Comprehensive Physiology Wiley Online Library

Glucagon‐Like Peptide‐1: Actions and Influence on Pancreatic Hormone Function

Full Article on Wiley Online Library


GLP‐1 was described as an incretin over 30 years ago. GLP‐1 is encoded by the preproglucagon gene (Gcg), which is expressed in the intestine, the pancreas, and the central nervous system. GLP‐1 activates GLP‐1 receptors (GLP‐1r) on the β‐cell to induce insulin secretion in a glucose‐dependent manner. GLP‐1 also inhibits α‐cell secretion of glucagon. As few, if any, GLP‐1r are expressed on α‐cells, indirect regulation, via β‐ or δ‐cell products has been thought to be the primary mechanism by which GLP‐1 inhibits glucagon secretion. However, recent work suggests that there is sufficient expression of GLP‐1r on α‐cells for direct regulation as well. Although the predominant source of circulating GLP‐1 is the intestine, the α‐cell becomes a source of GLP‐1 when the islet is metabolically stressed. Recent work suggests the possibility that this source of GLP‐1 is also be important in regulating nutrient‐induced insulin secretion in a paracrine fashion. More work is also accumulating regarding the role of glucagon, another Gcg‐derived protein produced by the α‐cell, in stimulating insulin secretion by acting on GLP‐1r. Altogether, these data clearly demonstrate the important role of Gcg‐derived peptides in regulating insulin secretion. Because of GLP‐1's important role in glucose homeostasis, it has been implicated in the success of bariatric surgery and has been successfully targeted for the treatment of type 2 diabetes mellitus. © 2020 American Physiological Society. Compr Physiol 10:577‐595, 2020.

Comprehensive Physiology offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images

Figure 1. Figure 1. The incretin effect: Glucose levels are lower while insulin levels are higher when the same dose of glucose is administered directly into the gut versus when administered intravenously (IV). This difference in insulin between the gut and venous infusion is the “incretin effect” which occurs in response to GLP‐1 and GIP secreted from the distal gut. Adapted, with permission, from McIntyre N, et al. 153.
Figure 2. Figure 2. Intestinal GLP‐1 secretion: Several factors have been linked to GLP‐1 secretion. The parasympathetic nervous system (PNS) stimulates GLP‐1 secretion via cholinergic muscarinic receptors (MR). Activation of α‐adrenergic (AR) receptors stimulates while activation of β‐adrenergic receptors inhibits GLP‐1 release. Various GPCRS including ones activated by bile acids and various fatty acids stimulate GLP‐1 through PKA signaling and increases in calcium‐induced exocytosis. Lastly, direct glucose sensing, predominantly via SGLT1 in humans, activates sodium (Na+), and calcium (Ca2+) voltage‐gated channels to lead to the release of GLP‐1.
Figure 3. Figure 3. Factors that impact α‐cell GLP‐1 production. Metabolic stress, systemic inflammation, exercise, hyperglycemia, obesity, and diabetes stimulate α‐cell GLP‐1 production. IL‐6 seems to be a primary factor that leads to this increase. The function of this increase is unknown but regulation of β‐cell mass and function is a likely endpoint.
Figure 4. Figure 4. Recent work highlights a more complexity to the role of Gcg‐derived peptides in the incretin effect. While historical work suggests intestinal GLP‐1 is important in regulating glucose homeostasis, there may be a role for α‐cell derived GLP‐1 as well. In addition, in response to amino acids, glucagon is secreted and acts on local GLP‐1r to regulate insulin secretion.
Figure 5. Figure 5. Postprandial GLP‐1 increases several‐fold after bariatric surgery and has been implicated as a mechanism in both positive and negative impacts of bariatric surgery. On the positive side, GLP‐1 has been implicated in increasing postprandial insulin levels to restrain postprandial glucose homeostasis, improvements in insulin sensitivity lead to reductions in fasting insulin, improved hepatic insulin sensitivity, and overall improved β‐cell function. However, on the negative side, the increase in postprandial insulin is thought to contribute to post‐bariatric hypoglycemia which occurs in as much as 30% of surgery patients.

Figure 1. The incretin effect: Glucose levels are lower while insulin levels are higher when the same dose of glucose is administered directly into the gut versus when administered intravenously (IV). This difference in insulin between the gut and venous infusion is the “incretin effect” which occurs in response to GLP‐1 and GIP secreted from the distal gut. Adapted, with permission, from McIntyre N, et al. 153.

Figure 2. Intestinal GLP‐1 secretion: Several factors have been linked to GLP‐1 secretion. The parasympathetic nervous system (PNS) stimulates GLP‐1 secretion via cholinergic muscarinic receptors (MR). Activation of α‐adrenergic (AR) receptors stimulates while activation of β‐adrenergic receptors inhibits GLP‐1 release. Various GPCRS including ones activated by bile acids and various fatty acids stimulate GLP‐1 through PKA signaling and increases in calcium‐induced exocytosis. Lastly, direct glucose sensing, predominantly via SGLT1 in humans, activates sodium (Na+), and calcium (Ca2+) voltage‐gated channels to lead to the release of GLP‐1.

Figure 3. Factors that impact α‐cell GLP‐1 production. Metabolic stress, systemic inflammation, exercise, hyperglycemia, obesity, and diabetes stimulate α‐cell GLP‐1 production. IL‐6 seems to be a primary factor that leads to this increase. The function of this increase is unknown but regulation of β‐cell mass and function is a likely endpoint.

Figure 4. Recent work highlights a more complexity to the role of Gcg‐derived peptides in the incretin effect. While historical work suggests intestinal GLP‐1 is important in regulating glucose homeostasis, there may be a role for α‐cell derived GLP‐1 as well. In addition, in response to amino acids, glucagon is secreted and acts on local GLP‐1r to regulate insulin secretion.

