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.
Diabetologia
; 54(11): 2820-31, 2011 Nov.
Article
em En
| MEDLINE
| ID: mdl-21822931
ABSTRACT
AIMS/HYPOTHESIS:
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 â¼50% 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/INTERPRETATION:
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Glucagon
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Polimorfismo de Nucleotídeo Único
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Diabetes Mellitus Tipo 2
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Peptídeo 1 Semelhante ao Glucagon
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Insulina
Tipo de estudo:
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Limite:
Adolescent
/
Adult
/
Aged
/
Child
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Child, preschool
/
Female
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Humans
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Infant
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Male
/
Middle aged
País/Região como assunto:
Europa
Idioma:
En
Revista:
Diabetologia
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
Dinamarca