Genetic and Functional Studies Implicate G6PC2 in the Regulation of Fasting Blood Glucose

Genome-wide association studies (GWAS) have shown that single-nucleotide polymorphisms (SNPs) in G6PC2 are the strongest common determinants of variations in fasting blood glucose (FBG) levels. Despite significant allelic heterogeneity, studies in diverse genetic backgrounds confirmed the role of this gene as a determinant of FBG in a manner independent from the risk of type 2 diabetes. Molecular studies examining the functional impact of these SNPs on G6PC2 gene transcription and splicing suggest that they affect FBG by directly modulating G6PC2 expression. This conclusion is supported by studies on G6pc2 knockout (KO) mice showing that G6pc2 represents a negative regulator of basal glucose-stimulated insulin secretion that acts by hydrolyzing glucose-6-phosphate, thereby reducing glycolytic flux and opposing the action of glucokinase. Suppression of G6PC2 activity might therefore represent a novel therapy to lower FBG and thereby perhaps influence the risk of cardiovascular-associated mortality. GWAS and G6pc2 KO mouse studies also suggest that G6PC2 affects other aspects of beta-cell function. The evolutionary benefit conferred by G6PC2 remains unclear, but it is likely to be related to its ability to acutely modulate glycolytic flux rather than establish the long-term set point for FBG.