Figure 5. Postprandial GLP‐1 increases several‐fold after bariatric surgery and has been implicated as a mechanism in both positive and negative impacts of bariatric surgery. On the positive side, GLP‐1 has been implicated in increasing postprandial insulin levels to restrain postprandial glucose homeostasis, improvements in insulin sensitivity lead to reductions in fasting insulin, improved hepatic insulin sensitivity, and overall improved β‐cell function. However, on the negative side, the increase in postprandial insulin is thought to contribute to post‐bariatric hypoglycemia which occurs in as much as 30% of surgery patients.
 1.Adams JM, Pei H, Sandoval DA, Seeley RJ, Chang RB, Liberles SD, Olson DP. Liraglutide modulates appetite and body weight through glucagon‐like peptide 1 receptor–expressing glutamatergic neurons. Diabetes 67: 1538‐1548, 2018.
 2.Ahren B, Schmitz O. GLP‐1 receptor agonists and DPP‐4 inhibitors in the treatment of type 2 diabetes. Horm Metab Res 36: 867‐876, 2004.
 3.Ambery P, Parker VE, Stumvoll M, Posch MG, Heise T, Plum‐Moerschel L, Tsai L‐F, Robertson D, Jain M, Petrone M, Rondinone C, Hirshberg B, Jermutus L. MEDI0382, a GLP‐1 and glucagon receptor dual agonist, in obese or overweight patients with type 2 diabetes: A randomised, controlled, double‐blind, ascending dose and phase 2a study. Lancet 391: 2607‐2618, 2018.
 4.Anini Y, Hansotia T, Brubaker PL. Muscarinic receptors control postprandial release of glucagon‐like peptide‐1: In vivo and in vitro studies in rats. Endocrinology 143: 2420‐2426, 2002.
 5.Aulinger BA, Bedorf A, Kutscherauer G, De Heer J, Holst JJ, Göke B, Schirra J. Defining the role of GLP‐1 in the enteroinsulinar axis in type 2 diabetes using DPP‐4 inhibition and GLP‐1 receptor blockade. Diabetes 63: 1079‐1092, 2014.
 6.Aung L, Lee W‐J, Chen SC, Ser K‐H, Wu C‐C, Chong K, Lee Y‐C, Chen J‐C. Bariatric surgery for patients with early‐onset vs late‐onset type 2 diabetes. JAMA Surg 151: 798, 2016.
 7.Baggio LL, Drucker DJ. Biology of incretins: GLP‐1 and GIP. Gastroenterology 132: 2131‐2157, 2007.
 8.Balks HJ, Holst JJ, Brabant G, Medizin ZI, Endokrinologie AK, Hannover MH. Rapid oscillations in plasma glucagon‐like peptide‐1 (GLP‐1) in humans: Cholinergic control of GLP‐1. J Clin Endocrinol Metab 82: 786‐790, 2014.
 9.Barrera JG, Sandoval DA, D'Alessio DA, Seeley RJ. GLP‐1 and energy balance: An integrated model of short‐term and long‐term control. Nat Rev Endocrinol 7: 507‐516, 2011.
 10.Bell GI, Santerre RF, Mullenbach GT. Hamster preproglucagon contains the sequence of glucagon and two related peptides. Nature 302: 716‐718, 1983.
 11.Brandsma E, Houben T, Fu J, Shiri‐Sverdlov R, Hofker MH. The immunity‐diet‐microbiota axis in the development of metabolic syndrome. Curr Opin Lipidol 26: 73‐81, 2015.
 12.Brubaker PL. Control of glucagon‐like immunoreactive peptide secretion from fetal rat intestinal cultures. Endocrinology 123: 220‐226, 1988.
 13.Brubaker PL. Glucagon‐like peptide‐2 and the regulation of intestinal growth and function. In: Comprehensive Physiology. Hoboken, NJ, USA: John Wiley & Sons, Inc., 2018, p. 1185‐1210.
 14.Brubaker PL, Anini Y. Direct and indirect mechanisms regulating secretion of glucagon‐like peptide‐1 and glucagon‐like peptide‐2. Can J Physiol Pharmacol 81: 1005‐1012, 2003.
 15.Brubaker PL, Vranic M. Glucagon‐like immunoreactive peptides in a rat ileal epithelial cell line (IEC‐18). Endocr Res 13: 229‐241, 1987.
 16.Buchan AM, Barber DL, Gregor M, Soll AH. Morphologic and physiologic studies of canine ileal enteroglucagon‐containing cells in short‐term culture. Gastroenterology 93: 791‐800, 1987.
 17.Burmeister MA, Ferre T, Ayala JE, King EM, Holt RM, Ayala JE. Acute activation of central GLP‐1 receptors enhances hepatic insulin action and insulin secretion in high‐fat‐fed, insulin resistant mice. Am J Physiol Endocrinol Metab 302: E334‐E343, 2012.
 18.Burmeister MA, Ayala JE, Smouse H, Landivar‐Rocha A, Brown JD, Drucker DJ, Stoffers DA, Sandoval DA, Seeley RJ, Ayala JE. The hypothalamic glucagon‐like peptide 1 receptor is sufficient but not necessary for the regulation of energy balance and glucose homeostasis in mice. Diabetes 66: 372‐384, 2017.
 19.Buse JB, Nauck M, Forst T, Sheu WH‐H, Shenouda SK, Heilmann CR, Hoogwerf BJ, Gao A, Boardman MK, Fineman M, Porter L, Schernthaner G. Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION‐6): A randomised, open‐label study. Lancet 381: 117‐124, 2013.
 20.Campbell JE, Drucker DJ. Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metab 17: 819‐837, 2013.
 21.Campos RV, Lee YC, Drucker DJ. Divergent tissue‐specific and developmental expression of receptors for glucagon and glucagon‐like peptide‐1 in the mouse. Endocrinology 134: 2156‐2164, 1994.
 22.Capozzi ME, Svendsen B, Encisco SE, Lewandowski SL, Martin MD, Lin H, Jaffe JL, Coch RW, Haldeman JM, MacDonald PE, Merrins MJ, D'Alessio DA, Campbell JE. β Cell tone is defined by proglucagon peptides through cAMP signaling. JCI Insight 4, 2019. DOI: 10.1172/jci.insight.126742.
 23.Capristo E, Panunzi S, De Gaetano A, Spuntarelli V, Bellantone R, Giustacchini P, Birkenfeld AL, Amiel S, Bornstein SR, Raffaelli M, Mingrone G. Incidence of hypoglycemia after gastric bypass versus sleeve gastrectomy: A randomized trial. J Clin Endocrinol Metab 103: 2136‐2146, 2018.
 24.Cavin J‐B, Couvelard A, Lebtahi R, Ducroc R, Arapis K, Voitellier E, Cluzeaud F, Gillard L, Hourseau M, Mikail N, Ribeiro‐Parenti L, Kapel N, Marmuse J‐P, Bado A, Le Gall M. Differences in alimentary glucose absorption and intestinal disposal of blood glucose following Roux‐en‐Y gastric bypass vs sleeve gastrectomy. Gastroenterology, 2016. DOI: 10.1053/j.gastro.2015.10.009.
 25.Chambers AP, Jessen L, Ryan KK, Sisley S, Wilson‐Perez HE, Stefater MA, Gaitonde SG, Sorrell JE, Toure M, Berger J, D'Alessio DA, Woods SC, Seeley RJ, Sandoval DA. Weight‐independent changes in blood glucose homeostasis after gastric bypass or vertical sleeve gastrectomy in rats. Gastroenterology 141: 950‐958, 2011.
 26.Chambers AP, Smith EP, Begg DP, Grayson BE, Sisley S, Greer T, Sorrell J, Lemmen L, Lasance K, Woods SC, Seeley RJ, D'Alessio DA, Sandoval DA. Regulation of gastric emptying rate and its role in nutrient‐induced GLP‐1 secretion in rats after vertical sleeve gastrectomy. Am J Physiol Endocrinol Metab 306: E424‐E432, 2014.
 27.Chambers AP, Sorrell JE, Haller A, Roelofs K, Hutch CR, Kim K‐S, Gutierrez‐Aguilar R, Li B, Drucker DJ, D'Alessio DA, Seeley RJ, Sandoval DA. The role of pancreatic preproglucagon in glucose homeostasis in mice. Cell Metab 25: 927‐934, 2017.
 28.Chiang Y‐T, Ip W, Jin T. The role of the Wnt signaling pathway in incretin hormone production and function. Front Physiol 3: 273, 2012.
 29.Chu Z‐L, Carroll C, Alfonso J, Gutierrez V, He H, Lucman A, Pedraza M, Mondala H, Gao H, Bagnol D, Chen R, Jones RM, Behan DP, Leonard J. A role for intestinal endocrine cell‐expressed g protein‐coupled receptor 119 in glycemic control by enhancing glucagon‐like Peptide‐1 and glucose‐dependent insulinotropic Peptide release. Endocrinology 149: 2038‐2047, 2008.
 30.Conarello SL, Jiang G, Mu J, Li Z, Woods J, Zycband E, Ronan J, Liu F, Roy RS, Zhu L, Charron MJ, Zhang BB. Glucagon receptor knockout mice are resistant to diet‐induced obesity and streptozotocin‐mediated beta cell loss and hyperglycaemia. Diabetologia 50: 142‐150, 2007.
 31.Cox AR, Lam CJ, Rankin MM, Rios JS, Chavez J, Bonnyman CW, King KB, Wells RA, Anthony D, Tu JX, Kim JJ, Li C, Kushner JA. Incretin therapies do not expand β‐cell mass or alter pancreatic histology in young male mice. Endocrinology 158: 1701‐1714, 2017.
 32.Craig CM, Liu L‐F, Deacon CF, Holst JJ, McLaughlin TL. Critical role for GLP‐1 in symptomatic post‐bariatric hypoglycaemia. Diabetologia 60: 531‐540, 2017.
 33.Craig CM, Liu L, Nguyen T, Price C, Bingham J, McLaughlin TL. Efficacy and pharmacokinetics of subcutaneous exendin (9‐39) in patients with post‐bariatric hypoglycaemia. Diabetes Obes Metab 20: 352‐361, 2018.
 34.Creutzfeldt WOC, Kleine N, Willms B, Orskov C, Holst JJ, Nauck MA. Glucagonostatic actions and reduction of fasting hyperglycemia by exogenous glucagon‐like peptide I(7‐36) amide in type I diabetic patients. Diabetes Care 19: 580‐586, 1996.
 35.D'Alessio D, Lu W, Sun W, Zheng S, Yang Q, Seeley R, Woods SC, Tso P. Fasting and postprandial concentrations of GLP‐1 in intestinal lymph and portal plasma: Evidence for selective release of GLP‐1 in the lymph system. Am J Physiol Regul Integr Comp Physiol 293: R2163‐R2169, 2007.
 36.Dai C, Hang Y, Shostak A, Poffenberger G, Hart N, Prasad N, Phillips N, Levy SE, Greiner DL, Shultz LD, Bottino R, Kim SK, Powers AC. Age‐dependent human β cell proliferation induced by glucagon‐like peptide 1 and calcineurin signaling. J Clin Invest 127: 3835‐3844, 2017.
 37.Day JW, Gelfanov V, Smiley D, Carrington PE, Eiermann G, Chicchi G, Erion MD, Gidda J, Thornberry NA, Tschöp MH, Marsh DJ, SinhaRoy R, DiMarchi R, Pocai A. Optimization of co‐agonism at GLP‐1 and glucagon receptors to safely maximize weight reduction in DIO‐rodents. Biopolymers 98: 443‐450, 2012.
 38.Day JW, Ottaway N, Patterson JT, Gelfanov V, Smiley D, Gidda J, Findeisen H, Bruemmer D, Drucker DJ, Chaudhary N, Holland J, Hembree J, Abplanalp W, Grant E, Ruehl J, Wilson H, Kirchner H, Lockie SH, Hofmann S, Woods SC, Nogueiras R, Pfluger PT, Perez‐Tilve D, DiMarchi R, Tschöp MH. A new glucagon and GLP‐1 co‐agonist eliminates obesity in rodents. Nat Chem Biol 5: 749‐757, 2009.
 39.Deacon CF, Nauck MA, Toft‐Nielsen M, Pridal L, Willms B, Holst JJ. Both subcutaneously and intravenously administered glucagon‐like peptide I are rapidly degraded from the NH2‐terminus in type II diabetic patients and in healthy subjects. Diabetes 44: 1126‐1131, 1995.
