Glucagon-like peptide 1 (GLP-1)

Molecular Metabolism - Tập 30 - Trang 72-130 - 2019
T.D. Müller1,2,3, B. Finan4, S.R. Bloom5, D. D'Alessio6, D.J. Drucker7, P.R. Flatt8, A. Fritsche2,9,10, F. Gribble11, H.J. Grill12, J.F. Habener13, J.J. Holst14, W. Langhans15, J.J. Meier16, M.A. Nauck17, D. Perez-Tilve18, A. Pocai19, F. Reimann11, D.A. Sandoval20, T.W. Schwartz21,22, R.J. Seeley20
1Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
2German Center for Diabetes Research (DZD), Neuherberg, Germany
3Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard-Karls-University Hospitals and Clinics, Tübingen, Germany
4Novo Nordisk Research Center Indianapolis, Indianapolis, IN, USA
5Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, UK
6Division of Endocrinology, Duke University Medical Center, Durham, NC, USA
7The Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Ontario, M5G1X5, Canada
8SAAD Centre for Pharmacy & Diabetes, Ulster University, Coleraine, Northern Ireland, UK
9Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
10Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, Department of Internal Medicine, University of Tübingen, Tübingen, Germany
11Metabolic Research Laboratories and Medical Research Council Metabolic Diseases Unit, Wellcome Trust-Medical Research Council, Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, CB2 0QQ, UK
12Institute of Diabetes, Obesity and Metabolism, Department of Psychology, University of Pennsylvania, Philadelphia, PA, 19104, USA
13Laboratory of Molecular Endocrinology, Massachusetts General Hospital, Harvard University, Boston, MA, USA
14Novo Nordisk Foundation Center for Basic Metabolic Research, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
15Physiology and Behavior Laboratory, ETH Zurich, Schwerzenbach, Switzerland
16Diabetes Division, St Josef Hospital, Ruhr-University Bochum, Bochum, Germany
17Diabetes Center Bochum-Hattingen, St Josef Hospital (Ruhr-Universität Bochum), Bochum, Germany
18Department of Internal Medicine, University of Cincinnati-College of Medicine, Cincinnati, OH, USA
19Cardiovascular & ImmunoMetabolism, Janssen Research & Development, Welsh and McKean Roads, Spring House, PA, 19477, USA
20Department of Surgery, University of Michigan Medical School, Ann Arbor, MI USA
21Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, DL-2200, Copenhagen, Denmark
22Department of Biomedical Sciences, University of Copenhagen, DK-2200, Copenhagen, Denmark

Tài liệu tham khảo

Collip, 1923, Delayed manifestation of the physiological effects of insulin following the administration of certain pancreatic extracts, American Journal of Physiology, 63, 391 Fisher, 1923, Preparation of insulin, American Journal of Physiology, 67, 57, 10.1152/ajplegacy.1923.67.1.57 Kimball, 1923, Aqueous extracts of pancreas III. Some precipitation reactions of insulin, Journal of Biological Chemistry, 58, 337, 10.1016/S0021-9258(18)85474-6 Muller, 2017, The new biology and pharmacology of glucagon, Physiological Reviews, 97, 721, 10.1152/physrev.00025.2016 Unger, 1976, Physiology and pathophysiology of glucagon, Physiological Reviews, 56, 778, 10.1152/physrev.1976.56.4.778 Bürger, 1935, Über das Glukagon (die hyperglykämisierende Substanz der Pankreas), Zeitschrift für die gesamte experimentelle Medizin, 96, 375, 10.1007/BF02595511 Bürger, 1929, Über den hepatischen Angriffspunkt des Insulins. Die primäre Paradoxe Insulinhyperglykämie, Zeitschrift für die gesamte experimentelle Medizin, 65, 487, 10.1007/BF02610017 Bürger, 1929, Primäre Hyperglykämie und Glykogenveränderung der Leber als Folge intraportaler Insulininjektion nach Untersuchungen am Hund, Zeitschrift für die gesamte experimentelle Medizin, 67, 441, 10.1007/BF02610898 Exton, 1968, Control of gluconeogenesis in liver. II. Effects of glucagon, catecholamines, and adenosine 3',5'-monophosphate on gluconeogenesis in the perfused rat liver, Journal of Biological Chemistry, 243, 4189, 10.1016/S0021-9258(18)93242-4 Garcia, 1966, Studies on the perfused rat liver. II. Effect of glucagon on gluconeogenesis, Diabetes, 15, 188, 10.2337/diab.15.3.188 Struck, 1965, Stimulation of gluconeogenesis by long chain fatty acids and glucagon, Biochemische Zeitschrift, 343, 107 Ui, 1973, Studies on the mechanism of action of glucagon on gluconeogenesis, Journal of Biological Chemistry, 248, 5344, 10.1016/S0021-9258(19)43607-7 Samols, 1965, Promotion of insulin secretion by glucagon, Lancet, 2, 415, 10.1016/S0140-6736(65)90761-0 Vuylsteke, 1952, Influence du traitment au cobalt sur le contenu en facteur HG du pancreas de cobaye, Archives Internationales de Physiologie, 60, 128, 10.3109/13813455209145047 Fodden, 1954, The activity of extracted pancreatic hyperglycemic-glycogenolytic factor after cobaltous chloride and synthalin A, Endocrinology, 54, 303, 10.1210/endo-54-3-303 Hellerstrom, 1964, The two types of pancreatic alpha cells and their relation to glucagon secretion, 117 Hellerstrom, 1962, Reactions of the two types of A cells in the islets of Langerhans after administration of glucagon, Acta Endocrinologica (Copenhagen), 41, 116, 10.1530/acta.0.0410116 Petersson, 1963, Effects of long term administration of glucagon on the pancreatic islet tissue of rats and Guinea-pigs, Acta Endocrinologica (Copenhagen), 44, 139, 10.1530/acta.0.0440139 Hellman, 1969, Inhibition of the in vitro secretion of insulin by an extract of pancreatic alpha-1 cells, Endocrinology, 84, 1484, 10.1210/endo-84-6-1484 Unger, 1959, Glucagon antibodies and their use for immunoassay for glucagon, Proceedings of The Society for Experimental Biology and Medicine, 102, 621, 10.3181/00379727-102-25338 Samols, 1967, New conceptions on the functional significance of glucagon (pancreatic and extra-pancreatic), Journees Annuelles de Diabetologie de l’Hotel-Dieu, 7, 43 Moody, 1970, The insulin releasing activites of extracts of pork intestine, Diabetologia, 6, 135, 10.1007/BF00421441 Murphy, 1971, Isolation of glucagon-like immunoreactivity of gut by affinity chromatography, Biochemical Journal, 125, 61P, 10.1042/bj1250061P Unger, 1961, Sites of origin of glucagon in dogs and humans, Clinical Research, 9, 53 Valverde, 1970, Characterization of glucagon-like immunoreactivity (GLI), Diabetes, 19, 614, 10.2337/diab.19.9.614 Unger, 1966, Distribution of immunoassayable glucagon in gastrointestinal tissues, Metabolism, 15, 865, 10.1016/0026-0495(66)90156-9 Unger, 1968, Characterization of the responses of circulating glucagon-like immunoreactivity to intraduodenal and intravenous administration of glucose, Journal of Clinical Investigation, 47, 48, 10.1172/JCI105714 Valverde, 1968, Demonstration and characterization of a second fraction of glucagon-like immunoreactivity in jejunal extracts, The American Journal of the Medical Sciences, 255, 415, 10.1097/00000441-196806000-00007 Grimelius, 1976, Cytochemical and ultrastructural differentiation of enteroglucagon and pancreatic-type glucagon cells of the gastrointestinal tract, Virchows Archiv B Cell Pathology, 20, 217, 10.1007/BF02890341 Buffa, 1978, Types of endocrine cells in the human colon and rectum, Cell and Tissue Research, 192, 227, 10.1007/BF00220741 Rigopoulou, 1970, Large glucagon immunoreactivity in extracts of pancreas, Journal of Biological Chemistry, 245, 496, 10.1016/S0021-9258(18)63360-5 Tung, 1971, Biosynthesis of glucagon in isolated pigeon islets, Biochemical and Biophysical Research Communications, 45, 387, 10.1016/0006-291X(71)90831-X Hellerstrom, 1972, An investigation of glucagon biosynthesis in isolated pancreatic islets of Guinea pigs, FEBS Letters, 27, 97, 10.1016/0014-5793(72)80418-6 Patzelt, 1979, Identification and processing of proglucagon in pancreatic islets, Nature, 282, 260, 10.1038/282260a0 Patzelt, 1981, The major proglucagon fragment: an abundant islet protein and secretory product, FEBS Letters, 129, 127, 10.1016/0014-5793(81)80772-7 Holst, 1982, Evidence that enteroglucagon (II) is identical with the C-terminal sequence (residues 33-69) of glicentin, Biochemical Journal, 207, 381, 10.1042/bj2070381 Jacobsen, 1977, Sequence analysis of porcine gut GLI-1, Biochimica et Biophysica Acta, 493, 452, 10.1016/0005-2795(77)90201-X Sundby, 1976, Purification and characterization of a protein from porcine gut with glucagon-like immunoreactivity, Hormone and Metabolic Research, 8, 366, 10.1055/s-0028-1093615 Thim, 1981, The amino acid sequence of porcine glicentin, Peptides, 2, 37, 10.1016/0196-9781(81)90007-3 Holst, 1980, Evidence that glicentin contains the entire sequence of glucagon, Biochemical Journal, 187, 337, 10.1042/bj1870337 Moody, 1981, Relationship of glicentin to proglucagon and glucagon in the porcine pancreas, Nature, 289, 514, 10.1038/289514a0 Bataille, 1982, Isolation of glucagon-37 (bioactive enteroglucagon/oxyntomodulin) from porcine jejuno-ileum. Characterization of the peptide, FEBS Letters, 146, 79, 10.1016/0014-5793(82)80709-6 Thim, 1982, Purification and chemical characterization of a glicentin-related pancreatic peptide (proglucagon fragment) from porcine pancreas, Biochimica et Biophysica Acta, 703, 134, 10.1016/0167-4838(82)90041-3 Lund, 1982, Pancreatic preproglucagon cDNA contains two glucagon-related coding sequences arranged in tandem, Proceedings of the National Academy of Sciences of the United States of America, 79, 345, 10.1073/pnas.79.2.345 Lund, 1981, Pancreatic pre-proglucagons are encoded by two separate mRNAs, Journal of Biological Chemistry, 256, 6515, 10.1016/S0021-9258(19)69015-0 Lund, 1983, Anglerfish islet pre-proglucagon II. Nucleotide and corresponding amino acid sequence of the cDNA, Journal of Biological Chemistry, 258, 3280, 10.1016/S0021-9258(18)32858-8 Heinrich, 1984, Glucagon gene sequence. Four of six exons encode separate functional domains of rat pre-proglucagon, Journal of Biological Chemistry, 259, 14082, 10.1016/S0021-9258(18)89859-3 Heinrich, 1984, Pre-proglucagon messenger ribonucleic acid: nucleotide and encoded amino acid sequences of the rat pancreatic complementary deoxyribonucleic acid, Endocrinology, 115, 2176, 10.1210/endo-115-6-2176 Bell, 1983, Hamster preproglucagon contains the sequence of glucagon and two related peptides, Nature, 302, 716, 10.1038/302716a0 Lopez, 1983, Mammalian pancreatic preproglucagon contains three glucagon-related peptides, Proceedings of the National Academy of Sciences of the United States of America, 80, 5485, 10.1073/pnas.80.18.5485 Bell, 1983, Exon duplication and divergence in the human preproglucagon gene, Nature, 304, 368, 10.1038/304368a0 Mojsov, 1986, Preproglucagon gene expression in pancreas and intestine diversifies at the level of post-translational processing, Journal of Biological Chemistry, 261, 11880, 10.1016/S0021-9258(18)67324-7 Orskov, 1986, Glucagon-like peptides GLP-1 and GLP-2, predicted products of the glucagon gene, are secreted separately from pig small intestine but not pancreas, Endocrinology, 119, 1467, 10.1210/endo-119-4-1467 Orskov, 1987, Pancreatic and intestinal processing of proglucagon in man, Diabetologia, 30, 874, 10.1007/BF00274797 Moore, 1906, On the treatment of Diabetus mellitus by acid extract of Duodenal Mucous Membrane, Biochemical Journal, 1, 28, 10.1042/bj0010028 Zunz, 1929, Contributiona a l'etude des variations physiologiques de la secretion interne du pancreas: relations entre les secretions externe et interne du pancreas, Archives Internationales de Physiologie et de Biochimie, 31, 20, 10.1080/13813455.1929.11864670 La Barre, 1932, Sur les possibilite's d'un traitement du diabète par l'incrétine, Bulletin de l'Academie Royale de Medecine de Belgique, 12, 620 Yalow, 1959, Assay of plasma insulin in human subjects by immunological methods, Nature, 184, 1648, 10.1038/1841648b0 Yalow, 1960, Immunoassay of endogenous plasma insulin in man, Journal of Clinical Investigation, 39, 1157, 10.1172/JCI104130 Dupre, 1966, Stimulation of release of insulin by an extract of intestinal mucosa, Diabetes, 15, 555, 10.2337/diab.15.8.555 Elrick, 1964, Plasma insulin response to oral and intravenous glucose administration, The Journal of Cinical Endocrinology and Metabolism, 24, 1076, 10.1210/jcem-24-10-1076 McIntyre, 1964, New interpretation of oral glucose tolerance, Lancet, 2, 20, 10.1016/S0140-6736(64)90011-X Perley, 1967, Plasma insulin responses to oral and intravenous glucose: studies in normal and diabetic sujbjects, Journal of Clinical Investigation, 46, 1954, 10.1172/JCI105685 Nauck, 2018, Incretin hormones: their role in health and disease, Diabetes Obesity and Metabolism, 20, 5, 10.1111/dom.13129 Nauck, 2016, The incretin effect in healthy individuals and those with type 2 diabetes: physiology, pathophysiology, and response to therapeutic interventions, Lancet Diabetes Endocrinology, 4, 525, 10.1016/S2213-8587(15)00482-9 Samols, 1965, Stimulation of glucagon secretion by oral glucose, Lancet, 2, 1257, 10.1016/S0140-6736(65)92278-6 Gregory, 1977, An assessment of Viktor Mutt's contributions, Gastroenterology, 72, 786, 10.1016/S0016-5085(77)80002-4 Brown, 1971, A gastric inhibitory polypeptide. II. The complete amino acid sequence, Canadian Journal of Biochemistry, 49, 867, 10.1139/o71-122 Brown, 1970, Further purification of a polypeptide demonstrating enterogastrone activity, Journal of Physiology, 209, 57, 10.1113/jphysiol.1970.sp009155 Brown, 1969, Preparation of highly active enterogastrone, Canadian Journal of Physiology and Pharmacology, 47, 113, 10.1139/y69-020 Dupre, 1973, Stimulation of insulin secretion by gastric inhibitory polypeptide in man, The Journal of Cinical Endocrinology and Metabolism, 37, 826, 10.1210/jcem-37-5-826 Schafer, 1979, Stimulation of (Pro-)insulin biosynthesis and release by gastric inhibitory polypeptide in isolated islets of rat pancreas, Acta Endocrinologica (Copenhagena), 91, 493, 10.1530/acta.0.0910493 Schauder, 1975, Gastric inhibitory polypeptide: effect on glucose-induced insulin release from isolated rat pancreatic islets in vitro, Diabetologia, 11, 483, 10.1007/BF00429919 Szecowka, 1982, Effect of GIP on the secretion of insulin and somatostatin and the accumulation of cyclic AMP in vitro in the rat, Acta Endocrinologica (Copenhagen), 99, 416, 10.1530/acta.0.0990416 Taminato, 1977, Synthetic gastric inhibitory polypeptide. Stimulatory effect on insulin and glucagon secretion in the rat, Diabetes, 26, 480, 10.2337/diab.26.5.480 Adrian, 1978, Pancreatic polypeptide, glucagon and insulin secretion from the isolated perfused canine pancreas, Diabetologia, 14, 413, 10.1007/BF01228136 Brunicardi, 1990, Selective neurohormonal interactions in islet cell secretion in the isolated perfused human pancreas, Journal of Surgical Research, 48, 273, 10.1016/0022-4804(90)90058-A Ebert, 1983, Preservation of incretin activity after removal of gastric inhibitory polypeptide (GIP) from rat gut extracts by immunoadsorption, Diabetologia, 24, 449, 10.1007/BF00257346 Lauritsen, 1980, Gastric inhibitory polypeptide (GIP) and insulin release after small-bowel resection in man, Scandinavian Journal of Gastroenterology, 15, 833, 10.3109/00365528009181538 Holst, 1987, Truncated glucagon-like peptide I, an insulin-releasing hormone from the distal gut, FEBS Letters, 211, 169, 10.1016/0014-5793(87)81430-8 Mojsov, 1987, Insulinotropin: glucagon-like peptide I (7-37) co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas, Journal of Clinical Investigation, 79, 616, 10.1172/JCI112855 Drucker, 1987, Glucagon-like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line, Proceedings of the National Academy of Sciences of the United States of America, 84, 3434, 10.1073/pnas.84.10.3434 Kreymann, 1987, Glucagon-like peptide-1 7-36: a physiological incretin in man, Lancet, 2, 1300, 10.1016/S0140-6736(87)91194-9 Drucker, 1988, Glucagon gene expression in vertebrate brain, Journal of Biological Chemistry, 263, 13475, 10.1016/S0021-9258(18)68261-4 Han, 1986, Cellular localization of proglucagon/glucagon-like peptide I messenger RNAs in rat brain, Journal of Neuroscience Research, 16, 97, 10.1002/jnr.490160110 Jin, 1988, Distribution of glucagonlike peptide I (GLP-I), glucagon, and glicentin in the rat brain: an immunocytochemical study, Journal of Comparative Neurology, 271, 519, 10.1002/cne.902710405 Sandoval, 2015, Physiology of proglucagon peptides: role of glucagon and GLP-1 in health and disease, Physiological Reviews, 95, 513, 10.1152/physrev.00013.2014 Nian, 1999, Divergent regulation of human and rat proglucagon gene promoters in vivo, American Journal of Physiology, 277, G829 Philippe, 1991, Structure and pancreatic expression of the insulin and glucagon genes, Endocrine Reviews, 12, 252, 10.1210/edrv-12-3-252 Holt, 2019, Preproglucagon neurons in the nucleus of the solitary tract are the main source of brain GLP-1, mediate stress-induced hypophagia, and limit unusually large intakes of food, Diabetes, 68, 21, 10.2337/db18-0729 Drucker, 1990, Glucagon and the glucagon-like peptides, Pancreas, 5, 484, 10.1097/00006676-199007000-00018 Tang-Christensen, 1996, Central administration of GLP-1-(7-36) amide inhibits food and water intake in rats, American Journal of Physiology, 271, R848 Lee, 1990, Developmental and tissue-specific regulation of proglucagon gene expression, Endocrinology, 127, 2217, 10.1210/endo-127-5-2217 Jin, 2008, Mechanisms underlying proglucagon gene expression, Journal of Endocrinology, 198, 17, 10.1677/JOE-08-0085 Efrat, 1988, Glucagon gene regulatory region directs oncoprotein expression to neurons and pancreatic alpha cells, Neuron, 1, 605, 10.1016/0896-6273(88)90110-9 Lee, 1992, Glucagon gene 5'-flanking sequences direct expression of simian virus 40 large T antigen to the intestine, producing carcinoma of the large bowel in transgenic mice, Journal of Biological Chemistry, 267, 10705, 10.1016/S0021-9258(19)50075-8 Zhou, 2006, Intron 1 sequences are required for pancreatic expression of the human proglucagon gene, American Journal of Physiology Regulatory Integrative and Comparative Physiology, 290, R634, 10.1152/ajpregu.00596.2005 Jin, 1996, Activation of proglucagon gene transcription through a novel promoter element by the caudal-related homeodomain protein cdx-2/3, Molecular and Cellular Biology, 16, 19, 10.1128/MCB.16.1.19 Knepel, 1990, A pancreatic islet cell-specific enhancer-like element in the glucagon gene contains two domains binding distinct cellular proteins, Journal of Biological Chemistry, 265, 8725, 10.1016/S0021-9258(19)38949-5 Gosmain, 2011, Glucagon gene expression in the endocrine pancreas: the role of the transcription factor Pax6 in alpha-cell differentiation, glucagon biosynthesis and secretion, Diabetes Obesity and Metabolism, 13, 31, 10.1111/j.1463-1326.2011.01445.x Gevrey, 2004, Protein hydrolysates stimulate proglucagon gene transcription in intestinal endocrine cells via two elements related to cyclic AMP response element, Diabetologia, 47, 926, 10.1007/s00125-004-1380-0 Herzig, 2000, Heterodimeric Pbx-Prep1 homeodomain protein binding to the glucagon gene restricting transcription in a cell type-dependent