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Animal Models

Gastrointestinal hormonal responses on GPR119 activation in lean and diseased rodent models of type 2 diabetes

International Journal of Obesity volume 38, pages 1365–1373 (2014)Cite this article

Subjects

Abstract

Background:

G protein-coupled receptor 119 (GPR119) has emerged as a potential target for the treatment of type 2 diabetes (T2D) and tool compounds have been critical in the evaluation of GPR119 functions.

Methods:

We synthesised a novel small-molecule GPR119 agonist, PSN-GPR119, to study GPR119 signalling activities in cells overexpressing GPR119. We measured GPR119-stimulated peptide hormone release from intestinal loops and oral glucose tolerance in vivo from lean (C57BL/6J mouse or Sprague-Dawley (SD) rat) and diabetic (ob/ob mouse or ZDF rat) models. To evaluate the direct effects of GPR119 agonism on gastrointestinal (GI) tissue, we measured vectorial ion transport (measured as ISC; short-circuit current) across rodent GI mucosae and from normal human colon specimens.

Results:

GPR119 activation by PSN-GPR119 increased cAMP accumulation in hGPR119-overexpressing HEK293 cells (EC50, 5.5 nM), stimulated glucagon-like peptide 1 (GLP-1) release from GLUTag cells (EC50, 75 nM) and insulin release from HIT-15 cells (EC50, 90 nM). In vivo, PSN-GPR119 improved glucose tolerance by ~50% in lean mice or rats and ~60% in the diabetic ob/ob mouse or ZDF rat models. Luminal addition of PSN-GPR119 to isolated loops of lean rat small intestine stimulated GLP-1, glucose insulinotropic peptide (GIP) and peptide YY (PYY) release under basal (5 mM) and high glucose (25 mM) conditions. Activation of GPR119 also reduced intestinal ion transport. Apical or basolateral PSN-GPR119 addition (1 μM) to lean or T2D rodent colon mucosae reduced ISC levels via PYY-mediated Y1 receptor agonism. The GPR119 response was glucose sensitive and was abolished by Y1 receptor antagonism. Similarly, in human colon, mucosa PSN-GPR119 acted via a Y1-specific mechanism.

Conclusions:

Our results show that functional GPR119 responses are similar in lean and diabetic rodent, and human colon; that GPR119 stimulation can result in glucose lowering through release of intestinal peptide hormones and that PSN-GPR119 is a useful tool compound for future studies.

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Acknowledgements

SP, OJM, JW, MS, UWB and T-AC were employees of Prosidion Ltd at the time of the study, and we thank RenaSci Ltd (Nottingham, UK) for conducting the oral glucose tolerance test studies.

Author Contributions

SP and HMC were responsible for the conception and design of the experiments and writing of the article. OJM, IRT and JW were also responsible for collection, analysis, interpretation and presentation of the data. UWB and T-AC were responsible for the oral glucose tolerance test studies. MS was responsible for reviewing the article.

Author information

Author notes

  1. S Patel

    Present address: 3Current address: Bioelectronics R&D, GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, UK.,

  2. O J Mace

    Present address: 4Current address: Heptares Therapeutics, Broadwater Road, Welwyn Garden City, AL7 3AX, UK,

  3. J White

    Present address: 5Current address: Argenta Discovery, 8/9 Spire Green Centre, Flex Meadow, Harlow, CM19 5TR, UK,

  4. T-A Cock

    Present address: 6Current address: Pharmaxis Ltd, 20 Rodborough Road, Locked Bag 5015, Frenchs Forest, NSW 2086, Australia,

  5. U Warpman Berglund

    Present address: 7Current address: Science for Life Laboratory, Department of Medical Biochemistry & Biophysics, Karolinska Institute, S-171 21 Stockholm, Sweden,

  6. M Schindler

    Present address: 8Current address: Astra Zeneca R&D Mölndal, Cardiovascular & Metabolic Diseases iMed, Pepparedsleden 1, SE-431 83 Mölndal, Sweden,

  7. S Patel, O J Mace and I R Tough: These authors contributed equally to this work.

Authors and Affiliations

  1. Prosidion Ltd, Oxford, UK

    S Patel, O J Mace, J White, T-A Cock, U Warpman Berglund & M Schindler

  2. King's College London, Wolfson Centre for Age-Related Diseases, London, UK

    I R Tough & H M Cox

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Correspondence to H M Cox.

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Patel, S., Mace, O., Tough, I. et al. Gastrointestinal hormonal responses on GPR119 activation in lean and diseased rodent models of type 2 diabetes. Int J Obes 38, 1365–1373 (2014). https://doi.org/10.1038/ijo.2014.10

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