 40.Dimick JB, Nicholas LH, Ryan AM, Thumma JR, Birkmeyer JD. Bariatric surgery complications before vs after implementation of a national policy restricting coverage to centers of excellence. JAMA 309: 792‐799, 2013.
 41.Ding L, Sousa KM, Jin L, Dong B, Kim B‐W, Ramirez R, Xiao Z, Gu Y, Yang Q, Wang J, Yu D, Pigazzi A, Schones D, Yang L, Moore D, Wang Z, Huang W. Vertical sleeve gastrectomy activates GPBAR‐1/TGR5 to sustain weight loss, improve fatty liver, and remit insulin resistance in mice. Hepatology 64: 760‐773, 2016.
 42.Ding X, Saxena NK, Lin S, Gupta NA, Gupta N, Anania FA. Exendin‐4, a glucagon‐like protein‐1 (GLP‐1) receptor agonist, reverses hepatic steatosis in ob/ob mice. Hepatology 43: 173‐181, 2006.
 43.Dirksen C, Bojsen‐Møller KN, Jørgensen NB, Jacobsen SH, Kristiansen VB, Naver LS, Hansen DL, Worm D, Holst JJ, Madsbad S. Exaggerated release and preserved insulinotropic action of glucagon‐like peptide‐1 underlie insulin hypersecretion in glucose‐tolerant individuals after Roux‐en‐Y gastric bypass. Diabetologia 56: 2679‐2687, 2013.
 44.Douros JD, Lewis AG, Smith EP, Niu J, Capozzi M, Wittmann A, Campbell J, Tong J, Wagner C, Mahbod P, Seeley R, D'Alessio DA. Enhanced glucose control following vertical sleeve gastrectomy does not require a β‐cell glucagon‐like peptide 1 receptor. Diabetes 67: 1504‐1511, 2018.
 45.Douros JD, Niu J, Sdao SM, Gregg T, Fisher‐Wellman KH, Bharadwaj MS, Molina A, Arumugam R, Martin MD, Petretto E, Merrins MJ, Herman MA, Tong J, Campbell JE, D'Alessio D. Sleeve gastrectomy rapidly enhances islet function independently of body weight. JCI Insight 4: 126688, 2019.
 46.Drucker DJ. Dipeptidyl peptidase‐4 inhibition and the treatment of type 2 diabetes: Preclinical biology and mechanisms of action. Diabetes Care 30: 1335‐1343, 2007.
 47.Drucker DJ. Incretin action in the pancreas: Potential promise, possible perils, and pathological pitfalls. Diabetes 62: 3316‐3323, 2013.
 48.Drucker DJ. The ascending GLP‐1 road from clinical safety to reduction of cardiovascular complications. Diabetes 67: 1710‐1719, 2018.
 49.Drucker DJ, Brubaker PL. Proglucagon gene expression is regulated by a cyclic AMP‐dependent pathway in rat intestine. Proc Natl Acad Sci U S A 86: 3953‐3957, 1989.
 50.Drucker DJ, Buse JB, Taylor K, Kendall DM, Trautmann M, Zhuang D, Porter L. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: A randomised, open‐label, non‐inferiority study. Lancet 372: 1240‐1250, 2008.
 51.Drucker DJ, Nauck MA. The incretin system: Glucagon‐like peptide‐1 receptor agonists and dipeptidyl peptidase‐4 inhibitors in type 2 diabetes. Lancet 368: 1696‐1705, 2006.
 52.Dumoulin V, Dakka T, Plaisancie P, Chayvialle JA, Cuber JC. Regulation of glucagon‐like peptide‐1‐(7‐36) amide, peptide YY, and neurotensin secretion by neurotransmitters and gut hormones in the isolated vascularly perfused rat ileum. Endocrinology 136: 5182‐5188, 1995.
 53.Dunning BE, Foley JE, Ahren B. Alpha cell function in health and disease: Influence of glucagon‐like peptide‐1. Diabetologia 48: 1700‐1713, 2005.
 54.Dupre J, Ross SA, Watson D, Brown JC. Stimulation of insulin secretion by gastric inhibitory peptide in man. J Clin Endocrinol Metab 37: 826‐828, 1973.
 55.Dutia R, Embrey M, O'Brien S, Haeusler RA, Agénor KK, Homel P, McGinty J, Vincent RP, Alaghband‐Zadeh J, Staels B, le Roux CW, Yu J, Laferrère B. Temporal changes in bile acid levels and 12α‐hydroxylation after Roux‐en‐Y gastric bypass surgery in type 2 diabetes. Int J Obes (Lond) 39: 806‐813, 2015.
 56.Ebert R, Unger H, Creutzfeldt W. Preservation of incretin activity after removal of gastric inhibitory polypeptide (GIP) from rat gut extracts by immunoadsorption. Diabetologia 24: 449‐454, 1983.
 57.Edfalk S, Steneberg P, Edlund H. Gpr40 is expressed in enteroendocrine cells and mediates free fatty acid stimulation of incretin secretion. Diabetes 57: 2280‐2287, 2008.
 58.Eissele R, Göke R, Willemer S, Harthus HP, Vermeer H, Arnold R, Göke B. Glucagon‐like peptide‐1 cells in the gastrointestinal tract and pancreas of rat, pig and man. Eur J Clin Invest 22: 283‐291, 1992.
 59.Ellingsgaard H, Ehses JA, Hammar EB, Van Lommel L, Quintens R, Martens G, Kerr‐Conte J, Pattou F, Berney T, Pipeleers D, Halban PA, Schuit FC, Donath MY. Interleukin‐6 regulates pancreatic alpha‐cell mass expansion. Proc Natl Acad Sci U S A 105: 13163‐13168, 2008.
 60.Ellingsgaard H, Hauselmann I, Schuler B, Habib AM, Baggio LL, Meier DT, Eppler E, Bouzakri K, Wueest S, Muller YD, Hansen AMK, Reinecke M, Konrad D, Gassmann M, Reimann F, Halban PA, Gromada J, Drucker DJ, Gribble FM, Ehses JA, Donath MY. Interleukin‐6 enhances insulin secretion by increasing glucagon‐like peptide‐1 secretion from L cells and alpha cells. Nat Med 17: 1481‐1489, 2011.
 61.Elrick H, Stimmer L, Hlad CJ, Arai Y. Plasma insulin response to oral and intravenous glucose administration. J Clin Endocrinol Metab 24: 1076‐1082, 1964.
 62.Falken Y, Hellstrom PM, Holst JJ, Naslund E. Changes in glucose homeostasis after Roux‐en‐Y gastric bypass surgery for obesity at day three, two months, and one year after surgery: Role of gut peptides. J Clin Endocrinol Metab 96: 2227‐2235, 2011.
 63.Ferraris RP, Yasharpour S, Lloyd KC, Mirzayan R, Diamond JM. Luminal glucose concentrations in the gut under normal conditions. Am J Physiol 259: G822‐G837, 1990.
 64.Fineman M, Weyer C, Maggs DG, Strobel S, Kolterman OG. The human amylin analog, pramlintide, reduces postprandial hyperglucagonemia in patients with type 2 diabetes mellitus. Horm Metab Res 34: 504‐508, 2002.
 65.Flannick J, Thorleifsson G, Beer NL, Jacobs SBR, Grarup N, Burtt NP, Mahajan A, Fuchsberger C, Atzmon G, Benediktsson R, Blangero J, Bowden DW, Brandslund I, Brosnan J, Burslem F, Chambers J, Cho YS, Christensen C, Douglas DA, Duggirala R, Dymek Z, Farjoun Y, Fennell T, Fontanillas P, Forsén T, Gabriel S, Glaser B, Gudbjartsson DF, Hanis C, Hansen T, Hreidarsson AB, Hveem K, Ingelsson E, Isomaa B, Johansson S, Jørgensen T, Jørgensen ME, Kathiresan S, Kong A, Kooner J, Kravic J, Laakso M, Lee J‐Y, Lind L, Lindgren CM, Linneberg A, Masson G, Meitinger T, Mohlke KL, Molven A, Morris AP, Potluri S, Rauramaa R, Ribel‐Madsen R, Richard A‐M, Rolph T, Salomaa V, Segrè AV, Skärstrand H, Steinthorsdottir V, Stringham HM, Sulem P, Tai ES, Teo YY, Teslovich T, Thorsteinsdottir U, Trimmer JK, Tuomi T, Tuomilehto J, Vaziri‐Sani F, Voight BF, Wilson JG, Boehnke M, McCarthy MI, Njølstad PR, Pedersen O, Groop L, Cox DR, Stefansson K, Altshuler D, Stefansson K, Altshuler D. Loss‐of‐function mutations in SLC30A8 protect against type 2 diabetes. Nat Genet 46: 357‐363, 2014.
 66.Flock G, Baggio LL, Longuet C, Drucker DJ. Incretin receptors for glucagon‐like peptide 1 and glucose‐dependent insulinotropic polypeptide are essential for the sustained metabolic actions of vildagliptin in mice. Diabetes 56: 3006‐3013, 2007.
 67.Frias JP, Nauck MA, Van J, Kutner ME, Cui X, Benson C, Urva S, Gimeno RE, Milicevic Z, Robins D, Haupt A. Efficacy and safety of LY3298176, a novel dual GIP and GLP‐1 receptor agonist, in patients with type 2 diabetes: A randomised, placebo‐controlled and active comparator‐controlled phase 2 trial. Lancet 392: 2180‐2193, 2018.
 68.Fusco J, Xiao X, Prasadan K, Sheng Q, Chen C, Ming Y‐C, Gittes G. GLP‐1/Exendin‐4 induces β‐cell proliferation via the epidermal growth factor receptor. Sci Rep 7: 9100, 2017.
 69.Garibay D, McGavigan AK, Lee SA, Ficorilli JV, Cox AL, Michael MD, Sloop KW, Cummings BP. β‐Cell glucagon‐like peptide‐1 receptor contributes to improved glucose tolerance after vertical sleeve gastrectomy. Endocrinology 157: 3405‐3409, 2016.
 70.Gedulin BR, Jodka CM, Herrmann K, Young AA. Role of endogenous amylin in glucagon secretion and gastric emptying in rats demonstrated with the selective antagonist, AC187. Regul Pept 137: 121‐127, 2006.
 71.Gedulin BR, Rink TJ, Young AA. Dose‐response for glucagonostatic effect of amylin in rats. Metabolism 46: 67‐70, 1997.
 72.Gerich JE, Langlois M, Schneider V, Karam JH, Noacco C. Effects of alterations of plasma free fatty acid levels on pancreatic glucagon secretion in man. J Clin Invest 53: 1284‐1289, 1974.
 73.Gevrey J‐C, Malapel M, Philippe J, Mithieux G, Chayvialle J, Abello J, Cordier‐Bussat M. Protein hydrolysates stimulate proglucagon gene transcription in intestinal endocrine cells via two elements related to cyclic AMP response element. Diabetologia 47: 926‐936, 2004.
 74.Goke R, Larsen PJ, Mikkelsen JD, Sheikh SP. Distribution of GLP‐1 binding sites in the rat brain: Evidence that exendin‐4 is a ligand of brain GLP‐1 binding sites. Eur J Neurosci 7: 2294‐2300, 1995.
 75.Goldfine AB, Mun EC, Devine E, Bernier R, Baz‐Hecht M, Jones DB, Schneider BE, Holst JJ, Patti ME. Patients with neuroglycopenia after gastric bypass surgery have exaggerated incretin and insulin secretory responses to a mixed meal. J Clin Endocrinol Metab 92: 4678‐4685, 2007.
 76.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 7: 90‐101, 2018.
 77.Gromada J, Franklin I, Wollheim CB. Alpha‐cells of the endocrine pancreas: 35 years of research but the enigma remains. Endocr Rev 28: 84‐116, 2007.
 78.Gupta NA, Mells J, Dunham RM, Grakoui A, Handy J, Saxena NK, Anania FA. Glucagon‐like peptide‐1 receptor is present on human hepatocytes and has a direct role in decreasing hepatic steatosis in vitro by modulating elements of the insulin signaling pathway. Hepatology 51: 1584‐1592, 2010.
 79.Gyulkhandanyan AV, Lu H, Lee SC, Bhattacharjee A, Wijesekara N, Fox JEM, MacDonald PE, Chimienti F, Dai FF, Wheeler MB. Investigation of transport mechanisms and regulation of intracellular Zn2+ in pancreatic alpha‐cells. J Biol Chem 283: 10184‐10197, 2008.
