The Gly482Ser missense mutation of the Peroxisome Proliferator-activated receptor gamma coactivator-1α (PGC-1α) gene associates with reduced insulin sensitivity in normal and glucose-intolerant obese subjects

Article type: Research Article

Authors: Fanelli, Marzia | Filippi, Emanuela | Sentinelli, Federica | Romeo, Stefano | Fallarino, Mara | Buzzetti, Raffaella | Leonetti, Frida | Baroni, Marco Giorgio^;

Affiliations: Department of Clinical Sciences, Division of Endocrinology, University of Rome "La Sapienza", Rome, Italy | Department of Medical Sciences, Endocrinology and Metabolism, University of Cagliari, Italy

Note: [] Corresponding author: Marco G. Baroni, MD PhD, Department of Medical Sciences, Endocrinology and Metabolism, University of Cagliari, Policlinico Universitario, I-09142, Monserrato (CA), Italy. Tel.: +39 070 51096044; Fax: +39 070 51096429; +39 06 49978378; E-mails: [email protected]; [email protected]

Abstract: Among the putative candidate genes for insulin resistance, the peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is a transcriptional coactivator of PPARγ and α, 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-1α 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-1α 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-1α gene and insulin resistance measured by HOMA_{IR}. 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-1α 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-1α gene on the genetic susceptibility to insulin resistance in obesity.

Keywords: PGC-1α gene, obesity, HOMAIR, BMI (body mass index), single nucleotide polymorphisms (SNPs)

Journal: Disease Markers, vol. 21, no. 4, pp. 175-180, 2005