manner, Journal of Biological Chemistry, 275, 27989, 10.1074/jbc.M003345200 Philippe, 1987, Glucagon gene transcription in an islet cell line is regulated via a protein kinase C-activated pathway, Journal of Biological Chemistry, 262, 1823, 10.1016/S0021-9258(19)75713-5 Gauthier, 2002, Hepatic nuclear factor-3 (HNF-3 or Foxa2) regulates glucagon gene transcription by binding to the G1 and G2 promoter elements, Molecular Endocrinology, 16, 170, 10.1210/mend.16.1.0752 Gosmain, 2007, Pax-6 and c-Maf functionally interact with the alpha-cell-specific DNA element G1 in vivo to promote glucagon gene expression, Journal of Biological Chemistry, 282, 35024, 10.1074/jbc.M702795200 Andersen, 1999, Pax6 and Cdx2/3 form a functional complex on the rat glucagon gene promoter G1-element, FEBS Letters, 445, 306, 10.1016/S0014-5793(99)00145-3 St-Onge, 1997, Pax6 is required for differentiation of glucagon-producing alpha-cells in mouse pancreas, Nature, 387, 406, 10.1038/387406a0 Trinh, 2003, Pax-6 activates endogenous proglucagon gene expression in the rodent gastrointestinal epithelium, Diabetes, 52, 425, 10.2337/diabetes.52.2.425 Hill, 1999, Essential requirement for Pax6 in control of enteroendocrine proglucagon gene transcription, Molecular Endocrinology, 13, 1474, 10.1210/mend.13.9.0340 Drucker, 1987, cis-acting DNA sequence controls glucagon gene expression in pancreatic islet cells, Transactions of the Association of American Physicians, 100, 109 Dumonteil, 1998, Differential regulation of the glucagon and insulin I gene promoters by the basic helix-loop-helix transcription factors E47 and BETA2, Journal of Biological Chemistry, 273, 19945, 10.1074/jbc.273.32.19945 Hussain, 1999, Glucagon gene transcription activation mediated by synergistic interactions of pax-6 and cdx-2 with the p300 co-activator, Journal of Biological Chemistry, 274, 28950, 10.1074/jbc.274.41.28950 Jin, 1997, The caudal homeobox protein cdx-2/3 activates endogenous proglucagon gene expression in InR1-G9 islet cells, Molecular Endocrinology, 11, 203, 10.1210/mend.11.2.9882 Laser, 1996, The caudal-related homeodomain protein Cdx-2/3 regulates glucagon gene expression in islet cells, Journal of Biological Chemistry, 271, 28984, 10.1074/jbc.271.46.28984 Philippe, 1994, Glucagon gene expression is negatively regulated by hepatocyte nuclear factor 3 beta, Molecular and Cellular Biology, 14, 3514 Ritz-Laser, 2000, The paired homeodomain transcription factor Pax-2 is expressed in the endocrine pancreas and transactivates the glucagon gene promoter, Journal of Biological Chemistry, 275, 32708, 10.1074/jbc.M005704200 Ritz-Laser, 1999, Pax-6 and Cdx-2/3 interact to activate glucagon gene expression on the G1 control element, Journal of Biological Chemistry, 274, 4124, 10.1074/jbc.274.7.4124 Wang, 1995, The LIM domain homeobox gene isl-1 is a positive regulator of islet cell-specific proglucagon gene transcription, Journal of Biological Chemistry, 270, 12646, 10.1074/jbc.270.21.12646 Kaestner, 1999, Inactivation of the winged helix transcription factor HNF3alpha affects glucose homeostasis and islet glucagon gene expression in vivo, Genes and Development, 13, 495, 10.1101/gad.13.4.495 Lee, 2005, Foxa2 is required for the differentiation of pancreatic alpha-cells, Developmental Biology, 278, 484, 10.1016/j.ydbio.2004.10.012 Sund, 2001, Tissue-specific deletion of Foxa2 in pancreatic beta cells results in hyperinsulinemic hypoglycemia, Genes and Development, 15, 1706, 10.1101/gad.901601 Dong, 1991, Islet cell and extrapancreatic expression of the LIM domain homeobox gene isl-1, Molecular Endocrinology, 5, 1633, 10.1210/mend-5-11-1633 Pfaff, 1996, Requirement for LIM homeobox gene Isl1 in motor neuron generation reveals a motor neuron-dependent step in interneuron differentiation, Cell, 84, 309, 10.1016/S0092-8674(00)80985-X Karlsson, 1990, Insulin gene enhancer binding protein Isl-1 is a member of a novel class of proteins containing both a homeo- and a Cys-His domain, Nature, 344, 879, 10.1038/344879a0 Vallejo, 1992, Somatostatin gene upstream enhancer element activated by a protein complex consisting of CREB, Isl-1-like, and alpha-CBF-like transcription factors, Journal of Biological Chemistry, 267, 12876, 10.1016/S0021-9258(18)42357-5 Drucker, 1989, Proglucagon gene expression is regulated by a cyclic AMP-dependent pathway in rat intestine, Proceedings of the National Academy of Sciences of the United States of America, 86, 3953, 10.1073/pnas.86.11.3953 Drucker, 1991, The rat glucagon gene is regulated by a protein kinase A-dependent pathway in pancreatic islet cells, Endocrinology, 128, 394, 10.1210/endo-128-1-394 Knepel, 1990, Transcriptional activation of the rat glucagon gene by the cyclic AMP-responsive element in pancreatic islet cells, Molecular and Cellular Biology, 10, 6799 Drucker, 1994, Activation of proglucagon gene transcription by protein kinase-A in a novel mouse enteroendocrine cell line, Molecular Endocrinology, 8, 1646 Gajic, 1993, Multiple cis-acting domains mediate basal and adenosine 3',5'-monophosphate-dependent glucagon gene transcription in a mouse neuroendocrine cell line, Endocrinology, 132, 1055, 10.1210/endo.132.3.7679966 Lu, 1996, Proglucagon gene expression is induced by gastrin-releasing peptide in a mouse enteroendocrine cell line, Endocrinology, 137, 3710, 10.1210/endo.137.9.8756537 Ni, 2003, Transcriptional activation of the proglucagon gene by lithium and beta-catenin in intestinal endocrine L cells, Journal of Biological Chemistry, 278, 1380, 10.1074/jbc.M206006200 Yi, 2008, Cross talk between the insulin and Wnt signaling pathways: evidence from intestinal endocrine L cells, Endocrinology, 149, 2341, 10.1210/en.2007-1142 Fang, 2000, Phosphorylation and inactivation of glycogen synthase kinase 3 by protein kinase A, Proceedings of the National Academy of Sciences of the United States of America, 97, 11960, 10.1073/pnas.220413597 Li, 2000, Cyclic AMP promotes neuronal survival by phosphorylation of glycogen synthase kinase 3beta, Molecular and Cellular Biology, 20, 9356, 10.1128/MCB.20.24.9356-9363.2000 Chen, 1989, Molecular and cellular responses of islets during perturbations of glucose homeostasis determined by in situ hybridization histochemistry, Proceedings of the National Academy of Sciences of the United States of America, 86, 1367, 10.1073/pnas.86.4.1367 Philippe, 1989, Glucagon gene transcription is negatively regulated by insulin in a hamster islet cell line, Journal of Clinical Investigation, 84, 672, 10.1172/JCI114214 Philippe, 1991, Insulin regulation of the glucagon gene is mediated by an insulin-responsive DNA element, Proceedings of the National Academy of Sciences of the United States of America, 88, 7224, 10.1073/pnas.88.16.7224 Gauthier, 2007, The beta-cell specific transcription factor Nkx6.1 inhibits glucagon gene transcription by interfering with Pax6, Biochemical Journal, 403, 593, 10.1042/BJ20070053 Ritz-Laser, 2002, The pancreatic beta-cell-specific transcription factor Pax-4 inhibits glucagon gene expression through Pax-6, Diabetologia, 45, 97, 10.1007/s125-002-8249-9 Fujita, 2008, Pax6 and Pdx1 are required for production of glucose-dependent insulinotropic polypeptide in proglucagon-expressing L cells, American Journal of Physiology Endocrinology and Metabolism, 295, E648, 10.1152/ajpendo.90440.2008 Flock, 2005, Pdx-1 is not sufficient for repression of proglucagon gene transcription in islet or enteroendocrine cells, Endocrinology, 146, 441, 10.1210/en.2004-0495 Yi, 2005, TCF-4 mediates cell type-specific regulation of proglucagon gene expression by beta-catenin and glycogen synthase kinase-3beta, Journal of Biological Chemistry, 280, 1457, 10.1074/jbc.M411487200 Larraufie, 2019, Important role of the GLP-1 Axis for glucose homeostasis after bariatric surgery, Cell Reports, 26, 1399, 10.1016/j.celrep.2019.01.047 Roberts, 2018, Gastrectomy with Roux-en-Y reconstruction as a lean model of bariatric surgery, Surgery for Obesity and Related Diseases, 14, 562, 10.1016/j.soard.2018.01.039 Roberts, 2019, Comparison of human and murine enteroendocrine cells by transcriptomic and peptidomic profiling, Diabetes, 68, 1062, 10.2337/db18-0883 Baggio, 2007, Biology of incretins: GLP-1 and GIP, Gastroenterology, 132, 2131, 10.1053/j.gastro.2007.03.054 Larsen, 1997, Distribution of glucagon-like peptide-1 and other preproglucagon-derived peptides in the rat hypothalamus and brainstem, Neuroscience, 77, 257, 10.1016/S0306-4522(96)00434-4 Tucker, 1996, Proglucagon processing in islet and intestinal cell lines, Regulatory Peptides, 62, 29, 10.1016/0167-0115(95)00167-0 Vrang, 2007, Characterization of brainstem preproglucagon projections to the paraventricular and dorsomedial hypothalamic nuclei, Brain Research, 1149, 118, 10.1016/j.brainres.2007.02.043 Rouille, 1995, Differential processing of proglucagon by the subtilisin-like prohormone convertases PC2 and PC3 to generate either glucagon or glucagon-like peptide, Journal of Biological Chemistry, 270, 26488, 10.1074/jbc.270.44.26488 Holst, 2007, The physiology of glucagon-like peptide 1, Physiological Reviews, 87, 1409, 10.1152/physrev.00034.2006 Holst, 1994, Proglucagon processing in porcine and human pancreas, Journal of Biological Chemistry, 269, 18827, 10.1016/S0021-9258(17)32241-X Furuta, 1997, Defective prohormone processing and altered pancreatic islet morphology in mice lacking active SPC2, Proceedings of the National Academy of Sciences of the United States of America, 94, 6646, 10.1073/pnas.94.13.6646 Furuta, 2001, Severe defect in proglucagon processing in islet A-cells of prohormone convertase 2 null mice, Journal of Biological Chemistry, 276, 27197, 10.1074/jbc.M103362200 Webb, 2002, Glucagon replacement via micro-osmotic pump corrects hypoglycemia and alpha-cell hyperplasia in prohormone convertase 2 knockout mice, Diabetes, 51, 398, 10.2337/diabetes.51.2.398 Kilimnik, 2010, Intraislet production of GLP-1 by activation of prohormone convertase 1/3 in pancreatic alpha-cells in mouse models of ss-cell regeneration, Islets, 2, 149, 10.4161/isl.2.3.11396 Nie, 2000, Regulation of pancreatic PC1 and PC2 associated with increased glucagon-like peptide 1 in diabetic rats, Journal of Clinical Investigation, 105, 955, 10.1172/JCI7456 Thyssen, 2006, Ontogeny of regeneration of beta-cells in the neonatal rat after treatment with streptozotocin, Endocrinology, 147, 2346, 10.1210/en.2005-0396 Wilson, 2002, Expression pattern of IAPP and prohormone convertase 1/3 reveals a distinctive set of endocrine cells in the embryonic pancreas, Mechanisms of Development, 115, 171, 10.1016/S0925-4773(02)00118-1 McGirr, 2005, Glucose dependence of the regulated secretory pathway in alphaTC1-6 cells, Endocrinology, 146, 4514, 10.1210/en.2005-0402 Whalley, 2011, Processing of proglucagon to GLP-1 in pancreatic alpha-cells: is this a paracrine mechanism enabling GLP-1 to act on beta-cells?, Journal of Endocrinology, 211, 99, 10.1530/JOE-11-0094 Ellingsgaard, 2008, Interleukin-6 regulates pancreatic alpha-cell mass expansion, Proceedings of the National Academy of Sciences of the United States of America, 105, 13163, 10.1073/pnas.0801059105 Ellingsgaard, 2011, Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells, Nature Medicine, 17, 1481, 10.1038/nm.2513 Wideman, 2006, Improving function and survival of pancreatic islets by endogenous production of glucagon-like peptide 1 (GLP-1), Proceedings of the National Academy of Sciences of the United States of America, 103, 13468, 10.1073/pnas.0600655103 Jun, 2015, Absence of glucagon and insulin action reveals a role for the GLP-1 receptor in endogenous glucose production, Diabetes, 64, 819, 10.2337/db14-1052 Omar, 2014, Fibroblast growth factor 21 (FGF21) and glucagon-like peptide 1 contribute to diabetes resistance in glucagon receptor-deficient mice, Diabetes, 63, 101, 10.2337/db13-0710 Moffett, 2014, Incretin receptor null mice reveal key role of GLP-1 but not GIP in pancreatic beta cell adaptation to pregnancy, PLoS One, 9, 10.1371/journal.pone.0096863 Vasu, 2014, Role of endogenous GLP-1 and GIP in beta cell compensatory responses to insulin resistance and cellular stress, PLoS One, 9, 10.1371/journal.pone.0101005 Chambers, 2017, The role of pancreatic preproglucagon in glucose homeostasis in mice, Cell Metabolism, 25, 927, 10.1016/j.cmet.2017.02.008 Lin, 2018, GPR142 prompts glucagon-like Peptide-1 release from islets to improve beta cell function, Molecular Metabolism, 11, 205, 10.1016/j.molmet.2018.02.008 Traub, 2017, Pancreatic alpha cell-derived glucagon-related peptides are required for beta cell adaptation and glucose homeostasis, Cell Reports, 18, 3192, 10.1016/j.celrep.2017.03.005 Capozzi, 2019, Beta Cell tone is defined by proglucagon peptides through cAMP signaling, JCI Insight, 4, 10.1172/jci.insight.126742 Orskov, 1989, Complete sequences of glucagon-like peptide-1 from human and pig small intestine, Journal of Biological Chemistry, 264, 12826, 10.1016/S0021-9258(18)51561-1 Orskov, 1994, Tissue and plasma concentrations of amidated and glycine-extended glucagon-like peptide I in humans, Diabetes, 43, 535, 10.2337/diab.43.4.535 Hansen, 2000, Somatostatin restrains the secretion of glucagon-like peptide-1 and -2 from isolated perfused porcine ileum, American Journal of Physiology Endocrinology and Metabolism, 278, E1010, 10.1152/ajpendo.2000.278.6.E1010 Mojsov, 1990, Both amidated and nonamidated forms of glucagon-like peptide I are synthesized in the rat intestine and the pancreas, Journal of Biological Chemistry, 265, 8001, 10.1016/S0021-9258(19)39030-1 Kuhre, 2014, GLP-1 amidation efficiency along the length of the intestine in mice, rats and pigs and in GLP-1 secreting cell lines, Peptides, 55, 52, 10.1016/j.peptides.2014.01.020 Philippe, 1986, Proglucagon processing in a rat islet cell line resembles phenotype of intestine rather than pancreas, Endocrinology, 119, 2833, 10.1210/endo-119-6-2833 Drucker, 1986, Cell-specific post-translational processing of preproglucagon expressed from a metallothionein-glucagon fusion gene, Journal of Biological Chemistry, 261, 9637, 10.1016/S0021-9258(18)67561-1 Orskov, 1993, Biological effects and metabolic rates of glucagonlike peptide-1 7-36 amide and glucagonlike peptide-1 7-37 in healthy subjects are indistinguishable, Diabetes, 42, 658, 10.2337/diab.42.5.658 Hui, 2002, The short half-life of glucagon-like peptide-1 in plasma does not reflect its long-lasting beneficial effects, European Journal of Endocrinology, 146, 863, 10.1530/eje.0.1460863 Deacon, 1996, Glucagon-like peptide 1 undergoes differential tissue-specific metabolism in the anesthetized pig, American Journal of Physiology, 271, E458 Meier, 2004, Secretion, degradation, and elimination of glucagon-like peptide 1 and gastric inhibitory polypeptide in patients with chronic renal insufficiency and healthy control subjects, Diabetes, 53, 654, 10.2337/diabetes.53.3.654 Deacon, 1995, Degradation of glucagon-like peptide-1 by human plasma in vitro yields an N-terminally truncated peptide that is a major endogenous metabolite in vivo, The Journal of Cinical Endocrinology and Metabolism, 80, 952 Kieffer, 1995, Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV, Endocrinology, 136, 3585, 10.1210/endo.136.8.7628397 Mentlein, 1993, Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7-36)amide, peptide histidine methionine and is responsible for their degradation in human serum, European Journal of Biochemistry, 214, 829, 10.1111/j.1432-1033.1993.tb17986.x De Meester, 1999, CD26, let it cut or cut it down, Immunology Today, 20, 367, 10.1016/S0167-5699(99)01486-3 Windelov, 2017, Why is it so difficult to measure glucagon-like peptide-1 in a mouse?, Diabetologia, 60, 2066, 10.1007/s00125-017-4347-7 Drucker, 2007, Dipeptidyl peptidase-4 inhibition and the treatment of type 2 diabetes: preclinical biology and mechanisms of action, Diabetes Care, 30, 1335, 10.2337/dc07-0228 Hansen, 1999, 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, 10.1210/endo.140.11.7143 Holst, 1998, Inhibition of the activity of dipeptidyl-peptidase IV as a treatment for type 2 diabetes, Diabetes, 47, 1663, 10.2337/diabetes.47.11.1663 Deacon, 1998, Dipeptidyl peptidase IV inhibition potentiates the insulinotropic effect of glucagon-like peptide 1 in the anesthetized pig, Diabetes, 47, 764, 10.2337/diabetes.47.5.764 Parkes, 2001, Pharmacokinetic actions of exendin-4 in the rat:comparison with glucagon-like peptide-1, Drug Development Research, 53, 260, 10.1002/ddr.1195 Nauck, 1998, Glucagon-like peptide 1 (GLP-1): a potent gut hormone with a possible therapeutic perspective, Acta Diabetologica, 35, 117, 10.1007/s005920050116 Vahl, 2003, Effects of GLP-1-(7-36)NH2, GLP-1-(7-37), and GLP-1- (9-36)NH2 on intravenous glucose tolerance and glucose-induced insulin secretion in healthy humans, The Journal of Cinical Endocrinology and Metabolism, 88, 1772, 10.1210/jc.2002-021479 Zander, 2006, The metabolite generated by dipeptidyl-peptidase 4 metabolism of glucagon-like peptide-1 has no influence on plasma glucose levels in patients with type 2 diabetes, Diabetologia, 49, 369, 10.1007/s00125-005-0098-y Elahi, 2008, GLP-1 (9-36) amide, cleavage product of GLP-1 (7-36) amide, is a glucoregulatory peptide, Obesity (Silver Spring), 16, 1501, 10.1038/oby.2008.229 Deacon, 2002, GLP-1-(9-36) amide reduces blood glucose in anesthetized pigs by a mechanism that does not involve insulin secretion, American Journal of Physiology Endocrinology and Metabolism, 282, E873, 10.1152/ajpendo.00452.2001 Meier, 2006, The glucagon-like peptide-1 metabolite GLP-1-(9-36) amide reduces postprandial glycemia independently of gastric emptying and insulin secretion in humans, American Journal of Physiology Endocrinology and Metabolism, 290, E1118, 10.1152/ajpendo.00576.2005 Ban, 2008, Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways, Circulation, 117, 2340, 10.1161/CIRCULATIONAHA.107.739938 Parker, 2006, Journal of Endocrinology, 191, 93, 10.1677/joe.1.06904 Porter, 2012, Actions of incretin metabolites on locomotor activity, cognitive function and in vivo hippocampal synaptic plasticity in high fat fed mice, Peptides, 35, 1, 10.1016/j.peptides.2012.03.014 Knudsen, 1996, Glucagon-like peptide-1-(9-36) amide is a major metabolite of glucagon-like peptide-1-(7-36) amide after in vivo administration to dogs, and it acts as an antagonist on the pancreatic receptor, European Journal of Pharmacology, 318, 429, 10.1016/S0014-2999(96)00795-9 Bryant, 1983, Measurement of gut hormonal peptides in biopsies from human stomach and proximal small intestine, Gut, 24, 114, 10.1136/gut.24.2.114 Damholt, 1999, Immunocytochemical evidence for a paracrine interaction between GIP and GLP-1-producing cells in canine small intestine, Cell and Tissue Research, 298, 287, 10.1007/s004419900093 Drucker, 2006, The biology of incretin hormones, Cell Metabolism, 3, 153, 10.1016/j.cmet.2006.01.004 Eissele, 1992, Glucagon-like peptide-1 cells in the gastrointestinal tract and pancreas of rat, pig and