The CTRB1/2 locus affects diabetes susceptibility and treatment via the incretin pathway

Leen M 't Hart; Andreas Fritsche; Giel Nijpels; Nienke van Leeuwen; Louise A Donnelly; Jacqueline M Dekker; Marjan Alssema; Joao Fadista; Françoise Carlotti; Anette P Gjesing; Colin N A Palmer; Timon W van Haeften; Silke A Herzberg-Schäfer; Annemarie M C Simonis-Bik; Jeanine J Houwing-Duistermaat; Quinta Helmer; Joris Deelen; Bruno Guigas; Torben Hansen; Fausto Machicao; Gonneke Willemsen; Robert J Heine; Mark Kramer; Jens Juul Holst; Eelco J P de Koning; Hans-Ulrich Häring; Oluf Pedersen; Leif Groop; Eco J C de Geus; P Eline Slagboom; Dorret I Boomsma; Elisabeth M W Eekhoff; Ewan R Pearson; Michaela Diamant

doi:10.2337/db13-0227

The CTRB1/2 locus affects diabetes susceptibility and treatment via the incretin pathway

Leen M 't Hart, Andreas Fritsche, Giel Nijpels, Nienke van Leeuwen, Louise A Donnelly, Jacqueline M Dekker, Marjan Alssema, Joao Fadista, Françoise Carlotti, Anette P Gjesing, Colin N A Palmer, Timon W van Haeften, Silke A Herzberg-Schäfer, Annemarie M C Simonis-Bik, Jeanine J Houwing-Duistermaat, Quinta Helmer, Joris Deelen, Bruno Guigas, Torben Hansen, Fausto MachicaoGonneke Willemsen, Robert J Heine, Mark Kramer, Jens Juul Holst, Eelco J P de Koning, Hans-Ulrich Häring, Oluf Pedersen, Leif Groop, Eco J C de Geus, P Eline Slagboom, Dorret I Boomsma, Elisabeth M W Eekhoff, Ewan R Pearson, Michaela Diamant

60 Citationer (Scopus)

Abstract

The incretin hormone glucagon-like peptide 1 (GLP-1) promotes glucose homeostasis and enhances b-cell function. GLP-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, which inhibit the physiological inactivation of endogenous GLP-1, are used for the treatment of type 2 diabetes. Using the Metabochip, we identified three novel genetic loci with large effects (3040%) on GLP-1stimulated insulin secretion during hyperglycemic clamps in nondiabetic Caucasian individuals (TMEM114; CHST3 and CTRB1/2; n = 232; all P ≤8.8 × 10^-7). rs7202877 near CTRB1/2, a known diabetes risk locus, also associated with an absolute 0.51 ± 0.16% (5.6 ± 1.7 mmol/mol) lower A1C response to DPP-4 inhibitor treatment in G-allele carriers, but there was no effect on GLP-1 RA treatment in type 2 diabetic patients (n = 527). Furthermore, in pancreatic tissue, we show that rs7202877 acts as expression quantitative trait locus for CTRB1 and CTRB2, encoding chymotrypsinogen, and increases fecal chymotrypsin activity in healthy carriers. Chymotrypsin is one of the most abundant digestive enzymes in the gut where it cleaves food proteins into smaller peptide fragments. Our data identify chymotrypsin in the regulation of the incretin pathway, development of diabetes, and response to DPP-4 inhibitor treatment.

Originalsprog	Engelsk
Tidsskrift	Diabetes
Vol/bind	62
Udgave nummer	9
Sider (fra-til)	3275-3281
Antal sider	6
ISSN	0012-1797
DOI	https://doi.org/10.2337/db13-0227
Status	Udgivet - sep. 2013

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't Hart, L. M., Fritsche, A., Nijpels, G., van Leeuwen, N., Donnelly, L. A., Dekker, J. M., Alssema, M., Fadista, J., Carlotti, F., Gjesing, A. P., Palmer, C. N. A., van Haeften, T. W., Herzberg-Schäfer, S. A., Simonis-Bik, A. M. C., Houwing-Duistermaat, J. J., Helmer, Q., Deelen, J., Guigas, B., Hansen, T., ... Diamant, M. (2013). The CTRB1/2 locus affects diabetes susceptibility and treatment via the incretin pathway. Diabetes, 62(9), 3275-3281. https://doi.org/10.2337/db13-0227

