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

Adult Blood Glucose Male 0301 basic medicine 0303 health sciences Genetic Variation Fasting Middle Aged Protein Serine-Threonine Kinases Polymorphism, Single Nucleotide Germinal Center Kinases 03 medical and health sciences Insulin-Secreting Cells Insulin Secretion Mexican Americans Glucose-6-Phosphatase Humans Insulin Original Article Female Aged
DOI: 10.2337/db09-0228 Publication Date: 2009-09-10T01:47:25Z
ABSTRACT
OBJECTIVE Glucokinase (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 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′ 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. CONCLUSIONS Our data suggest that variation in GCK and G6PC2 have additive effects on both fasting glucose and insulin secretion.
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