Additive Effects of Genetic Variation in GCK and G6PC2 on Insulin Secretion and Fasting Glucose

Abstract

OBJECTIVEGlucokinase (GCK) and glucose-6-phosphatase catalytic subunit 2 (G6PC2) regulate the glucose-cycling step in pancreatic β-cells and may regulate insulin secretion. GCK rs1799884 and G6PC2 rs560887 have been independently associated with fasting glucose, but their interaction on glucose-insulin relationships is not well characterized.RESEARCH DESIGN AND METHODSWe tested whether these variants are associated with diabetes-related quantitative traits in Mexican Americans from the BetaGene Study and attempted to replicate our findings in Finnish men from the METabolic Syndrome in Men (METSIM) Study.RESULTSrs1799884 was not associated with any quantitative trait (corrected P > 0.1), whereas rs560887 was significantly associated with the oral glucose tolerance test 30-min incremental insulin response (30′ Δinsulin, corrected P = 0.021). We found no association between quantitative traits and the multiplicative interaction between rs1799884 and rs560887 (P > 0.26). However, the additive effect of these single nucleotide polymorphisms was associated with fasting glucose (corrected P = 0.03) and 30′ Δinsulin (corrected P = 0.027). This additive association was replicated in METSIM (fasting glucose, P = 3.5 × 10−10 30′ Δinsulin, P = 0.028). When we examined the relationship between fasting glucose and 30′ Δinsulin stratified by GCK and G6PC2, we noted divergent changes in these quantitative traits for GCK but parallel changes for G6PC2. We observed a similar pattern in METSIM.CONCLUSIONSOur data suggest that variation in GCK and G6PC2 have additive effects on both fasting glucose and insulin secretion.

Moving on from GWAS: Functional Studies on the G6PC2 Gene Implicated in the Regulation of Fasting Blood Glucose

“…These observations in G6pc2 KO mice are consistent with earlier human GWAS data showing no association between G6PC2 and glucose tolerance [69–72]. GWAS data also showed that G6PC2 is not associated with variations in insulin sensitivity in humans [69–72], an observation that was confirmed in G6pc2 KO mice [28].…”

“…GWAS data also showed that G6PC2 is not associated with variations in insulin sensitivity in humans [69–72], an observation that was confirmed in G6pc2 KO mice [28]. …”

Glucokinase gene promoter -30G>A polymorphism: a cross-sectional association study with obesity, diabetes Mellitus, hyperlipidemia, hypertension and metabolic syndrome in an Iranian hospital

“…With regard to diabetes-related traits, there are also some previous reports indicating an association between this polymorphism and Fasting Plasma Glucose (FPG) 21,27 or low cell function (mainly in Japanese subjects) 12,[27][28][29] . However, these findings are challenged by those of other studies 12,24,[30][31][32] and so are not consistent. Furthermore, previous studies have failed to find any significant effect of this polymorphism on insulin secretion 20,24 .…”

Health Disparities in Endocrine Disorders: Biological, Clinical, and Nonclinical Factors—An Endocrine Society Scientific Statement

“…No studies have reported on the contribution of the polymorphisms to racial/ethnic differences in GDM in U.S. populations. The BetaGene study has found a link between polymorphisms of GCK and G6PC2 and impaired insulin secretion among MexicanAmerican women with histories of GDM and Finns with a similar impairment (159). In addition, the BetaGene study found a link between polymorphisms in IGF2BP2 (160), TCF7L2 (161), PPARG2 (162), and HNF4A (162) and altered insulin sensitivity in women with histories of GDM.…”