title: The CTRB1/2 locus affects diabetes susceptibility and treatment via the incretin pathway.
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.
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands. l.m.t_hart@lumc.nl
authors.forename: Leen M
authors.initials: LM
authors.lastname: 't Hart
authors.forename: Andreas
authors.initials: A
authors.lastname: Fritsche
authors.forename: Giel
authors.initials: G
authors.lastname: Nijpels
authors.forename: Nienke
authors.initials: N
authors.lastname: van Leeuwen
authors.forename: Louise A
authors.initials: LA
authors.lastname: Donnelly
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Dekker
authors.forename: Marjan
authors.initials: M
authors.lastname: Alssema
authors.forename: Joao
authors.initials: J
authors.lastname: Fadista
authors.forename: Françoise
authors.initials: F
authors.lastname: Carlotti
authors.forename: Anette P
authors.initials: AP
authors.lastname: Gjesing
authors.forename: Colin N A
authors.initials: CN
authors.lastname: Palmer
authors.forename: Timon W
authors.initials: TW
authors.lastname: van Haeften
authors.forename: Silke A
authors.initials: SA
authors.lastname: Herzberg-Schäfer
authors.forename: Annemarie M C
authors.initials: AM
authors.lastname: Simonis-Bik
authors.forename: Jeanine J
authors.initials: JJ
authors.lastname: Houwing-Duistermaat
authors.forename: Quinta
authors.initials: Q
authors.lastname: Helmer
authors.forename: Joris
authors.initials: J
authors.lastname: Deelen
authors.forename: Bruno
authors.initials: B
authors.lastname: Guigas
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
authors.forename: Fausto
authors.initials: F
authors.lastname: Machicao
authors.forename: Gonneke
authors.initials: G
authors.lastname: Willemsen
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Heine
authors.forename: Mark H H
authors.initials: MH
authors.lastname: Kramer
authors.forename: Jens J
authors.initials: JJ
authors.lastname: Holst
authors.forename: Eelco J P
authors.initials: EJ
authors.lastname: de Koning
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Häring
authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
authors.forename: Eco J C
authors.initials: EJ
authors.lastname: de Geus
authors.forename: P Eline
authors.initials: PE
authors.lastname: Slagboom
authors.forename: Dorret I
authors.initials: DI
authors.lastname: Boomsma
authors.forename: Elisabeth M W
authors.initials: EM
authors.lastname: Eekhoff
authors.forename: Ewan R
authors.initials: ER
authors.lastname: Pearson
authors.forename: Michaela
authors.initials: M
authors.lastname: Diamant
mesh_terms: D000328:Adult; D000368:Aged; D002918:Chymotrypsin / Q000235:genetics*; D003920:Diabetes Mellitus; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D005838:Genotype; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D054795:Incretins / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018027:Receptors, Glucagon / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D054795:Incretins; D007328:Insulin; D018027:Receptors, Glucagon; D052216:Glucagon-Like Peptide 1; D002918:Chymotrypsin; C117609:chymotrypsin B