man, European Journal of Clinical Investigation, 22, 283, 10.1111/j.1365-2362.1992.tb01464.x Larsson, 1975, Distribution and properties of glucagon immunoreactivity in the digestive tract of various mammals: an immunohistochemical and immunochemical study, Histochemistry, 44, 281, 10.1007/BF00490364 Layer, 1995, Ileal release of glucagon-like peptide-1 (GLP-1). Association with inhibition of gastric acid secretion in humans, Digestive Diseases and Sciences, 40, 1074, 10.1007/BF02064202 Caiazzo, 2018, Increased postprandial glucagon-like peptide-1 (GLP-1) production after endoscopic gastrointestinal bypass using the Cousin lumen-apposing stent in a porcine model, Endoscopy, 50, 14 Chambers, 2011, Weight-independent changes in blood glucose homeostasis after gastric bypass or vertical sleeve gastrectomy in rats, Gastroenterology, 141, 950, 10.1053/j.gastro.2011.05.050 Chambers, 2011, Similar effects of roux-en-Y gastric bypass and vertical sleeve gastrectomy on glucose regulation in rats, Physiology and Behavior, 105, 120, 10.1016/j.physbeh.2011.05.026 Cummings, 2005, Hormonal mechanisms of weight loss and diabetes resolution after bariatric surgery, Surgery for Obesity and Related Diseases, 1, 358, 10.1016/j.soard.2005.03.208 Peterli, 2009, Improvement in glucose metabolism after bariatric surgery: comparison of laparoscopic Roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy: a prospective randomized trial, Annals of Surgery, 250, 234, 10.1097/SLA.0b013e3181ae32e3 Verhaeghe, 2014, Gastric bypass increases postprandial insulin and GLP-1 in nonobese minipigs, European Surgical Research, 52, 41, 10.1159/000355678 Qualmann, 1995, Glucagon-like peptide 1 (7-36 amide) secretion in response to luminal sucrose from the upper and lower gut. A study using alpha-glucosidase inhibition (acarbose), Scandinavian Journal of Gastroenterology, 30, 892, 10.3109/00365529509101597 Seifarth, 1998, Prolonged and enhanced secretion of glucagon-like peptide 1 (7-36 amide) after oral sucrose due to alpha-glucosidase inhibition (acarbose) in Type 2 diabetic patients, Diabetic Medicine, 15, 485, 10.1002/(SICI)1096-9136(199806)15:6<485::AID-DIA610>3.0.CO;2-Y Craig, 2017, Critical role for GLP-1 in symptomatic post-bariatric hypoglycaemia, Diabetologia, 60, 531, 10.1007/s00125-016-4179-x Wilson-Perez, 2013, Vertical sleeve gastrectomy is effective in two genetic mouse models of glucagon-like Peptide 1 receptor deficiency, Diabetes, 62, 2380, 10.2337/db12-1498 Lutz, 2018, Considering our methods: methodological issues with rodent models of appetite and obesity research, Physiology & Behavior, 192, 182, 10.1016/j.physbeh.2018.02.026 Svane, 2019, Postprandial nutrient handling and gastrointestinal secretion of hormones after Roux-en-Y gastric bypass vs sleeve gastrectomy, Gastroenterology, 10.1053/j.gastro.2019.01.262 Ye, 2014, GLP-1 receptor signaling is not required for reduced body weight after RYGB in rodents, American Journal of Physiology Regulatory Integrative and Comparative Physiology, 306, R352, 10.1152/ajpregu.00491.2013 Svane, 2016, Peptide YY and glucagon-like peptide-1 contribute to decreased food intake after Roux-en-Y gastric bypass surgery, International Journal of Obesity (London), 10.1038/ijo.2016.121 Ten Kulve, 2017, Elevated postoperative endogenous GLP-1 levels mediate effects of Roux-en-Y gastric bypass on neural responsivity to food cues, Diabetes Care, 40, 1522, 10.2337/dc16-2113 Holst, 2018, Mechanisms in bariatric surgery: gut hormones, diabetes resolution, and weight loss, Surgery for Obesity and Related Diseases, 14, 708, 10.1016/j.soard.2018.03.003 Fujii, 2015, Ingestion of coffee polyphenols increases postprandial release of the active glucagon-like peptide-1 (GLP-1(7-36)) amide in C57BL/6J mice, Journal of Nutrition Sciences, 4, e9, 10.1017/jns.2014.71 Higuchi, 2013, Oral administration of corn zein hydrolysate stimulates GLP-1 and GIP secretion and improves glucose tolerance in male normal rats and Goto-Kakizaki rats, Endocrinology, 154, 3089, 10.1210/en.2012-2275 Jejelava, 2018, Intestinal lymph as a readout of meal-induced GLP-1 release in an unrestrained rat model, American Journal of Physiology Regulatory Integrative and Comparative Physiology, 10.1152/ajpregu.00120.2017 Moghadam, 2017, Alterations in circadian and meal-induced gut peptide levels in lean and obese rats, Experimental Biology and Medicine (Maywood), 242, 1786, 10.1177/1535370217732041 Nakajima, 2015, Postprandial glucagon-like peptide-1 secretion is increased during the progression of glucose intolerance and obesity in high-fat/high-sucrose diet-fed rats, British Journal of Nutrition, 113, 1477, 10.1017/S0007114515000550 Rocca, 2001, Monounsaturated fatty acid diets improve glycemic tolerance through increased secretion of glucagon-like peptide-1, Endocrinology, 142, 1148, 10.1210/endo.142.3.8034 Deshpande, 2011, Targeting enteral endocrinal L-cells with dietary carbohydrates, by increasing the availability of miglitol in the intestinal lumen, leads to multi-fold enhancement of plasma glucagon-like peptide-1 levels in non-diabetic canines, Drug Development and Industrial Pharmacy, 37, 506, 10.3109/03639045.2010.526123 Ionut, 2006, Exogenously imposed postprandial-like rises in systemic glucose and GLP-1 do not produce an incretin effect, suggesting an indirect mechanism of GLP-1 action, American Journal of Physiology Endocrinology and Metabolism, 291, E779, 10.1152/ajpendo.00106.2005 Lubbs, 2010, Dietary macronutrients and feeding frequency affect fasting and postprandial concentrations of hormones involved in appetite regulation in adult dogs, Journal of Animal Science, 88, 3945, 10.2527/jas.2010-2938 Orskov, 1996, Secretion of the incretin hormones glucagon-like peptide-1 and gastric inhibitory polypeptide correlates with insulin secretion in normal man throughout the day, Scandinavian Journal of Gastroenterology, 31, 665, 10.3109/00365529609009147 Vilsboll, 2003, Incretin secretion in relation to meal size and body weight in healthy subjects and people with type 1 and type 2 diabetes mellitus, The Journal of Cinical Endocrinology and Metabolism, 88, 2706, 10.1210/jc.2002-021873 Elliott, 1993, Glucagon-like peptide-1 (7-36)amide and glucose-dependent insulinotropic polypeptide secretion in response to nutrient ingestion in man: acute post-prandial and 24-h secretion patterns, Journal of Endocrinology, 138, 159, 10.1677/joe.0.1380159 Herrmann, 1995, Glucagon-like peptide-1 and glucose-dependent insulin-releasing polypeptide plasma levels in response to nutrients, Digestion, 56, 117, 10.1159/000201231 Kuhre, 2015, Measurement of the incretin hormones: glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, Journal of Diabetic Complications, 29, 445, 10.1016/j.jdiacomp.2014.12.006 Hjollund, 2011, Dipeptidyl peptidase-4 inhibition increases portal concentrations of intact glucagon-like peptide-1 (GLP-1) to a greater extent than peripheral concentrations in anaesthetised pigs, Diabetologia, 54, 2206, 10.1007/s00125-011-2168-7 Holst, 2005, Glucagon-like peptide-1 mediates the therapeutic actions of DPP-IV inhibitors, Diabetologia, 48, 612, 10.1007/s00125-005-1705-7 Toft-Nielson, 1996, The effect of glucagon-like peptide I (GLP-I) on glucose elimination in healthy subjects depends on the pancreatic glucoregulatory hormones, Diabetes, 45, 552, 10.2337/diab.45.5.552 Dailey, 2012, Disassociation between preprandial gut peptide release and food-anticipatory activity, Endocrinology, 153, 132, 10.1210/en.2011-1464 Vahl, 2010, Meal-anticipatory glucagon-like peptide-1 secretion in rats, Endocrinology, 151, 569, 10.1210/en.2009-1002 Balks, 1997, Rapid oscillations in plasma glucagon-like peptide-1 (GLP-1) in humans: cholinergic control of GLP-1 secretion via muscarinic receptors, The Journal of Cinical Endocrinology and Metabolism, 82, 786 Gribble, 2003, A novel glucose-sensing mechanism contributing to glucagon-like peptide-1 secretion from the GLUTag cell line, Diabetes, 52, 1147, 10.2337/diabetes.52.5.1147 Sugiyama, 1994, Stimulation of truncated glucagon-like peptide-1 release from the isolated perfused canine ileum by glucose absorption, Digestion, 55, 24, 10.1159/000201118 Kuhre, 2014, Fructose stimulates GLP-1 but not GIP secretion in mice, rats, and humans, American Journal of Physiology Gastrointestinal and Liver Physiology, 306, G622, 10.1152/ajpgi.00372.2013 Dumoulin, 1998, Peptide YY, glucagon-like peptide-1, and neurotensin responses to luminal factors in the isolated vascularly perfused rat ileum, Endocrinology, 139, 3780, 10.1210/endo.139.9.6202 Hirasawa, 2005, Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120, Nature Medicine, 11, 90, 10.1038/nm1168 Christensen, 2015, Vascular, but not luminal, activation of FFAR1 (GPR40) stimulates GLP-1 secretion from isolated perfused rat small intestine, Physics Reports, 3 Reimer, 2001, A human cellular model for studying the regulation of glucagon-like peptide-1 secretion, Endocrinology, 142, 4522, 10.1210/endo.142.10.8415 Gunnarsson, 2006, Glucose-induced incretin hormone release and inactivation are differently modulated by oral fat and protein in mice, Endocrinology, 147, 3173, 10.1210/en.2005-1442 Hall, 2003, Casein and whey exert different effects on plasma amino acid profiles, gastrointestinal hormone secretion and appetite, British Journal of Nutrition, 89, 239, 10.1079/BJN2002760 Hira, 2009, GLP-1 secretion is enhanced directly in the ileum but indirectly in the duodenum by a newly identified potent stimulator, zein hydrolysate, in rats, American Journal of Physiology Gastrointestinal and Liver Physiology, 297, G663, 10.1152/ajpgi.90635.2008 Mochida, 2010, The corn protein, zein hydrolysate, administered into the ileum attenuates hyperglycemia via its dual action on glucagon-like peptide-1 secretion and dipeptidyl peptidase-IV activity in rats, Endocrinology, 151, 3095, 10.1210/en.2009-1510 Gameiro, 2005, The neurotransmitters glycine and GABA stimulate glucagon-like peptide-1 release from the GLUTag cell line, Journal of Physiology, 569, 761, 10.1113/jphysiol.2005.098962 Reimann, 2004, Glutamine potently stimulates glucagon-like peptide-1 secretion from GLUTag cells, Diabetologia, 47, 1592, 10.1007/s00125-004-1498-0 Tolhurst, 2011, Glutamine triggers and potentiates glucagon-like peptide-1 secretion by raising cytosolic Ca2+ and cAMP, Endocrinology, 152, 405, 10.1210/en.2010-0956 Punjabi, 2014, Circulating glucagon-like peptide-1 (GLP-1) inhibits eating in male rats by acting in the hindbrain and without inducing avoidance, Endocrinology, 155, 1690, 10.1210/en.2013-1447 Faerch, 2015, GLP-1 response to oral glucose is reduced in prediabetes, screen-detected type 2 diabetes, and obesity and influenced by sex: the ADDITION-PRO study, Diabetes, 64, 2513, 10.2337/db14-1751 Calanna, 2013, Secretion of glucagon-like peptide-1 in patients with type 2 diabetes mellitus: systematic review and meta-analyses of clinical studies, Diabetologia, 56, 965, 10.1007/s00125-013-2841-0 Matikainen, 2014, GLP-1 responses are heritable and blunted in acquired obesity with high liver fat and insulin resistance, Diabetes Care, 37, 242, 10.2337/dc13-1283 Reimann, 2002, Glucose-sensing in glucagon-like peptide-1-secreting cells, Diabetes, 51, 2757, 10.2337/diabetes.51.9.2757 Tolhurst, 2009, Nutritional regulation of glucagon-like peptide-1 secretion, Journal of Physiology, 587, 27, 10.1113/jphysiol.2008.164012 Ashcroft, 1999, ATP-sensitive K+ channels and insulin secretion: their role in health and disease, Diabetologia, 42, 903, 10.1007/s001250051247 Ashcroft, 2013, K(ATP) channels and islet hormone secretion: new insights and controversies, Nature Reviews Endocrinology, 9, 660, 10.1038/nrendo.2013.166 Gribble, 2003, Sulphonylurea action revisited: the post-cloning era, Diabetologia, 46, 875, 10.1007/s00125-003-1143-3 Henquin, 1992, The fiftieth anniversary of hypoglycaemic sulphonamides. How did the mother compound work?, Diabetologia, 35, 907, 10.1007/BF00401417 Nielsen, 2007, 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, European Journal of Endocrinology, 156, 663, 10.1530/EJE-06-0756 Cani, 2007, GLUT2 and the incretin receptors are involved in glucose-induced incretin secretion, Molecular and Cellular Endocrinology, 276, 18, 10.1016/j.mce.2007.06.003 Parker, 2012, Predominant role of active versus facilitative glucose transport for glucagon-like peptide-1 secretion, Diabetologia, 55, 2445, 10.1007/s00125-012-2585-2 Gorboulev, 2012, Na(+)-D-glucose cotransporter SGLT1 is pivotal for intestinal glucose absorption and glucose-dependent incretin secretion, Diabetes, 61, 187, 10.2337/db11-1029 Moriya, 2009, Activation of sodium-glucose cotransporter 1 ameliorates hyperglycemia by mediating incretin secretion in mice, American Journal of Physiology Endocrinology and Metabolism, 297, E1358, 10.1152/ajpendo.00412.2009 Mace, 2012, The regulation of K- and L-cell activity by GLUT2 and the calcium-sensing receptor CasR in rat small intestine, Journal of Physiology, 590, 2917, 10.1113/jphysiol.2011.223800 Ezcurra, 2013, Molecular mechanisms of incretin hormone secretion, Current Opinion in Pharmacology, 13, 922, 10.1016/j.coph.2013.08.013 Reimann, 2016, Mechanisms underlying glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 secretion, Journal of Diabetes Investigation, 7, 13, 10.1111/jdi.12478 Steinert, 2011, Effects of carbohydrate sugars and artificial sweeteners on appetite and the secretion of gastrointestinal satiety peptides, British Journal of Nutrition, 105, 1320, 10.1017/S000711451000512X Jang, 2007, Gut-expressed gustducin and taste receptors regulate secretion of glucagon-like peptide-1, Proceedings of the National Academy of Sciences of the United States of America, 104, 15069, 10.1073/pnas.0706890104 Reimann, 2008, Glucose sensing in L cells: a primary cell study, Cell Metabolism, 8, 532, 10.1016/j.cmet.2008.11.002 Saltiel, 2017, Sweet taste receptor activation in the gut is of limited importance for glucose-stimulated GLP-1 and GIP secretion, Nutrients, 9, 10.3390/nu9040418 Ma, 2010, Effect of the artificial sweetener, sucralose, on small intestinal glucose absorption in healthy human subjects, British Journal of Nutrition, 104, 803, 10.1017/S0007114510001327 Maersk, 2012, 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, European Journal of Clinical Nutrition, 66, 523, 10.1038/ejcn.2011.223 Husted, 2017, GPCR-mediated signaling of metabolites, Cell Metabolism, 25, 777, 10.1016/j.cmet.2017.03.008 Ekberg, 2016, GPR119, a major enteroendocrine sensor of dietary triglyceride metabolites coacting in synergy with FFA1 (GPR40), Endocrinology, 157, 4561, 10.1210/en.2016-1334 Kuhre, 2016, Peptide production and secretion in GLUTag, NCI-H716, and STC-1 cells: a comparison to native L-cells, Journal of Molecular Endocrinology, 56, 201, 10.1530/JME-15-0293 Roberge, 1991, Secretion of proglucagon-derived peptides in response to intestinal luminal nutrients, Endocrinology, 128, 3169, 10.1210/endo-128-6-3169 Roberge, 1993, Regulation of intestinal proglucagon-derived peptide secretion by glucose-dependent insulinotropic peptide in a novel enteroendocrine loop, Endocrinology, 133, 233, 10.1210/endo.133.1.8319572 Thomsen, 1999, Differential effects of saturated and monounsaturated fatty acids on postprandial lipemia and incretin responses in healthy subjects, American Journal of Clinical Nutrition, 69, 1135, 10.1093/ajcn/69.6.1135 Thomsen, 2003, Differential effects of saturated and monounsaturated fats on postprandial lipemia and glucagon-like peptide 1 responses in patients with type 2 diabetes, American Journal of Clinical Nutrition, 77, 605, 10.1093/ajcn/77.3.605 Sidhu, 2000, Fatty acid-induced cholecystokinin secretion and changes in intracellular Ca2+ in two enteroendocrine cell lines, STC-1 and GLUTag, Journal of Physiology, 528, 165, 10.1111/j.1469-7793.2000.00165.x Engelstoft, 2016, Opposite regulation of ghrelin and glucagon-like peptide-1 by metabolite G-protein-coupled receptors, Trends in Endocrinology and Metabolism, 27, 665, 10.1016/j.tem.2016.07.001 Edfalk, 2008, Gpr40 is expressed in enteroendocrine cells and mediates free fatty acid stimulation of incretin secretion, Diabetes, 57, 2280, 10.2337/db08-0307 Hauge, 2015, GPR40 (FFAR1) - combined Gs and Gq signaling in vitro is associated with robust incretin secretagogue action ex vivo and in vivo, Molecular Metabolism, 4, 3, 10.1016/j.molmet.2014.10.002 Gorski, 2017, GPR40 reduces food intake and body weight through GLP-1, American Journal of Physiology Endocrinology and Metabolism, 313, E37, 10.1152/ajpendo.00435.2016 Xiong, 2013, Activation of FFA1 mediates GLP-1 secretion in mice. Evidence for allosterism at FFA1, Molecular and Cellular Endocrinology, 369, 119, 10.1016/j.mce.2013.01.009 Hansen, 2012, GPR119 as a fat sensor, Trends in Pharmacological Sciences, 33, 374, 10.1016/j.tips.2012.03.014 Mandoe, 2015, The 2-monoacylglycerol moiety of dietary fat appears to be responsible for the fat-induced release of GLP-1 in humans, American Journal of Clinical Nutrition, 102, 548, 10.3945/ajcn.115.106799 Hauge, 2017, Gq and Gs signaling acting in synergy to control GLP-1 secretion, Molecular and Cellular Endocrinology, 449, 64, 10.1016/j.mce.2016.11.024 Clara, 2016, Oleic acid stimulates glucagon-like peptide-1 release from enteroendocrine cells by modulating cell respiration and glycolysis, Metabolism, 65, 8, 10.1016/j.metabol.2015.10.003 Diakogiannaki, 2013, Oligopeptides stimulate glucagon-like peptide-1 secretion in mice through proton-coupled uptake and the calcium-sensing receptor, Diabetologia, 56, 2688, 10.1007/s00125-013-3037-3 Chen, 2009, Dairy protein and leucine alter GLP-1 release and mRNA of genes involved in intestinal lipid metabolism in vitro, Nutrition, 25, 340, 10.1016/j.nut.2008.08.012 Plaisancie, 1995, Luminal glucagon-like peptide-1(7-36) amide-releasing factors in the isolated vascularly perfused rat colon, Journal of Endocrinology, 145, 521, 10.1677/joe.0.1450521 Clemmensen, 2013, Oral L-arginine stimulates GLP-1 secretion to improve glucose tolerance in male mice, Endocrinology, 154, 3978, 10.1210/en.2013-1529 Kato, 2017, Low-molecular fraction of wheat protein hydrolysate stimulates glucagon-like peptide-1 secretion in an enteroendocrine L cell line and improves glucose tolerance in rats, Nutrition Research, 37, 37, 10.1016/j.nutres.2016.12.002 Greenfield, 2009, Oral glutamine increases circulating glucagon-like peptide 1, glucagon, and insulin concentrations in lean, obese, and type 2 diabetic subjects, American Journal of Clinical Nutrition, 89, 106, 10.3945/ajcn.2008.26362 Lejeune, 2006, Ghrelin and glucagon-like peptide 1 concentrations, 24-h satiety, and energy and substrate metabolism during a high-protein diet and measured in a respiration chamber, American Journal of Clinical Nutrition, 83, 89, 10.1093/ajcn/83.1.89 Floyd, 1966, Stimulation of insulin secretion by amino acids, Journal of Clinical Investigation, 45, 1487, 10.1172/JCI105456 Reimer, 2006, Meat hydrolysate and essential amino acid-induced