Homozygous carriers of the G allele of rs4664447 of the glucagon gene (GCG) are characterised by decreased fasting and stimulated levels of insulin, glucagon and glucagon-like peptide (GLP)-1
Abstract
The glucagon gene (GCG) encodes several hormones important for energy metabolism: glucagon, oxyntomodulin and glucagon-like peptide (GLP)-1 and -2. Variants in GCG may associate with type 2 diabetes, obesity and/or related metabolic traits.
GCG was re-sequenced as a candidate gene in 865 European individuals. Twenty-nine variants were identified.
Four variants that were considered to have a likelihood for altered functionality: rs4664447, rs7581952, Ile158Val and Trp169Ter, were genotyped in 17,584 Danes. When examined in 5,760 treatment-naive individuals, homozygous carriers of the low frequency (minor allele frequency 2.3%) G allele of rs4664447, predicted to disrupt an essential splice enhancer binding site, had lower levels of fasting plasma glucose (mean +/- SD, 4.8 +/- 1.2 vs 5.5 +/- 0.8 mmol/l, p = 0.004); fasting serum insulin (22 +/- 14 vs 42 +/- 27 pmol/l, p = 0.04); glucose-stimulated serum insulin (159 +/- 83 vs 290 +/- 183 pmol/l, p = 0.01) and adult height (165 +/- 10 vs 172 +/- 9 cm, p = 0.0009) compared with A allele carriers.
During oral glucose tolerance and hyperglycaemic arginine stimulation tests, the plasma AUC for GLP-1 (730 +/- 69 vs 1,334 +/- 288 pmol/l x min, p = 0.0002) and basal and stimulated levels of serum insulin and plasma glucagon were similar to 50% decreased (p < 0.001) among three homozygous carriers compared with nine matched wild-type carriers. rs7581952, Ile158Val and Trp169Ter (where 'Ter' indicates 'termination') variants of GCG did not significantly associate or co-segregate with the metabolic traits examined. Re-sequencing of GCG revealed a low frequency intronic variant, rs4664447, and follow-up physiological studies suggest that this variant in homozygous form may cause decreased fasting and stimulated levels of insulin, glucagon and GLP-1.
Overall, our findings suggest that variation in GCG has no major impact on carbohydrate metabolism in the study populations examined.