A novel functional polymorphism (−336A/G) in the promoter of the partitioning-defective protein-6α gene is associated with increased glucose tolerance and lower concentrations of serum non-esterified fatty acids

Partitioning-defective protein-6α (Par6α) has recently been demonstrated to negatively regulate insulin signalling in murine myoblasts. To address whether Par6α plays a role in human physiology, the present study investigated whether mutations exist in the Par6α gene and whether these mutations, if present, are associated with pre-diabetic phenotypes in non-diabetic subjects.

The complete gene (part of the promoter [2.1 kb], all exons/introns and the 3′ untranslated region) encoding Par6α was analysed in 664 non-diabetic subjects. We investigated possible associations between single nucleotide polymorphisms and percentage of body fat, glucose tolerance (as determined by OGTT), serum NEFA concentrations and whole-body insulin sensitivity (estimated during the OGTT, and for a subgroup of 242 subjects determined by the euglycaemic–hyperinsulinaemic clamp).

A rare A/G polymorphism was found 336-bp upstream of the translational start codon (allele frequency 0.03). The data for subjects homozygous and heterozygous for −336G (R/G, n=43) were combined and compared with those for subjects homozygous for −336A (A/A, n=621). Subjects with the R/G genotype had lower fasting (4.84±0.09 mmol/l, means±SEM, p=0.049) and 2-h (5.50±0.02 mmol/l, p=0.050) plasma glucose concentrations than subjects with the A/A genotype (5.02±0.02 and 5.94±0.06 mmol/l, respectively). Subjects with the R/G genotype also had lower fasting (448±31 μmol/l, p=0.018) and 2-h serum NEFA concentrations (61±7 μmol/l, p=0.015) than subjects with the A/A genotype (529±9 and 75±2 μmol/l, respectively), adjusted for age, sex and percentage of body fat. There were no differences in adiposity or whole-body insulin sensitivity between the two genotype groups (all p>0.36). A luciferase reporter gene assay revealed that the −336G promoter variant had a significantly lower (−22.8%, p=0.006) transcriptional activity in transfected C2C12 murine myoblasts than the −336A promoter variant.

A novel functional variant in the promoter of the Par6α gene is associated with reduced fasting glycaemia, increased glucose tolerance and reduced serum NEFA concentrations.