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

OBJECTIVE-Glucokinase (GCK) and glucose-6-phosphatase catalytic subunit 2 (G6PC2) regulate the glucose-cycling step in pancreatic beta-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 METHODS-We 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. RESULTS-rs1799884 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' Delta insulin, corrected P = 0.021). We found no association 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' Delta insulin (corrected P = 0.027). This additive association was replicated in METSIM (fasting glucose, P = 3.5 x 10(-10) 30' Delta insulin, P = 0.028). When we examined the relationship between fasting glucose and 30' Delta insulin 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. CONCLUSIONS-Our data suggest that variation in GCK and G6PC2 have additive effects on both fasting glucose and insulin secretion. Diabetes 58:2946-2953, 2009.