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

S S Torekov; L Ma; N Grarup; B Hartmann; I A Hainerová; U Kielgast; H Kissow; M Rosenkilde; J Lebl; D R Witte; T Jørgensen; A Sandbaek; T Lauritzen; O D Madsen; J Wang; A Linneberg; S Madsbad; J J Holst; T Hansen; O Pedersen; GIANT Consortium

doi:10.1007/s00125-011-2265-7

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

S S Torekov, L Ma, N Grarup, B Hartmann, I A Hainerová, U Kielgast, H Kissow, M Rosenkilde, J Lebl, D R Witte, T Jørgensen, A Sandbaek, T Lauritzen, O D Madsen, J Wang, A Linneberg, S Madsbad, J J Holst, T Hansen, O PedersenGIANT Consortium

13 Citations (Scopus)

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 ∼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/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.

Original language	English
Journal	Diabetologia
Volume	54
Issue number	11
Pages (from-to)	2820-31
Number of pages	12
ISSN	0012-186X
DOIs	https://doi.org/10.1007/s00125-011-2265-7
Publication status	Published - Nov 2011

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10.1007/s00125-011-2265-7

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Torekov, S. S., Ma, L., Grarup, N., Hartmann, B., Hainerová, I. A., Kielgast, U., Kissow, H., Rosenkilde, M., Lebl, J., Witte, D. R., Jørgensen, T., Sandbaek, A., Lauritzen, T., Madsen, O. D., Wang, J., Linneberg, A., Madsbad, S., Holst, J. J., Hansen, T., ... GIANT Consortium (2011). 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. https://doi.org/10.1007/s00125-011-2265-7

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. / Torekov, S S; Ma, L; Grarup, N et al.

In: Diabetologia, Vol. 54, No. 11, 11.2011, p. 2820-31.

Research output: Contribution to journal › Journal article › Research › peer-review

Torekov, SS, Ma, L, Grarup, N , Hartmann, B, Hainerová, IA, Kielgast, U, Kissow, H , Rosenkilde, M, Lebl, J, Witte, DR, Jørgensen, T, Sandbaek, A, Lauritzen, T, Madsen, OD, Wang, J, Linneberg, A , Madsbad, S , Holst, JJ , Hansen, T , Pedersen, O & GIANT Consortium 2011, '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, vol. 54, no. 11, pp. 2820-31. https://doi.org/10.1007/s00125-011-2265-7

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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 = "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 ∼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/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.",

author = "Torekov, {S S} and L Ma and N Grarup and B Hartmann and Hainerov{\'a}, {I A} and U Kielgast and H Kissow and M Rosenkilde and J Lebl and Witte, {D R} and T J{\o}rgensen and A Sandbaek and T Lauritzen and Madsen, {O D} and J Wang and A Linneberg and S Madsbad and Holst, {J J} and T Hansen and O Pedersen and {GIANT Consortium}",

year = "2011",

month = nov,

doi = "10.1007/s00125-011-2265-7",

language = "English",

volume = "54",

pages = "2820--31",

journal = "Diabetologia",

issn = "0012-186X",

publisher = "Springer",

number = "11",

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TY - JOUR

T1 - 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

AU - Torekov, S S

AU - Ma, L

AU - Grarup, N

AU - Hartmann, B

AU - Hainerová, I A

AU - Kielgast, U

AU - Kissow, H

AU - Rosenkilde, M

AU - Lebl, J

AU - Witte, D R

AU - Jørgensen, T

AU - Sandbaek, A

AU - Lauritzen, T

AU - Madsen, O D

AU - Wang, J

AU - Linneberg, A

AU - Madsbad, S

AU - Holst, J J

AU - Hansen, T

AU - Pedersen, O

AU - GIANT Consortium

PY - 2011/11

Y1 - 2011/11

N2 - 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 ∼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/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.

AB - 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 ∼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/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.

U2 - 10.1007/s00125-011-2265-7

DO - 10.1007/s00125-011-2265-7

M3 - Journal article

C2 - 21822931

SN - 0012-186X

VL - 54

SP - 2820

EP - 2831

JO - Diabetologia

JF - Diabetologia

IS - 11

ER -

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

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