glucagon-like peptide-1 secretion, in the human NCI-H716 enteroendocrine cell line, is regulated by extracellular signal-regulated kinase1/2 and p38 mitogen-activated protein kinases, Journal of Endocrinology, 191, 159, 10.1677/joe.1.06557 Calbet, 2004, Gastric emptying, gastric secretion and enterogastrone response after administration of milk proteins or their peptide hydrolysates in humans, European Journal of Nutrition, 43, 127, 10.1007/s00394-004-0448-4 Mortensen, 2009, Differential effects of protein quality on postprandial lipemia in response to a fat-rich meal in type 2 diabetes: comparison of whey, casein, gluten, and cod protein, American Journal of Clinical Nutrition, 90, 41, 10.3945/ajcn.2008.27281 Nilsson, 2004, Glycemia and insulinemia in healthy subjects after lactose-equivalent meals of milk and other food proteins: the role of plasma amino acids and incretins, American Journal of Clinical Nutrition, 80, 1246, 10.1093/ajcn/80.5.1246 Belza, 2013, Contribution of gastroenteropancreatic appetite hormones to protein-induced satiety, American Journal of Clinical Nutrition, 97, 980, 10.3945/ajcn.112.047563 Rudenko, 2019, The aromatic amino acid sensor GPR142 controls metabolism through balanced regulation of pancreatic and gut hormones, Molecular Metabolism, 19, 49, 10.1016/j.molmet.2018.10.012 Theodorakis, 2006, Human duodenal enteroendocrine cells: source of both incretin peptides, GLP-1 and GIP, American Journal of Physiology Endocrinology and Metabolism, 290, E550, 10.1152/ajpendo.00326.2004 Jorsal, 2018, Enteroendocrine K and L cells in healthy and type 2 diabetic individuals, Diabetologia, 61, 284, 10.1007/s00125-017-4450-9 Svendsen, 2015, An analysis of cosecretion and coexpression of gut hormones from male rat proximal and distal small intestine, Endocrinology, 156, 847, 10.1210/en.2014-1710 Anini, 2002, Muscarinic receptors control postprandial release of glucagon-like peptide-1: in vivo and in vitro studies in rats, Endocrinology, 143, 2420, 10.1210/endo.143.6.8840 Lim, 2006, Glucagon-like peptide 1 secretion by the L-cell - the view from within, Diabetes, 55, S70, 10.2337/db06-S020 Lim, 2009, Insulin regulates glucagon-like peptide-1 secretion from the enteroendocrine L cell, Endocrinology, 150, 580, 10.1210/en.2008-0726 Gagnon, 2015, Ghrelin is a novel regulator of GLP-1 secretion, Diabetes, 64, 1513, 10.2337/db14-1176 Brubaker, 1991, Regulation of intestinal proglucagon-derived peptide secretion by intestinal regulatory peptides, Endocrinology, 128, 3175, 10.1210/endo-128-6-3175 Brubaker, 2003, Direct and indirect mechanisms regulating secretion of glucagon-like peptide-1 and glucagon-like peptide-2, Canadian Journal of Physiology and Pharmacology, 81, 1005, 10.1139/y03-107 Cleator, 1975, Release of immunoreactive gastric inhibitory polypeptide (IR-GIP) by oral ingestion of food substances, Americas Journal of Surgery, 130, 128, 10.1016/0002-9610(75)90360-8 Burhol, 1979, The effect of a test meal on plasma vasoactive intestinal polypeptide (VIP), gastric inhibitory polypeptide (GIP), and secretin in man, Scandinavian Journal of Gastroenterology, 14, 939 Rocca, 1999, Role of the vagus nerve in mediating proximal nutrient-induced glucagon-like peptide-1 secretion, Endocrinology, 140, 1687, 10.1210/endo.140.4.6643 Nauck, 1993, 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, Journal of Clinical Investigation, 91, 301, 10.1172/JCI116186 Mentis, 2011, GIP does not potentiate the antidiabetic effects of GLP-1 in hyperglycemic patients with type 2 diabetes, Diabetes, 60, 1270, 10.2337/db10-1332 Fieseler, 1995, Physiological augmentation of amino acid-induced insulin secretion by GIP and GLP-I but not by CCK-8, American Journal of Physiology, 268, E949 Schirra, 1996, Gastric emptying and release of incretin hormones after glucose ingestion in humans, Journal of Clinical Investigation, 97, 92, 10.1172/JCI118411 Zhang, 2019, Comparative effects of proximal and distal small intestinal glucose exposure on glycemia, incretin hormone secretion, and the incretin effect in health and type 2 diabetes, Diabetes Care, 42, 520, 10.2337/dc18-2156 Beglinger, 2010, Role of fat hydrolysis in regulating glucagon-like Peptide-1 secretion, The Journal of Cinical Endocrinology and Metabolism, 95, 879, 10.1210/jc.2009-1062 Hansen, 2002, The effects of duodenal peptides on glucagon-like peptide-1 secretion from the ileum. A duodeno--ileal loop?, Regulatory Peptides, 110, 39, 10.1016/S0167-0115(02)00157-X Herrmann-Rinke, 1995, Regulation of glucagon-like peptide-1 secretion from rat ileum by neurotransmitters and peptides, Journal of Endocrinology, 147, 25, 10.1677/joe.0.1470025 Anini, 2003, Muscarinic receptors control glucagon-like peptide 1 secretion by human endocrine L cells, Endocrinology, 144, 3244, 10.1210/en.2003-0143 Hansen, 2004, Neural regulation of glucagon-like peptide-1 secretion in pigs, American Journal of Physiology Endocrinology and Metabolism, 287, E939, 10.1152/ajpendo.00197.2004 Moghimzadeh, 1983, Neuronal gastrin-releasing peptide in the mammalian gut and pancreas, Neuroscience, 10, 553, 10.1016/0306-4522(83)90152-5 Roberge, 1996, Gastrin-releasing peptide is a novel mediator of proximal nutrient-induced proglucagon-derived peptide secretion from the distal gut, Endocrinology, 137, 2383, 10.1210/endo.137.6.8641190 Hermansen, 1990, Gastrin releasing peptide stimulates the secretion of insulin, but not that of glucagon or somatostatin, from the isolated perfused dog pancreas, Acta Physiologica Scandinavica, 138, 175, 10.1111/j.1748-1716.1990.tb08830.x Lenz, 1988, CNS regulation of gastric and autonomic functions in dogs by gastrin-releasing peptide, American Journal of Physiology, 255, G298 Yegen, 1996, Inhibitory effects of gastrin releasing peptide on gastric emptying in rats, Regulatory Peptides, 61, 175, 10.1016/0167-0115(95)00151-4 Persson, 2000, Reduced GLP-1 and insulin responses and glucose intolerance after gastric glucose in GRP receptor-deleted mice, American Journal of Physiology Endocrinology and Metabolism, 279, E956, 10.1152/ajpendo.2000.279.5.E956 Steinert, 2017, Ghrelin, CCK, GLP-1, and PYY(3-36): secretory controls and physiological roles in eating and glycemia in health, obesity, and after RYGB, Physiological Reviews, 97, 411, 10.1152/physrev.00031.2014 Han, 2018, Olfactory receptor OR51E1 mediates GLP-1 secretion in human and rodent enteroendocrine L cells, Journal of Endocrine Society, 2, 1251, 10.1210/js.2018-00165 Llewellyn-Smith, 2011, Preproglucagon neurons project widely to autonomic control areas in the mouse brain, Neuroscience, 180, 111, 10.1016/j.neuroscience.2011.02.023 Merchenthaler, 1999, Distribution of pre-pro-glucagon and glucagon-like peptide-1 receptor messenger RNAs in the rat central nervous system, Journal of Comparative Neurology, 403, 261, 10.1002/(SICI)1096-9861(19990111)403:2<261::AID-CNE8>3.0.CO;2-5 Trapp, 2011, Glucagon-like peptide 1 and the brain: central actions-central sources?, Autonomic Neuroscience, 161, 14, 10.1016/j.autneu.2010.09.008 Elias, 2000, Chemical characterization of leptin-activated neurons in the rat brain, Journal of Comparative Neurology, 423, 261, 10.1002/1096-9861(20000724)423:2<261::AID-CNE6>3.0.CO;2-6 Vrang, 2003, Gastric distension induces c-Fos in medullary GLP-1/2-containing neurons, American Journal of Physiology Regulatory Integrative and Comparative Physiology, 285, R470, 10.1152/ajpregu.00732.2002 Hisadome, 2010, Leptin directly depolarizes preproglucagon neurons in the nucleus tractus solitarius: electrical properties of glucagon-like Peptide 1 neurons, Diabetes, 59, 1890, 10.2337/db10-0128 Hisadome, 2011, CCK stimulation of GLP-1 neurons involves alpha1-adrenoceptor-mediated increase in glutamatergic synaptic inputs, Diabetes, 60, 2701, 10.2337/db11-0489 Garfield, 2012, Neurochemical characterization of body weight-regulating leptin receptor neurons in the nucleus of the solitary tract, Endocrinology, 153, 4600, 10.1210/en.2012-1282 Rinaman, 1999, Interoceptive stress activates glucagon-like peptide-1 neurons that project to the hypothalamus, American Journal of Physiology, 277, R582 Baptista, 2007, Effects of cholecystokinin-8s in the nucleus tractus solitarius of vagally deafferented rats, American Journal of Physiology Regulatory Integrative and Comparative Physiology, 292, R1092, 10.1152/ajpregu.00517.2006 Louis, 1990, Evolving concerns relating to occupational disorders of the upper extremity, Clinical Orthopaedics and Related Research, 140 Gaykema, 2017, Activation of murine pre-proglucagon-producing neurons reduces food intake and body weight, Journal of Clinical Investigation, 127, 1031, 10.1172/JCI81335 Harmar, 2001, Family-B G-protein-coupled receptors, Genome Biology, 2, 10.1186/gb-2001-2-12-reviews3013 Mayo, 2003, International Union of Pharmacology. XXXV. The glucagon receptor family, Pharmacological Reviews, 55, 167, 10.1124/pr.55.1.6 Thorens, 1992, Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone glucagon-like peptide 1, Proceedings of the National Academy of Sciences of the United States of America, 89, 8641, 10.1073/pnas.89.18.8641 Dillon, 1993, Cloning and functional expression of the human glucagon-like peptide-1 (GLP-1) receptor, Endocrinology, 133, 1907, 10.1210/endo.133.4.8404634 Graziano, 1993, Cloning and functional expression of a human glucagon-like peptide-1 receptor, Biochemical and Biophysical Research Communications, 196, 141, 10.1006/bbrc.1993.2226 Thorens, 1993, Cloning and functional expression of the human islet GLP-1 receptor. Demonstration that exendin-4 is an agonist and exendin-(9-39) an antagonist of the receptor, Diabetes, 42, 1678, 10.2337/diab.42.11.1678 van Eyll, 1994, Signal transduction of the GLP-1-receptor cloned from a human insulinoma, FEBS Letters, 348, 7, 10.1016/0014-5793(94)00553-2 Svendsen, 2018, Insulin secretion depends on intra-islet glucagon signaling, Cell Reports, 25, 1127, 10.1016/j.celrep.2018.10.018 Raufman, 1992, Truncated glucagon-like peptide-1 interacts with exendin receptors on dispersed acini from Guinea pig pancreas. Identification of a mammalian analogue of the reptilian peptide exendin-4, Journal of Biological Chemistry, 267, 21432, 10.1016/S0021-9258(19)36628-1 Raufman, 1991, Journal of Biological Chemistry, 266, 2897, 10.1016/S0021-9258(18)49932-2 Goke, 1988, Receptors for glucagon-like peptide-1(7-36) amide on rat insulinoma-derived cells, Journal of Endocrinology, 116, 357, 10.1677/joe.0.1160357 Orskov, 1988, Truncated glucagon-like peptide-1 (proglucagon 78-107 amide), an intestinal insulin-releasing peptide, has specific receptors on rat insulinoma cells (RIN 5AH), FEBS Letters, 229, 175, 10.1016/0014-5793(88)80821-4 Fehmann, 1991, Functional receptors for the insulinotropic hormone glucagon-like peptide-I(7-37) on a somatostatin secreting cell line, FEBS Letters, 279, 335, 10.1016/0014-5793(91)80182-3 Fehmann, 1991, Homologous desensitization of the insulinotropic glucagon-like peptide-I (7-37) receptor on insulinoma (HIT-T15) cells, Endocrinology, 128, 2880, 10.1210/endo-128-6-2880 Fehmann, 1992, Insulinotropic hormone glucagon-like peptide-I(7-37) stimulation of proinsulin gene expression and proinsulin biosynthesis in insulinoma beta TC-1 cells, Endocrinology, 130, 159, 10.1210/endo.130.1.1309325 Fehmann, 1992, Galanin inhibits proinsulin gene expression stimulated by the insulinotropic hormone glucagon-like peptide-I(7-37) in mouse insulinoma beta TC-1 cells, Endocrinology, 130, 2890, 10.1210/endo.130.5.1374016 Gallwitz, 1993, Binding specificity and signal transduction of receptors for glucagon-like peptide-1(7-36)amide and gastric inhibitory polypeptide on RINm5F insulinoma cells, Journal of Molecular Endocrinology, 10, 259, 10.1677/jme.0.0100259 Gros, 1992, Characterization of binding sites for oxyntomodulin on a somatostatin-secreting cell line (RIN T3), Endocrinology, 130, 1263 Matsumura, 1992, Glucagonlike peptide-1(7-36)amide suppresses glucagon secretion and decreases cyclic AMP concentration in cultured In-R1-G9 cells, Biochemical and Biophysical Research Communications, 186, 503, 10.1016/S0006-291X(05)80836-8 Moens, 1996, Expression and functional activity of glucagon, glucagon-like peptide I, and glucose-dependent insulinotropic peptide receptors in rat pancreatic islet cells, Diabetes, 45, 257, 10.2337/diab.45.2.257 Fehmann, 1995, The effects of glucagon-like peptide-I (GLP-I) on hormone secretion from isolated human pancreatic islets, Pancreas, 11, 196, 10.1097/00006676-199508000-00014 Lankat-Buttgereit, 1994, Molecular cloning of a cDNA encoding for the GLP-1 receptor expressed in rat lung, Experimental and Clinical Endocrinology, 102, 341, 10.1055/s-0029-1211301 Bullock, 1996, Tissue distribution of messenger ribonucleic acid encoding the rat glucagon-like peptide-1 receptor, Endocrinology, 137, 2968, 10.1210/endo.137.7.8770921 Wei, 1995, Tissue-specific expression of the human receptor for glucagon-like peptide-I: brain, heart and pancreatic forms have the same deduced amino acid sequences, FEBS Letters, 358, 219, 10.1016/0014-5793(94)01430-9 Chen, 2017, GLP-1/GLP-1R signaling in regulation of adipocyte differentiation and lipogenesis, Cellular Physiology and Biochemistry, 42, 1165, 10.1159/000478872 Egan, 1994, Glucagon-like peptide-1(7-36) amide (GLP-1) enhances insulin-stimulated glucose metabolism in 3T3-L1 adipocytes: one of several potential extrapancreatic sites of GLP-1 action, Endocrinology, 135, 2070, 10.1210/endo.135.5.7956929 Challa, 2012, Regulation of adipocyte formation by GLP-1/GLP-1R signaling, Journal of Biological Chemistry, 287, 6421, 10.1074/jbc.M111.310342 Sanz, 2010, Signaling and biological effects of glucagon-like peptide 1 on the differentiation of mesenchymal stem cells from human bone marrow, American Journal of Physiology. Endocrinology and Metabolism, 298, E634, 10.1152/ajpendo.00460.2009 Iacobellis, 2017, Human epicardial fat expresses glucagon-like peptide 1 and 2 receptors genes, Hormone and Metabolic Research, 49, 625, 10.1055/s-0043-109563 Vendrell, 2011, Study of the potential association of adipose tissue GLP-1 receptor with obesity and insulin resistance, Endocrinology, 152, 4072, 10.1210/en.2011-1070 Goke, 1995, Distribution of GLP-1 binding sites in the rat brain: evidence that exendin-4 is a ligand of brain GLP-1 binding sites, European Journal of Neuroscience, 7, 2294, 10.1111/j.1460-9568.1995.tb00650.x Heppner, 2015, Expression and distribution of glucagon-like peptide-1 receptor mRNA, protein and binding in the male nonhuman primate (Macaca mulatta) brain, Endocrinology, 156, 255, 10.1210/en.2014-1675 Alvarez, 2005, The expression of GLP-1 receptor mRNA and protein allows the effect of GLP-1 on glucose metabolism in the human hypothalamus and brainstem, Journal of Neurochemistry, 92, 798, 10.1111/j.1471-4159.2004.02914.x Panjwani, 2013, GLP-1 receptor activation indirectly reduces hepatic lipid accumulation but does not attenuate development of atherosclerosis in diabetic male ApoE(-/-) mice, Endocrinology, 154, 127, 10.1210/en.2012-1937 Pyke, 2014, GLP-1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody, Endocrinology, 155, 1280, 10.1210/en.2013-1934 Jensen, 2018, Characterization of the glucagonlike peptide-1 receptor in male mouse brain using a novel antibody and in situ hybridization, Endocrinology, 159, 665, 10.1210/en.2017-00812 Pyke, 2013, The glucagon-like peptide-1 receptor--or not?, Endocrinology, 154, 4, 10.1210/en.2012-2124 Richards, 2014, Identification and characterization of GLP-1 receptor-expressing cells using a new transgenic mouse model, Diabetes, 63, 1224, 10.2337/db13-1440 Cork, 2015, Distribution and characterisation of Glucagon-like peptide-1 receptor expressing cells in the mouse brain, Molecular Metabolism, 4, 718, 10.1016/j.molmet.2015.07.008 Muraro, 2016, A single-cell transcriptome atlas of the human pancreas, Cellular Systems, 3, 385, 10.1016/j.cels.2016.09.002 Segerstolpe, 2016, Single-cell transcriptome profiling of human pancreatic islets in health and type 2 diabetes, Cell Metabolism, 24, 593, 10.1016/j.cmet.2016.08.020 Waser, 2015, Glucagon-like-peptide-1 receptor expression in normal and diseased human thyroid and pancreas, Modern Pathology, 28, 391, 10.1038/modpathol.2014.113 Ast, 2019, LUXendins reveal endogenous glucagon-like peptide-1 receptor distribution and dynamics, bioRxiv, 557132 Moon, 2012, Structural and molecular conservation of glucagon-like Peptide-1 and its receptor confers selective ligand-receptor interaction, Frontiers in Endocrinology (Lausanne), 3, 141 Alken, 2005, The signal peptide of the rat corticotropin-releasing factor receptor 1 promotes receptor expression but is not essential for establishing a functional receptor, Biochemical Journal, 390, 455, 10.1042/BJ20050113 Couvineau, 2004, Presence of a N-terminal signal peptide in class II G protein-coupled receptors: crucial role for expression of the human VPAC1 receptor, Regulatory Peptides, 123, 181, 10.1016/j.regpep.2004.06.025 Huang, 2010, Role of the signal peptide in the synthesis and processing of the glucagon-like peptide-1 receptor, British Journal of Pharmacology, 159, 237, 10.1111/j.1476-5381.2009.00517.x Parthier, 2007, Crystal structure of the incretin-bound extracellular domain of a G protein-coupled receptor, Proceedings of the National Academy of Sciences of the United States of America, 104, 13942, 10.1073/pnas.0706404104 Parthier, 2009, Passing the baton in class B GPCRs: peptide hormone activation via helix induction?, Trends in Biochemical Sciences, 34, 303, 10.1016/j.tibs.2009.02.004 Runge, 2008, Crystal structure of the ligand-bound glucagon-like peptide-1 receptor extracellular domain, Journal of Biological Chemistry, 283, 11340, 10.1074/jbc.M708740200 Tan, 2006, Peptide agonist docking in the N-terminal ectodomain of a class II G protein-coupled receptor, the VPAC1 receptor. Photoaffinity, NMR, and molecular modeling, Journal of Biological Chemistry, 281, 12792, 10.1074/jbc.M513305200 Underwood, 2010, Crystal structure of glucagon-like peptide-1 in complex with the extracellular domain of the glucagon-like peptide-1 receptor, Journal of Biological Chemistry, 285, 723, 10.1074/jbc.M109.033829 Adelhorst, 1994, Structure-activity studies of glucagon-like peptide-1, Journal of Biological Chemistry, 269, 6275, 10.1016/S0021-9258(17)37366-0 Gallwitz, 1994, Structure/activity characterization of glucagon-like peptide-1, European Journal of Biochemistry, 225, 1151, 10.1111/j.1432-1033.1994.1151b.x Hinke, 2004, In depth analysis of the N-terminal bioactive domain of gastric inhibitory polypeptide, Life Sciences, 75, 1857, 10.1016/j.lfs.2004.03.024 Graziano, 1996, The amino terminal domain of the glucagon-like peptide-1 receptor is a critical determinant of subtype specificity, Receptors and Channels, 4, 9 Runge, 2003, Different domains of the glucagon and glucagon-like peptide-1 receptors provide the critical determinants of ligand selectivity, British Journal of Pharmacology, 138, 787, 10.1038/sj.bjp.0705120 Van Eyll, 1996, Exchange of W39 by