G-allele of intronic rs10830963 in MTNR1B confers increased risk of impaired fasting glycemia and type 2 diabetes through an impaired glucose-stimulated insulin release: studies involving 19,605 Europeans

Thomas Sparsø; Amélie Bonnefond; Ehm Andersson; Nabila Bouatia-Naji; Johan Holmkvist; Lise Wegner; Niels Grarup; Anette P Gjesing; Karina Banasik; Christine Cavalcanti-Proença; Marion Marchand; Martine Vaxillaire; Guillaume Charpentier; Marjo-Riitta Jarvelin; Jean Tichet; Beverley Balkau; Michel Marre; Claire Lévy-Marchal; Kristine Faerch; Knut Borch-Johnsen; Torben Jørgensen; Sten Madsbad; Pernille Poulsen; Allan Vaag; Christian Dina; Torben Hansen; Oluf Pedersen; Philippe Froguel; Thomas Sparsø; Amélie Bonnefond; Ehm Andersson; Nabila Bouatia-Naji; Johan Holmkvist; Lise Wegner; Niels Grarup; Anette P Gjesing; Karina Banasik; Christine Cavalcanti-Proença; Marion Marchand; Martine Vaxillaire; Guillaume Charpentier; Marjo-Riitta Jarvelin; Jean Tichet; Beverley Balkau; Michel Marre; Claire Lévy-Marchal; Kristine Faerch; Knut Borch-Johnsen; Torben Jørgensen; Sten Madsbad; Pernille Poulsen; Allan Vaag; Christian Dina; Torben Hansen; Oluf Pedersen; Philippe Froguel

doi:10.2337/db08-1660

G-allele of intronic rs10830963 in MTNR1B confers increased risk of impaired fasting glycemia and type 2 diabetes through an impaired glucose-stimulated insulin release: studies involving 19,605 Europeans

Thomas Sparsø, Amélie Bonnefond, Ehm Andersson, Nabila Bouatia-Naji, Johan Holmkvist, Lise Wegner, Niels Grarup, Anette P Gjesing, Karina Banasik, Christine Cavalcanti-Proença, Marion Marchand, Martine Vaxillaire, Guillaume Charpentier, Marjo-Riitta Jarvelin, Jean Tichet, Beverley Balkau, Michel Marre, Claire Lévy-Marchal, Kristine Faerch, Knut Borch-JohnsenTorben Jørgensen, Sten Madsbad, Pernille Poulsen, Allan Vaag, Christian Dina, Torben Hansen, Oluf Pedersen, Philippe Froguel, Thomas Sparsø, Amélie Bonnefond, Ehm Andersson, Nabila Bouatia-Naji, Johan Holmkvist, Lise Wegner, Niels Grarup, Anette P Gjesing, Karina Banasik, Christine Cavalcanti-Proença, Marion Marchand, Martine Vaxillaire, Guillaume Charpentier, Marjo-Riitta Jarvelin, Jean Tichet, Beverley Balkau, Michel Marre, Claire Lévy-Marchal, Kristine Faerch, Knut Borch-Johnsen, Torben Jørgensen, Sten Madsbad, Pernille Poulsen, Allan Vaag, Christian Dina, Torben Hansen, Oluf Pedersen, Philippe Froguel

107 Citations (Scopus)

Abstract

OBJECTIVE: Genome-wide association studies have identified several variants within the MTNR1B locus that are associated with fasting plasma glucose (FPG) and type 2 diabetes. We refined the association signal by direct genotyping and examined for associations of the variant displaying the most independent effect on FPG with isolated impaired fasting glycemia (i-IFG), isolated impaired glucose tolerance (i-IGT), type 2 diabetes, and measures of insulin release and peripheral and hepatic insulin sensitivity. RESEARCH DESIGN AND METHODS: We examined European-descent participants in the Inter99 study (n = 5,553), in a sample of young healthy Danes (n = 372), in Danish twins (n = 77 elderly and n = 97 young), in additional Danish type 2 diabetic patients (n = 1,626) and control subjects (n = 505), in the Data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study (n = 4,656), in the North Finland Birth Cohort 86 (n = 5,258), and in the Haguenau study (n = 1,461). RESULTS: The MTNR1B intronic variant, rs10830963, carried most of the effect on FPG and showed the strongest association with FPG (combined P = 5.3 x 10(-31)) and type 2 diabetes. The rs10830963 G-allele increased the risk of i-IFG (odds ratio [OR] 1.64, P = 5.5 x 10(-11)) but not i-IGT. The G-allele was associated with a decreased insulin release after oral and intravenous glucose challenges (P < 0.01) but not after injection of tolbutamide. In elderly twins, the G-allele associated with hepatic insulin resistance (P = 0.017). CONCLUSIONS: The G-allele of MTNR1B rs10830963 increases risk of type 2 diabetes through a state of i-IFG and not through i-IGT. The same allele associates with estimates of beta-cell dysfunction and hepatic insulin resistance.