 80.Habegger KM, Heppner KM, Amburgy SE, Ottaway N, Holland J, Raver C, Bartley E, Müller TD, Pfluger PT, Berger J, Toure M, Benoit SC, Dimarchi RD, Perez‐Tilve D, D'Alessio DA, Seeley RJ, Tschöp MH. GLP‐1R responsiveness predicts individual gastric bypass efficacy on glucose tolerance in rats. Diabetes, 2014. DOI: 10.2337/db13‐0511.
 81.Han VKM, Hynes MA, Jin C, Towle AC, Lauder JM, Lund PK. Cellular localization of proglucagon/glucagon‐like peptide 1 messenger RNAs in rat brain. J Neurosci 16: 97‐107, 1986.
 82.Hansen L, Deacon CF, Ørskov C, Holst JJ. Glucagon‐like peptide‐1‐(7‐36) amide is transformed to glucagon‐like peptide‐1‐(9‐36) amide by dipeptidyl peptidase IV in the capillaries supplying the L cells of the porcine intestine. Endocrinology 140: 5356‐5363, 1999.
 83.Hansen L, Holst JJ. The effects of duodenal peptides on glucagon‐like peptide‐1 secretion from the ileum. A duodeno–ileal loop? Regul Pept 110: 39‐45, 2002.
 84.Hansen L, Lampert S, Mineo H, Holst JJ. Neural regulation of glucagon‐like peptide‐1 secretion in pigs. Am J Physiol Endocrinol Metab 287: E939‐E947, 2004.
 85.Hansotia T, Baggio LL, Delmeire D, Hinke SA, Yamada Y, Tsukiyama K, Seino Y, Holst JJ, Schuit F, Drucker DJ. Double incretin receptor knockout (DIRKO) mice reveal an essential role for the enteroinsular axis in transducing the glucoregulatory actions of DPP‐IV inhibitors. Diabetes 53: 1326‐1335, 2004.
 86.Hare KJ, Vilsbøll T, Asmar M, Deacon CF, Knop FK, Holst JJ. The glucagonostatic and insulinotropic effects of glucagon‐like peptide 1 contribute equally to its glucose‐lowering action. Diabetes 59: 1765‐1770, 2010.
 87.Hauge M, Ekberg JP, Engelstoft MS, Timshel P, Madsen AN, Schwartz TW. Gq and Gs signaling acting in synergy to control GLP‐1 secretion. Mol Cell Endocrinol 449: 64‐73, 2017.
 88.Hayes MR, Leichner TM, Zhao S, Lee GS, Chowansky A, Zimmer D, De Jonghe BC, Kanoski SE, Grill HJ, Bence KK. Intracellular signals mediating the food intake‐suppressive effects of hindbrain glucagon‐like peptide‐1 receptor activation. Cell Metab 13: 320‐330, 2011. Heer J, Rasmussen C, Coy DH, Holst JJ. Glucagon‐like peptide‐1, but not glucose‐dependent insulinotropic peptide, inhibits glucagon secretion via somatostatin (receptor subtype 2) in the perfused rat pancreas. Diabetologia 51: 2263‐2270, 2008.
 90.Hira T, Mochida T, Miyashita K, Hara H. GLP‐1 secretion is enhanced directly in the ileum but indirectly in the duodenum by a newly identified potent stimulator, zein hydrolysate, in rats. Am J Physiol Gastrointest Liver Physiol 297: G663‐G671, 2009.
 91.Hirasawa A, Tsumaya K, Awaji T, Katsuma S, Adachi T, Yamada M, Sugimoto Y, Miyazaki S, Tsujimoto G. Free fatty acids regulate gut incretin glucagon‐like peptide‐1 secretion through GPR120. Nat Med 11: 90‐94, 2005.
 92.Holst JJ, Bersani M, Johnsen AH, Kofod H, Hartmann B, Orskov C. Proglucagon processing in porcine and human pancreas. J Biol Chem 269: 18827‐18833, 1994.
 93.Holst JJ, Deacon CF. Glucagon‐like peptide‐1 mediates the therapeutic actions of DPP‐IV inhibitors. Diabetologia 48: 612‐615, 2005.
 94.Holz GG. Epac: A new cAMP‐binding protein in support of glucagon‐like peptide‐1 receptor‐mediated signal transduction in the pancreatic beta‐cell. Diabetes 53: 5‐13, 2004.
 95.Honka H, Koffert J, Hannukainen JC, Tuulari JJ, Karlsson HK, Immonen H, Oikonen V, Tolvanen T, Soinio M, Salminen P, Kudomi N, Mari A, Iozzo P, Nuutila P. The effects of bariatric surgery on pancreatic lipid metabolism and blood flow. J Clin Endocrinol Metab 100: 2015‐2023, 2015.
 96.Hudson BD, Smith NJ, Milligan G. Experimental challenges to targeting poorly characterized GPCRs: Uncovering the therapeutic potential for free fatty acid receptors. Adv Pharmacol 62: 175‐218, 2011.
 97.Hui H, Nourparvar A, Zhao X, Perfetti R. Glucagon‐like peptide‐1 inhibits apoptosis of insulin‐secreting cells via a cyclic 5′‐adenosine monophosphate‐dependent protein kinase A‐ and a phosphatidylinositol 3‐kinase‐dependent pathway. Endocrinology 144: 1444‐1455, 2003.
 98.Hurren KM, Pinelli NR. Drug‐drug interactions with glucagon‐like peptide‐1 receptor agonists. Ann Pharmacother 46: 710‐717, 2012.
 99.Ichimura A, Hirasawa A, Poulain‐Godefroy O, Bonnefond A, Hara T, Yengo L, Kimura I, Leloire A, Liu N, Iida K, Choquet H, Besnard P, Lecoeur C, Vivequin S, Ayukawa K, Takeuchi M, Ozawa K, Tauber M, Maffeis C, Morandi A, Buzzetti R, Elliott P, Pouta A, Jarvelin M‐R, Körner A, Kiess W, Pigeyre M, Caiazzo R, Van Hul W, Van Gaal L, Horber F, Balkau B, Lévy‐Marchal C, Rouskas K, Kouvatsi A, Hebebrand J, Hinney A, Scherag A, Pattou F, Meyre D, Koshimizu T, Wolowczuk I, Tsujimoto G, Froguel P. Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human. Nature 483: 350‐354, 2012.
 100.Ishihara H, Maechler P, Gjinovci A, Herrera P‐L, Wollheim CB. Islet beta‐cell secretion determines glucagon release from neighbouring alpha‐cells. Nat Cell Biol 5: 330‐335, 2003.
 101.Islam D, Zhang N, Wang P, Li H, Brubaker PL, Gaisano HY, Wang Q, Jin T. Epac is involved in cAMP‐stimulated proglucagon expression and hormone production but not hormone secretion in pancreatic alpha‐ and intestinal L‐cell lines. Am J Physiol Endocrinol Metab 296: E174‐E181, 2009.
 102.Jang H‐J, Kokrashvili Z, Theodorakis MJ, Carlson OD, Kim B‐J, Zhou J, Kim HH, Xu X, Chan SL, Juhaszova M, Bernier M, Mosinger B, Margolskee RF, Egan JM. Gut‐expressed gustducin and taste receptors regulate secretion of glucagon‐like peptide‐1. Proc Natl Acad Sci U S A 104: 15069‐15074, 2007.
 103.Jensen PB, Blume N, Mikkelsen JD, Larsen PJ, Jensen HI, Holst JJ, Madsen OD. Transplantable rat glucagonomas cause acute onset of severe anorexia and adipsia despite highly elevated NPY mRNA levels in the hypothalamic arcuate nucleus. J Clin Invest 101: 503‐510, 1998.
 104.Jessen L, Smith EP, Ulrich‐Lai Y, Herman JP, Seeley RJ, Sandoval D, D'Alessio D. Central nervous system GLP‐1 receptors regulate islet hormone secretion and glucose homeostasis in male rats. Endocrinology 158: 2124‐2133, 2017.
 105.Jiménez A, Casamitjana R, Viaplana‐Masclans J, Lacy A, Vidal J. GLP‐1 action and glucose tolerance in subjects with remission of type 2 diabetes after gastric bypass surgery. Diabetes Care 36: 2062‐2069, 2013.
 106.Jiménez A, Ceriello A, Casamitjana R, Flores L, Viaplana‐Masclans J, Vidal J. Remission of type 2 diabetes after Roux‐en‐Y gastric bypass or sleeve gastrectomy is associated with a distinct glycemic profile. Ann Surg 261: 316‐322, 2015.
 107.Jiménez A, Mari A, Casamitjana R, Lacy A, Ferrannini E, Vidal J. GLP‐1 and glucose tolerance after sleeve gastrectomy in morbidly obese subjects with type 2 diabetes. Diabetes 63: 3372‐3377, 2014.
 108.Jin SL, Han VKM, Simmons JG, Towle AC, Lauder JM, Lund PK. Distribution of glucagonlike peptide 1, glucagon, and glicentin in the rat brain: An immunocytochemical study. J Comp Neurol 271: 519‐532, 1988.
 109.Jin T. Mechanisms underlying proglucagon gene expression. J Endocrinol 198: 17‐28, 2008.
 110.Jørgensen NB, Dirksen C, Bojsen‐Møller KN, Jacobsen SH, Worm D, Hansen DL, Kristiansen VB, Naver L, Madsbad S, Holst JJ. 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 62: 3044‐3052, 2013.
 111.Kahles F, Meyer C, Möllmann J, Diebold S, Findeisen HM, Lebherz C, Trautwein C, Koch A, Tacke F, Marx N, Lehrke M. GLP‐1 secretion is increased by inflammatory stimuli in an IL‐6‐dependent manner, leading to hyperinsulinemia and blood glucose lowering. Diabetes 63: 3221‐3229, 2014.
 112.Kang JH, Le QA. Effectiveness of bariatric surgical procedures: A systematic review and network meta‐analysis of randomized controlled trials. Medicine (Baltimore) 96: e8632, 2017.
 113.Kanoski SE, Rupprecht LE, Fortin SM, De Jonghe BC, Hayes MR. The role of nausea in food intake and body weight suppression by peripheral GLP‐1 receptor agonists, exendin‐4 and liraglutide. Neuropharmacology 62: 1916‐1927, 2012.
 114.Kapodistria K, Tsilibary E‐P, Kotsopoulou E, Moustardas P, Kitsiou P. Liraglutide, a human glucagon‐like peptide‐1 analogue, stimulates AKT‐dependent survival signalling and inhibits pancreatic β‐cell apoptosis. J Cell Mol Med 22: 2970‐2980, 2018.
 115.Katsuma S, Hirasawa A, Tsujimoto G. Bile acids promote glucagon‐like peptide‐1 secretion through TGR5 in a murine enteroendocrine cell line STC‐1. Biochem Biophys Res Commun 329: 386‐390, 2005.
 116.Katz LB, Gambale JJ, Rothenberg PL, Vanapalli SR, Vaccaro N, Xi L, Sarich TC, Stein PP. Effects of JNJ‐38431055, a novel GPR119 receptor agonist, in randomized, double‐blind, placebo‐controlled studies in subjects with type 2 diabetes. Diabetes Obes Metab 14: 709‐716, 2012.
 117.Kielgast U, Asmar M, Madsbad S, Holst JJ. Effect of glucagon‐like peptide‐1 on alpha‐ and beta‐cell function in C‐peptide‐negative type 1 diabetic patients. J Clin Endocrinol Metab 95: 2492‐2496, 2010.
 118.Kilimnik G, Kim A, Steiner DF, Friedman TC, Hara M. Intraislet production of GLP‐1 by activation of prohormone convertase 1/3 in pancreatic α‐cells in mouse models of ß‐cell regeneration. Islets 2: 149‐155, 2010.
 119.Kim K‐S, Seeley RJ, Sandoval DA. Signalling from the periphery to the brain that regulates energy homeostasis. Nat Rev Neurosci 19: 185‐196, 2018.
 120.Kindel TL, Yang Q, Yoder SM, Tso P. Nutrient‐driven incretin secretion into intestinal lymph is different between diabetic Goto‐Kakizaki rats and Wistar rats. Am J Physiol Gastrointest Liver Physiol 296: G168‐G174, 2009.
 121.Kinzig KP, D'Alessio DA, Herman JP, Sakai RR, Vahl TP, Figueiredo HF, Murphy EK, Seeley RJ. CNS glucagon‐like peptide‐1 receptors mediate endocrine and anxiety responses to interoceptive and psychogenic stressors. J Neurosci 23: 6163‐6170, 2003.
 122.Knauf C, Cani PD, Perrin C, Iglesias MA, Maury JF, Bernard E, Benhamed F, Gremeaux T, Drucker DJ, Kahn CR, Girard J, Tanti JF, Delzenne NM, Postic C, Burcelin R. Brain glucagon‐like peptide‐1 increases insulin secretion and muscle insulin resistance to favor hepatic glycogen storage. J Clin Invest 115: 3554‐3563, 2005.
