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.

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.