A within the N-terminal extracellular domain of the GLP-1 receptor results in a loss of receptor function, Peptides, 17, 565, 10.1016/0196-9781(96)00019-8 Wilmen, 1996, The isolated N-terminal extracellular domain of the glucagon-like peptide-1 (GLP)-1 receptor has intrinsic binding activity, FEBS Letters, 398, 43, 10.1016/S0014-5793(96)01214-8 During, 2003, Glucagon-like peptide-1 receptor is involved in learning and neuroprotection, Nature Medicine, 9, 1173, 10.1038/nm919 Moon, 2010, Tyr1 and Ile7 of glucose-dependent insulinotropic polypeptide (GIP) confer differential ligand selectivity toward GIP and glucagon-like peptide-1 receptors, Molecules and Cells, 30, 149, 10.1007/s10059-010-0100-5 Moon, 2012, Evolutionarily conserved residues at glucagon-like peptide-1 (GLP-1) receptor core confer ligand-induced receptor activation, Journal of Biological Chemistry, 287, 3873, 10.1074/jbc.M111.276808 Moon, 2015, Ligand binding pocket formed by evolutionarily conserved residues in the glucagon-like peptide-1 (GLP-1) receptor core domain, Journal of Biological Chemistry, 290, 5696, 10.1074/jbc.M114.612606 Al-Sabah, 2003, A model for receptor-peptide binding at the glucagon-like peptide-1 (GLP-1) receptor through the analysis of truncated ligands and receptors, British Journal of Pharmacology, 140, 339, 10.1038/sj.bjp.0705453 Lopez de Maturana, 2003, The isolated N-terminal domain of the glucagon-like peptide-1 (GLP-1) receptor binds exendin peptides with much higher affinity than GLP-1, Journal of Biological Chemistry, 278, 10195, 10.1074/jbc.M212147200 Song, 2017, Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators, Nature, 546, 312, 10.1038/nature22378 Zhang, 2017, Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein, Nature, 546, 248, 10.1038/nature22394 Jazayeri, 2017, Crystal structure of the GLP-1 receptor bound to a peptide agonist, Nature, 546, 254, 10.1038/nature22800 Rankovic, 2016, Biased agonism: an emerging paradigm in GPCR drug discovery, Bioorganic and Medicinal Chemistry Letters, 26, 241, 10.1016/j.bmcl.2015.12.024 Koole, 2010, Allosteric ligands of the glucagon-like peptide 1 receptor (GLP-1R) differentially modulate endogenous and exogenous peptide responses in a pathway-selective manner: implications for drug screening, Molecular Pharmacology, 78, 456, 10.1124/mol.110.065664 Montrose-Rafizadeh, 1999, Pancreatic glucagon-like peptide-1 receptor couples to multiple G proteins and activates mitogen-activated protein kinase pathways in Chinese hamster ovary cells, Endocrinology, 140, 1132, 10.1210/endo.140.3.6550 Sonoda, 2008, Beta-Arrestin-1 mediates glucagon-like peptide-1 signaling to insulin secretion in cultured pancreatic beta cells, Proceedings of the National Academy of Sciences of the United States of America, 105, 6614, 10.1073/pnas.0710402105 Wheeler, 1993, Functional expression of the rat glucagon-like peptide-I receptor, evidence for coupling to both adenylyl cyclase and phospholipase-C, Endocrinology, 133, 57, 10.1210/endo.133.1.8391428 Wootten, 2016, The extracellular surface of the GLP-1 receptor is a molecular trigger for biased agonism, Cell, 165, 1632, 10.1016/j.cell.2016.05.023 Wootten, 2013, Differential activation and modulation of the glucagon-like peptide-1 receptor by small molecule ligands, Molecular Pharmacology, 83, 822, 10.1124/mol.112.084525 Quoyer, 2010, GLP-1 mediates antiapoptotic effect by phosphorylating Bad through a beta-arrestin 1-mediated ERK1/2 activation in pancreatic beta-cells, Journal of Biological Chemistry, 285, 1989, 10.1074/jbc.M109.067207 Zhang, 2015, Autocrine selection of a GLP-1R G-protein biased agonist with potent antidiabetic effects, Nature Communications, 6, 8918, 10.1038/ncomms9918 Liang, 2018, Phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor-Gs complex, Nature, 555, 121, 10.1038/nature25773 Ferguson, 1996, G-protein-coupled receptor regulation: role of G-protein-coupled receptor kinases and arrestins, Canadian Journal of Physiology and Pharmacology, 74, 1095, 10.1139/y96-124 Krupnick, 1998, The role of receptor kinases and arrestins in G protein-coupled receptor regulation, Annual Review of Pharmacology and Toxicology, 38, 289, 10.1146/annurev.pharmtox.38.1.289 Pak, 1996, Agonist-induced functional desensitization of the mu-opioid receptor is mediated by loss of membrane receptors rather than uncoupling from G protein, Molecular Pharmacology, 50, 1214 Yang, 1995, Mutation of carboxyl-terminal threonine residues in human m3 muscarinic acetylcholine receptor modulates the extent of sequestration and desensitization, Molecular Pharmacology, 48, 477 Chuang, 1980, A biochemical study of receptor internalization during beta-adrenergic receptor desensitization in frog erythrocytes, Molecular Pharmacology, 18, 348 Hertel, 1985, A comparison of catecholamine-induced internalization of beta-adrenergic receptors and receptor-mediated endocytosis of epidermal growth factor in human astrocytoma cells. Inhibition by phenylarsine oxide, Journal of Biological Chemistry, 260, 12547, 10.1016/S0021-9258(17)38906-8 Homburger, 1980, Further evidence that desensitization of beta-adrenergic-sensitive adenylate cyclase proceeds in two steps. Modification of the coupling and loss of beta-adrenergic receptors, Journal of Biological Chemistry, 255, 10436, 10.1016/S0021-9258(19)70483-9 Pippig, 1995, Sequestration and recycling of beta 2-adrenergic receptors permit receptor resensitization, Molecular Pharmacology, 47, 666 Thomas, 1995, Stable expression of a truncated AT1A receptor in CHO-K1 cells. The carboxyl-terminal region directs agonist-induced internalization but not receptor signaling or desensitization, Journal of Biological Chemistry, 270, 207, 10.1074/jbc.270.1.207 Ng, 1995, Agonist-induced desensitization of dopamine D1 receptor-stimulated adenylyl cyclase activity is temporally and biochemically separated from D1 receptor internalization, Proceedings of the National Academy of Sciences of the United States of America, 92, 10157, 10.1073/pnas.92.22.10157 Pals-Rylaarsdam, 1995, Desensitization and internalization of the m2 muscarinic acetylcholine receptor are directed by independent mechanisms, Journal of Biological Chemistry, 270, 29004, 10.1074/jbc.270.48.29004 Garland, 1996, Mechanisms of desensitization and resensitization of G protein-coupled neurokinin1 and neurokinin2 receptors, Molecular Pharmacology, 49, 438 Fukushima, 1997, Role of the C terminus in histamine H2 receptor signaling, desensitization, and agonist-induced internalization, Journal of Biological Chemistry, 272, 19464, 10.1074/jbc.272.31.19464 Holtmann, 1996, Role of receptor phosphorylation in desensitization and internalization of the secretin receptor, Journal of Biological Chemistry, 271, 23566, 10.1074/jbc.271.38.23566 Kuna, 2013, Glucagon-like peptide-1 receptor-mediated endosomal cAMP generation promotes glucose-stimulated insulin secretion in pancreatic beta-cells, American Journal of Physiology Endocrinology and Metabolism, 305, E161, 10.1152/ajpendo.00551.2012 Thompson, 2015, Agonist-induced internalisation of the glucagon-like peptide-1 receptor is mediated by the Galphaq pathway, Biochemical Pharmacology, 93, 72, 10.1016/j.bcp.2014.10.015 Girada, 2017, Galphas regulates Glucagon-Like Peptide 1 Receptor-mediated cyclic AMP generation at Rab5 endosomal compartment, Molecular Metabolism, 6, 1173, 10.1016/j.molmet.2017.08.002 Widmann, 1995, Agonist-induced internalization and recycling of the glucagon-like peptide-1 receptor in transfected fibroblasts and in insulinomas, Biochemical Journal, 310, 203, 10.1042/bj3100203 Goke, 1989, Internalization of glucagon-like peptide-1(7-36)amide in rat insulinoma cells, Research in Experimental Medicine(Berlin), 189, 257, 10.1007/BF01852257 Jones, 2018, Targeting GLP-1 receptor trafficking to improve agonist efficacy, Nature Communications, 9, 1602, 10.1038/s41467-018-03941-2 Vilardaga, 2011, Molecular basis of parathyroid hormone receptor signaling and trafficking: a family B GPCR paradigm, Cellular and Molecular Life Sciences, 68, 1, 10.1007/s00018-010-0465-9 Calebiro, 2009, Persistent cAMP-signals triggered by internalized G-protein-coupled receptors, PLoS Biology, 7, 10.1371/journal.pbio.1000172 Mullershausen, 2009, Persistent signaling induced by FTY720-phosphate is mediated by internalized S1P1 receptors, Nature Chemical Biology, 5, 428, 10.1038/nchembio.173 Hothersall, 2016, Can residence time offer a useful strategy to target agonist drugs for sustained GPCR responses?, Drug Discovery Today, 21, 90, 10.1016/j.drudis.2015.07.015 Scrocchi, 1996, Glucose intolerance but normal satiety in mice with a null mutation in the glucagon-like peptide 1 receptor gene, Nature Medicine, 2, 1254, 10.1038/nm1196-1254 Scrocchi, 1998, Identification of glucagon-like peptide 1 (GLP-1) actions essential for glucose homeostasis in mice with disruption of GLP-1 receptor signaling, Diabetes, 47, 632, 10.2337/diabetes.47.4.632 Scrocchi, 1998, Effects of aging and a high fat diet on body weight and glucose tolerance in glucagon-like peptide-1 receptor -/- mice, Endocrinology, 139, 3127, 10.1210/endo.139.7.6092 Goke, 1993, Exendin-4 is a high potency agonist and truncated exendin-(9-39)-amide an antagonist at the glucagon-like peptide 1-(7-36)-amide receptor of insulin-secreting beta-cells, Journal of Biological Chemistry, 268, 19650, 10.1016/S0021-9258(19)36565-2 Wang, 1995, Glucagon-like peptide-1 affects gene transcription and messenger ribonucleic acid stability of components of the insulin secretory system in RIN 1046-38 cells, Endocrinology, 136, 4910, 10.1210/endo.136.11.7588224 Finan, 2013, Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans, Science Translational Medicine, 5, 10.1126/scitranslmed.3007218 Finan, 2015, A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents, Nature Medicine, 21, 27, 10.1038/nm.3761 Finan, 2012, Targeted estrogen delivery reverses the metabolic syndrome, Nature Medicine, 18, 1847, 10.1038/nm.3009 Ahren, 2005, Endocrinology, 146, 2055, 10.1210/en.2004-1174 Fernandez, 1999, Glucose-dependent stimulatory effect of glucagon-like peptide 1(7-36) amide on the electrical activity of pancreatic beta-cells recorded in vivo, Diabetes, 48, 754, 10.2337/diabetes.48.4.754 Simonsson, 1998, Potentiated beta-cell response to non-glucose stimuli in insulin-resistant C57BL/6J mice, European Journal of Pharmacology, 350, 243, 10.1016/S0014-2999(98)00236-2 Ahren, 1995, Effects of GLP-1 and 2,5-anhydro-D-mannitol on insulin secretion and plasma glucose in mice, Endocrine Research, 21, 583, 10.1080/07435809509030475 Fehmann, 1989, Synergistic stimulatory effect of glucagon-like peptide-1 (7-36) amide and glucose-dependent insulin-releasing polypeptide on the endocrine rat pancreas, FEBS Letters, 252, 109, 10.1016/0014-5793(89)80899-3 Kawai, 1989, Comparison of the effects of glucagon-like peptide-1-(1-37) and -(7-37) and glucagon on islet hormone release from isolated perfused canine and rat pancreases, Endocrinology, 124, 1768, 10.1210/endo-124-4-1768 Komatsu, 1989, Glucagonostatic and insulinotropic action of glucagonlike peptide I-(7-36)-amide, Diabetes, 38, 902, 10.2337/diab.38.7.902 Orskov, 1988, Effect of truncated glucagon-like peptide-1 [proglucagon-(78-107) amide] on endocrine secretion from pig pancreas, antrum, and nonantral stomach, Endocrinology, 123, 2009, 10.1210/endo-123-4-2009 Gromada, 1997, Multisite regulation of insulin secretion by cAMP-increasing agonists: evidence that glucagon-like peptide 1 and glucagon act via distinct receptors, Pflügers Archiv, 434, 515, 10.1007/s004240050431 Clark, 1990, Modulation of glucose-induced insulin secretion from a rat clonal beta-cell line, Endocrinology, 127, 2779, 10.1210/endo-127-6-2779 Gromada, 1995, Glucagon-like peptide I increases cytoplasmic calcium in insulin-secreting beta TC3-cells by enhancement of intracellular calcium mobilization, Diabetes, 44, 767, 10.2337/diab.44.7.767 Gromada, 1996, Desensitization of glucagon-like peptide 1 receptors in insulin-secreting beta TC3 cells: role of PKA-independent mechanisms, British Journal of Pharmacology, 118, 769, 10.1111/j.1476-5381.1996.tb15466.x Weir, 1989, Glucagonlike peptide I (7-37) actions on endocrine pancreas, Diabetes, 38, 338, 10.2337/diab.38.3.338 Hansotia, 2004, 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, 10.2337/diabetes.53.5.1326 Hansotia, 2005, GIP and GLP-1 as incretin hormones: lessons from single and double incretin receptor knockout mice, Regulatory Peptides, 128, 125, 10.1016/j.regpep.2004.07.019 Preitner, 2004, Gluco-incretins control insulin secretion at multiple levels as revealed in mice lacking GLP-1 and GIP receptors, Journal of Clinical Investigation, 113, 635, 10.1172/JCI200420518 Montrose-Rafizadeh, 1997, Overexpression of glucagon-like peptide-1 receptor in an insulin-secreting cell line enhances glucose responsiveness, Molecular and Cellular Endocrinology, 130, 109, 10.1016/S0303-7207(97)00079-8 Harndahl, 2002, Important role of phosphodiesterase 3B for the stimulatory action of cAMP on pancreatic beta-cell exocytosis and release of insulin, Journal of Biological Chemistry, 277, 37446, 10.1074/jbc.M205401200 Zhao, 1997, Attenuation of insulin secretion by insulin-like growth factor 1 is mediated through activation of phosphodiesterase 3B, Proceedings of the National Academy of Sciences of the United States of America, 94, 3223, 10.1073/pnas.94.7.3223 Harndahl, 2004, Beta-cell-targeted overexpression of phosphodiesterase 3B in mice causes impaired insulin secretion, glucose intolerance, and deranged islet morphology, Journal of Biological Chemistry, 279, 15214, 10.1074/jbc.M308952200 Doyle, 2007, Mechanisms of action of glucagon-like peptide 1 in the pancreas, Pharmacology and Therapeutics, 113, 546, 10.1016/j.pharmthera.2006.11.007 Holz, 2004, 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, 10.2337/diabetes.53.1.5 Wang, 2001, Glucagon-like peptide-1 causes pancreatic duodenal homeobox-1 protein translocation from the cytoplasm to the nucleus of pancreatic beta-cells by a cyclic adenosine monophosphate/protein kinase A-dependent mechanism, Endocrinology, 142, 1820, 10.1210/endo.142.5.8128 Bunemann, 1999, Functional regulation of L-type calcium channels via protein kinase A-mediated phosphorylation of the beta(2) subunit, Journal of Biological Chemistry, 274, 33851, 10.1074/jbc.274.48.33851 MacDonald, 2003, Antagonism of rat beta-cell voltage-dependent K+ currents by exendin 4 requires dual activation of the cAMP/protein kinase A and phosphatidylinositol 3-kinase signaling pathways, Journal of Biological Chemistry, 278, 52446, 10.1074/jbc.M307612200 Kashima, 2001, Critical role of cAMP-GEFII--Rim2 complex in incretin-potentiated insulin secretion, Journal of Biological Chemistry, 276, 46046, 10.1074/jbc.M108378200 de Rooij, 1998, Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP, Nature, 396, 474, 10.1038/24884 Kawasaki, 1998, A family of cAMP-binding proteins that directly activate Rap1, Science, 282, 2275, 10.1126/science.282.5397.2275 Cheng, 2008, Epac and PKA: a tale of two intracellular cAMP receptors, Acta Biochimica et Biophysica Sinica (Shanghai), 40, 651, 10.1111/j.1745-7270.2008.00438.x Leech, 2000, Expression of cAMP-regulated guanine nucleotide exchange factors in pancreatic beta-cells, Biochemical and Biophysical Research Communications, 278, 44, 10.1006/bbrc.2000.3763 Holz, 1999, cAMP-dependent mobilization of intracellular Ca2+ stores by activation of ryanodine receptors in pancreatic beta-cells. A Ca2+ signaling system stimulated by the insulinotropic hormone glucagon-like peptide-1-(7-37), Journal of Biological Chemistry, 274, 14147, 10.1074/jbc.274.20.14147 Kang, 2001, cAMP-regulated guanine nucleotide exchange factor II (Epac2) mediates Ca2+-induced Ca2+ release in INS-1 pancreatic beta-cells, Journal of Physiology, 536, 375, 10.1111/j.1469-7793.2001.0375c.xd Tsuboi, 2003, Glucagon-like peptide-1 mobilizes intracellular Ca2+ and stimulates mitochondrial ATP synthesis in pancreatic MIN6 beta-cells, Biochemical Journal, 369, 287, 10.1042/bj20021288 Irie, 2008, Tolerability, pharmacokinetics and pharmacodynamics of the once-daily human GLP-1 analog liraglutide in Japanese healthy subjects: a randomized, double-blind, placebo-controlled dose-escalation study, International Journal of Clinical Pharmacology and Therapeutics, 46, 273, 10.5414/CPP46273 Seino, 2008, Dose-dependent improvement in glycemia with once-daily liraglutide without hypoglycemia or weight gain: a double-blind, randomized, controlled trial in Japanese patients with type 2 diabetes, Diabetes Research and Clinical Practice, 81, 161, 10.1016/j.diabres.2008.03.018 Vilsboll, 2007, Liraglutide, a long-acting human glucagon-like peptide-1 analog, given as monotherapy significantly improves glycemic control and lowers body weight without risk of hypoglycemia in patients with type 2 diabetes, Diabetes Care, 30, 1608, 10.2337/dc06-2593 Ponzani, 2016, Effectiveness and safety of liraglutide after three years of treatment, Minerva Endocrinologica, 41, 35 Tanaka, 2015, Efficacy and safety of liraglutide monotherapy compared with metformin in Japanese overweight/obese patients with type 2 diabetes, Endocrine Journal, 62, 399, 10.1507/endocrj.EJ14-0602 Vilsboll, 2001, No reactive hypoglycaemia in Type 2 diabetic patients after subcutaneous administration of GLP-1 and intravenous glucose, Diabetic Medicine, 18, 144, 10.1046/j.1464-5491.2001.00424.x Nauck, 2002, Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers, The Journal of Cinical Endocrinology and Metabolism, 87, 1239, 10.1210/jcem.87.3.8355 Gromada, 2004, Glucagon-like peptide-1: regulation of insulin secretion and therapeutic potential, Basic and Clinical Pharmacology and Toxicology, 95, 252, 10.1111/j.1742-7843.2004.t01-1-pto950502.x Renstrom, 1997, Protein kinase A-dependent and -independent stimulation of exocytosis by cAMP in mouse pancreatic B-cells, Journal of Physiology, 502, 105, 10.1111/j.1469-7793.1997.105bl.x Gromada, 1998, Glucagon-like peptide 1 (7-36) amide stimulates exocytosis in human pancreatic beta-cells by both proximal and distal regulatory steps in stimulus-secretion coupling, Diabetes, 47, 57, 10.2337/diab.47.1.57 Shibasaki, 2004, Interaction of ATP sensor, cAMP sensor, Ca2+ sensor, and voltage-dependent Ca2+ channel in insulin granule exocytosis, Journal of Biological Chemistry, 279, 7956, 10.1074/jbc.M309068200 Fujimoto, 2002, Piccolo, a Ca2+ sensor in pancreatic beta-cells. Involvement of cAMP-GEFII.Rim2. Piccolo complex in cAMP-dependent exocytosis, Journal of Biological Chemistry, 277, 50497, 10.1074/jbc.M210146200 Ozaki, 2000, cAMP-GEFII is a direct target of cAMP in regulated exocytosis, Nature Cell Biology, 2, 805, 10.1038/35041046 Shigeto, 2015, GLP-1 stimulates insulin secretion by PKC-dependent TRPM4 and TRPM5 activation, Journal of Clinical Investigation, 125, 4714, 10.1172/JCI81975 Murao, 2017, Essential roles of aspartate aminotransferase 1 and vesicular glutamate transporters in beta-cell glutamate