 123.Knop FK, Aaboe K, Vilsbøll T, Vølund A, Holst JJ, Krarup T, Madsbad S. Impaired incretin effect and fasting hyperglucagonaemia characterizing type 2 diabetic subjects are early signs of dysmetabolism in obesity. Diabetes Obes Metab 14: 500‐510, 2012.
 124.Kohli R, Bradley D, Setchell KD, Eagon JC, Abumrad N, Klein S. Weight loss induced by Roux‐en‐Y gastric bypass but not laparoscopic adjustable gastric banding increases circulating bile acids. J Clin Endocrinol Metab 98: E708‐E712, 2013.
 125.Koopmann MC, Nelson DW, Murali SG, Liu X, Brownfield MS, Holst JJ, Ney DM. Exogenous glucagon‐like peptide‐2 (GLP‐2) augments GLP‐2 receptor mRNA and maintains proglucagon mRNA levels in resected rats. JPEN J Parenter Enteral Nutr 32: 254‐265.
 126.Kreymann B, Ghatei MA, Domin J, Kanse S, Bloom SR. Developmental patterns of glucagon‐like peptide‐1‐(7–36) amide and peptide‐YY in rat pancreas and gut. Endocrinology 129: 1001‐1005, 1991.
 127.Kreymann B, Ghatei MA, Williams G, Bloom SR. Glucagon‐like peptide‐1 7‐36: A physiological incretin in man. Lancet 2: 1300‐1303, 1987.
 128.Kuhre RE, Frost CR, Svendsen B, Holst JJ. Molecular mechanisms of glucose‐stimulated GLP‐1 secretion from perfused rat small intestine. Diabetes 64: 370‐382, 2015.
 129.Lachey JL, D'Alessio DA, Rinaman L, Elmquist JK, Drucker DJ, Seeley RJ. The role of central glucagon‐like peptide‐1 in mediating the effects of visceral illness: Differential effects in rats and mice. Endocrinology 146: 458‐462, 2005.
 130.Laferrere B, Heshka S, Wang K, Khan Y, McGinty J, Teixeira J, Hart AB, Olivan B. Incretin levels and effect are markedly enhanced 1 month after Roux‐en‐Y gastric bypass surgery in obese patients with type 2 diabetes. Diabetes Care 30: 1709‐1716, 2007.
 131.Lamont BJ, Li Y, Kwan E, Brown TJ, Gaisano H, Drucker DJ. Pancreatic GLP‐1 receptor activation is sufficient for incretin control of glucose metabolism in mice. J Clin Invest 122: 388‐402, 2012.
 132.Lan H, Vassileva G, Corona A, Liu L, Baker H, Golovko A, Abbondanzo SJ, Hu W, Yang S, Ning Y, Del Vecchio RA, Poulet F, Laverty M, Gustafson EL, Hedrick JA, Kowalski TJ. GPR119 is required for physiological regulation of glucagon‐like peptide‐1 secretion but not for metabolic homeostasis. J Endocrinol 201: 219‐230, 2009.
 133.Langlois A, Dal S, Vivot K, Mura C, Seyfritz E, Bietiger W, Dollinger C, Peronet C, Maillard E, Pinget M, Jeandidier N, Sigrist S. Improvement of islet graft function using liraglutide is correlated with its anti‐inflammatory properties. Br J Pharmacol 173: 3443‐3453, 2016.
 134.Larsen PJ, Tang‐Christensen M, Holst JJ, Orskov C. Distribution of glucagon‐like peptide‐1 and other preproglucagon‐derived peptides in the rat hypothalamus and brainstem. Neuroscience 77: 257‐270, 1997.
 135.Lee CJ, Wood GC, Lazo M, Brown TT, Clark JM, Still C, Benotti P. Risk of post‐gastric bypass surgery hypoglycemia in nondiabetic individuals: A single center experience. Obesity 24: 1342‐1348, 2016.
 136.Light PE, Manning Fox JE, Riedel MJ, Wheeler MB. Glucagon‐like peptide‐1 inhibits pancreatic ATP‐sensitive potassium channels via a protein kinase A‐ and ADP‐dependent mechanism. Mol Endocrinol 16: 2135‐2144, 2002.
 137.Lin HV, Wang J, Wang J, Li W, Wang X, Alston JT, Thomas MK, Briere DA, Syed SK, Efanov AM. GPR142 prompts glucagon‐like Peptide‐1 release from islets to improve β cell function. Mol Metab 11: 205‐211, 2018.
 138.Linnemann AK, Neuman JC, Battiola TJ, Wisinski JA, Kimple ME, Davis DB. Glucagon‐like peptide‐1 regulates cholecystokinin production in β‐cells to protect from apoptosis. Mol Endocrinol 29: 978‐987, 2015.
 139.Liu Z, Habener JF. Glucagon‐like peptide‐1 activation of TCF7L2‐dependent Wnt signaling enhances pancreatic beta cell proliferation. J Biol Chem 283: 8723‐8735, 2008.
 140.Lotfi S, Li Z, Sun J, Zuo Y, Lam PPL, Kang Y, Rahimi M, Islam D, Wang P, Gaisano HY, Jin T. Role of the exchange protein directly activated by cyclic adenosine 5′‐monophosphate (Epac) pathway in regulating proglucagon gene expression in intestinal endocrine L cells. Endocrinology 147: 3727‐3736, 2006.
 141.Lü F, Jin T, Drucker DJ. Proglucagon gene expression is induced by gastrin‐releasing peptide in a mouse enteroendocrine cell line. Endocrinology 137: 3710‐3716, 1996.
 142.Lund PK, Goodman RH, Dee PC, Habener JF. Pancreatic preproglucagon cDNA contains two glucagon‐related coding sequences arranged in tandem. Proc Natl Acad Sci U S A 79: 345‐349, 1982.
 143.Luo J, Swaminath G, Brown SP, Zhang J, Guo Q, Chen M, Nguyen K, Tran T, Miao L, Dransfield PJ, Vimolratana M, Houze JB, Wong S, Toteva M, Shan B, Li F, Zhuang R, Lin DC‐H. A potent class of GPR40 full agonists engages the enteroinsular axis to promote glucose control in rodents. PLoS One 7: e46300, 2012.
 144.MacDonald PE, Salapatek AMF, Wheeler MB. Glucagon‐like peptide‐1 receptor activation antagonizes voltage‐dependent repolarizing K(+) currents in beta‐cells: A possible glucose‐dependent insulinotropic mechanism. Diabetes 51 (Suppl 3): S443‐S447, 2002.
 145.Mace OJ, Schindler M, Patel S. The regulation of K‐ and L‐cell activity by GLUT2 and the calcium‐sensing receptor CasR in rat small intestine. J Physiol 590: 2917‐2936, 2012.
 146.Maersk M, Belza A, Holst JJ, Fenger‐Grøn M, Pedersen SB, Astrup A, Richelsen B. Satiety scores and satiety hormone response after sucrose‐sweetened soft drink compared with isocaloric semi‐skimmed milk and with non‐caloric soft drink: A controlled trial. Eur J Clin Nutr 66: 523‐529, 2012.
 147.Le Marchand SJ, Piston DW. Glucose suppression of glucagon secretion: Metabolic and calcium responses from alpha‐cells in intact mouse pancreatic islets. J Biol Chem 285: 14389‐14398, 2010.
 148.De Marinis YZ, Salehi A, Ward CE, Zhang Q, Abdulkader F, Bengtsson M, Braha O, Braun M, Ramracheya R, Amisten S, Habib AM, Moritoh Y, Zhang E, Reimann F, Rosengren AH, Shibasaki T, Gribble F, Renström E, Seino S, Eliasson L, Rorsman P. GLP‐1 inhibits and adrenaline stimulates glucagon release by differential modulation of N‐ and L‐type Ca2+ channel‐dependent exocytosis. Cell Metab 11: 543‐553, 2010.
 149.Marre M, Penfornis A. GLP‐1 receptor agonists today. Diabetes Res Clin Pract 93: 317‐327, 2011.
 150.Marsk R, Jonas E, Rasmussen F, Näslund E. Nationwide cohort study of post‐gastric bypass hypoglycaemia including 5,040 patients undergoing surgery for obesity in 1986–2006 in Sweden. Diabetologia 53: 2307‐2311, 2010.
 151.McGavigan AK, Garibay D, Henseler ZM, Chen J, Bettaieb A, Haj FG, Ley RE, Chouinard ML, Cummings BP. TGR5 contributes to glucoregulatory improvements after vertical sleeve gastrectomy in mice. Gut, 2017. DOI: 10.1136/gutjnl‐2015‐309871.
 152.McGirr R, Ejbick CE, Carter DE, Andrews JD, Nie Y, Friedman TC, Dhanvantari S. Glucose dependence of the regulated secretory pathway in alphaTC1‐6 cells. Endocrinology 146: 4514‐4523, 2005.
 153.McIntyre N, Holsworth DC, Turner DS. New interpretation of oral glucose tolerance. Lancet 2: 20‐21, 1964.
 154.Melissas J, Koukouraki S, Askoxylakis J, Stathaki M, Daskalakis M, Perisinakis K, Karkavitsas N. Sleeve gastrectomy—A restrictive procedure? Obes Surg 17: 57, 2007.
 155.Moens K, Flamez D, Van Schravendijk C, Ling Z, Pipeleers D, Schuit F. Dual glucagon recognition by pancreatic beta‐cells via glucagon and glucagon‐like peptide 1 receptors. Diabetes 47: 66‐72, 1998.
 156.Mojsov S, Heinrich G, Wilson IB, Ravazzola M, Orci L, Habener JF. Pre‐proglucagon gene expression in pancreas and intestine diversifies at the level of post‐translational procesing. J Biol Chem 261: 11880‐11889, 1996.
 157.Mokadem M, Zechner JF, Margolskee RF, Drucker DJ, Aguirre V. Effects of Roux‐en‐Y gastric bypass on energy and glucose homeostasis are preserved in two mouse models of functional glucagon‐like peptide‐1 deficiency. Mol Metab 3: 191‐201, 2014.
 158.Moriya R, Shirakura T, Ito J, Mashiko S, Seo T. Activation of sodium‐glucose cotransporter 1 ameliorates hyperglycemia by mediating incretin secretion in mice. Am J Physiol Endocrinol Metab 297: E1358‐E1365, 2009.
 159.Mul JD, Begg DP, Barrera JG, Li B, Matter EK, D'Alessio DA, Woods SC, Seeley RJ, Sandoval DA. High‐fat diet changes the temporal profile of GLP‐1 receptor‐mediated hypophagia in rats. Am J Physiol Regul Integr Comp Physiol 305: R68‐R77, 2013.
 160.Mulvihill EE, Drucker DJ. Pharmacology, physiology, and mechanisms of action of dipeptidyl peptidase‐4 inhibitors. Endocr Rev 35: 992‐1019, 2014.
 161.Mumphrey MB, Hao Z, Townsend RL, Patterson LM, Berthoud H‐R. Sleeve gastrectomy does not cause hypertrophy and reprogramming of intestinal glucose metabolism in rats. Obes Surg 25: 1468‐1473, 2015.
 162.Mumphrey MB, Patterson LM, 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 25: e70‐e79, 2013.
 163.Nannipieri M, Baldi S, Mari A, Colligiani D, Guarino D, Camastra S, Barsotti E, Berta R, Moriconi D, Bellini R, Anselmino M, Ferrannini E. Roux‐en‐Y gastric bypass and sleeve gastrectomy: Mechanisms of diabetes remission and role of gut hormones. J Clin Endocrinol Metab 98: 4391‐4399, 2013.
 164.Nauck MA, Vardarli I, Deacon CF, Holst JJ, Meier JJ. Secretion of glucagon‐like peptide‐1 (GLP‐1) in type 2 diabetes: What is up, what is down? Diabetologia 54: 10‐18, 2011.
 165.Nauck M, Stöckmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non‐insulin‐dependent) diabetes. Diabetologia 29: 46‐52, 1986.
 166.Nauck MA, Bartels E, Orskov C, Ebert R, Creutzfeldt W. Additive insulinotropic effects of exogenous synthetic human gastric inhibitory polypeptide and glucagon‐like peptide‐1‐(7‐36) amide infused at near‐physiological insulinotropic hormone and glucose concentrations. J Clin Endocrinol Metab 76: 912‐917, 1993.