Original language	English
Journal	Diabetes
Volume	58
Issue number	6
Pages (from-to)	1450-6
Number of pages	6
ISSN	0012-1797
DOIs	https://doi.org/10.2337/db08-1660 https://doi.org/10.2337/db08-1660
Publication status	Published - 2009

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Sparsø, T., Bonnefond, A., Andersson, E., Bouatia-Naji, N., Holmkvist, J., Wegner, L., Grarup, N., Gjesing, A. P., Banasik, K., Cavalcanti-Proença, C., Marchand, M., Vaxillaire, M., Charpentier, G., Jarvelin, M-R., Tichet, J., Balkau, B., Marre, M., Lévy-Marchal, C., Faerch, K., ... Froguel, P. (2009). G-allele of intronic rs10830963 in MTNR1B confers increased risk of impaired fasting glycemia and type 2 diabetes through an impaired glucose-stimulated insulin release: studies involving 19,605 Europeans. Diabetes, 58(6), 1450-6. https://doi.org/10.2337/db08-1660, https://doi.org/10.2337/db08-1660

G-allele of intronic rs10830963 in MTNR1B confers increased risk of impaired fasting glycemia and type 2 diabetes through an impaired glucose-stimulated insulin release: studies involving 19,605 Europeans. / Sparsø, Thomas; Bonnefond, Amélie; Andersson, Ehm et al.

In: Diabetes, Vol. 58, No. 6, 2009, p. 1450-6.

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

Sparsø, T, Bonnefond, A, Andersson, E, Bouatia-Naji, N, Holmkvist, J, Wegner, L, Grarup, N , Gjesing, AP , Banasik, K, Cavalcanti-Proença, C, Marchand, M, Vaxillaire, M, Charpentier, G, Jarvelin, M-R, Tichet, J, Balkau, B, Marre, M, Lévy-Marchal, C, Faerch, K, Borch-Johnsen, K, Jørgensen, T, Madsbad, S, Poulsen, P, Vaag, A, Dina, C, Hansen, T, Pedersen, O, Froguel, P, Sparsø, T, Bonnefond, A, Andersson, E, Bouatia-Naji, N, Holmkvist, J, Wegner, L, Grarup, N, Gjesing, AP, Banasik, K, Cavalcanti-Proença, C, Marchand, M, Vaxillaire, M, Charpentier, G, Jarvelin, M-R, Tichet, J, Balkau, B, Marre, M, Lévy-Marchal, C, Faerch, K, Borch-Johnsen, K, Jørgensen, T, Madsbad, S, Poulsen, P, Vaag, A, Dina, C, Hansen, T, Pedersen, O & Froguel, P 2009, 'G-allele of intronic rs10830963 in MTNR1B confers increased risk of impaired fasting glycemia and type 2 diabetes through an impaired glucose-stimulated insulin release: studies involving 19,605 Europeans', Diabetes, vol. 58, no. 6, pp. 1450-6. https://doi.org/10.2337/db08-1660, https://doi.org/10.2337/db08-1660

Sparsø T, Bonnefond A, Andersson E, Bouatia-Naji N, Holmkvist J, Wegner L et al. G-allele of intronic rs10830963 in MTNR1B confers increased risk of impaired fasting glycemia and type 2 diabetes through an impaired glucose-stimulated insulin release: studies involving 19,605 Europeans. Diabetes. 2009;58(6):1450-6. doi: 10.2337/db08-1660, http://dx.doi.org/10.2337/db08-1660

@article{88e4bbf0333111df8ed1000ea68e967b,

title = "G-allele of intronic rs10830963 in MTNR1B confers increased risk of impaired fasting glycemia and type 2 diabetes through an impaired glucose-stimulated insulin release: studies involving 19,605 Europeans",

