title: Homozygous carriers of the G allele of rs4664447 of the glucagon gene (GCG) are characterised by decreased fasting and stimulated levels of insulin, glucagon and glucagon-like peptide (GLP)-1.
abstract: OBJECTIVE
  The glucagon gene (GCG) encodes several hormones important for energy metabolism: glucagon, oxyntomodulin and glucagon-like peptide (GLP)-1 and -2. Variants in GCG may associate with type 2 diabetes, obesity and/or related metabolic traits.
  
  
  METHODS
  GCG was re-sequenced as a candidate gene in 865 European individuals. Twenty-nine variants were identified. Four variants that were considered to have a likelihood for altered functionality: rs4664447, rs7581952, Ile158Val and Trp169Ter, were genotyped in 17,584 Danes.
  
  
  RESULTS
  When examined in 5,760 treatment-naive individuals, homozygous carriers of the low frequency (minor allele frequency 2.3%) G allele of rs4664447, predicted to disrupt an essential splice enhancer binding site, had lower levels of fasting plasma glucose (mean ± SD, 4.8 ± 1.2 vs 5.5 ± 0.8 mmol/l, p = 0.004); fasting serum insulin (22 ± 14 vs 42 ± 27 pmol/l, p = 0.04); glucose-stimulated serum insulin (159 ± 83 vs 290 ± 183 pmol/l, p = 0.01) and adult height (165 ± 10 vs 172 ± 9 cm, p = 0.0009) compared with A allele carriers. During oral glucose tolerance and hyperglycaemic arginine stimulation tests, the plasma AUC for GLP-1 (730 ± 69 vs 1,334 ± 288 pmol/l × min, p = 0.0002) and basal and stimulated levels of serum insulin and plasma glucagon were ∼50% decreased (p < 0.001) among three homozygous carriers compared with nine matched wild-type carriers. rs7581952, Ile158Val and Trp169Ter (where 'Ter' indicates 'termination') variants of GCG did not significantly associate or co-segregate with the metabolic traits examined.
  
  
  CONCLUSIONS
  Re-sequencing of GCG revealed a low frequency intronic variant, rs4664447, and follow-up physiological studies suggest that this variant in homozygous form may cause decreased fasting and stimulated levels of insulin, glucagon and GLP-1. Overall, our findings suggest that variation in GCG has no major impact on carbohydrate metabolism in the study populations examined.
authors.affiliation: Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, 2200 Copenhagen, Denmark. Torekov@sund.ku.dk
authors.forename: S S
authors.initials: SS
authors.lastname: Torekov
authors.forename: L
authors.initials: L
authors.lastname: Ma
authors.forename: N
authors.initials: N
authors.lastname: Grarup
authors.forename: B
authors.initials: B
authors.lastname: Hartmann
authors.forename: I A
authors.initials: IA
authors.lastname: Hainerová
authors.forename: U
authors.initials: U
authors.lastname: Kielgast
authors.forename: H
authors.initials: H
authors.lastname: Kissow
authors.forename: M
authors.initials: M
authors.lastname: Rosenkilde
authors.forename: J
authors.initials: J
authors.lastname: Lebl
authors.forename: D R
authors.initials: DR
authors.lastname: Witte
authors.forename: T
authors.initials: T
authors.lastname: Jørgensen
authors.forename: A
authors.initials: A
authors.lastname: Sandbaek
authors.forename: T
authors.initials: T
authors.lastname: Lauritzen
authors.forename: O D
authors.initials: OD
authors.lastname: Madsen
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: A
authors.initials: A
authors.lastname: Linneberg
authors.forename: S
authors.initials: S
authors.lastname: Madsbad
authors.forename: J J
authors.initials: JJ
authors.lastname: Holst
authors.forename: T
authors.initials: T
authors.lastname: Hansen
authors.forename: O
authors.initials: O
authors.lastname: Pedersen
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003604:Czechoslovakia; D003718:Denmark; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000150:complications / Q000235:genetics*; D005060:Europe; D005260:Female; D056726:Genetic Association Studies; D005934:Glucagon / Q000097:blood* / Q000235:genetics*; D052216:Glucagon-Like Peptide 1 / Q000097:blood* / Q000235:genetics; D006720:Homozygote; D006801:Humans; D007223:Infant; D007328:Insulin / Q000097:blood* / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000097:blood / Q000150:complications / Q000235:genetics; D020641:Polymorphism, Single Nucleotide
chemical_list: D007328:Insulin; D052216:Glucagon-Like Peptide 1; D005934:Glucagon