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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 ?-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.

SUBMITTER: 't Hart LM

PROVIDER: S-EPMC3749354 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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

't Hart Leen M LM Fritsche Andreas A Nijpels Giel G van Leeuwen Nienke N Donnelly Louise A LA Dekker Jacqueline M JM Alssema Marjan M Fadista Joao J Fadista Joao J Carlotti Françoise F Gjesing Anette P AP Palmer Colin N A CN van Haeften Timon W TW Herzberg-Schäfer Silke A SA Simonis-Bik Annemarie M C AM Houwing-Duistermaat Jeanine J JJ Helmer Quinta Q Deelen Joris J Guigas Bruno B Hansen Torben T Machicao Fausto F Willemsen Gonneke G Heine Robert J RJ Kramer Mark H H MH Holst Jens J JJ de Koning Eelco J P EJ Häring Hans-Ulrich HU Pedersen Oluf O Groop Leif L de Geus Eco J C EJ Slagboom P Eline PE Boomsma Dorret I DI Eekhoff Elisabeth M W EM Pearson Ewan R ER Diamant Michaela M

Diabetes 20130514 9

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 ...[more]

PMID: 23674605

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Project description:Incretin hormones (glucose-dependent insulinotropic polypeptide [GIP] and glucagon-like peptide-1 [GLP-1]) play a role in the pathophysiology of type 2 diabetes. Along with their derivatives they have shown therapeutic success in type 2 diabetes, with the potential for further improvements in glycaemic, cardiorenal and body weight-related outcomes. In type 2 diabetes, the incretin effect (greater insulin secretory response after oral glucose than with 'isoglycaemic' i.v. glucose, i.e. with an identical glycaemic stimulus) is markedly reduced or absent. This appears to be because of a reduced ability of GIP to stimulate insulin secretion, related either to an overall impairment of beta cell function or to specific defects in the GIP signalling pathway. It is likely that a reduced incretin effect impacts on postprandial glycaemic excursions and, thus, may play a role in the deterioration of glycaemic control. In contrast, the insulinotropic potency of GLP-1 appears to be much less impaired, such that exogenous GLP-1 can stimulate insulin secretion, suppress glucagon secretion and reduce plasma glucose concentrations in the fasting and postprandial states. This has led to the development of incretin-based glucose-lowering medications (selective GLP-1 receptor agonists or, more recently, co-agonists, e.g. that stimulate GIP and GLP-1 receptors). Tirzepatide (a GIP/GLP-1 receptor co-agonist), for example, reduces HbA1c and body weight in individuals with type 2 diabetes more effectively than selective GLP-1 receptor agonists (e.g. semaglutide). The mechanisms by which GIP receptor agonism may contribute to better glycaemic control and weight loss after long-term exposure to tirzepatide are a matter of active research and may change the pessimistic view that developed after the disappointing lack of insulinotropic activity in people with type 2 diabetes when exposed to GIP in short-term experiments. Future medications that stimulate incretin hormone and other receptors simultaneously may have the potential to further increase the ability to control plasma glucose concentrations and induce weight loss.

Dataset Information

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

Publications

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

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