A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes

Ida Moltke; Niels Grarup; Marit E. Jørgensen; Peter Bjerregaard; Jonas Thue Treebak; Matteo Fumagalli; Thorfinn Sand Korneliussen; Marianne Agerholm Andersen; Thomas Svava Nielsen; Nikolaj Thure Krarup; Anette Marianne Prior Gjesing; Juleen R. Zierath; Allan Linneberg; Xueli Wu; Guangqing Sun; Xin Jin; Jumana Al-Aama; Jun Wang; Knut Borch-Johnsen; Oluf Pedersen; Rasmus Nielsen; Anders Albrechtsen; Torben Hansen

doi:10.1038/nature13425

A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes

Ida Moltke, Niels Grarup, Marit E. Jørgensen, Peter Bjerregaard, Jonas Thue Treebak, Matteo Fumagalli, Thorfinn Sand Korneliussen, Marianne Agerholm Andersen, Thomas Svava Nielsen, Nikolaj Thure Krarup, Anette Marianne Prior Gjesing, Juleen R. Zierath, Allan Linneberg, Xueli Wu, Guangqing Sun, Xin Jin, Jumana Al-Aama, Jun Wang, Knut Borch-Johnsen, Oluf PedersenRasmus Nielsen, Anders Albrechtsen, Torben Hansen

211 Citations (Scopus)

Abstract

TheGreenlandic population, a small and historically isolated founder population comprising about 57,000 inhabitants, has experienced a dramatic increase in type 2 diabetes (T2D) prevalence during the past 25 years ¹.Motivated by this,we performedassociationmapping ofT2Drelated quantitative traits in up to 2,575 Greenlandic individuals without knowndiabetes. Using array-based genotyping and exome sequencing, we discovered a nonsense p.Arg684Ter variant (in which arginine is replaced by a termination codon) in the geneTBC1D4 with an allele frequency of 17%.Herewe show that homozygous carriers of this variant havemarkedlyhigherconcentrationsofplasmaglucose(β53.8mmol l^-1, P 52.5310^-35) and serum insulin (β5165pmoll^-1,P51. 5310^-20) 2 hours after an oral glucose load compared with individuals with other genotypes (both non-carriers and heterozygous carriers). Furthermore, homozygous carriers have marginally lower concentrations of fasting plasma glucose (β520.18 mmoll^-1,P51.1310^-6) andfasting serum insulin (β528.3pmoll^-1, P50.0014), and their T2D risk is markedly increased (odds ratio (OR)510.3,P 51.6310^-24). Heterozygous carriers have amoderately higher plasmaglucose concentration 2 hours after an oral glucose load than non-carriers (β50.43 mmoll ^-1,P 5 5.3310^-5). Analyses of skeletal muscle biopsies showed lower messenger RNA and protein levels of the long isoform of TBC1D4, and lower muscle protein levels of the glucose transporter GLUT4, with increasing number of p.Arg684Ter alleles. These findings are concomitant with a severely decreased insulin-stimulated glucose uptake inmuscle, leading to postprandial hyperglycaemia, impaired glucose tolerance and T2D. The observed effect sizes are several times larger than any previous findings in large-scale genome-wide association studies of these traits2-4 and constitute further proof of the value of conducting genetic association studies outside the traditional setting of large homogeneous populations.

Original language	English
Journal	Nature
Volume	512
Issue number	7513
Pages (from-to)	190-193
Number of pages	4
ISSN	0028-0836
DOIs	https://doi.org/10.1038/nature13425
Publication status	Published - 14 Aug 2014

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Moltke, I., Grarup, N., Jørgensen, M. E., Bjerregaard, P., Treebak, J. T., Fumagalli, M., Korneliussen, T. S., Andersen, M. A., Nielsen, T. S., Krarup, N. T., Gjesing, A. M. P., Zierath, J. R., Linneberg, A., Wu, X., Sun, G., Jin, X., Al-Aama, J., Wang, J., Borch-Johnsen, K., ... Hansen, T. (2014). A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes. Nature, 512(7513), 190-193. https://doi.org/10.1038/nature13425