 167.Nauck MA, Kind J, Köthe LD, Holst JJ, Deacon CF, Broschag M, He YL, Kjems L, Foley J. Quantification of the contribution of GLP‐1 to mediating insulinotropic effects of DPP‐4 inhibition with vildagliptin in healthy subjects and patients with type 2 diabetes using exendin [9‐39] as a GLP‐1 receptor antagonist. Diabetes 65: 2440‐2447, 2016.
 168.Nauck MA, Meier JJ, Cavender MA, Abd El Aziz M, Drucker DJ. Cardiovascular actions and clinical outcomes with glucagon‐like peptide‐1 receptor agonists and dipeptidyl peptidase‐4 inhibitors. Circulation 136: 849‐870, 2017.
 169.Nguyen NQ, Debreceni TL, Bambrick JE, Bellon M, Wishart J, Standfield S, Rayner CK, Horowitz M. Rapid gastric and intestinal transit is a major determinant of changes in blood glucose, intestinal hormones, glucose absorption, and postprandial symptoms after gastric bypass. Obesity (Silver Spring) 22: 2003‐2009, 2014.
 170.Nian M, Drucker DJ, Irwin D. Divergent regulation of human and rat proglucagon gene promoters in vivo. Am J Physiol Liver Physiol 277: G829‐G837, 1999.
 171.Nian M, Gu J, Irwin DM, Drucker DJ. Human glucagon gene promoter sequences regulating tissue‐specific versus nutrient‐regulated gene expression. Am J Physiol Regul Integr Comp Physiol 282: R173‐R183, 2002.
 172.Nie Y, Nakashima M, Brubaker PL, Li QL, Perfetti R, Jansen E, Zambre Y, Pipeleers D, Friedman TC. Regulation of pancreatic PC1 and PC2 associated with increased glucagon‐like peptide 1 in diabetic rats. J Clin Invest 105: 955‐965, 2000.
 173.Nielsen LB, Ploug KB, Swift P, Ørskov C, Jansen‐Olesen I, Chiarelli F, Holst JJ, Hougaard P, Pörksen S, Holl R, de Beaufort C, Gammeltoft S, Rorsman P, Mortensen HB, Hansen L. Co‐localisation of the Kir6.2/SUR1 channel complex with glucagon‐like peptide‐1 and glucose‐dependent insulinotrophic polypeptide expression in human ileal cells and implications for glycaemic control in new onset type 1 diabetes. Eur J Endocrinol 156: 663‐671, 2007.
 174.Omar BA, Andersen B, Hald J, Raun K, Nishimura E, Ahrén B. Fibroblast growth factor 21 (FGF21) and glucagon‐like peptide 1 contribute to diabetes resistance in glucagon receptor‐deficient mice. Diabetes 63: 101‐110, 2014.
 175.Orskov C, Holst JJ, Nielsen C. Effect of truncated glucagon‐like peptide‐1 (proglucagon‐(78‐107)amide) on endocrine secretion from pig pancreas, antrum, and nonatral stomach. Endocrinology 123: 2009‐2013, 1988.
 176.Panjwani N, Mulvihill EE, Longuet C, Yusta B, Campbell JE, Brown TJ, Streutker C, Holland D, Cao X, Baggio LL, Drucker DJ. GLP‐1 receptor activation indirectly reduces hepatic lipid accumulation but does not attenuate development of atherosclerosis in diabetic male ApoE(−/−) mice. Endocrinology 154: 127‐139, 2013.
 177.Papamargaritis D, Koukoulis G, Sioka E, Zachari E, Bargiota A, Zacharoulis D, Tzovaras G. Dumping symptoms and incidence of hypoglycaemia after provocation test at 6 and 12 months after laparoscopic sleeve gastrectomy. Obes Surg 22: 1600‐1606, 2012.
 178.Parker HE, Adriaenssens A, Rogers G, Richards P, Koepsell H, Reimann F, Gribble FM. Predominant role of active versus facilitative glucose transport for glucagon‐like peptide‐1 secretion. Diabetologia 55: 2445‐2455, 2012.
 179.Parker HE, Reimann F, Gribble FM. Molecular mechanisms underlying nutrient‐stimulated incretin secretion. Expert Rev Mol Med 12: e1, 2010.
 180.Parker HE, Wallis K, le Roux CW, Wong KY, Reimann F, Gribble FM. Molecular mechanisms underlying bile acid‐stimulated glucagon‐like peptide‐1 secretion. Br J Pharmacol 165: 414‐423, 2012.
 181.Perl SH, Bloch O, Zelnic‐Yuval D, Love I, Mendel‐Cohen L, Flor H, Rapoport MJ. Sepsis‐induced activation of endogenous GLP‐1 system is enhanced in type 2 diabetes. Diabetes Metab Res Rev 34: e2982, 2018.
 182.Plaisancie P, Bernard C, Chayvialle JA, Cuber JC. Regulation of glucagon‐like peptide‐1‐(7‐36) amide secretion by intestinal neurotransmitters and hormones in the isolated vascularly perfused rat colon. Endocrinology 135: 2398‐2403, 1994.
 183.Pocai A, Carrington PE, Adams JR, Wright M, Eiermann G, Zhu L, Du X, Petrov A, Lassman ME, Jiang G, Liu F, Miller C, Tota LM, Zhou G, Zhang X, Sountis MM, Santoprete A, Capito' E, Chicchi GG, Thornberry N, Bianchi E, Pessi A, Marsh DJ, SinhaRoy R. Glucagon‐like peptide 1/glucagon receptor dual agonism reverses obesity in mice. Diabetes 58: 2258‐2266, 2009.
 184.Prigeon RL, Quddusi S, Paty B, D'Alessio DA. Suppression of glucose production by GLP‐1 independent of islet hormones: A novel extrapancreatic effect. Am J Physiol Endocrinol Metab 285: E701‐E707, 2003.
 185.Printz H, Reiter S, Samadi N, Ebrahimsade S, Kirchner R, Arnold R, Göke B. GLP‐1 release in man after lower large bowel resection or intrarectal glucose administration. Digestion 59: 689‐695, 1998.
 186.Quoyer J, Longuet C, Broca C, Linck N, Costes S, Varin E, Bockaert J, Bertrand G, Dalle S. GLP‐1 mediates antiapoptotic effect by phosphorylating Bad through a beta‐arrestin 1‐mediated ERK1/2 activation in pancreatic beta‐cells. J Biol Chem 285: 1989‐2002, 2010.
 187.Ramracheya R, Chapman C, Chibalina M, Dou H, Miranda C, González A, Moritoh Y, Shigeto M, Zhang Q, Braun M, Clark A, Johnson PR, Rorsman P, Briant LJB. GLP‐1 suppresses glucagon secretion in human pancreatic alpha‐cells by inhibition of P/Q‐type Ca2+ channels. Physiol Rep 6: e13852, 2018.
 188.Ravier MA, Rutter GA. Glucose or insulin, but not zinc ions, inhibit glucagon secretion from mouse pancreatic alpha‐cells. Diabetes 54: 1789‐1797, 2005.
 189.Rayner CK, Horowitz M. Agonism of receptors in the gut–pancreas axis in type 2 diabetes: Are two better than one? Lancet 391: 2577‐2578, 2018.
 190.Reimann F, Gribble FM. Glucose‐sensing in glucagon‐like peptide‐1‐secreting cells. Diabetes 51: 2757‐2763, 2002.
 191.Reimann F, Habib AM, Tolhurst G, Parker HE, Rogers GJ, Gribble FM. Glucose sensing in L cells: A primary cell study. Cell Metab, 2008. DOI: 10.1016/j.cmet.2008.11.002.
 192.Reimer RA, Darimont C, Gremlich S, Nicolas‐Métral V, Rüegg UT, Macé K. A human cellular model for studying the regulation of glucagon‐like peptide‐1 secretion. Endocrinology 142: 4522‐4528, 2001.
 193.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 63: 1224, 2014.
 194.Ridge T, Moretto T, Macconell L, Pencek R, Han J, Schulteis C, Porter L. Comparison of safety and tolerability with continuous (exenatide once weekly) or intermittent (exenatide twice daily) GLP‐1 receptor agonism in patients with type 2 diabetes. Diabetes Obes Metab, 2012. DOI: 10.1111/j.1463‐1326.2012.01639.x.
 195.Ritzel R, Orskov C, Holst JJ, Nauck MA. Pharmacokinetic, insulinotropic, and glucagonostatic properties of GLP‐1 [7‐36 amide] after subcutaneous injection in healthy volunteers. Dose‐response‐relationships. Diabetologia 38: 720‐725, 1995.
 196.Rocca AS, Brubaker PL. Role of the vagus nerve in mediating proximal nutrient‐induced glucagon‐like peptide‐1 secretion. Endocrinology 140: 1687‐1694, 1999.
 197.Röder PV, Geillinger KE, Zietek TS, Thorens B, Koepsell H, Daniel H. The role of SGLT1 and GLUT2 in intestinal glucose transport and sensing. PLoS One 9: e89977, 2014.
 198.Rouille Y, Martin S, Steiner DF. Differential processing of proglucagon by the subtilisin‐like prohormone convertases PC2 and PC3 to generate either glucagon or glucagon‐like peptide. J Biol Chem 270: 26488‐26496, 1995.
 199.le Roux CW, Welbourn R, Werling M, Osborne A, Kokkinos A, Laurenius A, Lönroth H, Fändriks L, Ghatei MA, Bloom SR, Olbers T. Gut hormones as mediators of appetite and weight loss after Roux‐en‐Y gastric bypass. Ann Surg 246: 780‐785, 2007.
 200.Rowlands J, Heng J, Newsholme P, Carlessi R. Pleiotropic effects of GLP‐1 and analogs on cell signaling, metabolism, and function. Front Endocrinol (Lausanne) 9: 672, 2018.
 201.Ryan KK, Tremaroli V, Clemmensen C, Kovatcheva‐Datchary P, Myronovych A, Karns R, Wilson‐Perez HE, Sandoval DA, Kohli R, Backhed F, Seeley RJ. FXR is a molecular target for the effects of vertical sleeve gastrectomy. Nature 509: 183‐188, 2014.
 202.Sadry SA, Drucker DJ. Emerging combinatorial hormone therapies for the treatment of obesity and T2DM. Nat Rev Endocrinol 9: 425‐433, 2013.
 203.Saeidi N, Meoli L, Nestoridi E, Gupta NK, Kvas S, Kucharczyk J, Bonab AA, Fischman AJ, Yarmush ML, Stylopoulos N. Reprogramming of intestinal glucose metabolism and glycemic control in rats after gastric bypass. Science 341: 406‐410, 2013.
 204.Salehi M, Gastaldelli A, D'Alessio DA. Altered islet function and insulin clearance cause hyperinsulinemia in gastric bypass patients with symptoms of postprandial hypoglycemia. J Clin Endocrinol Metab 2014, 2014. (Epub).
 205.Salehi M, Gastaldelli A, D'Alessio DA. Blockade of glucagon‐like peptide 1 receptor corrects postprandial hypoglycemia after gastric bypass. Gastroenterology 146: 669.e2‐680.e2, 2014.
 206.Salehi M, Prigeon RL, D'Alessio DA. Gastric bypass surgery enhances glucagon‐like peptide 1‐stimulated postprandial insulin secretion in humans. Diabetes 60: 2308‐2314, 2011.
 207.Salehi M, Vella A, Mclaughlin T, Patti M, Society E. Hypoglycemia after gastric bypass surgery: Current concepts and controversies. J Clin Endocrinol Metab 103: 2815‐2826, 2018.
 208.Saltiel M, Kuhre R, Christiansen C, Eliasen R, Conde‐Frieboes K, Rosenkilde M, Holst J. Sweet taste receptor activation in the gut is of limited importance for glucose‐stimulated GLP‐1 and GIP secretion. Nutrients 9: 418, 2017.
 209.Sandoval DA, Bagnol D, Woods SC, D'Alessio DA, Seeley RJ. Arcuate glucagon‐like peptide 1 receptors regulate glucose homeostasis but not food intake. Diabetes 57: 2046‐2054, 2008.
 210.Schmidt WE, Siegel EG, Creutzfeldt W. Glucagon‐like peptide‐1 but not glucagon‐like peptide‐2 stimulates insulin release from isolated rat pancreatic islets. Diabetologia 28: 704‐707, 1985.
