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 H H Kramer; Jens J 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 H H Kramer, Jens J 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

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Abstract

The incretin hormone glucagon-like-peptide 1 (GLP-1) promotes glucose homeostasis and enhances beta-cell function. GLP-1 receptor agonists (GLP-1 RA) 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 (30-40%) on GLP-1 stimulated insulin secretion during hyperglycemic clamps in non-diabetic 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 diabetes 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.

Original language	English
Journal	Diabetes
Early online date	14 May 2013
DOIs	https://doi.org/10.2337/db13-0227
Publication status	Published - 2013

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10.2337/db13-0227

DNA variant affects diabetes risk and treatment response
Pearson, E. R., Palmer, C. N. A. & Donnelly, L. A.
1/05/13
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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. https://doi.org/10.2337/db13-0227

@article{8d02f905582c464aaf03db5d4da49d85,

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 beta-cell function. GLP-1 receptor agonists (GLP-1 RA) 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 (30-40%) on GLP-1 stimulated insulin secretion during hyperglycemic clamps in non-diabetic 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 diabetes 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 Kramer, {Mark H H} and Holst, {Jens J} 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",

doi = "10.2337/db13-0227",

language = "English",

journal = "Diabetes",

issn = "0012-1797",

publisher = "American Diabetes Association",

}

'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, MHH, 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. https://doi.org/10.2337/db13-0227

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 H H

AU - Holst, Jens J

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

Y1 - 2013

N2 - The incretin hormone glucagon-like-peptide 1 (GLP-1) promotes glucose homeostasis and enhances beta-cell function. GLP-1 receptor agonists (GLP-1 RA) 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 (30-40%) on GLP-1 stimulated insulin secretion during hyperglycemic clamps in non-diabetic 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 diabetes 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 beta-cell function. GLP-1 receptor agonists (GLP-1 RA) 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 (30-40%) on GLP-1 stimulated insulin secretion during hyperglycemic clamps in non-diabetic 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 diabetes 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 - Article

C2 - 23674605

SN - 0012-1797

JO - Diabetes

JF - Diabetes

ER -

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

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