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

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Author

  • Leen M. 't Hart
  • Andreas Fritsche
  • Giel Nijpels
  • Nienke van Leeuwen
  • Louise A. Donnelly
  • Jacqueline M. Dekker
  • Marjan Alssema
  • Joao Fadista
  • Francoise Carlotti
  • Anette P. Gjesing
  • Colin N. A. Palmer
  • Timon W. van Haeften
  • Silke A. Herzberg-Schaefer
  • 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 Haering
  • 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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Summary, in English

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.

Publishing year

2013

Language

English

Pages

3275-3281

Publication/Series

Diabetes

Volume

62

Issue

9

Document type

Journal article

Publisher

American Diabetes Association Inc.

Topic

  • Endocrinology and Diabetes

Status

Published

Research group

  • Translational Muscle Research

ISBN/ISSN/Other

  • ISSN: 1939-327X