Common genetic variation in the glucokinase gene (GCK) is associated with type 2 diabetes and rates of carbohydrate oxidation and energy expenditure.

Glucokinase (GCK) plays a role in glucose metabolism and glucose-stimulated insulin secretion. Rare mutations in GCK cause MODY. We investigated whether common variation (minor allele frequency ≥0.01) in GCK is associated with metabolic traits and type 2 diabetes. Four exonic single-nucleotide polymorphisms (SNPs) and three SNPs predicted to cause loss of promoter function were identified in whole-genome sequence data from 234 Pima Indians. These seven tag SNPs and rs4607517, a type 2 diabetes variant established in other studies, were analysed in 415 full-heritage non-diabetic Pima Indians characterised for metabolic traits, and 7,667 American Indians who had data on type 2 diabetes and BMI. A novel 3' untranslated region (3'UTR) SNP, chr7:44184184-G/A, was associated with the rate of carbohydrate oxidation post-absorptively (β = 0.22 mg [kg estimated metabolic body size (EMBS)](-1) min(-1), p = 0.005) and during a hyperinsulinaemic-euglycaemic clamp (β = 0.24 mg [kg EMBS](-1) min(-1), p = 0.0002), the rate of carbohydrate oxidation in a respiratory chamber (β = 311 kJ/day, p = 0.03) and 24 h energy expenditure, which was attributable to the thermic effect of food (β = 520 kJ/day, p = 3.39 × 10(-6)). This 3'UTR SNP was also associated with diabetes (OR 1.36, 95% CI 1.11, 1.65, p = 0.002), where the A allele (allele frequency 0.05) was associated with a lower rate of carbohydrate oxidation, lower 24 h energy expenditure and higher risk for diabetes. In a Cox proportional hazards model, a rate of insulin-stimulated carbohydrate oxidation lower than the mean rate at baseline predicted a higher risk for developing diabetes than for those above the mean (hazard rate ratio 2.2, 95% CI 1.3, 3.6, p = 0.002). Common variation in GCK influences the rate of carbohydrate oxidation, 24 h energy expenditure and diabetes risk in Pima Indians.