Hormones from the gut are central to the control of appetite and insulin release. Drugs based on the gut hormone glucagon-like peptide-1 (GLP-1) have proved highly successful for treating type 2 diabetes, and also suppress food intake. In collaboration with Frank Reimann our group researches how gut hormones are released and their actions on target tissues. We hope this will lead to the development of new drugs or diets that treat diabetes and obesity by targeting gut hormone release.
The release of gut hormones such as GLP-1 and PYY after a meal conveys signals to the brain to stop eating, to the pancreas to produce insulin and to the gut to coordinate digestion. We are particularly interested in establishing how gut hormones are released after food ingestion, and how the gut endocrine system is affected after gastric bypass surgery.
Our research encompasses a range of experimental approaches, from physiological studies in humans to analysis of single cells in vitro. We use optical and electrophysiological recording techniques to monitor stimulus detection and vesicle release from endocrine cells in primary intestinal cultures, intestinal organoids and immortalized cell lines. To identify living gut endocrine cells, we have generated transgenic models in which hormone producing cells, or cellular targets of gut hormones, are labelled by cell-specific fluorescent markers and reporters of cytoplasmic signalling pathways. The mechanisms by which cells detect stimuli are identified by combining methods such as live cell imaging, electrophysiology, transcriptomics and measurements of hormone secretion using immunoassays and LC-MS.
Galvin SG, Kay RG, Foreman R, Larraufie P, Meek CL, Biggs E, Ravn P, Jermutus L, Reimann F, Gribble FM. The Human and Mouse Islet Peptidome: Effects of Obesity and Type 2 Diabetes, and Assessment of Intraislet Production of Glucagon-like Peptide-1. J Proteome Res. 2021 Sep 3;20(9):4507-4517. doi: 10.1021/acs.jproteome.1c00463. Epub 2021 Aug 23. PMID: 34423991 PMCID:PMC8419866
Yang M, Darwish T, Larraufie P, Rimmington D, Cimino I, Goldspink DA, Jenkins B, Koulman A, Brighton CA, Ma M, Lam BYH, Coll AP, O’Rahilly S, Reimann F, Gribble FM. Inhibition of mitochondrial function by metformin increases glucose uptake, glycolysis and GDF-15 release from intestinal cells. Sci Rep. 2021 Jan 28;11(1):2529. doi: 10.1038/s41598-021-81349-7. PMID: 33510216 PMCID: PMC7843649
Goldspink DA, Lu VB, Miedzybrodzka EL, Smith CA, Foreman RE, Billing LJ, Kay RG, Reimann F, Gribble FM. Labeling and Characterization of Human GLP-1-Secreting L-cells in Primary Ileal Organoid Culture. Cell Rep. 2020 Jun 30;31(13):107833. doi: 10.1016/j.celrep.2020.107833. PMID: 32610134. PMCID: PMC7342002
Lewis JE, Miedzybrodzka EL, Foreman RE, Woodward ORM, Kay RG, Goldspink DA, Gribble FM, Reimann F. Selective stimulation of colonic L cells improves metabolic outcomes in mice. Diabetologia. 2020 Jul;63(7):1396-1407. doi: 10.1007/s00125-020-05149-w. Epub 2020 Apr 27. PMID: 32342115. PMCID: PMC7286941
Adriaenssens AE, Biggs EK, Darwish T, Tadross J, Sukthankar T, Girish M, Polex-Wolf J, Lam BY, Zvetkova I, Pan W, Chiarugi D, Yeo GSH, Blouet C, Gribble FM, Reimann F. Glucose-dependent insulinotropic polypeptide receptor-expressing cells in the hypothalamus regulate food intake. Cell Metab. 30(5):987-996 PMID:31447324, PMCID: PMC6838660
Lu VB, Rievaj J, O’Flaherty EA, Smith CA, Pais R, Pattison LA, Tolhurst G, Leiter AB, Bulmer DC, Gribble FM, Reimann F. Adenosine triphosphate is co-secreted with glucagon-like peptide-1 to modulate intestinal enterocytes and afferent neurons. Nat Commun. 2019 Mar 4;10(1):1029. doi: 10.1038/s41467-019-09045-9.PMID: 30833673 PMCID: PMC6399286
Larraufie P, Roberts GP, McGavigan A, Kay RG, Li J, Leiter A, Melvin A, Biggs EK, Ravn P, Davy K, Hornigold D, Yeo G, Hardwick RH, Reimann F, Gribble FM. Important role of the GLP-1 axis for glucose homeostasis after bariatric surgery. Cell Rep. 2019 Feb 5;26(6):1399-1408 PMID:30726726 PMCID: PMC6367566
Biggs EK, Liang L, Naylor J, Madalli S, Collier R, Coghlan MP, Baker DJ, Hornigold DC, Ravn P, Reimann F, Gribble FM. Development and characterisation of a novel glucagon like peptide-1 receptor antibody. Diabetologia. 2018 Mar;61(3):711-721. PMID: 29119245 PMCID: PMC5890879
Grosse J, Heffron H, Burling K, Hossain MA, Habib AM, Rogers GJ, Richards P, Larder R, Rimmington D, Adriaenssens AE, Parton L, Powell J, Binda M, Colledge WH, Doran J, Toyoda Y, Wade JD, Aparicio S, Carlton M, Coll AP, Reimann F, O’Rahilly S, Gribble FM. Insulin-like peptide 5 is an orexigenic gastro-intestinal hormone. Proc Natl Acad Sci U S A 2014:111:11133-8 PMID: 25028498 PMCID: PMC4121845
Richards P, Parker HE, Adriaenssens AE, Hodgson JM, Cork SC, Trapp S, Gribble FM, Reimann F. Identification and characterisation of glucagon-like peptide-1 receptor expressing cells using a new transgenic mouse model. Diabetes. 2014; 63:1224-33 PMID: 24296712 PMCID: PMC4092212