Important Role of the GLP-1 Axis for Glucose Homeostasis after Bariatric Surgery
Pierre Larraufie, Geoffrey P Roberts, Anne K McGavigan, Richard G Kay, Joyce Li, Andrew Leiter, Audrey Melvin, Emma K Biggs, Peter Ravn, Kathleen Davy, David C Hornigold, Giles S H Yeo, Richard H Hardwick, Frank Reimann, Fiona M Gribble, Pierre Larraufie, Geoffrey P Roberts, Anne K McGavigan, Richard G Kay, Joyce Li, Andrew Leiter, Audrey Melvin, Emma K Biggs, Peter Ravn, Kathleen Davy, David C Hornigold, Giles S H Yeo, Richard H Hardwick, Frank Reimann, Fiona M Gribble
Abstract
Bariatric surgery is widely used to treat obesity and improves type 2 diabetes beyond expectations from the degree of weight loss. Elevated post-prandial concentrations of glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and insulin are widely reported, but the importance of GLP-1 in post-bariatric physiology remains debated. Here, we show that GLP-1 is a major driver of insulin secretion after bariatric surgery, as demonstrated by blocking GLP-1 receptors (GLP1Rs) post-gastrectomy in lean humans using Exendin-9 or in mice using an anti-GLP1R antibody. Transcriptomics and peptidomics analyses revealed that human and mouse enteroendocrine cells were unaltered post-surgery; instead, we found that elevated plasma GLP-1 and PYY correlated with increased nutrient delivery to the distal gut in mice. We conclude that increased GLP-1 secretion after bariatric surgery arises from rapid nutrient delivery to the distal gut and is a key driver of enhanced insulin secretion.
Keywords: GLP-1; bariatric surgery; enteroendocrine cells; gut hormones; intestinal transit; mass spectrometry; peptidomics; transcriptomics.
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
Figures
References
- Biggs E.K., Liang L., Naylor J., Madalli S., Collier R., Coghlan M.P., Baker D.J., Hornigold D.C., Ravn P., Reimann F., Gribble F.M. Development and characterisation of a novel glucagon like peptide-1 receptor antibody. Diabetologia. 2018;61:711–721.
- Billing L.J., Smith C.A., Larraufie P., Goldspink D.A., Galvin S., Kay R.G., Howe J.D., Walker R., Pruna M., Glass L. 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;16:65–75.
- Calabria A.C., Charles L., Givler S., De León D.D. Postprandial hypoglycemia in children after gastric surgery: clinical characterization and pathophysiology. Horm. Res. Paediatr. 2016;85:140–146.
- Chambers A.P., Sorrell J.E., Haller A., Roelofs K., Hutch C.R., Kim K.S., Gutierrez-Aguilar R., Li B., Drucker D.J., D’Alessio D.A. The role of pancreatic preproglucagon in glucose homeostasis in mice. Cell Metab. 2017;25:927–934.
- Craig C.M., Liu L.F., Deacon C.F., Holst J.J., McLaughlin T.L. Critical role for GLP-1 in symptomatic post-bariatric hypoglycaemia. Diabetologia. 2017;60:531–540.
- Dirksen C., Hansen D.L., Madsbad S., Hvolris L.E., Naver L.S., Holst J.J., Worm D. Postprandial diabetic glucose tolerance is normalized by gastric bypass feeding as opposed to gastric feeding and is associated with exaggerated GLP-1 secretion: a case report. Diabetes Care. 2010;33:375–377.
- Dobin A., Davis C.A., Schlesinger F., Drenkow J., Zaleski C., Jha S., Batut P., Chaisson M., Gingeras T.R. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29:15–21.
- Donath M.Y., Burcelin R. GLP-1 effects on islets: hormonal, neuronal, or paracrine? Diabetes Care. 2013;36(Suppl 2):S145–S148.
- Douros J.D., Lewis A.G., Smith E.P., Niu J., Capozzi M., Wittmann A., Campbell J., Tong J., Wagner C., Mahbod P. Enhanced glucose control following vertical sleeve gastrectomy does not require a β-cell glucagon-like peptide 1 receptor. Diabetes. 2018;67:1504–1511.
- Garibay D., McGavigan A.K., Lee S.A., Ficorilli J.V., Cox A.L., Michael M.D., Sloop K.W., Cummings B.P. β-cell glucagon-like peptide-1 receptor contributes to improved glucose tolerance after vertical sleeve gastrectomy. Endocrinology. 2016;157:3405–3409.