signaling for incretin-induced insulin secretion, PLoS One, 12, 10.1371/journal.pone.0187213 Creutzfeldt, 1996, 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, 10.2337/diacare.19.6.580 Gutniak, 1992, Antidiabetogenic effect of glucagon-like peptide-1 (7-36)amide in normal subjects and patients with diabetes mellitus, New England Journal of Medicine, 326, 1316, 10.1056/NEJM199205143262003 Krieger, 2016, Knockdown of GLP-1 receptors in vagal afferents affects normal food intake and glycemia, Diabetes, 65, 34, 10.2337/db15-0973 Grasset, 2017, A specific gut microbiota dysbiosis of type 2 diabetic mice induces GLP-1 resistance through an enteric NO-dependent and gut-brain Axis mechanism, Cell Metabolism, 25, 1075, 10.1016/j.cmet.2017.04.013 Varin, 2019, Distinct neural sites of GLP-1r expression mediate physiological versus pharmacological control of incretin action, Cell Reports, 27, 3371, 10.1016/j.celrep.2019.05.055 Hay, 2005, Glucagon-like peptide-1 stimulates human insulin promoter activity in part through cAMP-responsive elements that lie upstream and downstream of the transcription start site, Journal of Endocrinology, 186, 353, 10.1677/joe.1.06205 Hani, 1999, Defective mutations in the insulin promoter factor-1 (IPF-1) gene in late-onset type 2 diabetes mellitus, Journal of Clinical Investigation, 104, R41, 10.1172/JCI7469 Macfarlane, 1999, Missense mutations in the insulin promoter factor-1 gene predispose to type 2 diabetes, Journal of Clinical Investigation, 104, R33, 10.1172/JCI7449 Wang, 1999, Glucagon-like peptide-1 regulates the beta cell transcription factor, PDX-1, in insulinoma cells, Endocrinology, 140, 4904, 10.1210/endo.140.10.7158 Fujitani, 2018, How does glucagon-like peptide 1 stimulate human beta-cell proliferation? A lesson from islet graft experiments, Journal of Diabetes Investigation, 9, 1255, 10.1111/jdi.12861 Butler, 2003, Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes, Diabetes, 52, 102, 10.2337/diabetes.52.1.102 Maclean, 1955, Quantitative estimation of the pancreatic islet tissue in diabetic subjects, Diabetes, 4, 367, 10.2337/diab.4.5.367 Rahier, 2008, Pancreatic beta-cell mass in European subjects with type 2 diabetes, Diabetes Obesity and Metabolism, 10, 32, 10.1111/j.1463-1326.2008.00969.x Saito, 1978, Islet morphometry in the diabetic pancreas of man, Tohoku Journal of Experimental Medicine, 125, 185, 10.1620/tjem.125.185 Westermark, 1978, The influence of amyloid deposits on the islet volume in maturity onset diabetes mellitus, Diabetologia, 15, 417, 10.1007/BF01219652 Butler, 2007, The replication of beta cells in normal physiology, in disease and for therapy, Nature Clinical Practice Endocrinology and Metabolism, 3, 758, 10.1038/ncpendmet0647 Cnop, 2010, The long lifespan and low turnover of human islet beta cells estimated by mathematical modelling of lipofuscin accumulation, Diabetologia, 53, 321, 10.1007/s00125-009-1562-x Meier, 2008, Beta-cell replication is the primary mechanism subserving the postnatal expansion of beta-cell mass in humans, Diabetes, 57, 1584, 10.2337/db07-1369 Chen, 2011, PDGF signalling controls age-dependent proliferation in pancreatic beta-cells, Nature, 478, 349, 10.1038/nature10502 Chen, 2009, Polycomb protein Ezh2 regulates pancreatic beta-cell Ink4a/Arf expression and regeneration in diabetes mellitus, Genes and Development, 23, 975, 10.1101/gad.1742509 Gregg, 2012, Formation of a human beta-cell population within pancreatic islets is set early in life, The Journal of Cinical Endocrinology and Metabolism, 97, 3197, 10.1210/jc.2012-1206 Teta, 2005, Very slow turnover of beta-cells in aged adult mice, Diabetes, 54, 2557, 10.2337/diabetes.54.9.2557 Bonner-Weir, 2001, beta-cell turnover: its assessment and implications, Diabetes, 50, S20, 10.2337/diabetes.50.2007.S20 Cinti, 2016, Evidence of beta-cell dedifferentiation in human type 2 diabetes, The Journal of Cinical Endocrinology and Metabolism, 101, 1044, 10.1210/jc.2015-2860 Arakawa, 2009, Effects of exendin-4 on glucose tolerance, insulin secretion, and beta-cell proliferation depend on treatment dose, treatment duration and meal contents, Biochemical and Biophysical Research Communications, 390, 809, 10.1016/j.bbrc.2009.10.054 Kawamori, 2017, GLP-1 signalling compensates for impaired insulin signalling in regulating beta cell proliferation in betaIRKO mice, Diabetologia, 60, 1442, 10.1007/s00125-017-4303-6 Li, 2005, beta-Cell Pdx1 expression is essential for the glucoregulatory, proliferative, and cytoprotective actions of glucagon-like peptide-1, Diabetes, 54, 482, 10.2337/diabetes.54.2.482 Li, 2003, Glucagon-like peptide-1 receptor signaling modulates beta cell apoptosis, Journal of Biological Chemistry, 278, 471, 10.1074/jbc.M209423200 Park, 2006, Exendin-4 uses Irs2 signaling to mediate pancreatic beta cell growth and function, Journal of Biological Chemistry, 281, 1159, 10.1074/jbc.M508307200 Buteau, 2004, Glucagon-like peptide-1 prevents beta cell glucolipotoxicity, Diabetologia, 47, 806, 10.1007/s00125-004-1379-6 Jhala, 2003, cAMP promotes pancreatic beta-cell survival via CREB-mediated induction of IRS2, Genes and Development, 17, 1575, 10.1101/gad.1097103 White, 2003, Insulin signaling in health and disease, Science, 302, 1710, 10.1126/science.1092952 Tschen, 2009, Age-dependent decline in beta-cell proliferation restricts the capacity of beta-cell regeneration in mice, Diabetes, 58, 1312, 10.2337/db08-1651 Smits, 2017, Pancreatic effects of liraglutide or sitagliptin in overweight patients with type 2 diabetes: a 12-week randomized, placebo-controlled trial, Diabetes Care, 40, 301, 10.2337/dc16-0836 Kapodistria, 2018, Liraglutide, a human glucagon-like peptide-1 analogue, stimulates AKT-dependent survival signalling and inhibits pancreatic beta-cell apoptosis, Journal of Cellular and Molecular Medicine, 22, 2970, 10.1111/jcmm.13259 Sun, 2015, Novel pentapeptide GLP-1 (32-36) amide inhibits beta-cell apoptosis in vitro and improves glucose disposal in streptozotocin-induced diabetic mice, Chemical Biology and Drug Design, 86, 1482, 10.1111/cbdd.12615 Fang, 2018, Neuroprotection of rhGLP-1 in diabetic rats with cerebral ischemia/reperfusion injury via regulation of oxidative stress, EAAT2, and apoptosis, Drug Development Research, 79, 249, 10.1002/ddr.21439 Li, 2018, Effects of Exendin-4 on pancreatic islets function in treating hyperglycemia post severe scald injury in rats, Journal of Trauma Acute Care Surgery, 85, 1072, 10.1097/TA.0000000000002066 Khalilnezhad, 2018, Protective effects of glucagon-like peptide-1 (GLP-1) analogue exenatide against glucose and fructose-induced neurotoxicity, International Journal of Neuroscience, 1 Liao, 2017, GLP-1 and ghrelin attenuate high glucose/high lipid-induced apoptosis and senescence of human microvascular endothelial cells, Cellular Physiology and Biochemistry, 44, 1842, 10.1159/000485820 Farilla, 2003, Glucagon-like peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets, Endocrinology, 144, 5149, 10.1210/en.2003-0323 Dai, 2017, Age-dependent human beta cell proliferation induced by glucagon-like peptide 1 and calcineurin signaling, Journal of Clinical Investigation, 127, 3835, 10.1172/JCI91761 Simonis-Bik, 2009, Genetic influences on the insulin response of the beta cell to different secretagogues, Diabetologia, 52, 2570, 10.1007/s00125-009-1532-3 Schafer, 2007, Impaired glucagon-like peptide-1-induced insulin secretion in carriers of transcription factor 7-like 2 (TCF7L2) gene polymorphisms, Diabetologia, 50, 2443, 10.1007/s00125-007-0753-6 Lyssenko, 2007, Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes, Journal of Clinical Investigation, 117, 2155, 10.1172/JCI30706 Pilgaard, 2009, The T allele of rs7903146 TCF7L2 is associated with impaired insulinotropic action of incretin hormones, reduced 24 h profiles of plasma insulin and glucagon, and increased hepatic glucose production in young healthy men, Diabetologia, 52, 1298, 10.1007/s00125-009-1307-x Villareal, 2010, TCF7L2 variant rs7903146 affects the risk of type 2 diabetes by modulating incretin action, Diabetes, 59, 479, 10.2337/db09-1169 Sathananthan, 2010, Common genetic variation in GLP1R and insulin secretion in response to exogenous GLP-1 in nondiabetic subjects: a pilot study, Diabetes Care, 33, 2074, 10.2337/dc10-0200 Schafer, 2009, A common genetic variant in WFS1 determines impaired glucagon-like peptide-1-induced insulin secretion, Diabetologia, 52, 1075, 10.1007/s00125-009-1344-5 t Hart, 2013, The CTRB1/2 locus affects diabetes susceptibility and treatment via the incretin pathway, Diabetes, 62, 3275, 10.2337/db13-0227 Mussig, 2010, Genetic variants affecting incretin sensitivity and incretin secretion, Diabetologia, 53, 2289, 10.1007/s00125-010-1876-8 Ordelheide, 2013, Nor-1, a novel incretin-responsive regulator of insulin genes and insulin secretion, Molecular Metabolism, 2, 243, 10.1016/j.molmet.2013.06.003 Kirchhoff, 2008, Polymorphisms in the TCF7L2, CDKAL1 and SLC30A8 genes are associated with impaired proinsulin conversion, Diabetologia, 51, 597, 10.1007/s00125-008-0926-y Shu, 2009, Decreased TCF7L2 protein levels in type 2 diabetes mellitus correlate with downregulation of GIP- and GLP-1 receptors and impaired beta-cell function, Human Molecular Genetics, 18, 2388, 10.1093/hmg/ddp178 Gudmundsdottir, 2018, Integrative network analysis highlights biological processes underlying GLP-1 stimulated insulin secretion: a DIRECT study, PLoS One, 13, 10.1371/journal.pone.0189886 Herzberg-Schafer, 2012, Impairment of GLP1-induced insulin secretion: role of genetic background, insulin resistance and hyperglycaemia, Diabetes Obesity and Metabolism, 14, 85, 10.1111/j.1463-1326.2012.01648.x Heni, 2010, Glycemia determines the effect of type 2 diabetes risk genes on insulin secretion, Diabetes, 59, 3247, 10.2337/db10-0674 Willms, 1996, Gastric emptying, glucose responses, and insulin secretion after a liquid test meal: effects of exogenous glucagon-like peptide-1 (GLP-1)-(7-36) amide in type 2 (noninsulin-dependent) diabetic patients, The Journal of Cinical Endocrinology and Metabolism, 81, 327 Drucker, 2018, Mechanisms of action and therapeutic application of glucagon-like peptide-1, Cell Metabolism, 27, 740, 10.1016/j.cmet.2018.03.001 Fridolf, 1991, GLP-1 and GLP-1(7-36) amide: influences on basal and stimulated insulin and glucagon secretion in the mouse, Pancreas, 6, 208, 10.1097/00006676-199103000-00013 Freyse, 1997, Blood glucose lowering and glucagonostatic effects of glucagon-like peptide I in insulin-deprived diabetic dogs, Diabetes, 46, 824, 10.2337/diab.46.5.824 Hare, 2009, Preserved inhibitory potency of GLP-1 on glucagon secretion in type 2 diabetes mellitus, The Journal of Cinical Endocrinology and Metabolism, 94, 4679, 10.1210/jc.2009-0921 Hare, 2010, The glucagonostatic and insulinotropic effects of glucagon-like peptide 1 contribute equally to its glucose-lowering action, Diabetes, 59, 1765, 10.2337/db09-1414 Hvidberg, 1994, Effect of glucagon-like peptide-1 (proglucagon 78-107amide) on hepatic glucose production in healthy man, Metabolism, 43, 104, 10.1016/0026-0495(94)90164-3 Junker, 2016, Effects of glucagon-like peptide-1 on glucagon secretion in patients with non-alcoholic fatty liver disease, Journal of Hepatology, 64, 908, 10.1016/j.jhep.2015.11.014 Plamboeck, 2015, The role of efferent cholinergic transmission for the insulinotropic and glucagonostatic effects of GLP-1, American Journal of Physiology Regulatory Integrative and Comparative Physiology, 309, R544, 10.1152/ajpregu.00123.2015 de Heer, 2008, 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, 10.1007/s00125-008-1149-y De Marinis, 2010, GLP-1 inhibits and adrenaline stimulates glucagon release by differential modulation of N- and L-type Ca2+ channel-dependent exocytosis, Cell Metabolism, 11, 543, 10.1016/j.cmet.2010.04.007 Gerich, 1974, Effects of somatostatin on plasma glucose and glucagon levels in human diabetes mellitus. Pathophysiologic and therapeutic implications, New England Journal of Medicine, 291, 544, 10.1056/NEJM197409122911102 Barden, 1978, Secretion of somatostatin by rat islets of Langerhans and gastric mucosa and a role for pancreatic somatostatin in the regulation of glucagon release, Metabolism, 27, 1215, 10.1016/0026-0495(78)90045-8 Barden, 1977, Stimulation of glucagon release by addition of anti-stomatostatin serum to islets of Langerhans in vitro, Endocrinology, 101, 635, 10.1210/endo-101-2-635 Kaneko, 1999, Insulin inhibits glucagon secretion by the activation of PI3-kinase in In-R1-G9 cells, Diabetes Research and Clinical Practice, 44, 83, 10.1016/S0168-8227(99)00021-2 Xu, 2006, Intra-islet insulin suppresses glucagon release via GABA-GABAA receptor system, Cell Metabolism, 3, 47, 10.1016/j.cmet.2005.11.015 Wendt, 2004, Glucose inhibition of glucagon secretion from rat alpha-cells is mediated by GABA released from neighboring beta-cells, Diabetes, 53, 1038, 10.2337/diabetes.53.4.1038 Blundell, 1972, The crystal structure of rhombohedral 2 zinc insulin, Cold Spring Harbor Symposia on Quantitative Biology, 36, 233, 10.1101/SQB.1972.036.01.031 Blundell, 1971, The structure and biology of insulin, Biochemical Journal, 125, 50P, 10.1042/bj1250050P Gee, 2002, Detection and imaging of zinc secretion from pancreatic beta-cells using a new fluorescent zinc indicator, Journal of the American Chemical Society, 124, 776, 10.1021/ja011774y Franklin, 2005, Beta-cell secretory products activate alpha-cell ATP-dependent potassium channels to inhibit glucagon release, Diabetes, 54, 1808, 10.2337/diabetes.54.6.1808 Ishihara, 2003, Islet beta-cell secretion determines glucagon release from neighbouring alpha-cells, Nature Cell Biology, 5, 330, 10.1038/ncb951 Zhou, 2007, Zinc, not insulin, regulates the rat alpha-cell response to hypoglycemia in vivo, Diabetes, 56, 1107, 10.2337/db06-1454 Gyulkhandanyan, 2006, The Zn2+-transporting pathways in pancreatic beta-cells: a role for the L-type voltage-gated Ca2+ channel, Journal of Biological Chemistry, 281, 9361, 10.1074/jbc.M508542200 Gedulin, 1997, Dose-response for glucagonostatic effect of amylin in rats, Metabolism, 46, 67, 10.1016/S0026-0495(97)90170-0 Gedulin, 2006, Role of endogenous amylin in glucagon secretion and gastric emptying in rats demonstrated with the selective antagonist, AC187, Regulatory Peptides, 137, 121, 10.1016/j.regpep.2006.06.004 Levetan, 2003, Impact of pramlintide on glucose fluctuations and postprandial glucose, glucagon, and triglyceride excursions among patients with type 1 diabetes intensively treated with insulin pumps, Diabetes Care, 26, 1, 10.2337/diacare.26.1.1 Nyholm, 1999, The amylin analog pramlintide improves glycemic control and reduces postprandial glucagon concentrations in patients with type 1 diabetes mellitus, Metabolism, 48, 935, 10.1016/S0026-0495(99)90232-9 Broderick, 1991, Human and rat amylin have no effects on insulin secretion in isolated rat pancreatic islets, Biochemical and Biophysical Research Communications, 177, 932, 10.1016/0006-291X(91)90628-K Inoue, 1993, Effects of amylin on the release of insulin and glucagon from the perfused rat pancreas, Hormone and Metabolic Research, 25, 135, 10.1055/s-2007-1002062 Silvestre, 1990, Inhibitory effect of rat amylin on the insulin responses to glucose and arginine in the perfused rat pancreas, Regulatory Peptides, 31, 23, 10.1016/0167-0115(90)90192-Y Ding, 1997, Glucagon-like peptide I and glucose-dependent insulinotropic polypeptide stimulate Ca2+-induced secretion in rat alpha-cells by a protein kinase A-mediated mechanism, Diabetes, 46, 792, 10.2337/diab.46.5.792 Dunning, 2005, Alpha cell function in health and disease: influence of glucagon-like peptide-1, Diabetologia, 48, 1700, 10.1007/s00125-005-1878-0 Ma, 2005, Glucagon stimulates exocytosis in mouse and rat pancreatic alpha-cells by binding to glucagon receptors, Molecular Endocrinology, 19, 198, 10.1210/me.2004-0059 Zhang, 2019, GLP-1 receptor in pancreatic alpha-cells regulates glucagon secretion in a glucose-dependent bidirectional manner, Diabetes, 68, 34, 10.2337/db18-0317 Ramracheya, 2018, GLP-1 suppresses glucagon secretion in human pancreatic alpha-cells by inhibition of P/Q-type Ca(2+) channels, Physics Reports, 6 Wei, 1996, Distribution of GLP-1 and PACAP receptors in human tissues, Acta Physiologica Scandinavica, 157, 355, 10.1046/j.1365-201X.1996.42256000.x Bhashyam, 2010, Glucagon-like peptide-1 increases myocardial glucose uptake via p38alpha MAP kinase-mediated, nitric oxide-dependent mechanisms in conscious dogs with dilated cardiomyopathy, Circulatory Heart Failure, 3, 512, 10.1161/CIRCHEARTFAILURE.109.900282 Sivertsen, 2012, The effect of glucagon-like peptide 1 on cardiovascular risk, Nature Reviews Cardiology, 9, 209, 10.1038/nrcardio.2011.211 Nystrom, 2004, Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease, American Journal of Physiology Endocrinology and Metabolism, 287, E1209, 10.1152/ajpendo.00237.2004 Baggio, 2018, GLP-1 receptor expression within the human heart, Endocrinology, 159, 1570, 10.1210/en.2018-00004 Noyan-Ashraf, 2009, GLP-1R agonist liraglutide activates cytoprotective pathways and improves outcomes after experimental myocardial infarction in mice, Diabetes, 58, 975, 10.2337/db08-1193 Wang, 2010, Effect of glucagon-like peptide-1 on hypoxia-reoxygenation induced injury in neonatal rat cardiomyocytes, Zhonghua Xinxueguanbing Zazhi, 38, 72 Ceriello, 2011, The possible protective role of glucagon-like peptide 1 on endothelium during the meal and evidence for an "endothelial resistance" to glucagon-like peptide 1 in diabetes, Diabetes Care, 34, 697, 10.2337/dc10-1949 Nikolaidis, 2004, Recombinant glucagon-like peptide-1 increases myocardial glucose uptake and improves left ventricular performance in conscious dogs with pacing-induced dilated cardiomyopathy, Circulation, 110, 955, 10.1161/01.CIR.0000139339.85840.DD Nikolaidis, 2005, Glucagon-like peptide-1 limits myocardial stunning following brief coronary occlusion and reperfusion in conscious canines, Journal of Pharmacology and Experimental Therapeutics, 312, 303, 10.1124/jpet.104.073890 Nikolaidis, 2004, Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion, Circulation, 109, 962, 10.1161/01.CIR.0000120505.91348.58 Sun, 2015, Impact of GLP-1 receptor agonists on blood pressure, heart rate and hypertension among patients with type 2 diabetes: a systematic review and network meta-analysis, Diabetes Research and Clinical Practice, 110, 26, 10.1016/j.diabres.2015.07.015 Marso, 2016, Liraglutide and cardiovascular outcomes in type 2 diabetes, New England Journal of Medicine, 375, 311, 10.1056/NEJMoa1603827 Ussher, 2012, Cardiovascular biology of the incretin system, Endocrine Reviews, 33, 187, 10.1210/er.2011-1052 Ceriello, 2016, The simultaneous control of hyperglycemia and GLP-1 infusion normalize endothelial function in type 1 diabetes, Diabetes Research and Clinical Practice, 114, 64, 10.1016/j.diabres.2016.01.019 Green, 2008, GLP-1 and related peptides cause