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 Citationer (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.

Originalsprog	Engelsk
Tidsskrift	Diabetologia
Vol/bind	54
Udgave nummer	11
Sider (fra-til)	2820-31
Antal sider	12
ISSN	0012-186X
DOI	https://doi.org/10.1007/s00125-011-2265-7
Status	Udgivet - 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.
I: Diabetologia, Bind 54, Nr. 11, 11.2011, s. 2820-31.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › 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, bind 54, nr. 11, s. 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",

}

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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