title: The Gly482Ser missense mutation of the peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) gene associates with reduced insulin sensitivity in normal and glucose-intolerant obese subjects.
abstract: Among the putative candidate genes for insulin resistance, the peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) is a transcriptional coactivator of PPARgamma and alpha, regulating a wide range of processes involved in energy production and utilization, such as thermogenesis, liver gluconeogenesis, glucose uptake in muscle. In population studies a Gly482Ser substitution in PGC-1alpha has been reported to be associated with increased risk of type diabetes 2 and insulin resistance. In the present study we have analysed the association between the Gly482Ser missense mutation of the PGC-1alpha gene and insulin sensitivity and glucose tolerance in a population of obese non-diabetic subjects. The Gly482Ser SNPs was detected by PCR-RFLP in a cohort of 358 Caucasian obese subjects (223 with normal glucose tolerance (NGT) and 125 with impaired glucose tolerance (IGT). We observed a significant association (p <0.007) between carriers of the Gly482Ser variant of the PGC-1alpha gene and insulin resistance measured by HOMAIR. Multivariate analysis confirmed that the Gly482Ser SNP was a significant (p < 0.02) determinant of decreased insulin sensitivity, independently from other well-known modulators of insulin action. In conclusion, we have found significant association between the Gly482Ser variant of the PGC-1alpha gene and reduced insulin sensitivity in obese subjects. This association resulted independent from all other known modulators of insulin resistance, and suggests a primary role for the PGC-1alpha gene on the genetic susceptibility to insulin resistance in obesity.
authors.affiliation: Department of Clinical Sciences, Division of Endocrinology, University of Rome La Sapienza, Rome, Italy.
authors.forename: Marzia
authors.initials: M
authors.lastname: Fanelli
authors.forename: Emanuela
authors.initials: E
authors.lastname: Filippi
authors.forename: Federica
authors.initials: F
authors.lastname: Sentinelli
authors.forename: Stefano
authors.initials: S
authors.lastname: Romeo
authors.forename: Mara
authors.initials: M
authors.lastname: Fallarino
authors.forename: Raffaella
authors.initials: R
authors.lastname: Buzzetti
authors.forename: Frida
authors.initials: F
authors.lastname: Leonetti
authors.forename: Marco Giorgio
authors.initials: MG
authors.lastname: Baroni
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D018149:Glucose Intolerance / Q000235:genetics* / Q000378:metabolism; D005998:Glycine / Q000235:genetics; D006360:Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics* / Q000502:physiology; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012694:Serine / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D006360:Heat-Shock Proteins; D047493:PPAR alpha; D047495:PPAR gamma; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D015534:Trans-Activators; D014157:Transcription Factors; D012694:Serine; D005998:Glycine