difference in plasma NEFA concentrations observed? By measuring plasma concentrations of stable isotopes derived from the meal containing [1,1,[1][2][3][4][5][6][7][8][9][10][11][12][13] C] tripalmitin, we were able to assess the generation of NEFAs from dietary triglycerides; there was no difference between Ala12 carriers and Pro12 homozygotes. This use of stable isotopes addressed the question of whether there was an increased spillover of fatty acids from the intravascular lipolysis of chylomicron triglycerides.…”

“…To quantify the proportion of fatty acids derived from the meal, we measured concentrations of [1][2][3][4][5][6][7][8][9][10][11][12][13] C]palmitic acid in the triglyceride fraction and NEFA fraction. [ 13 …”

“…Epidemiological studies have shown an association of the Pro12 allele with an increased risk of developing type 2 diabetes, with a populationattributable risk of 25% [3,4]. In vivo in humans, Ala12 allele carriers are more insulin-sensitive than Pro12 homozygotes [5][6][7][8][9]. Although PPARγ activation by thiazolidinediones leads to insulin sensitisation, in vitro studies of the polymorphism have shown that the substitution of Ala for Pro results in reduced transcriptional activity of PPARG [5,10].…”

“…Materials and methods: From a comprehensive population register, subjects were recruited into a biobank, which was genotyped for the Pro12Ala polymorphism. Twelve healthy male Ala12 carriers and 12 matched Pro12 homozygotes underwent detailed physiological phenotyping using stable isotope techniques, and measurements of blood flow and arteriovenous differences in adipose tissue and muscle in response to a mixed meal containing [1,1,[1][2][3][4][5][6][7][8][9][10][11][12][13] …”