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.
Billing JL, Larraufie P, Lewis J, Leiter A, Li J, Lam B, Yeo GSH, Goldspink DA, Kay RG, Gribble FM, Reimann F. Single cell transcriptomic profiling of large intestinal enteroendocrine cells in mice – identification of selective stimuli for Insulin-like peptide-5 and Glucagon-like peptide-1 co-expressing cells. Mol Metab. 2019 Nov;29:158-169. PMID: 31668387. PMCID: PMC6812004
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
Roberts GP, Larraufie P, Richards P, G Kay RG, Galvin SG, Miedzybrodzka EL, Leiter A, Li HJ, Glass LL, Ma MKL, Lam B, Yeo GSH, Scharfmann R, Chiarugi D, Hardwick RH, Reimann F, Gribble FM. Comparison of human and murine enteroendocrine cells by transcriptomic and peptidomic profiling. Diabetes. 2019 May;68(5):1062-1072. PMID: 30733330 PMCID: PMC6477899
Billing LJ, Smith CA, Larraufie P, Goldspink DA, Galvin S, Kay RG, Howe JD, Walker R, Pruna M, Glass L, Pais R, Gribble FM, Reimann F. Co-storage and release of Insulin-like peptide-5, glucagon-like peptide-1 and peptideYY from murine and human colonic enteroendocrine cells. Mol Metab. 2018 Oct;16:65-75. PMID: 30104166 PMCID: PMC6158034
Kay RG, Challis BG, Casey RT, Roberts GP, MeekCL, Reimann F, Gribble FM. Peptidomic analysis of endogenous plasma peptides from patients with pancreatic neuroendocrine tumours. Rapid Commun Mass Spectrom. 2018 Aug 30;32(16):1414-1424. PMID: 29857350 PMCID: PMC6099210
Goldspink DA, Lu VB, Billing LJ, Larraufie P, Tolhurst G, Gribble FM, Reimann F. Mechanistic insights into the detection of free fatty and bile acids by ileal glucagon-like peptide-1 secreting cells. Mol Metab. 2017 Nov 11. pii: S2212-8778(17)30750-0. doi: 10.1016/j.molmet.2017.11.005. PMID: 29167062.
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
Roberts GP, Kay RG, Howard J, Hardwick RH, Reimann F, Gribble FM. Gastrectomy with Roux-en-Y reconstruction as a lean model of bariatric surgery. Surg Obes Relat Dis. 2018 Feb 3. pii: S1550-7289(18)30054-6. doi: 10.1016/j.soard.2018.01.039. PMID: 29548882
Psichas A, Larraufie PF, Goldspink DA, Gribble FM, Reimann F. Chylomicrons stimulate incretin secretion in mouse and human cells. Diabetologia. 2017 60:2475-2485 PMID: 28866808
Kay RG, Galvin S, Larraufie P, Reimann F, Gribble FM. Detection and quantitation of INSL5 in human and murine tissues using LC/MS. Rapid Communications in Mass Spectrometry 2017 31(23):1963-1973 PMID: 28857318
Glass LL, Calero-Nieto FJ, Jawaid W, Larraufie P, Kay RG, Göttgens B, Reimann F, Gribble FM. Single-cell RNA-sequencing reveals a distinct population of proglucagon-expressing cells specific to the mouse upper small intestine. Mol Metab 2017 Oct;6(10):1296-1303 PMID: 29031728
Adriaenssens AE, Svendsen B, Lam BY, Yeo GS, Holst JJ, Reimann F, Gribble FM. Transcriptomic profiling of pancreatic alpha, beta and delta cell populations identifies delta cells as a principal target for ghrelin in mouse islets. Diabetologia. 2016; 59:2156-65 PMID: 27390011
Brighton CA, Rievaj J, Kuhre RE, Glass LL, Schoonjans K, Holst JJ, Gribble FM, Reimann F. Bile Acids Trigger GLP-1 Release Predominantly by Accessing Basolaterally Located G Protein-Coupled Bile Acid Receptors. Endocrinology. 2015 Nov;156(11):3961-70 PMID: 26280129
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
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
Habib AM, Richards P, Cairns LS, Rogers GJ, Bannon CA, Parker HE, Morley TC, Yeo GS, Reimann F, Gribble FM. Overlap of endocrine hormone expression in the mouse intestine revealed by transcriptional profiling and flow cytometry. Endocrinology. 2012; 153:3054-65 PMID: 22685263
Tolhurst G, Heffron H, Lam YS, Parker HE, Habib AM, Diakogiannaki E, Cameron J, Grosse J, Reimann F, Gribble FM. Short-Chain Fatty Acids Stimulate Glucagon-Like Peptide-1 Secretion via the G-Protein-Coupled Receptor FFAR2. Diabetes. 2012; 61:364-71. PMID: 2219064
Reimann F, Habib AM, Tolhurst G, Parker HE, Rogers GJ, Gribble FM. Glucose-sensing in L-cells: a primary cell study. Cell Metab. 2008; 8:532-539. PMID: 19041768