Linking Metabolic Disease With the PGC-1α Gly482Ser Polymorphism

Peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) is a highly conserved transcriptional coactivator enriched in metabolically active tissues including liver, adipose, pancreas, and muscle. It plays a role in regulating whole body energy metabolism and its deregulation has been implicated in type 2 diabetes (T2D). A single nucleotide variant of the PPARGC1A gene (rs8192678) is associated with T2D susceptibility, relative risk of obesity and insulin resistance, and lower indices of β cell function. This common polymorphism is within a highly conserved region of the bioactive protein and leads to a single amino acid substitution (glycine 482 to serine). Its prevalence and effects on metabolic parameters appear to vary depending on factors including ethnicity and sex, suggesting important interactions between genetics and cultural/environmental factors and associated disease risk. Interestingly, carriers of the serine allele respond better to some T2D interventions, illustrating the importance of understanding functional impacts of genetic variance on PGC-1α when targeting this pathway for personalized medicine. This review summarizes a growing body of literature surrounding possible links between the PGC-1α Gly482Ser single nucleotide polymorphism and diabetes, with focus on key clinical findings, affected metabolic systems, potential molecular mechanisms, and the influence of geographical or ethnic background on associated risk.