 211.Scow RO, Cornfield J. Quantitative relations between the oral and intravenous glucose tolerance curves. Am J Physiol Content 179: 435‐438, 1954.
 212.Simonen M, Dali‐Youcef N, Kaminska D, Venesmaa S, Käkelä P, Pääkkönen M, Hallikainen M, Kolehmainen M, Uusitupa M, Moilanen L, Laakso M, Gylling H, Patti ME, Auwerx J, Pihlajamäki J. Conjugated bile acids associate with altered rates of glucose and lipid oxidation after Roux‐en‐Y gastric bypass. Obes Surg 22: 1473‐1480, 2012.
 213.Sisley S, Gutierrez‐aguilar R, Scott M, Alessio DAD, Sandoval DA, Seeley RJ. Neuronal GLP1R mediates liraglutide's anorectic but not glucose‐lowering effect. J Clin Invest 124: 2456‐2463, 2014.
 214.Smith EP, An Z, Wagner C, Lewis AG, Cohen EB, Li B, Mahbod P, Sandoval D, Perez‐Tilve D, Tamarina N, Philipson LH, Stoffers DA, Seeley RJ, D'Alessio DA. The role of β cell glucagon‐like peptide‐1 signaling in glucose regulation and response to diabetes drugs. Cell Metab 19: 1050‐1057, 2014.
 215.Solloway MJ, Madjidi A, Gu C, Eastham‐Anderson J, Clarke HJ, Kljavin N, Zavala‐Solorio J, Kates L, Friedman B, Brauer M, Wang J, Fiehn O, Kolumam G, Stern H, Lowe JB, Peterson AS, Allan BB. Glucagon couples hepatic amino acid catabolism to mTOR‐dependent regulation of α‐cell mass. Cell Rep 12: 495‐510, 2015.
 216.Sonoda N, Imamura T, Yoshizaki T, Babendure JL, Lu J‐C, Olefsky JM. Beta‐Arrestin‐1 mediates glucagon‐like peptide‐1 signaling to insulin secretion in cultured pancreatic beta cells. Proc Natl Acad Sci U S A 105: 6614‐6619, 2008.
 217.Steinert RE, Gerspach AC, Gutmann H, Asarian L, Drewe J, Beglinger C. The functional involvement of gut‐expressed sweet taste receptors in glucose‐stimulated secretion of glucagon‐like peptide‐1 (GLP‐1) and peptide YY (PYY). Clin Nutr 30: 524‐532, 2011.
 218.Sun EW, de Fontgalland D, Rabbitt P, Hollington P, Sposato L, Due SL, Wattchow DA, Rayner CK, Deane AM, Young RL, Keating DJ. Mechanisms controlling glucose‐induced GLP‐1 secretion in human small intestine. Diabetes 66: 2144‐2149, 2017.
 219.Svane MS, Bojsen‐Møller KN, Nielsen S, Jørgensen NB, Dirksen C, Bendtsen F, Kristiansen VB, Hartmann B, Holst JJ, Madsbad S. Effects of endogenous GLP‐1 and GIP on glucose tolerance after Roux‐en‐Y gastric bypass surgery. Am J Physiol Endocrinol Metab 310: E505‐E514, 2016.
 220.Svegliati‐Baroni G, Saccomanno S, Rychlicki C, Agostinelli L, De Minicis S, Candelaresi C, Faraci G, Pacetti D, Vivarelli M, Nicolini D, Garelli P, Casini A, Manco M, Mingrone G, Risaliti A, Frega GN, Benedetti A, Gastaldelli A. Glucagon‐like peptide‐1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signalling alteration induced by a high‐fat diet in nonalcoholic steatohepatitis. Liver Int 31: 1285‐1297, 2011.
 221.Svendsen B, Larsen O, Buur M, Gabe N, Christiansen CB, Rosenkilde MM, Drucker DJ, Juul J, Correspondence H, Holst JJ. Insulin secretion depends on intra‐islet glucagon signaling. Cell Rep 25: 1127‐1134, 2018.
 222.Theodorakis MJ, Carlson O, Michopoulos S, Doyle ME, Juhaszova M, Petraki K, Egan JM. Human duodenal enteroendocrine cells: Source of both incretin peptides, GLP‐1 and GIP. Am J Physiol Endocrinol Metab 290: E550‐E559, 2006.
 223.Thorens B. Expression cloning of the pancreatic b‐cell receptor for the gluco‐incretin hormone glucagon‐like peptide 1. Proc Natl Acad Sci U S A 89: 8641‐8645, 1992.
 224.Thyssen S, Arany E, Hill DJ. Ontogeny of regeneration of beta‐cells in the neonatal rat after treatment with streptozotocin. Endocrinology 147: 2346‐2356, 2006.
 225.Toda N, Hao X, Ogawa Y, Oda K, Yu M, Fu Z, Chen Y, Kim Y, Lizarzaburu M, Lively S, Lawlis S, Murakoshi M, Nara F, Watanabe N, Reagan JD, Tian H, Fu A, Motani A, Liu Q, Lin Y‐J, Zhuang R, Xiong Y, Fan P, Medina J, Li L, Izumi M, Okuyama R, Shibuya S. Potent and orally bioavailable GPR142 agonists as novel insulin secretagogues for the treatment of type 2 diabetes. ACS Med Chem Lett 4: 790‐794, 2013.
 226.Tornehave D, Kristensen P, Rømer J, Knudsen LB, Heller RS. Expression of the GLP‐1 receptor in mouse, rat, and human pancreas. J Histochem Cytochem 56: 841‐851, 2008.
 227.Traub S, Meier DT, Schulze F, Dror E, Nordmann TM, Goetz N, Koch N, Dalmas E, Stawiski M, Makshana V, Thorel F, Herrera PL, Böni‐Schnetzler M, Donath MY. Pancreatic α cell‐derived glucagon‐related peptides are required for β cell adaptation and glucose homeostasis. Cell Rep 18: 3192‐3203, 2017.
 228.Tucker JD, Dhanvantari S, Brubaker PL. Proglucagon processing in islet and intestinal cell lines. Regul Pept 62: 29‐35, 1996.
 229.Tudurí E, Beiroa D, Porteiro B, López M, Diéguez C, Nogueiras R. Acute but not chronic activation of brain glucagon‐like peptide‐1 receptors enhances glucose‐stimulated insulin secretion in mice. Diabetes Obes Metab 17: 789‐799, 2015.
 230.Tzovaras G, Papamargaritis D, Sioka E, Zachari E, Baloyiannis I, Zacharoulis D, Koukoulis G. Symptoms suggestive of dumping syndrome after provocation in patients after laparoscopic sleeve gastrectomy. Obes Surg 22: 23‐28, 2012.
 231.Umeda LM, Silva EA, Carneiro G, Arasaki CH, Geloneze B, Zanella MT. Early improvement in glycemic control after bariatric surgery and its relationships with insulin, GLP‐1, and glucagon secretion in type 2 diabetic patients. Obes Surg 21: 896‐901, 2011.
 232.Unger RH, Aguilar‐Parada E, Müller WA, Eisentraut AM. Studies of pancreatic alpha cell function in normal and diabetic subjects. J Clin Invest 49: 837‐848, 1970.
 233.Unger RH, Orci L. Paracrinology of islets and the paracrinopathy of diabetes. Proc Natl Acad Sci 107: 16009‐16012, 2010.
 234.Vahl TP, Tauchi M, Durler TS, Elfers EE, Fernandes TM, Bitner RD, Ellis KS, Woods SC, Seeley RJ, Herman JP, D'Alessio DA. Glucagon‐like peptide‐1 (GLP‐1) receptors expressed on nerve terminals in the portal vein mediate the effects of endogenous GLP‐1 on glucose tolerance in rats. Endocrinology 148: 4965‐4973, 2007.
 235.Vidal J, de Hollanda A, Jiménez A. GLP‐1 is not the key mediator of the health benefits of metabolic surgery. Surg Obes Relat Dis 12: 1225‐1229, 2016.
 236.Vilsbøll T, Christensen M, Junker AE, Knop FK, Gluud LL. Effects of glucagon‐like peptide‐1 receptor agonists on weight loss: Systematic review and meta‐analyses of randomised controlled trials. BMJ 344: d7771, 2012.
 237.Vilsbøll T, Krarup T, Madsbad S, Holst JJ. Both GLP‐1 and GIP are insulinotropic at basal and postprandial glucose levels and contribute nearly equally to the incretin effect of a meal in healthy subjects. Regul Pept 114: 115‐121, 2003.
 238.Vrang N, Hansen M, Larsen PJ, Tang‐Christensen M. Characterization of brainstem preproglucagon projections to the paraventricular and dorsomedial hypothalamic nuclei. Brain Res 1149: 118‐126, 2007.
 239.Wang J, Carrillo JJ, Lin HV. GPR142 agonists stimulate glucose‐dependent insulin secretion via Gq‐dependent signaling. PLoS One 11: e0154452, 2016.
 240.Whalley NM, Pritchard LE, Smith DM, White A. Processing of proglucagon to GLP‐1 in pancreatic α‐cells: Is this a paracrine mechanism enabling GLP‐1 to act on β‐cells? J Endocrinol 211: 99‐106, 2011.
 241.Wideman RD, Yu ILY, Webber TD, Verchere CB, Johnson JD, Cheung AT, Kieffer TJ. Improving function and survival of pancreatic islets by endogenous production of glucagon‐like peptide 1 (GLP‐1). Proc Natl Acad Sci U S A 103: 13468‐13473, 2006.
 242.Willert K, Jones KA. Wnt signaling: Is the party in the nucleus? Genes Dev 20: 1394‐1404, 2006.
 243.Williams DL, Baskin DG, Schwartz MW. Leptin regulation of the anorexic response to glucagon‐like peptide‐1 receptor stimulation. Diabetes 55: 3387‐3393, 2006.
 244.Wilson‐Pérez HE, Chambers AP, Ryan KK, Li B, Sandoval DA, Stoffers D, Drucker DJ, Pérez‐Tilve D, Seeley RJ. Vertical sleeve gastrectomy is effective in two genetic mouse models of glucagon‐like peptide‐1 receptor deficiency. Diabetes 62: 2380‐2385, 2013.
 245.Wilson ME, Kalamaras JA, German MS. Expression pattern of IAPP and prohormone convertase 1/3 reveals a distinctive set of endocrine cells in the embryonic pancreas. Mech Dev 115: 171‐176, 2002.
 246.Xu E, Kumar M, Zhang Y, Ju W, Obata T, Zhang N, Liu S, Wendt A, Deng S, Ebina Y, Wheeler MB, Braun M, Wang Q. Intra‐islet insulin suppresses glucagon release via GABA‐GABAA receptor system. Cell Metab 3: 47‐58, 2006.
 247.Yanay O, Bailey AL, Kernan K, Zimmerman JJ, Osborne WR. Effects of exendin‐4, a glucagon like peptide‐1 receptor agonist, on neutrophil count and inflammatory cytokines in a rat model of endotoxemia. J Inflamm Res 8: 129, 2015.
 248.Ye J, Hao Z, Mumphrey MB, Townsend RL, Patterson LM, Stylopoulos N, Munzberg H, Morrison CD, Drucker DJ, 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 306: R352‐R362, 2014.
 249.Yoder SM, Yang Q, Kindel TL, Tso P. Stimulation of incretin secretion by dietary lipid: Is it dose dependent? Am J Physiol Gastrointest Liver Physiol 297: G299‐G305, 2009.
 250.Yu Z, Jin T. New insights into the role of cAMP in the production and function of the incretin hormone glucagon‐like peptide‐1 (GLP‐1). Cell Signal 22: 1‐8, 2010.
 251.Zhang Y, Parajuli KR, Fava GE, Gupta R, Xu W, Nguyen LU, Zakaria AF, Fonseca VA, Wang H, Mauvais‐Jarvis F, Sloop KW, Wu H. GLP‐1 receptor in pancreatic α‐cells regulates glucagon secretion in a glucose‐dependent bidirectional manner. Diabetes 68: 34‐44, 2019.
 252.Zhou H, Zhang T, Harmon JS, Bryan J, Robertson RP. Zinc, not insulin, regulates the rat alpha‐cell response to hypoglycemia in vivo. Diabetes 56: 1107‐1112, 2007.
 253.Zhu L, Dattaroy D, Pham J, Wang L, Barella LF, Cui Y, Wilkins KJ, Roth BL, Hochgeschwender U, Matschinsky FM, Kaestner KH, Doliba NM, Wess J. Intra‐islet glucagon signaling is critical for maintaining glucose homeostasis. JCI Insight 5, 2019. DOI: 10.1172/jci.insight.127994.

