The Gly482Ser Missense Mutation of the Peroxisome Proliferator-Activated Receptor γ Coactivator-1α (PGC-1α) Gene Associates with Reduced Insulin Sensitivity in Normal and Glucose-Intolerant Obese Subjects

Marzia Fanelli,Emanuela Filippi,Marco Giorgio Baroni,Federica Sentinelli,Mara Fallarino,Raffaella Buzzetti,Stefano Romeo,Frida Leonetti

doi:10.1155/2005/576748

Marzia Fanelli, Emanuela Filippi + Show 6 more

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https://doi.org/10.1155/2005/576748

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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 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-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.

Highlights

Insulin resistance precedes and predicts the development of common disorders such as type 2 diabetes, hypertension and atherosclerosis
The PGC-1α gene is induced in the liver by fasting and stimulates hepatic gluconeogenesis by increasing gene transcription of phosphoenolpyruvate carboxykinase (PEPCK) and glucose6-phosphatase (G6Pase) [6,7,8,9,10,11,12,13,14,15,16,17,18,19]
To help to clarify if the PGC-1α gene plays a primary role in insulin resistance, we have investigated in a population of obese, non-diabetic subjects the possible association of the Gly482Ser polymorphism with insulin sensitivity and glucose tolerance

Summary

Introduction

Insulin resistance precedes and predicts the development of common disorders such as type 2 diabetes, hypertension and atherosclerosis. In the liver, β-oxidation of fatty acids and ketogenesis are other adaptative mechanisms in the fasted state, and PGC-1α has been shown to induce several key genes involved in both these processes, playing a more general and important role in the fasted state [13]. In support of the key role played by PGC-1α it has been shown that its expression is greatly increased in mouse models of diabetes, such as the ob/ob mouse, contributing to the insulin resistance of these animals [5]. To help to clarify if the PGC-1α gene plays a primary role in insulin resistance, we have investigated in a population of obese, non-diabetic subjects the possible association of the Gly482Ser polymorphism with insulin sensitivity and glucose tolerance

Subjects

Biological measurements

Genotyping

Statistical analysis

Results

Discussion