- Gribble F.M., Reimann F. Enteroendocrine cells: chemosensors in the intestinal epithelium. Annu. Rev. Physiol. 2016;78:277–299.
- Gromada J., Holst J.J., Rorsman P. Cellular regulation of islet hormone secretion by the incretin hormone glucagon-like peptide 1. Pflugers Arch. 1998;435:583–594.
- Habib A.M., Richards P., Rogers G.J., Reimann F., Gribble F.M. Co-localisation and secretion of glucagon-like peptide 1 and peptide YY from primary cultured human L cells. Diabetologia. 2013;56:1413–1416.
- Hansen L., Hartmann B., Bisgaard T., Mineo H., Jørgensen P.N., Holst J.J. Somatostatin restrains the secretion of glucagon-like peptide-1 and -2 from isolated perfused porcine ileum. Am. J. Physiol. Endocrinol. Metab. 2000;278:E1010–E1018.
- Heruc G.A., Horowitz M., Deacon C.F., Feinle-Bisset C., Rayner C.K., Luscombe-Marsh N., Little T.J. Effects of dipeptidyl peptidase IV inhibition on glycemic, gut hormone, triglyceride, energy expenditure, and energy intake responses to fat in healthy males. Am. J. Physiol. Endocrinol. Metab. 2014;307:E830–E837.
- Hrvatin S., Deng F., O’Donnell C.W., Gifford D.K., Melton D.A. MARIS: method for analyzing RNA following intracellular sorting. PLoS ONE. 2014;9:e89459.
- Hutch C.R., Sandoval D. The role of GLP-1 in the metabolic success of bariatric surgery. Endocrinology. 2017;158:4139–4151.
- Jacobsen S.H., Bojsen-Møller K.N., Dirksen C., Jørgensen N.B., Clausen T.R., Wulff B.S., Kristiansen V.B., Worm D., Hansen D.L., Holst J.J. Effects of gastric bypass surgery on glucose absorption and metabolism during a mixed meal in glucose-tolerant individuals. Diabetologia. 2013;56:2250–2254.
- Jørgensen N.B., Dirksen C., Bojsen-Møller K.N., Jacobsen S.H., Worm D., Hansen D.L., Kristiansen V.B., Naver L., Madsbad S., Holst J.J. Exaggerated glucagon-like peptide 1 response is important for improved β-cell function and glucose tolerance after Roux-en-Y gastric bypass in patients with type 2 diabetes. Diabetes. 2013;62:3044–3052.
- Kay R.G., Galvin S., Larraufie P., Reimann F., Gribble F.M. Liquid chromatography/mass spectrometry based detection and semi-quantitative analysis of INSL5 in human and murine tissues. Rapid Commun. Mass Spectrom. 2017;31:1963–1973.
- Kittrell H., Graber W., Mariani E., Czaja K., Hajnal A., Di Lorenzo P.M. Taste and odor preferences following Roux-en-Y surgery in humans. PLoS ONE. 2018;13:e0199508.
- Knop F.K. EJE prize 2018: a gut feeling about glucagon. Eur. J. Endocrinol. 2018;178:R267–R280.
- Li H.J., Kapoor A., Giel-Moloney M., Rindi G., Leiter A.B. Notch signaling differentially regulates the cell fate of early endocrine precursor cells and their maturing descendants in the mouse pancreas and intestine. Dev. Biol. 2012;371:156–169.
- Love M.I., Huber W., Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550.
- Mathes C.M., Spector A.C. Food selection and taste changes in humans after Roux-en-Y gastric bypass surgery: a direct-measures approach. Physiol. Behav. 2012;107:476–483.
- McGavigan A.K., Garibay D., Henseler Z.M., Chen J., Bettaieb A., Haj F.G., Ley R.E., Chouinard M.L., Cummings B.P. TGR5 contributes to glucoregulatory improvements after vertical sleeve gastrectomy in mice. Gut. 2017;66:226–234.
- Miholic J., Orskov C., Holst J.J., Kotzerke J., Meyer H.J. Emptying of the gastric substitute, glucagon-like peptide-1 (GLP-1), and reactive hypoglycemia after total gastrectomy. Dig. Dis. Sci. 1991;36:1361–1370.
- Miller M.S., Galligan J.J., Burks T.F. Accurate measurement of intestinal transit in the rat. J. Pharmacol. Methods. 1981;6:211–217.
- Miras A.D., Jackson R.N., Jackson S.N., Goldstone A.P., Olbers T., Hackenberg T., Spector A.C., le Roux C.W. Gastric bypass surgery for obesity decreases the reward value of a sweet-fat stimulus as assessed in a progressive ratio task. Am. J. Clin. Nutr. 2012;96:467–473.
