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The CTRB1/2 Locus Affects Diabetes Susceptibility and Treatment via the Incretin Pathway

't Hart, Leen M.; Fritsche, Andreas; Nijpels, Giel; van Leeuwen, Nienke; Donnelly, Louise A.; Dekker, Jacqueline M.; Alssema, Marjan; Fadista, Joao LU ; Carlotti, Francoise and Gjesing, Anette P., et al. (2013) In Diabetes 62(9). p.3275-3281
Abstract
The incretin hormone glucagon-like peptide 1 (GLP-1) promotes glucose homeostasis and enhances -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 (30-40%) on GLP-1-stimulated insulin secretion during hyperglycemic clamps in nondiabetic Caucasian individuals (TMEM114; CHST3 and CTRB1/2; n = 232; all P 8.8 x 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... (More)
The incretin hormone glucagon-like peptide 1 (GLP-1) promotes glucose homeostasis and enhances -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 (30-40%) on GLP-1-stimulated insulin secretion during hyperglycemic clamps in nondiabetic Caucasian individuals (TMEM114; CHST3 and CTRB1/2; n = 232; all P 8.8 x 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. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Diabetes
volume
62
issue
9
pages
3275 - 3281
publisher
American Diabetes Association Inc.
external identifiers
  • wos:000323421000036
  • scopus:84885215197
ISSN
1939-327X
DOI
10.2337/db13-0227
language
English
LU publication?
yes
id
edb83e05-d57f-481a-a3f8-936553421f9b (old id 4025604)
date added to LUP
2013-10-01 15:26:00
date last changed
2019-10-08 01:46:32
@article{edb83e05-d57f-481a-a3f8-936553421f9b,
  abstract     = {The incretin hormone glucagon-like peptide 1 (GLP-1) promotes glucose homeostasis and enhances -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 (30-40%) on GLP-1-stimulated insulin secretion during hyperglycemic clamps in nondiabetic Caucasian individuals (TMEM114; CHST3 and CTRB1/2; n = 232; all P 8.8 x 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 Fritsche, Andreas and Nijpels, Giel and van Leeuwen, Nienke and Donnelly, Louise A. and Dekker, Jacqueline M. and Alssema, Marjan and Fadista, Joao and Carlotti, Francoise and Gjesing, Anette P. and Palmer, Colin N. A. and van Haeften, Timon W. and Herzberg-Schaefer, Silke A. and Simonis-Bik, Annemarie M. C. and Houwing-Duistermaat, Jeanine J. and Helmer, Quinta and Deelen, Joris and Guigas, Bruno and Hansen, Torben and Machicao, Fausto and Willemsen, Gonneke and Heine, Robert J. and Kramer, Mark H. H. and Holst, Jens J. and de Koning, Eelco J. P. and Haering, Hans-Ulrich and Pedersen, Oluf and Groop, Leif and de Geus, Eco J. C. and Slagboom, P. Eline and Boomsma, Dorret I. and Eekhoff, Elisabeth M. W. and Pearson, Ewan R. and Diamant, Michaela},
  issn         = {1939-327X},
  language     = {eng},
  number       = {9},
  pages        = {3275--3281},
  publisher    = {American Diabetes Association Inc.},
  series       = {Diabetes},
  title        = {The CTRB1/2 Locus Affects Diabetes Susceptibility and Treatment via the Incretin Pathway},
  url          = {http://dx.doi.org/10.2337/db13-0227},
  volume       = {62},
  year         = {2013},
}