title: Common genetic variation in the glucokinase gene (GCK) is associated with type 2 diabetes and rates of carbohydrate oxidation and energy expenditure.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  Common variation in GCK influences the rate of carbohydrate oxidation, 24 h energy expenditure and diabetes risk in Pima Indians.
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, 445 North 5th street, Phoenix, AZ, 85004, USA.
authors.forename: Yunhua L
authors.initials: YL
authors.lastname: Muller
authors.forename: Paolo
authors.initials: P
authors.lastname: Piaggi
authors.forename: Duncan
authors.initials: D
authors.lastname: Hoffman
authors.forename: Ke
authors.initials: K
authors.lastname: Huang
authors.forename: Brittany
authors.initials: B
authors.lastname: Gene
authors.forename: Sayuko
authors.initials: S
authors.lastname: Kobes
authors.forename: Marie S
authors.initials: MS
authors.lastname: Thearle
authors.forename: William C
authors.initials: WC
authors.lastname: Knowler
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hanson
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Baier
authors.forename: Clifton
authors.initials: C
authors.lastname: Bogardus
mesh_terms: D000328:Adult; D000483:Alleles; D050260:Carbohydrate Metabolism / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D004734:Energy Metabolism / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005941:Glucokinase / Q000235:genetics*; D006801:Humans; D007198:Indians, North American / Q000235:genetics; D008297:Male; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: D005941:Glucokinase
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