abstract = "OBJECTIVE: Genome-wide association studies have identified several variants within the MTNR1B locus that are associated with fasting plasma glucose (FPG) and type 2 diabetes. We refined the association signal by direct genotyping and examined for associations of the variant displaying the most independent effect on FPG with isolated impaired fasting glycemia (i-IFG), isolated impaired glucose tolerance (i-IGT), type 2 diabetes, and measures of insulin release and peripheral and hepatic insulin sensitivity. RESEARCH DESIGN AND METHODS: We examined European-descent participants in the Inter99 study (n = 5,553), in a sample of young healthy Danes (n = 372), in Danish twins (n = 77 elderly and n = 97 young), in additional Danish type 2 diabetic patients (n = 1,626) and control subjects (n = 505), in the Data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study (n = 4,656), in the North Finland Birth Cohort 86 (n = 5,258), and in the Haguenau study (n = 1,461). RESULTS: The MTNR1B intronic variant, rs10830963, carried most of the effect on FPG and showed the strongest association with FPG (combined P = 5.3 x 10(-31)) and type 2 diabetes. The rs10830963 G-allele increased the risk of i-IFG (odds ratio [OR] 1.64, P = 5.5 x 10(-11)) but not i-IGT. The G-allele was associated with a decreased insulin release after oral and intravenous glucose challenges (P < 0.01) but not after injection of tolbutamide. In elderly twins, the G-allele associated with hepatic insulin resistance (P = 0.017). CONCLUSIONS: The G-allele of MTNR1B rs10830963 increases risk of type 2 diabetes through a state of i-IFG and not through i-IGT. The same allele associates with estimates of beta-cell dysfunction and hepatic insulin resistance.",

author = "Thomas Spars{\o} and Am{\'e}lie Bonnefond and Ehm Andersson and Nabila Bouatia-Naji and Johan Holmkvist and Lise Wegner and Niels Grarup and Gjesing, {Anette P} and Karina Banasik and Christine Cavalcanti-Proen{\c c}a and Marion Marchand and Martine Vaxillaire and Guillaume Charpentier and Marjo-Riitta Jarvelin and Jean Tichet and Beverley Balkau and Michel Marre and Claire L{\'e}vy-Marchal and Kristine Faerch and Knut Borch-Johnsen and Torben J{\o}rgensen and Sten Madsbad and Pernille Poulsen and Allan Vaag and Christian Dina and Torben Hansen and Oluf Pedersen and Philippe Froguel and Thomas Spars{\o} and Am{\'e}lie Bonnefond and Ehm Andersson and Nabila Bouatia-Naji and Johan Holmkvist and Lise Wegner and Niels Grarup and Gjesing, {Anette P} and Karina Banasik and Christine Cavalcanti-Proen{\c c}a and Marion Marchand and Martine Vaxillaire and Guillaume Charpentier and Marjo-Riitta Jarvelin and Jean Tichet and Beverley Balkau and Michel Marre and Claire L{\'e}vy-Marchal and Kristine Faerch and Knut Borch-Johnsen and Torben J{\o}rgensen and Sten Madsbad and Pernille Poulsen and Allan Vaag and Christian Dina and Torben Hansen and Oluf Pedersen and Philippe Froguel",

note = "Keywords: Adult; Aged; Blood Glucose; Denmark; Diabetes Mellitus, Type 2; European Continental Ancestry Group; Genetic Variation; Glucose; Humans; Insulin; Insulin Resistance; Insulin-Secreting Cells; Introns; Liver; Quantitative Trait Loci; Receptor, Melatonin, MT1; Risk Factors; Twins",

year = "2009",

doi = "10.2337/db08-1660",

language = "English",

volume = "58",

pages = "1450--6",

journal = "Diabetes",

issn = "0012-1797",

publisher = "American Diabetes Association",

number = "6",

}

TY - JOUR

T1 - G-allele of intronic rs10830963 in MTNR1B confers increased risk of impaired fasting glycemia and type 2 diabetes through an impaired glucose-stimulated insulin release: studies involving 19,605 Europeans