't Hart, LM, Fritsche, A, Nijpels, G, van Leeuwen, N, Donnelly, LA, Dekker, JM, Alssema, M, Fadista, J, Carlotti, F, Gjesing, AP, Palmer, CNA, van Haeften, TW, Herzberg-Schäfer, SA, Simonis-Bik, AMC, Houwing-Duistermaat, JJ, Helmer, Q, Deelen, J, Guigas, B, Hansen, T, Machicao, F, Willemsen, G, Heine, RJ, Kramer, M, Holst, JJ, de Koning, EJP, Häring, H-U, Pedersen, O, Groop, L, de Geus, EJC, Slagboom, PE, Boomsma, DI, Eekhoff, EMW, Pearson, ER & Diamant, M 2013, 'The CTRB1/2 locus affects diabetes susceptibility and treatment via the incretin pathway', Diabetes, bind 62, nr. 9, s. 3275-3281. https://doi.org/10.2337/db13-0227

@article{392eb864396949b1b185bb777d949d41,

title = "The CTRB1/2 locus affects diabetes susceptibility and treatment via the incretin pathway",

abstract = "The incretin hormone glucagon-like peptide 1 (GLP-1) promotes glucose homeostasis and enhances b-cell function. GLP-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, which inhibit the physiological inactivation of endogenous GLP-1, are used for the treatment of type 2 diabetes. Using the Metabochip, we identified three novel genetic loci with large effects (3040%) on GLP-1stimulated insulin secretion during hyperglycemic clamps in nondiabetic Caucasian individuals (TMEM114; CHST3 and CTRB1/2; n = 232; all P ≤8.8 × 10-7). rs7202877 near CTRB1/2, a known diabetes risk locus, also associated with an absolute 0.51 ± 0.16% (5.6 ± 1.7 mmol/mol) lower A1C response to DPP-4 inhibitor treatment in G-allele carriers, but there was no effect on GLP-1 RA treatment in type 2 diabetic patients (n = 527). Furthermore, in pancreatic tissue, we show that rs7202877 acts as expression quantitative trait locus for CTRB1 and CTRB2, encoding chymotrypsinogen, and increases fecal chymotrypsin activity in healthy carriers. Chymotrypsin is one of the most abundant digestive enzymes in the gut where it cleaves food proteins into smaller peptide fragments. Our data identify chymotrypsin in the regulation of the incretin pathway, development of diabetes, and response to DPP-4 inhibitor treatment.",

author = "{'t Hart}, {Leen M} and Andreas Fritsche and Giel Nijpels and {van Leeuwen}, Nienke and Donnelly, {Louise A} and Dekker, {Jacqueline M} and Marjan Alssema and Joao Fadista and Fran{\c c}oise Carlotti and Gjesing, {Anette P} and Palmer, {Colin N A} and {van Haeften}, {Timon W} and Herzberg-Sch{\"a}fer, {Silke A} and Simonis-Bik, {Annemarie M C} and Houwing-Duistermaat, {Jeanine J} and Quinta Helmer and Joris Deelen and Bruno Guigas and Torben Hansen and Fausto Machicao and Gonneke Willemsen and Heine, {Robert J} and Mark Kramer and Holst, {Jens Juul} and {de Koning}, {Eelco J P} and Hans-Ulrich H{\"a}ring and Oluf Pedersen and Leif Groop and {de Geus}, {Eco J C} and Slagboom, {P Eline} and Boomsma, {Dorret I} and Eekhoff, {Elisabeth M W} and Pearson, {Ewan R} and Michaela Diamant",

year = "2013",

month = sep,

doi = "10.2337/db13-0227",

language = "English",

volume = "62",

pages = "3275--3281",

journal = "Diabetes",

issn = "0012-1797",

publisher = "American Diabetes Association",

number = "9",

}

TY - JOUR

T1 - The CTRB1/2 locus affects diabetes susceptibility and treatment via the incretin pathway

