PPARGC1A coding variation may initiate impaired NEFA clearance during glucose challenge.
Diabetologia 2006 ; 50: 569-73.
Franks PW, Ekelund U, Brage S, Luan J, Schafer AJ, O'Rahilly S, Barroso I, and Wareham NJ
DOI : 10.1007/s00125-006-0580-1
PubMed ID : 17216277
PMCID : UKMS4352
The peroxisome proliferator-activated receptor gamma coactivator 1-alpha protein, encoded by the PPARGC1A gene, transcriptionally activates a complex pathway of lipid and glucose metabolism and is expressed primarily in tissues of high metabolic activity such as liver, heart and exercising oxidative skeletal muscle fibre. Ppargc1a-null mice develop systemic dyslipidaemia and hepatic steatosis. In humans, NEFAs downregulate PPARGC1A expression in skeletal muscle. Furthermore, a common non-synonymous coding variant at PPARGC1A (Gly482Ser, rs8192678) is associated with decreased PPARGC1A mRNA levels and increased type 2 diabetes risk.
In a population-based sample of 691 healthy middle-aged Europids we assessed whether Gly482Ser is associated with levels of NEFA when fasting and in response to an oral glucose challenge. We also assessed the potential effect-modifying role of adipose tissue mass on these phenotypes.
After adjustment for age, sex, fat mass and fat-free mass, the Ser482 allele associated with higher NEFA at 30 min and 2 h and with NEFA AUC (all values p
Our observations indicate that NEFA clearance is blunted following a glucose load in carriers of the PPARCG1A Ser482 allele. This association is augmented by obesity.