title: The common PPAR-gamma2 Pro12Ala variant is associated with greater insulin sensitivity.
abstract: Several genetic variants of peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2) 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-gamma2 on insulin sensitivity in a large Italian population sample, n=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 beta-cell function, HOMA-beta%) was utilized to evaluate beta-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=0.01 after correction for multiple comparisons) in all subjects. Consistent with this finding, significantly lower HOMA-IR was observed in X12Ala carriers (P=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.
authors.affiliation: Endocrinology, Department of Clinical Sciences, University of Rome La Sapienza, Rome, Italy. raffaella.buzzetti@uniroma1@it
authors.forename: Raffaella
authors.initials: R
authors.lastname: Buzzetti
authors.forename: Antonio
authors.initials: A
authors.lastname: Petrone
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Ribaudo
authors.forename: Irene
authors.initials: I
authors.lastname: Alemanno
authors.forename: Sara
authors.initials: S
authors.lastname: Zavarella
authors.forename: Charles A
authors.initials: CA
authors.lastname: Mein
authors.forename: Francesca
authors.initials: F
authors.lastname: Maiani
authors.forename: Claudio
authors.initials: C
authors.lastname: Tiberti
authors.forename: Marco Giorgio
authors.initials: MG
authors.lastname: Baroni
authors.forename: Elio
authors.initials: E
authors.lastname: Vecci
authors.forename: Marcello
authors.initials: M
authors.lastname: Arca
authors.forename: Frida
authors.initials: F
authors.lastname: Leonetti
authors.forename: Umberto
authors.initials: U
authors.lastname: Di Mario
mesh_terms: D019943:Amino Acid Substitution; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics* / Q000502:physiology; D009154:Mutation; D047495:PPAR gamma / Q000235:genetics* / Q000378:metabolism*
chemical_list: D007328:Insulin; D047495:PPAR gamma