AU - 't Hart, Leen M

AU - Fritsche, Andreas

AU - Nijpels, Giel

AU - van Leeuwen, Nienke

AU - Donnelly, Louise A

AU - Dekker, Jacqueline M

AU - Alssema, Marjan

AU - Fadista, Joao

AU - Carlotti, Françoise

AU - Gjesing, Anette P

AU - Palmer, Colin N A

AU - van Haeften, Timon W

AU - Herzberg-Schäfer, Silke A

AU - Simonis-Bik, Annemarie M C

AU - Houwing-Duistermaat, Jeanine J

AU - Helmer, Quinta

AU - Deelen, Joris

AU - Guigas, Bruno

AU - Hansen, Torben

AU - Machicao, Fausto

AU - Willemsen, Gonneke

AU - Heine, Robert J

AU - Kramer, Mark

AU - Holst, Jens Juul

AU - de Koning, Eelco J P

AU - Häring, Hans-Ulrich

AU - Pedersen, Oluf

AU - Groop, Leif

AU - de Geus, Eco J C

AU - Slagboom, P Eline

AU - Boomsma, Dorret I

AU - Eekhoff, Elisabeth M W

AU - Pearson, Ewan R

AU - Diamant, Michaela

PY - 2013/9

Y1 - 2013/9

N2 - The incretin hormone glucagon-like peptide 1 (GLP-1) promotes glucose homeostasis and enhances b-cell function. GLP-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, which inhibit the physiological inactivation of endogenous GLP-1, are used for the treatment of type 2 diabetes. Using the Metabochip, we identified three novel genetic loci with large effects (3040%) on GLP-1stimulated insulin secretion during hyperglycemic clamps in nondiabetic Caucasian individuals (TMEM114; CHST3 and CTRB1/2; n = 232; all P ≤8.8 × 10-7). rs7202877 near CTRB1/2, a known diabetes risk locus, also associated with an absolute 0.51 ± 0.16% (5.6 ± 1.7 mmol/mol) lower A1C response to DPP-4 inhibitor treatment in G-allele carriers, but there was no effect on GLP-1 RA treatment in type 2 diabetic patients (n = 527). Furthermore, in pancreatic tissue, we show that rs7202877 acts as expression quantitative trait locus for CTRB1 and CTRB2, encoding chymotrypsinogen, and increases fecal chymotrypsin activity in healthy carriers. Chymotrypsin is one of the most abundant digestive enzymes in the gut where it cleaves food proteins into smaller peptide fragments. Our data identify chymotrypsin in the regulation of the incretin pathway, development of diabetes, and response to DPP-4 inhibitor treatment.

AB - The incretin hormone glucagon-like peptide 1 (GLP-1) promotes glucose homeostasis and enhances b-cell function. GLP-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, which inhibit the physiological inactivation of endogenous GLP-1, are used for the treatment of type 2 diabetes. Using the Metabochip, we identified three novel genetic loci with large effects (3040%) on GLP-1stimulated insulin secretion during hyperglycemic clamps in nondiabetic Caucasian individuals (TMEM114; CHST3 and CTRB1/2; n = 232; all P ≤8.8 × 10-7). rs7202877 near CTRB1/2, a known diabetes risk locus, also associated with an absolute 0.51 ± 0.16% (5.6 ± 1.7 mmol/mol) lower A1C response to DPP-4 inhibitor treatment in G-allele carriers, but there was no effect on GLP-1 RA treatment in type 2 diabetic patients (n = 527). Furthermore, in pancreatic tissue, we show that rs7202877 acts as expression quantitative trait locus for CTRB1 and CTRB2, encoding chymotrypsinogen, and increases fecal chymotrypsin activity in healthy carriers. Chymotrypsin is one of the most abundant digestive enzymes in the gut where it cleaves food proteins into smaller peptide fragments. Our data identify chymotrypsin in the regulation of the incretin pathway, development of diabetes, and response to DPP-4 inhibitor treatment.

U2 - 10.2337/db13-0227

DO - 10.2337/db13-0227

M3 - Journal article

C2 - 23674605

SN - 0012-1797

VL - 62

SP - 3275

EP - 3281

JO - Diabetes

JF - Diabetes

IS - 9

ER -

The CTRB1/2 locus affects diabetes susceptibility and treatment via the incretin pathway

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