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

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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 & 14 others 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

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 languageEnglish
JournalDiabetes
Volume62
Issue number9
Pages (from-to)3275-3281
Number of pages6
ISSN0012-1797
DOIs
Publication statusPublished - 14 May 2013

ID: 45842994