Moltke, I , Grarup, N, Jørgensen, ME, Bjerregaard, P, Treebak, JT, Fumagalli, M, Korneliussen, TS, Andersen, MA, Nielsen, TS, Krarup, NT, Gjesing, AMP , Zierath, JR , Linneberg, A, Wu, X, Sun, G, Jin, X, Al-Aama, J, Wang, J, Borch-Johnsen, K, Pedersen, O, Nielsen, R, Albrechtsen, A & Hansen, T 2014, 'A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes', Nature, vol. 512, no. 7513, pp. 190-193. https://doi.org/10.1038/nature13425

@article{4019b81e41ac410b8984f45f65a27031,

title = "A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes",

abstract = "TheGreenlandic population, a small and historically isolated founder population comprising about 57,000 inhabitants, has experienced a dramatic increase in type 2 diabetes (T2D) prevalence during the past 25 years 1.Motivated by this,we performedassociationmapping ofT2Drelated quantitative traits in up to 2,575 Greenlandic individuals without knowndiabetes. Using array-based genotyping and exome sequencing, we discovered a nonsense p.Arg684Ter variant (in which arginine is replaced by a termination codon) in the geneTBC1D4 with an allele frequency of 17%.Herewe show that homozygous carriers of this variant havemarkedlyhigherconcentrationsofplasmaglucose(β53.8mmol l-1, P 52.5310-35) and serum insulin (β5165pmoll-1,P51. 5310-20) 2 hours after an oral glucose load compared with individuals with other genotypes (both non-carriers and heterozygous carriers). Furthermore, homozygous carriers have marginally lower concentrations of fasting plasma glucose (β520.18 mmoll-1,P51.1310-6) andfasting serum insulin (β528.3pmoll-1, P50.0014), and their T2D risk is markedly increased (odds ratio (OR)510.3,P 51.6310-24). Heterozygous carriers have amoderately higher plasmaglucose concentration 2 hours after an oral glucose load than non-carriers (β50.43 mmoll -1,P 5 5.3310-5). Analyses of skeletal muscle biopsies showed lower messenger RNA and protein levels of the long isoform of TBC1D4, and lower muscle protein levels of the glucose transporter GLUT4, with increasing number of p.Arg684Ter alleles. These findings are concomitant with a severely decreased insulin-stimulated glucose uptake inmuscle, leading to postprandial hyperglycaemia, impaired glucose tolerance and T2D. The observed effect sizes are several times larger than any previous findings in large-scale genome-wide association studies of these traits2-4 and constitute further proof of the value of conducting genetic association studies outside the traditional setting of large homogeneous populations.",

author = "Ida Moltke and Niels Grarup and J{\o}rgensen, {Marit E.} and Peter Bjerregaard and Treebak, {Jonas Thue} and Matteo Fumagalli and Korneliussen, {Thorfinn Sand} and Andersen, {Marianne Agerholm} and Nielsen, {Thomas Svava} and Krarup, {Nikolaj Thure} and Gjesing, {Anette Marianne Prior} and Zierath, {Juleen R.} and Allan Linneberg and Xueli Wu and Guangqing Sun and Xin Jin and Jumana Al-Aama and Jun Wang and Knut Borch-Johnsen and Oluf Pedersen and Rasmus Nielsen and Anders Albrechtsen and Torben Hansen",

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doi = "10.1038/nature13425",

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T1 - A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes

AU - Moltke, Ida

AU - Grarup, Niels

AU - Jørgensen, Marit E.

AU - Bjerregaard, Peter

AU - Treebak, Jonas Thue

AU - Fumagalli, Matteo

AU - Korneliussen, Thorfinn Sand

AU - Andersen, Marianne Agerholm

AU - Nielsen, Thomas Svava

AU - Krarup, Nikolaj Thure

AU - Gjesing, Anette Marianne Prior

AU - Zierath, Juleen R.