AU - Sparsø, Thomas

AU - Bonnefond, Amélie

AU - Andersson, Ehm

AU - Bouatia-Naji, Nabila

AU - Holmkvist, Johan

AU - Wegner, Lise

AU - Grarup, Niels

AU - Gjesing, Anette P

AU - Banasik, Karina

AU - Cavalcanti-Proença, Christine

AU - Marchand, Marion

AU - Vaxillaire, Martine

AU - Charpentier, Guillaume

AU - Jarvelin, Marjo-Riitta

AU - Tichet, Jean

AU - Balkau, Beverley

AU - Marre, Michel

AU - Lévy-Marchal, Claire

AU - Faerch, Kristine

AU - Borch-Johnsen, Knut

AU - Jørgensen, Torben

AU - Madsbad, Sten

AU - Poulsen, Pernille

AU - Vaag, Allan

AU - Dina, Christian

AU - Hansen, Torben

AU - Pedersen, Oluf

AU - Froguel, Philippe

AU - Sparsø, Thomas

AU - Bonnefond, Amélie

AU - Andersson, Ehm

AU - Bouatia-Naji, Nabila

AU - Holmkvist, Johan

AU - Wegner, Lise

AU - Grarup, Niels

AU - Gjesing, Anette P

AU - Banasik, Karina

AU - Cavalcanti-Proença, Christine

AU - Marchand, Marion

AU - Vaxillaire, Martine

AU - Charpentier, Guillaume

AU - Jarvelin, Marjo-Riitta

AU - Tichet, Jean

AU - Balkau, Beverley

AU - Marre, Michel

AU - Lévy-Marchal, Claire

AU - Faerch, Kristine

AU - Borch-Johnsen, Knut

AU - Jørgensen, Torben

AU - Madsbad, Sten

AU - Poulsen, Pernille

AU - Vaag, Allan

AU - Dina, Christian

AU - Hansen, Torben

AU - Pedersen, Oluf

AU - Froguel, Philippe

N1 - Keywords: Adult; Aged; Blood Glucose; Denmark; Diabetes Mellitus, Type 2; European Continental Ancestry Group; Genetic Variation; Glucose; Humans; Insulin; Insulin Resistance; Insulin-Secreting Cells; Introns; Liver; Quantitative Trait Loci; Receptor, Melatonin, MT1; Risk Factors; Twins

PY - 2009

Y1 - 2009

N2 - OBJECTIVE: Genome-wide association studies have identified several variants within the MTNR1B locus that are associated with fasting plasma glucose (FPG) and type 2 diabetes. We refined the association signal by direct genotyping and examined for associations of the variant displaying the most independent effect on FPG with isolated impaired fasting glycemia (i-IFG), isolated impaired glucose tolerance (i-IGT), type 2 diabetes, and measures of insulin release and peripheral and hepatic insulin sensitivity. RESEARCH DESIGN AND METHODS: We examined European-descent participants in the Inter99 study (n = 5,553), in a sample of young healthy Danes (n = 372), in Danish twins (n = 77 elderly and n = 97 young), in additional Danish type 2 diabetic patients (n = 1,626) and control subjects (n = 505), in the Data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study (n = 4,656), in the North Finland Birth Cohort 86 (n = 5,258), and in the Haguenau study (n = 1,461). RESULTS: The MTNR1B intronic variant, rs10830963, carried most of the effect on FPG and showed the strongest association with FPG (combined P = 5.3 x 10(-31)) and type 2 diabetes. The rs10830963 G-allele increased the risk of i-IFG (odds ratio [OR] 1.64, P = 5.5 x 10(-11)) but not i-IGT. The G-allele was associated with a decreased insulin release after oral and intravenous glucose challenges (P < 0.01) but not after injection of tolbutamide. In elderly twins, the G-allele associated with hepatic insulin resistance (P = 0.017). CONCLUSIONS: The G-allele of MTNR1B rs10830963 increases risk of type 2 diabetes through a state of i-IFG and not through i-IGT. The same allele associates with estimates of beta-cell dysfunction and hepatic insulin resistance.

AB - OBJECTIVE: Genome-wide association studies have identified several variants within the MTNR1B locus that are associated with fasting plasma glucose (FPG) and type 2 diabetes. We refined the association signal by direct genotyping and examined for associations of the variant displaying the most independent effect on FPG with isolated impaired fasting glycemia (i-IFG), isolated impaired glucose tolerance (i-IGT), type 2 diabetes, and measures of insulin release and peripheral and hepatic insulin sensitivity. RESEARCH DESIGN AND METHODS: We examined European-descent participants in the Inter99 study (n = 5,553), in a sample of young healthy Danes (n = 372), in Danish twins (n = 77 elderly and n = 97 young), in additional Danish type 2 diabetic patients (n = 1,626) and control subjects (n = 505), in the Data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study (n = 4,656), in the North Finland Birth Cohort 86 (n = 5,258), and in the Haguenau study (n = 1,461). RESULTS: The MTNR1B intronic variant, rs10830963, carried most of the effect on FPG and showed the strongest association with FPG (combined P = 5.3 x 10(-31)) and type 2 diabetes. The rs10830963 G-allele increased the risk of i-IFG (odds ratio [OR] 1.64, P = 5.5 x 10(-11)) but not i-IGT. The G-allele was associated with a decreased insulin release after oral and intravenous glucose challenges (P < 0.01) but not after injection of tolbutamide. In elderly twins, the G-allele associated with hepatic insulin resistance (P = 0.017). CONCLUSIONS: The G-allele of MTNR1B rs10830963 increases risk of type 2 diabetes through a state of i-IFG and not through i-IGT. The same allele associates with estimates of beta-cell dysfunction and hepatic insulin resistance.

U2 - 10.2337/db08-1660

DO - 10.2337/db08-1660

M3 - Journal article

C2 - 19324940

SN - 0012-1797

VL - 58

SP - 1450

EP - 1456

JO - Diabetes

JF - Diabetes

IS - 6

ER -