concentration-dependent relaxation of rat aorta through a pathway involving KATP and cAMP, Archives of Biochemistry and Biophysics, 478, 136, 10.1016/j.abb.2008.08.001 Bose, 2005, Glucagon-like peptide 1 can directly protect the heart against ischemia/reperfusion injury, Diabetes, 54, 146, 10.2337/diabetes.54.1.146 Sonne, 2008, Protective effects of GLP-1 analogues exendin-4 and GLP-1(9-36) amide against ischemia-reperfusion injury in rat heart, Regulatory Peptides, 146, 243, 10.1016/j.regpep.2007.10.001 Vila Petroff, 2001, Glucagon-like peptide-1 increases cAMP but fails to augment contraction in adult rat cardiac myocytes, Circulation Research, 89, 445, 10.1161/hh1701.095716 Zhao, 2006, Direct effects of glucagon-like peptide-1 on myocardial contractility and glucose uptake in normal and postischemic isolated rat hearts, Journal of Pharmacology and Experimental Therapeutics, 317, 1106, 10.1124/jpet.106.100982 Gros, 2003, Cardiac function in mice lacking the glucagon-like peptide-1 receptor, Endocrinology, 144, 2242, 10.1210/en.2003-0007 Ussher, 2014, Inactivation of the cardiomyocyte glucagon-like peptide-1 receptor (GLP-1R) unmasks cardiomyocyte-independent GLP-1R-mediated cardioprotection, Molecular Metabolism, 3, 507, 10.1016/j.molmet.2014.04.009 Ban, 2010, Glucagon-like peptide (GLP)-1(9-36)amide-mediated cytoprotection is blocked by exendin(9-39) yet does not require the known GLP-1 receptor, Endocrinology, 151, 1520, 10.1210/en.2009-1197 Rose, 2010, Mitogen-activated protein kinase signaling in the heart: angels versus demons in a heart-breaking tale, Physiological Reviews, 90, 1507, 10.1152/physrev.00054.2009 Sussman, 2011, Myocardial AKT: the omnipresent nexus, Physiological Reviews, 91, 1023, 10.1152/physrev.00024.2010 Barragan, 1994, Changes in arterial blood pressure and heart rate induced by glucagon-like peptide-1-(7-36) amide in rats, American Journal of Physiology, 266, E459 Barragan, 1996, Interactions of exendin-(9-39) with the effects of glucagon-like peptide-1-(7-36) amide and of exendin-4 on arterial blood pressure and heart rate in rats, Regulatory Peptides, 67, 63, 10.1016/S0167-0115(96)00113-9 Barragan, 1999, Neural contribution to the effect of glucagon-like peptide-1-(7-36) amide on arterial blood pressure in rats, American Journal of Physiology, 277, E784 Griffioen, 2011, GLP-1 receptor stimulation depresses heart rate variability and inhibits neurotransmission to cardiac vagal neurons, Cardiovascular Research, 89, 72, 10.1093/cvr/cvq271 Yamamoto, 2002, Glucagon-like peptide-1 receptor stimulation increases blood pressure and heart rate and activates autonomic regulatory neurons, Journal of Clinical Investigation, 110, 43, 10.1172/JCI0215595 Gardiner, 2006, Mesenteric vasoconstriction and hindquarters vasodilatation accompany the pressor actions of exendin-4 in conscious rats, Journal of Pharmacology and Experimental Therapeutics, 316, 852, 10.1124/jpet.105.093104 Kim, 2013, GLP-1 receptor activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure, Nature Medicine, 19, 567, 10.1038/nm.3128 Hirata, 2009, Exendin-4 has an anti-hypertensive effect in salt-sensitive mice model, Biochemical and Biophysical Research Communications, 380, 44, 10.1016/j.bbrc.2009.01.003 Yu, 2003, Antihypertensive effect of glucagon-like peptide 1 in Dahl salt-sensitive rats, Journal of Hypertension, 21, 1125, 10.1097/00004872-200306000-00012 Edwards, 1997, Cardiovascular and pancreatic endocrine responses to glucagon-like peptide-1(7-36) amide in the conscious calf, Experimental Physiology, 82, 709, 10.1113/expphysiol.1997.sp004059 Bremholm, 2017, Acute effects of glucagon-like peptide-1, GLP-19-36 amide, and exenatide on mesenteric blood flow, cardiovascular parameters, and biomarkers in healthy volunteers, Physics Reports, 5 Drucker, 2006, The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes, Lancet, 368, 1696, 10.1016/S0140-6736(06)69705-5 Kumarathurai, 2017, Effects of the glucagon-like peptide-1 receptor agonist liraglutide on 24-h ambulatory blood pressure in patients with type 2 diabetes and stable coronary artery disease: a randomized, double-blind, placebo-controlled, crossover study, Journal of Hypertension, 35, 1070, 10.1097/HJH.0000000000001275 Kumarathurai, 2017, Effects of liraglutide on heart rate and heart rate variability: a randomized, double-blind, placebo-controlled crossover study, Diabetes Care, 40, 117, 10.2337/dc16-1580 Srivastava, 2018, Current pharmacotherapy for obesity, Nature Reviews Endocrinology, 14, 12, 10.1038/nrendo.2017.122 Ussher, 2014, Cardiovascular actions of incretin-based therapies, Circulation Research, 114, 1788, 10.1161/CIRCRESAHA.114.301958 Asmar, 2017, Glucagon-like peptide-1 elicits vasodilation in adipose tissue and skeletal muscle in healthy men, Physics Reports, 5 Asmar, 2016, The blunted effect of glucose-dependent insulinotropic polypeptide in subcutaneous abdominal adipose tissue in obese subjects is partly reversed by weight loss, Nutrition and Diabetes, 6, e208, 10.1038/nutd.2016.15 Asmar, 2014, Glucose-dependent insulinotropic polypeptide has impaired effect on abdominal, subcutaneous adipose tissue metabolism in obese subjects, International Journal of Obesity (London), 38, 259, 10.1038/ijo.2013.73 Asmar, 2016, Insulin plays a permissive role for the vasoactive effect of GIP regulating adipose tissue metabolism in humans, The Journal of Cinical Endocrinology and Metabolism, 101, 3155, 10.1210/jc.2016-1933 Asmar, 2010, Glucose-dependent insulinotropic polypeptide may enhance fatty acid re-esterification in subcutaneous abdominal adipose tissue in lean humans, Diabetes, 59, 2160, 10.2337/db10-0098 Mannucci, 2017, Cardiovascular safety of incretin-based therapies in type 2 diabetes: systematic review of integrated analyses and randomized controlled trials, Advances in Therapy, 34, 1, 10.1007/s12325-016-0432-4 Chai, 2012, Glucagon-like peptide 1 recruits microvasculature and increases glucose use in muscle via a nitric oxide-dependent mechanism, Diabetes, 61, 888, 10.2337/db11-1073 Asmar, 2019, Extracellular fluid volume expansion uncovers a natriuretic action of GLP-1: a functional GLP-1-renal axis in man, The Journal of Cinical Endocrinology and Metabolism, 10.1210/jc.2019-00004 Guyton, 1972, Circulation: overall regulation, Annual Review of Physiology, 34, 13, 10.1146/annurev.ph.34.030172.000305 Ivy, 2014, Pressure natriuresis and the renal control of arterial blood pressure, Journal of Physiology, 592, 3955, 10.1113/jphysiol.2014.271676 Crajoinas, 2011, Mechanisms mediating the diuretic and natriuretic actions of the incretin hormone glucagon-like peptide-1, American Journal of Physiology Renal Physiology, 301, F355, 10.1152/ajprenal.00729.2010 Gutzwiller, 2004, Glucagon-like peptide 1 induces natriuresis in healthy subjects and in insulin-resistant obese men, The Journal of Cinical Endocrinology and Metabolism, 89, 3055, 10.1210/jc.2003-031403 Lovshin, 2015, Liraglutide promotes natriuresis but does not increase circulating levels of atrial natriuretic peptide in hypertensive subjects with type 2 diabetes, Diabetes Care, 38, 132, 10.2337/dc14-1958 Skov, 2013, Glucagon-like peptide-1 (GLP-1): effect on kidney hemodynamics and renin-angiotensin-aldosterone system in healthy men, The Journal of Cinical Endocrinology and Metabolism, 98, E664, 10.1210/jc.2012-3855 Skov, 2014, Glucagon-like peptide-1: effect on pro-atrial natriuretic peptide in healthy males, Endocrine Connectivity, 3, 11, 10.1530/EC-13-0087 Henderson, 2016, Robust anti-obesity and metabolic effects of a dual GLP-1/glucagon receptor peptide agonist in rodents and non-human primates, Diabetes Obesity and Metabolism, 18, 1176, 10.1111/dom.12735 Beiroa, 2014, GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK, Diabetes, 63, 3346, 10.2337/db14-0302 Donahey, 1998, Intraventricular GLP-1 reduces short- but not long-term food intake or body weight in lean and obese rats, Brain Research, 779, 75, 10.1016/S0006-8993(97)01057-3 Turton, 1996, A role for glucagon-like peptide-1 in the central regulation of feeding, Nature, 379, 69, 10.1038/379069a0 Furuse, 1997, Intracerebroventricular injection of mammalian and chicken glucagon-like peptide-1 inhibits food intake of the neonatal chick, Brain Research, 755, 167, 10.1016/S0006-8993(97)00190-X Shousha, 2007, Effect of glucagon-like peptide-1 and -2 on regulation of food intake, body temperature and locomotor activity in the Japanese quail, Neuroscience Letters, 415, 102, 10.1016/j.neulet.2007.01.007 Raun, 2007, Liraglutide, a once-daily human glucagon-like peptide-1 analog, minimizes food intake in severely obese minipigs, Obesity (Silver Spring), 15, 1710, 10.1038/oby.2007.204 Renner, 2018, Metabolic syndrome and extensive adipose tissue inflammation in morbidly obese Gottingen minipigs, Molecular Metabolism, 10.1016/j.molmet.2018.06.015 Elvert, 2018, Team players or opponents: coadministration of selective glucagon and GLP-1 receptor agonists in obese diabetic monkeys, Endocrinology, 159, 3105, 10.1210/en.2018-00399 Scott, 2007, The GLP-1 agonist exendin-4 reduces food intake in nonhuman primates through changes in meal size, American Journal of Physiology Regulatory Integrative and Comparative Physiology, 293, R983, 10.1152/ajpregu.00323.2007 Gutzwiller, 1999, Glucagon-like peptide-1 promotes satiety and reduces food intake in patients with diabetes mellitus type 2, American Journal of Physiology, 276, R1541 Gutzwiller, 1999, Glucagon-like peptide-1: a potent regulator of food intake in humans, Gut, 44, 81, 10.1136/gut.44.1.81 Verdich, 2001, A meta-analysis of the effect of glucagon-like peptide-1 (7-36) amide on ad libitum energy intake in humans, The Journal of Cinical Endocrinology and Metabolism, 86, 4382 Flint, 1998, Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans, Journal of Clinical Investigation, 101, 515, 10.1172/JCI990 De Silva, 2011, The gut hormones PYY 3-36 and GLP-1 7-36 amide reduce food intake and modulate brain activity in appetite centers in humans, Cell Metabolism, 14, 700, 10.1016/j.cmet.2011.09.010 Schlogl, 2013, Exenatide-induced reduction in energy intake is associated with increase in hypothalamic connectivity, Diabetes Care, 36, 1933, 10.2337/dc12-1925 Ten Kulve, 2016, Liraglutide reduces CNS activation in response to visual food cues only after short-term treatment in patients with type 2 diabetes, Diabetes Care, 39, 214, 10.2337/dc15-0772 van Bloemendaal, 2014, GLP-1 receptor activation modulates appetite- and reward-related brain areas in humans, Diabetes, 63, 4186, 10.2337/db14-0849 van Bloemendaal, 2015, Emotional eating is associated with increased brain responses to food-cues and reduced sensitivity to GLP-1 receptor activation, Obesity (Silver Spring), 23, 2075, 10.1002/oby.21200 van Bloemendaal, 2015, Brain reward-system activation in response to anticipation and consumption of palatable food is altered by glucagon-like peptide-1 receptor activation in humans, Diabetes Obesity and Metabolism, 17, 878, 10.1111/dom.12506 Clemmensen, 2015, Dual melanocortin-4 receptor and GLP-1 receptor agonism amplifies metabolic benefits in diet-induced obese mice, EMBO Molecular Medicine, 7, 288, 10.15252/emmm.201404508 Secher, 2014, The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss, Journal of Clinical Investigation, 124, 4473, 10.1172/JCI75276 Kanoski, 2011, Peripheral and central GLP-1 receptor populations mediate the anorectic effects of peripherally administered GLP-1 receptor agonists, liraglutide and exendin-4, Endocrinology, 152, 3103, 10.1210/en.2011-0174 Sisley, 2014, Neuronal GLP1R mediates liraglutide's anorectic but not glucose-lowering effect, Journal of Clinical Investigation, 124, 2456, 10.1172/JCI72434 Swick, 2015, Parabrachial nucleus contributions to glucagon-like peptide-1 receptor agonist-induced hypophagia, Neuropdsychopharmacology, 40, 2001, 10.1038/npp.2015.50 Baggio, 2004, Oxyntomodulin and glucagon-like peptide-1 differentially regulate murine food intake and energy expenditure, Gastroenterology, 127, 546, 10.1053/j.gastro.2004.04.063 Labouesse, 2012, Vagal afferents mediate early satiation and prevent flavour avoidance learning in response to intraperitoneally infused exendin-4, Journal of Neuroendocrinology, 24, 1505, 10.1111/j.1365-2826.2012.02364.x Baumgartner, 2010, Hepatic-portal vein infusions of glucagon-like peptide-1 reduce meal size and increase c-Fos expression in the nucleus tractus solitarii, area postrema and central nucleus of the amygdala in rats, Journal of Neuroendocrinology, 22, 557, 10.1111/j.1365-2826.2010.01995.x Bucinskaite, 2009, Receptor-mediated activation of gastric vagal afferents by glucagon-like peptide-1 in the rat, Neurogastroenterology and Motility, 21, 978, 10.1111/j.1365-2982.2009.01317.x Ruttimann, 2009, Intrameal hepatic portal and intraperitoneal infusions of glucagon-like peptide-1 reduce spontaneous meal size in the rat via different mechanisms, Endocrinology, 150, 1174, 10.1210/en.2008-1221 Plamboeck, 2013, The effect of exogenous GLP-1 on food intake is lost in male truncally vagotomized subjects with pyloroplasty, American Journal of Physiology Gastrointestinal and Liver Physiology, 304, G1117, 10.1152/ajpgi.00035.2013 Van Dijk, 1996, Central infusions of leptin and GLP-1-(7-36) amide differentially stimulate c-FLI in the rat brain, American Journal of Physiology, 271, R1096 Kim, 2009, The effects of GLP-1 infusion in the hepatic portal region on food intake, Regulatory Peptides, 155, 110, 10.1016/j.regpep.2009.03.002 Larsen, 1997, Central administration of glucagon-like peptide-1 activates hypothalamic neuroendocrine neurons in the rat, Endocrinology, 138, 4445, 10.1210/endo.138.10.5270 Alhadeff, 2017, Endogenous glucagon-like peptide-1 receptor signaling in the nucleus tractus solitarius is required for food intake control, Neuropsychopharmacology, 42, 1471, 10.1038/npp.2016.246 Barrera, 2011, Hyperphagia and increased fat accumulation in two models of chronic CNS glucagon-like peptide-1 loss of function, Journal of Neuroscience, 31, 3904, 10.1523/JNEUROSCI.2212-10.2011 Dickson, 2012, The glucagon-like peptide 1 (GLP-1) analogue, exendin-4, decreases the rewarding value of food: a new role for mesolimbic GLP-1 receptors, Journal of Neuroscience, 32, 4812, 10.1523/JNEUROSCI.6326-11.2012 Hsu, 2015, Hippocampal GLP-1 receptors influence food intake, meal size, and effort-based responding for food through volume transmission, Neuropsychopharmacology, 40, 327, 10.1038/npp.2014.175 Mietlicki-Baase, 2013, The food intake-suppressive effects of glucagon-like peptide-1 receptor signaling in the ventral tegmental area are mediated by AMPA/kainate receptors, American Journal of Physiology Endocrinology and Metabolism, 305, E1367, 10.1152/ajpendo.00413.2013 Ong, 2017, Paraventricular thalamic control of food intake and reward: role of glucagon-like peptide-1 receptor signaling, Neuropsychopharmacology, 42, 2387, 10.1038/npp.2017.150 Terrill, 2019, Endogenous GLP-1 in lateral septum promotes satiety and suppresses motivation for food in mice, Physiology and Behavior, 206, 191, 10.1016/j.physbeh.2019.04.008 Hayes, 2011, Intracellular signals mediating the food intake-suppressive effects of hindbrain glucagon-like peptide-1 receptor activation, Cell Metabolism, 13, 320, 10.1016/j.cmet.2011.02.001 Minokoshi, 2004, AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus, Nature, 428, 569, 10.1038/nature02440 Fan, 2009, Hypothalamic AMP-activated protein kinase activation with AICAR amplifies counterregulatory responses to hypoglycemia in a rodent model of type 1 diabetes, American Journal of Physiology Regulatory Integrative and Comparative Physiology, 296, R1702, 10.1152/ajpregu.90600.2008 McCrimmon, 2004, Potential role for AMP-activated protein kinase in hypoglycemia sensing in the ventromedial hypothalamus, Diabetes, 53, 1953, 10.2337/diabetes.53.8.1953 McCrimmon, 2008, Key role for AMP-activated protein kinase in the ventromedial hypothalamus in regulating counterregulatory hormone responses to acute hypoglycemia, Diabetes, 57, 444, 10.2337/db07-0837 Kohno, 2011, AMP-activated protein kinase activates neuropeptide Y neurons in the hypothalamic arcuate nucleus to increase food intake in rats, Neuroscience Letters, 499, 194, 10.1016/j.neulet.2011.05.060 Burmeister, 2012, Acute activation of central GLP-1 receptors enhances hepatic insulin action and insulin secretion in high-fat-fed, insulin resistant mice, American Journal of Physiology Endocrinology and Metabolism, 302, E334, 10.1152/ajpendo.00409.2011 Seo, 2008, Acute effects of glucagon-like peptide-1 on hypothalamic neuropeptide and AMP activated kinase expression in fasted rats, Endocrine Journal, 55, 867, 10.1507/endocrj.K08E-091 Burmeister, 2013, Central glucagon-like peptide 1 receptor-induced anorexia requires glucose metabolism-mediated suppression of AMPK and is impaired by central fructose, American Journal of Physiology Endocrinology and Metabolism, 304, E677, 10.1152/ajpendo.00446.2012 Burmeister, 2017, The glucagon-like peptide-1 receptor in the ventromedial hypothalamus reduces short-term food intake in male mice by regulating nutrient sensor activity, American Journal of Physiology Endocrinology and Metabolism, 313, E651, 10.1152/ajpendo.00113.2017 Alhadeff, 2014, Hindbrain nucleus tractus solitarius glucagon-like peptide-1 receptor signaling reduces appetitive and motivational aspects of feeding, American Journal of Physiology Regulatory Integrative and Comparative Physiology, 307, R465, 10.1152/ajpregu.00179.2014 Hayes, 2009, Endogenous hindbrain glucagon-like peptide-1 receptor activation contributes to the control of food intake by mediating gastric satiation signaling, Endocrinology, 150, 2654, 10.1210/en.2008-1479 Adams, 2018, Liraglutide modulates appetite and body weight through glucagon-like peptide 1 receptor-expressing glutamatergic neurons, Diabetes, 67, 1538, 10.2337/db17-1385 Chaudhri, 2006, Differential hypothalamic neuronal activation following peripheral injection of GLP-1 and oxyntomodulin in mice detected by manganese-enhanced magnetic resonance imaging, Biochemical and Biophysical Research Communications, 350, 298, 10.1016/j.bbrc.2006.09.033 Parkinson, 2009, Differential patterns of neuronal activation in the brainstem and hypothalamus following peripheral injection of GLP-1, oxyntomodulin and lithium chloride in mice detected by manganese-enhanced magnetic resonance imaging (MEMRI), Neuroimage, 44, 1022, 10.1016/j.neuroimage.2008.09.047 Schick, 2003, Peptides that regulate food intake: glucagon-like peptide 1-(7-36) amide acts at lateral and medial hypothalamic sites to suppress feeding in rats, American Journal of Physiology Regulatory Integrative and Comparative Physiology, 284, R1427, 10.1152/ajpregu.00479.2002 McMahon, 1997, Decreased intake of a liquid diet in nonfood-deprived rats following intra-PVN injections of GLP-1 (7-36) amide, Pharmacology Biochemistry and Behavior, 58, 673, 10.1016/S0091-3057(97)90017-4 McMahon, 1998, PVN infusion of GLP-1-(7-36) amide