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

  1. Michaela Diamant12
  1. 1Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands.
  2. 2Section of Molecular Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
  3. 3Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, Department of Internal Medicine, Eberhard Karls University Tübingen, Member of the German Centre for Diabetes Research (DZD), Tübingen, Germany
  4. 4The EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, the Netherlands
  5. 5Department of General Practice, VU University Medical Center, Amsterdam, the Netherlands
  6. 6Division of Cardiovascular and Diabetes Medicine, Medical Research Institute, University of Dundee, Dundee, U.K.
  7. 7Department of Epidemiology and Statistics, VU University Medical Center, Amsterdam, the Netherlands
  8. 8Lund University Diabetes Center, Department of Clinical Sciences, Diabetes, and Endocrinology, Skåne University Hospital Malmö, Lund University, Malmö, Sweden
  9. 9Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands
  10. 10The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, University of Copenhagen, Copenhagen, Denmark
  11. 11Department of Internal Medicine, Utrecht University Medical Center, Utrecht, the Netherlands
  12. 12Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam, the Netherlands
  13. 13Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands.
  14. 14Department of Parasitology, Leiden University Medical Center, Leiden, the Netherlands
  15. 15Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
  16. 16Department of Biological Psychology, VU University, Amsterdam, the Netherlands
  17. 17Eli Lilly and Company, Indianapolis, Indiana
  18. 18Department of Internal Medicine, VU University Medical Center, Amsterdam, the Netherlands
  19. 19The Novo Nordisk Foundation Center for Basic Metabolic Research, Department of Biomedical Sciences, Panum Institute, University of Copenhagen, Copenhagen, Denmark
  20. 20Department of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands
  21. 21Hubrecht Institute, Utrecht, the Netherlands
  22. 22Faculty of Health Sciences, University of Aarhus, Aarhus, Denmark
  23. 23Netherlands Consortium for Healthy Aging, Leiden, the Netherlands
  1. Corresponding author: Leen M. ‘t Hart, l.m.t_hart{at}lumc.nl.
  1. A.F., G.N., N.v.L., D.I.B., E.M.W.E., E.R.P., and M.D. contributed equally to this study.

  • M.A. is currently affiliated with Unilever Research and Development, Vlaardingen, the Netherlands; and R.J.H. is currently affiliated with Eli Lilly and Company, Indianapolis, Indiana.

Abstract

The incretin hormone glucagon-like peptide 1 (GLP-1) promotes glucose homeostasis and enhances β-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 × 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.

Footnotes

  • Received February 8, 2013.
  • Accepted April 30, 2013.

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  1. Diabetes vol. 62 no. 9 3275-3281
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