Teaching Material

Ellen M. Davis and Darleen A. Sandoval. Glucagon-like Peptide-1: Actions and Influence on Pancreatic Hormone Function. Compr Physiol 10 : 2020, 577-595.

Didactic Synopsis

Major Teaching Points:

1. Glucagon-like peptide-1 (GLP-1) is an important postprandial stimulus of pancreatic insulin secretion and regulator of glucose homeostasis.

2. GLP-1 is coded by the preproglucagon gene which is expressed in the gut, brain, and ?-cells of the pancreas.

3. Due to tissue-specific post-translational processing, GLP-1 is predominantly made in the gut and brain but can also be made in the pancreatic ?-cells in response to nutrients and under times of stress.

4. Recent work suggests that ?-cell GLP-1 and glucagon, another preproglucagon-derived peptide, can stimulate insulin secretion through the GLP-1r.

5. GLP-1 has been implicated as a cause of the metabolic success of surgeries performed to correct obesity but research in genetic mouse models challenges this assumption.

6. GLP-1 has been targeted very successfully for treatment of both type 2 diabetes and obesity.

Didactic Legends

The following legends to the figures that appear throughout the article are written to be useful for teaching.

Figure 1. Teaching Points. The incretin effect was originally a hypothesis used to explain why plasma insulin levels could be higher when the same dose of glucose was administered orally vs. when administered into the veins. The difference in insulin levels was thought to be due to a factor secreted by the gut. We now know that GLP-1 and GIP are both such factors that are secreted from the distal gut and also stimulate insulin secretion. Adapted from McIntyre N, et al. Lancet. 1964;41:20-21.

Figure 2. Teaching points. This figure illustrates some of the many cellular mechanisms that have been linked to GLP-1 secretion. Two branches of the nervous system that innervate the gut impact GLP-1 secretion. These are the parasympathetic nervous system (PNS) stimulates GLP-1 secretion via specific muscarinic receptors that bind to acetylcholine (MR). The sympathetic branch of the nervous system increases GLP-1 secretion via activation of specific ?-adrenergic (AR) receptors but can inhibit GLP-1 secretion via activation of β-adrenergic receptors. Nutrients and nutrient by-products act via GPCRs to increase a protein kinase A signaling pathway to induce GLP-1 secretion. Glucose absorption via two different transport mechanisms; one being GLUT2 and one being SGLT1 also lead to the release of GLP-1.

Figure 3. Teaching points. This figure illustrates some of the many factors that impact ?-cell GLP-1 production. Stress from excessive metabolites and/or inflammation resulting from infection, exercise, hyperglycemia, obesity, and diabetes all stimulate ?-cell GLP-1 production. Activation of a particular inflammatory cytokine (IL-6) seems to be a primary factor that leads to this increase. The function of this increase is unknown but regulation of the number and function of β-cells is a likely endpoint.

Figure 4. Teaching points. This figure highlights an advancement to the incretin model where GLP-1 and another peptide, glucagon, that is encoded by the same Gcg gene acts on local GLP-1r to regulate insulin secretion in response to high levels of amino acids.


Figure 5. Teaching points. This figure highlights the potential positive and negative effects of the several-fold increase in postprandial GLP-1 that occurs in bariatric surgery patients. 

Related Articles:

Gut Glucagon
Distribution and Stimulus Secretion Coupling of Enteroendocrine Cells along the Intestinal Tract
Interactions of Gut Endocrine Cells with Epithelium and Neurons
Identification of Physiological Function of Gut Peptides
Endocrine Function after Bariatric Surgery
Teaching Material

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite

Ellen M. Davis, Darleen A. Sandoval. Glucagon‐Like Peptide‐1: Actions and Influence on Pancreatic Hormone Function. Compr Physiol 2020, 10: 577-595. doi: 10.1002/cphy.c190025