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

AU - Holst, Jens Juul

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 - 2013/5/14

Y1 - 2013/5/14

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 - Journal article

C2 - 23674605

VL - 62

SP - 3275

EP - 3281

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 9

ER -