AU - Linneberg, Allan

AU - Wu, Xueli

AU - Sun, Guangqing

AU - Jin, Xin

AU - Al-Aama, Jumana

AU - Wang, Jun

AU - Borch-Johnsen, Knut

AU - Pedersen, Oluf

AU - Nielsen, Rasmus

AU - Albrechtsen, Anders

AU - Hansen, Torben

PY - 2014/8/14

Y1 - 2014/8/14

N2 - TheGreenlandic population, a small and historically isolated founder population comprising about 57,000 inhabitants, has experienced a dramatic increase in type 2 diabetes (T2D) prevalence during the past 25 years 1.Motivated by this,we performedassociationmapping ofT2Drelated quantitative traits in up to 2,575 Greenlandic individuals without knowndiabetes. Using array-based genotyping and exome sequencing, we discovered a nonsense p.Arg684Ter variant (in which arginine is replaced by a termination codon) in the geneTBC1D4 with an allele frequency of 17%.Herewe show that homozygous carriers of this variant havemarkedlyhigherconcentrationsofplasmaglucose(β53.8mmol l-1, P 52.5310-35) and serum insulin (β5165pmoll-1,P51. 5310-20) 2 hours after an oral glucose load compared with individuals with other genotypes (both non-carriers and heterozygous carriers). Furthermore, homozygous carriers have marginally lower concentrations of fasting plasma glucose (β520.18 mmoll-1,P51.1310-6) andfasting serum insulin (β528.3pmoll-1, P50.0014), and their T2D risk is markedly increased (odds ratio (OR)510.3,P 51.6310-24). Heterozygous carriers have amoderately higher plasmaglucose concentration 2 hours after an oral glucose load than non-carriers (β50.43 mmoll -1,P 5 5.3310-5). Analyses of skeletal muscle biopsies showed lower messenger RNA and protein levels of the long isoform of TBC1D4, and lower muscle protein levels of the glucose transporter GLUT4, with increasing number of p.Arg684Ter alleles. These findings are concomitant with a severely decreased insulin-stimulated glucose uptake inmuscle, leading to postprandial hyperglycaemia, impaired glucose tolerance and T2D. The observed effect sizes are several times larger than any previous findings in large-scale genome-wide association studies of these traits2-4 and constitute further proof of the value of conducting genetic association studies outside the traditional setting of large homogeneous populations.

AB - TheGreenlandic population, a small and historically isolated founder population comprising about 57,000 inhabitants, has experienced a dramatic increase in type 2 diabetes (T2D) prevalence during the past 25 years 1.Motivated by this,we performedassociationmapping ofT2Drelated quantitative traits in up to 2,575 Greenlandic individuals without knowndiabetes. Using array-based genotyping and exome sequencing, we discovered a nonsense p.Arg684Ter variant (in which arginine is replaced by a termination codon) in the geneTBC1D4 with an allele frequency of 17%.Herewe show that homozygous carriers of this variant havemarkedlyhigherconcentrationsofplasmaglucose(β53.8mmol l-1, P 52.5310-35) and serum insulin (β5165pmoll-1,P51. 5310-20) 2 hours after an oral glucose load compared with individuals with other genotypes (both non-carriers and heterozygous carriers). Furthermore, homozygous carriers have marginally lower concentrations of fasting plasma glucose (β520.18 mmoll-1,P51.1310-6) andfasting serum insulin (β528.3pmoll-1, P50.0014), and their T2D risk is markedly increased (odds ratio (OR)510.3,P 51.6310-24). Heterozygous carriers have amoderately higher plasmaglucose concentration 2 hours after an oral glucose load than non-carriers (β50.43 mmoll -1,P 5 5.3310-5). Analyses of skeletal muscle biopsies showed lower messenger RNA and protein levels of the long isoform of TBC1D4, and lower muscle protein levels of the glucose transporter GLUT4, with increasing number of p.Arg684Ter alleles. These findings are concomitant with a severely decreased insulin-stimulated glucose uptake inmuscle, leading to postprandial hyperglycaemia, impaired glucose tolerance and T2D. The observed effect sizes are several times larger than any previous findings in large-scale genome-wide association studies of these traits2-4 and constitute further proof of the value of conducting genetic association studies outside the traditional setting of large homogeneous populations.

U2 - 10.1038/nature13425

DO - 10.1038/nature13425

M3 - Letter

C2 - 25043022

SN - 0028-0836

VL - 512

SP - 190

EP - 193

JO - Nature

JF - Nature

IS - 7513

ER -

A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes

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