- Mumphrey M.B., Patterson L.M., Zheng H., Berthoud H.R. Roux-en-Y gastric bypass surgery increases number but not density of CCK-, GLP-1-, 5-HT-, and neurotensin-expressing enteroendocrine cells in rats. Neurogastroenterol. Motil. 2013;25:e70–e79.
- Nauck M.A., Meier J.J. Incretin hormones: their role in health and disease. Diabetes Obes. Metab. 2018;20(Suppl 1):5–21.
- Nauck M.A., Heimesaat M.M., Orskov C., Holst J.J., Ebert R., Creutzfeldt W. Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J. Clin. Invest. 1993;91:301–307.
- Pok E.H., Lee W.J. Gastrointestinal metabolic surgery for the treatment of type 2 diabetes mellitus. World J. Gastroenterol. 2014;20:14315–14328.
- Rhee N.A., Wahlgren C.D., Pedersen J., Mortensen B., Langholz E., Wandall E.P., Friis S.U., Vilmann P., Paulsen S.J., Kristiansen V.B. Effect of Roux-en-Y gastric bypass on the distribution and hormone expression of small-intestinal enteroendocrine cells in obese patients with type 2 diabetes. Diabetologia. 2015;58:2254–2258.
- Roberts G., Larraufie P., Richards P., Kay R., Galvin S., Miedzybrodzka E., Leiter A., Li J., Glass L., Ma M. Bioarchives; 2018. Comparison of Human and Murine Enteroendocrine Cells by Transcriptomic and Peptidomic Profiling.
- Roberts G.P., Kay R.G., Howard J., Hardwick R.H., Reimann F., Gribble F.M. Gastrectomy with Roux-en-Y reconstruction as a lean model of bariatric surgery. Surg. Obes. Relat. Dis. 2018;14:562–568.
- Salehi M., Gastaldelli A., D’Alessio D.A. Blockade of glucagon-like peptide 1 receptor corrects postprandial hypoglycemia after gastric bypass. Gastroenterology. 2014;146:669–680.
- Salehi M., Vella A., McLaughlin T., Patti M.E. Hypoglycemia after gastric bypass surgery: current concepts and controversies. J. Clin. Endocrinol. Metab. 2018;103:2815–2826.
- Sjöström L. Review of the key results from the Swedish obese subjects (SOS) trial—a prospective controlled intervention study of bariatric surgery. J. Intern. Med. 2013;273:219–234.
- Smith E.P., Polanco G., Yaqub A., Salehi M. Altered glucose metabolism after bariatric surgery: what’s GLP-1 got to do with it? Metabolism. 2018;83:159–166.
- Svane M.S., Jørgensen N.B., Bojsen-Møller K.N., Dirksen C., Nielsen S., Kristiansen V.B., Toräng S., Wewer Albrechtsen N.J., Rehfeld J.F., Hartmann B. Peptide YY and glucagon-like peptide-1 contribute to decreased food intake after Roux-en-Y gastric bypass surgery. Int. J. Obes. 2016;40:1699–1706.
- Sze L., Purtell L., Jenkins A., Loughnan G., Smith E., Herzog H., Sainsbury A., Steinbeck K., Campbell L.V., Viardot A. Effects of a single dose of exenatide on appetite, gut hormones, and glucose homeostasis in adults with Prader-Willi syndrome. J. Clin. Endocrinol. Metab. 2011;96:E1314–E1319.
- Waser B., Reubi J.C. Value of the radiolabelled GLP-1 receptor antagonist exendin(9–39) for targeting of GLP-1 receptor-expressing pancreatic tissues in mice and humans. Eur. J. Nucl. Med. Mol. Imaging. 2011;38:1054–1058.
- Wilson-Pérez H.E., Chambers A.P., Ryan K.K., Li B., Sandoval D.A., Stoffers D., Drucker D.J., Pérez-Tilve D., Seeley R.J. Vertical sleeve gastrectomy is effective in two genetic mouse models of glucagon-like peptide 1 receptor deficiency. Diabetes. 2013;62:2380–2385.
- Ye J., Hao Z., Mumphrey M.B., Townsend R.L., Patterson L.M., Stylopoulos N., Münzberg H., Morrison C.D., Drucker D.J., Berthoud H.R. GLP-1 receptor signaling is not required for reduced body weight after RYGB in rodents. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2014;306:R352–R362.
Source: PubMed