suppresses feeding but does not induce aversion or alter locomotion in rats, American Journal of Physiology, 274, R23 Curtis, 1994, Lithium chloride-induced anorexia, but not conditioned taste aversions, in rats with area postrema lesions, Brain Research, 663, 30, 10.1016/0006-8993(94)90459-6 Rabin, 1992, Relationship between vomiting and taste aversion learning in the ferret: studies with ionizing radiation, lithium chloride, and amphetamine, Behavioral and Neural Biology, 58, 83, 10.1016/0163-1047(92)90291-B Thiele, 1996, c-Fos induction in rat brainstem in response to ethanol- and lithium chloride-induced conditioned taste aversions, Alcoholism Clinical and Experimental Research, 20, 1023, 10.1111/j.1530-0277.1996.tb01941.x Mitchell, 1976, Poison induced pica in rats, Physiology and Behavior, 17, 691, 10.1016/0031-9384(76)90171-2 Pelchat, 1983, Quality of acquired responses to tastes by Rattus norvegicus depends on type of associated discomfort, Journal of Comparative Psychology, 97, 140, 10.1037/0735-7036.97.2.140 Swank, 1994, c-Fos induction in response to a conditioned stimulus after single trial taste aversion learning, Brain Research, 636, 202, 10.1016/0006-8993(94)91018-9 Thiele, 1998, Central infusion of glucagon-like peptide-1-(7-36) amide (GLP-1) receptor antagonist attenuates lithium chloride-induced c-Fos induction in rat brainstem, Brain Research, 801, 164, 10.1016/S0006-8993(98)00584-8 Meachum, 1992, Behavioral conditioned responses to contextual and odor stimuli paired with LiCl administration, Physiology and Behavior, 52, 895, 10.1016/0031-9384(92)90368-C Bernstein, 1992, Area postrema mediation of physiological and behavioral effects of lithium chloride in the rat, Brain Research, 575, 132, 10.1016/0006-8993(92)90432-9 O'Shea, 1996, A role for central glucagon-like peptide-1 in temperature regulation, Neuroreport, 7, 830, 10.1097/00001756-199602290-00035 Bettge, 2017, Occurrence of nausea, vomiting and diarrhoea reported as adverse events in clinical trials studying glucagon-like peptide-1 receptor agonists: A systematic analysis of published clinical trials, Diabetes Obesity and Metabolism, 19, 336, 10.1111/dom.12824 Shiomi, 2018, Clinical factors associated with the occurrence of nausea and vomiting in type 2 diabetes patients treated with glucagon-like peptide-1 receptor agonists, Journal of Diabetes Investigation Thiele, 1997, Central infusion of GLP-1, but not leptin, produces conditioned taste aversions in rats, American Journal of Physiology, 272, R726 van Dijk, 1997, Glucagon-like peptide-1 and satiety, Nature, 385, 214, 10.1038/385214a0 Borner, 2018, Brainstem GLP-1 signalling contributes to cancer anorexia-cachexia syndrome in the rat, Neuropharmacology, 131, 282, 10.1016/j.neuropharm.2017.12.024 Grill, 2004, Attenuation of lipopolysaccharide anorexia by antagonism of caudal brain stem but not forebrain GLP-1-R, American Journal of Physiology Regulatory Integrative and Comparative Physiology, 287, R1190, 10.1152/ajpregu.00163.2004 Alhadeff, 2014, Glucagon-like Peptide-1 receptor signaling in the lateral parabrachial nucleus contributes to the control of food intake and motivation to feed, Neuropsychopharmacology, 39, 2233, 10.1038/npp.2014.74 Alhadeff, 2012, GLP-1 neurons in the nucleus of the solitary tract project directly to the ventral tegmental area and nucleus accumbens to control for food intake, Endocrinology, 153, 647, 10.1210/en.2011-1443 Jelsing, 2012, Liraglutide: short-lived effect on gastric emptying - long lasting effects on body weight, Diabetes Obesity and Metabolism, 14, 531, 10.1111/j.1463-1326.2012.01557.x ten Kulve, 2015, Endogenous GLP-1 mediates postprandial reductions in activation in central reward and satiety areas in patients with type 2 diabetes, Diabetologia, 58, 2688, 10.1007/s00125-015-3754-x Dossat, 2011, Glucagon-like peptide 1 receptors in nucleus accumbens affect food intake, Journal of Neuroscience, 31, 14453, 10.1523/JNEUROSCI.3262-11.2011 Terrill, 2016, Role of lateral septum glucagon-like peptide 1 receptors in food intake, American Journal of Physiology Regulatory Integrative and Comparative Physiology, 311, R124, 10.1152/ajpregu.00460.2015 Decarie-Spain, 2019, GLP-1/dexamethasone inhibits food reward without inducing mood and memory deficits in mice, Neuropharmacology, 151, 55, 10.1016/j.neuropharm.2019.03.035 Egecioglu, 2013, The glucagon-like peptide 1 analogue Exendin-4 attenuates alcohol mediated behaviors in rodents, Psychoneuroendocrinology, 38, 1259, 10.1016/j.psyneuen.2012.11.009 Sirohi, 2016, Central & peripheral glucagon-like peptide-1 receptor signaling differentially regulate addictive behaviors, Physiology and Behavior, 161, 140, 10.1016/j.physbeh.2016.04.013 Dossat, 2013, Nucleus accumbens GLP-1 receptors influence meal size and palatability, American Journal of Physiology Endocrinology and Metabolism, 304, E1314, 10.1152/ajpendo.00137.2013 Hunter, 2012, Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis, BMC Neuroscience, 13, 33, 10.1186/1471-2202-13-33 Kastin, 2003, Entry of exendin-4 into brain is rapid but may be limited at high doses, International Journal of Obesity and Related Metabolic Disorders, 27, 313, 10.1038/sj.ijo.0802206 Kastin, 2002, Interactions of glucagon-like peptide-1 (GLP-1) with the blood-brain barrier, Journal of Molecular Neuroscience, 18, 7, 10.1385/JMN:18:1-2:07 Salinas, 2018, Integrated Brain Atlas for Unbiased Mapping of Nervous System Effects Following Liraglutide Treatment, Scientific Reports, 8, 10310, 10.1038/s41598-018-28496-6 Orskov, 1996, Glucagon-like peptide I receptors in the subfornical organ and the area postrema are accessible to circulating glucagon-like peptide I, Diabetes, 45, 832, 10.2337/diab.45.6.832 Gutzwiller, 2006, Glucagon-like peptide-1 is involved in sodium and water homeostasis in humans, Digestion, 73, 142, 10.1159/000094334 McKay, 2013, Glucagon-like peptide-1 receptor agonist administration suppresses both water and saline intake in rats, Journal of Neuroendocrinology, 25, 929, 10.1111/jne.12086 McKay, 2014, Endogenous glucagon-like peptide-1 reduces drinking behavior and is differentially engaged by water and food intakes in rats, Journal of Neuroscience, 34, 16417, 10.1523/JNEUROSCI.3267-14.2014 McKay, 2011, Glucagon-like peptide-1 receptor agonists suppress water intake independent of effects on food intake, American Journal of Physiology Regulatory Integrative and Comparative Physiology, 301, R1755, 10.1152/ajpregu.00472.2011 Navarro, 1996, Colocalization of glucagon-like peptide-1 (GLP-1) receptors, glucose transporter GLUT-2, and glucokinase mRNAs in rat hypothalamic cells: evidence for a role of GLP-1 receptor agonists as an inhibitory signal for food and water intake, Journal of Neurochemistry, 67, 1982, 10.1046/j.1471-4159.1996.67051982.x Tang-Christensen, 1998, Glucagon-like peptide 1(7-36) amide's central inhibition of feeding and peripheral inhibition of drinking are abolished by neonatal monosodium glutamate treatment, Diabetes, 47, 530, 10.2337/diabetes.47.4.530 Moreno, 2002, Renal effects of glucagon-like peptide in rats, European Journal of Pharmacology, 434, 163, 10.1016/S0014-2999(01)01542-4 Muskiet, 2016, Acute renal haemodynamic effects of glucagon-like peptide-1 receptor agonist exenatide in healthy overweight men, Diabetes Obesity and Metabolism, 18, 178, 10.1111/dom.12601 Skov, 2016, Short-term effects of liraglutide on kidney function and vasoactive hormones in type 2 diabetes: a randomized clinical trial, Diabetes Obesity and Metabolism, 18, 581, 10.1111/dom.12651 Tonneijck, 2016, Acute renal effects of the GLP-1 receptor agonist exenatide in overweight type 2 diabetes patients: a randomised, double-blind, placebo-controlled trial, Diabetologia, 59, 1412, 10.1007/s00125-016-3938-z Tonneijck, 2016, Renal Effects of DPP-4 Inhibitor Sitagliptin or GLP-1 Receptor Agonist Liraglutide in Overweight Patients With Type 2 Diabetes: A 12-Week, Randomized, Double-Blind, Placebo-Controlled Trial, Diabetes Care, 39, 2042, 10.2337/dc16-1371 Fujita, 2014, The protective roles of GLP-1R signaling in diabetic nephropathy: possible mechanism and therapeutic potential, Kidney International, 85, 579, 10.1038/ki.2013.427 Korner, 2007, GLP-1 receptor expression in human tumors and human normal tissues: potential for in vivo targeting, Journal of Nuclear Medicine, 48, 736, 10.2967/jnumed.106.038679 Schlatter, 2007, Glucagon-like peptide 1 receptor expression in primary porcine proximal tubular cells, Regulatory Peptides, 141, 120, 10.1016/j.regpep.2006.12.016 Pacheco, 2011, Dipeptidyl peptidase IV inhibition attenuates blood pressure rising in young spontaneously hypertensive rats, Journal of Hypertension, 29, 520, 10.1097/HJH.0b013e328341939d Thomson, 2013, Glucagon-like peptide-1 receptor stimulation increases GFR and suppresses proximal reabsorption in the rat, American Journal of Physiology Renal Physiology, 304, F137, 10.1152/ajprenal.00064.2012 Carraro-Lacroix, 2009, Regulation of Na+/H+ exchanger NHE3 by glucagon-like peptide 1 receptor agonist exendin-4 in renal proximal tubule cells, American Journal of Physiology Renal Physiology, 297, F1647, 10.1152/ajprenal.00082.2009 Farah, 2016, The physiological role of glucagon-like peptide-1 in the regulation of renal function, American Journal of Physiology Renal Physiology, 310, F123, 10.1152/ajprenal.00394.2015 Lockie, 2012, Direct control of brown adipose tissue thermogenesis by central nervous system glucagon-like peptide-1 receptor signaling, Diabetes, 61, 2753, 10.2337/db11-1556 Heppner, 2015, Contribution of brown adipose tissue activity to the control of energy balance by GLP-1 receptor signalling in mice, Diabetologia, 58, 2124, 10.1007/s00125-015-3651-3 Cannon, 2011, Nonshivering thermogenesis and its adequate measurement in metabolic studies, Journal of Experimental Biology, 214, 242, 10.1242/jeb.050989 Morrison, 2014, Central neural regulation of brown adipose tissue thermogenesis and energy expenditure, Cell Metabolism, 19, 741, 10.1016/j.cmet.2014.02.007 Lee, 2018, Loss of dorsomedial hypothalamic GLP-1 signaling reduces BAT thermogenesis and increases adiposity, Molecular Metabolism, 11, 33, 10.1016/j.molmet.2018.03.008 Shi, 2017, Acute activation of GLP-1-expressing neurons promotes glucose homeostasis and insulin sensitivity, Molecular Metabolism, 6, 1350, 10.1016/j.molmet.2017.08.009 Hwa, 1998, Differential effects of intracerebroventricular glucagon-like peptide-1 on feeding and energy expenditure regulation, Peptides, 19, 869, 10.1016/S0196-9781(98)00033-3 Osaka, 2005, Energy expenditure by intravenous administration of glucagon-like peptide-1 mediated by the lower brainstem and sympathoadrenal system, Peptides, 26, 1623, 10.1016/j.peptides.2005.02.016 Krieger, 2018, Glucagon-like peptide-1 regulates brown adipose tissue thermogenesis via the gut-brain axis in rats, American Journal of Physiology Regulatory Integrative and Comparative Physiology, 315, R708, 10.1152/ajpregu.00068.2018 Skibicka, 2009, Hindbrain cocaine- and amphetamine-regulated transcript induces hypothermia mediated by GLP-1 receptors, Journal of Neuroscience, 29, 6973, 10.1523/JNEUROSCI.6144-08.2009 Cegla, 2014, Coinfusion of low-dose GLP-1 and glucagon in man results in a reduction in food intake, Diabetes, 63, 3711, 10.2337/db14-0242 Tan, 2017, The Effect of a Subcutaneous Infusion of GLP-1, OXM, and PYY on Energy Intake and Expenditure in Obese Volunteers, The Journal of Cinical Endocrinology and Metabolism, 102, 2364, 10.1210/jc.2017-00469 Tan, 2013, Coadministration of glucagon-like peptide-1 during glucagon infusion in humans results in increased energy expenditure and amelioration of hyperglycemia, Diabetes, 62, 1131, 10.2337/db12-0797 Bagger, 2015, Effect of Oxyntomodulin, Glucagon, GLP-1, and Combined Glucagon +GLP-1 Infusion on Food Intake, Appetite, and Resting Energy Expenditure, The Journal of Cinical Endocrinology and Metabolism, 100, 4541, 10.1210/jc.2015-2335 Bergmann, 2019, Effects of combined GIP and GLP-1 infusion on energy intake, appetite and energy expenditure in overweight/obese individuals: a randomised, crossover study, Diabetologia, 62, 665, 10.1007/s00125-018-4810-0 Flint, 2000, The effect of glucagon-like peptide-1 on energy expenditure and substrate metabolism in humans, International Journal of Obesity and Related Metabolic Disorders, 24, 288, 10.1038/sj.ijo.0801126 Linnebjerg, 2008, Effect of exenatide on gastric emptying and relationship to postprandial glycemia in type 2 diabetes, Regulatory Peptides, 151, 123, 10.1016/j.regpep.2008.07.003 Little, 2006, Effects of intravenous glucagon-like peptide-1 on gastric emptying and intragastric distribution in healthy subjects: relationships with postprandial glycemic and insulinemic responses, The Journal of Cinical Endocrinology and Metabolism, 91, 1916, 10.1210/jc.2005-2220 Wettergren, 1993, Truncated GLP-1 (proglucagon 78-107-amide) inhibits gastric and pancreatic functions in man, Digestive Diseases and Sciences, 38, 665, 10.1007/BF01316798 Tatarkiewicz, 2014, Long-term metabolic benefits of exenatide in mice are mediated solely via the known glucagon-like peptide 1 receptor, American Journal of Physiology Regulatory Integrative and Comparative Physiology, 306, R490, 10.1152/ajpregu.00495.2013 Bozkurt, 2002, GLP-1 and GLP-2 act in concert to inhibit fasted, but not fed, small bowel motility in the rat, Regulatory Peptides, 107, 129, 10.1016/S0167-0115(02)00095-2 Giralt, 1998, Sympathetic pathways mediate GLP-1 actions in the gastrointestinal tract of the rat, Regulatory Peptides, 74, 19, 10.1016/S0167-0115(98)00010-X Imeryuz, 1997, Glucagon-like peptide-1 inhibits gastric emptying via vagal afferent-mediated central mechanisms, American Journal of Physiology, 273, G920 Anvari, 1998, Effects of GLP-1 on gastric emptying, antropyloric motility, and transpyloric flow in response to a nonnutrient liquid, Digestive Diseases and Sciences, 43, 1133, 10.1023/A:1018863716749 Ionut, 2008, Exenatide can reduce glucose independent of islet hormones or gastric emptying, American Journal of Physiology Endocrinology and Metabolism, 295, E269, 10.1152/ajpendo.90222.2008 Moore, 2013, Effect of the glucagon-like peptide-1 receptor agonist lixisenatide on postprandial hepatic glucose metabolism in the conscious dog, American Journal of Physiology Endocrinology and Metabolism, 305, E1473, 10.1152/ajpendo.00354.2013 Nagell, 2006, Inhibitory effect of GLP-1 on gastric motility persists after vagal deafferentation in pigs, Scandinavian Journal of Gastroenterology, 41, 667, 10.1080/00365520500408253 Wettergren, 1998, Glucagon-like peptide-1 inhibits gastropancreatic function by inhibiting central parasympathetic outflow, American Journal of Physiology, 275, G984 Halim, 2018, Glucagon-Like Peptide-1 Inhibits Prandial Gastrointestinal Motility Through Myenteric Neuronal Mechanisms in Humans, The Journal of Cinical Endocrinology and Metabolism, 103, 575, 10.1210/jc.2017-02006 Nakatani, 2017, Effect of GLP-1 receptor agonist on gastrointestinal tract motility and residue rates as evaluated by capsule endoscopy, Diabetes and Metabolism, 43, 430, 10.1016/j.diabet.2017.05.009 Nauck, 2011, Rapid tachyphylaxis of the glucagon-like peptide 1-induced deceleration of gastric emptying in humans, Diabetes, 60, 1561, 10.2337/db10-0474 Nauck, 1996, Effects of subcutaneous glucagon-like peptide 1 (GLP-1 [7-36 amide]) in patients with NIDDM, Diabetologia, 39, 1546, 10.1007/s001250050613 Thazhath, 2016, The Glucagon-like peptide 1 receptor agonist exenatide inhibits small intestinal motility, flow, transit, and absorption of glucose in healthy subjects and patients with type 2 diabetes: a randomized controlled trial, Diabetes, 65, 269, 10.2337/db15-0893 Hayes, 2008, Caudal brainstem processing is sufficient for behavioral, sympathetic, and parasympathetic responses driven by peripheral and hindbrain glucagon-like-peptide-1 receptor stimulation, Endocrinology, 149, 4059, 10.1210/en.2007-1743 Wettergren, 1997, The inhibitory effect of glucagon-like peptide-1 (GLP-1) 7-36 amide on gastric acid secretion in humans depends on an intact vagal innervation, Gut, 40, 597, 10.1136/gut.40.5.597 Halawi, 2017, Effects of liraglutide on weight, satiation, and gastric functions in obesity: a randomised, placebo-controlled pilot trial, Lancet Gastroenterology and Hepatology, 2, 890, 10.1016/S2468-1253(17)30285-6 Nauck, 1997, Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans, American Journal of Physiology, 273, E981 Nauck, 1999, Is glucagon-like peptide 1 an incretin hormone?, Diabetologia, 42, 373, 10.1007/s001250051165 Herman, 2018, Regulation of hypothalamo-pituitary-adrenocortical responses to stressors by the nucleus of the solitary tract/dorsal vagal complex, Cellular and Molecular Neurobiology, 38, 25, 10.1007/s10571-017-0543-8 Sarkar, 2003, Glucagon like peptide-1 (7-36) amide (GLP-1) nerve terminals densely innervate corticotropin-releasing hormone neurons in the hypothalamic paraventricular nucleus, Brain Research, 985, 163, 10.1016/S0006-8993(03)03117-2 Ghosal, 2017, Disruption of glucagon-like peptide 1 signaling in Sim1 neurons reduces physiological and behavioral reactivity to acute and chronic stress, Journal of Neuroscience, 37, 184, 10.1523/JNEUROSCI.1104-16.2016 Rowland, 1997, Comparison of Fos induced in rat brain by GLP-1 and amylin, Regulatory Peptides, 71, 171, 10.1016/S0167-0115(97)01034-3 Gil-Lozano, 2010, GLP-1(7-36)-amide and Exendin-4 stimulate the HPA axis in rodents and humans, Endocrinology, 151, 2629, 10.1210/en.2009-0915 Malendowicz, 2003, Prolonged exendin-4 administration stimulates pituitary-adrenocortical axis of normal and streptozotocin-induced diabetic rats, International Journal of Molecular Medicine, 12, 593 Malendowicz, 2003, Exendin-4, a GLP-1 receptor agonist, stimulates pituitary-adrenocortical axis in the rat: Investigations into the mechanism(s) underlying Ex4 effect, International Journal of Molecular Medicine, 12, 237 Krass, 2015, GLP-1 receptor agonists have a sustained stimulatory effect on corticosterone release after chronic treatment, Acta Neuropsychiatrica, 27, 25, 10.1017/neu.2014.36 Lee, 2016, Limiting glucocorticoid secretion increases the anorexigenic property of Exendin-4, Molecular Metabolism, 5, 552, 10.1016/j.molmet.2016.04.008 Quarta, 2017, Molecular integration of incretin and glucocorticoid action reverses immunometabolic dysfunction and obesity, Cell Metabolism, 26, 620, 10.1016/j.cmet.2017.08.023 Alvarez, 1996, Expression of the glucagon-like peptide-1 receptor gene in rat brain, Journal of Neurochemistry, 66, 920, 10.1046/j.1471-4159.1996.66030920.x Rebosio, 2018, Presynaptic GLP-1 receptors enhance the depolarization-evoked release of glutamate and GABA in the mouse cortex and hippocampus, Biofactors, 44, 148, 10.1002/biof.1406 Kandel, 2001, The molecular biology of memory storage: a dialogue between genes and synapses, Science, 294, 1030, 10.1126/science.1067020 Lamsa, 2018, Long-term plasticity of hippocampal interneurons during in vivo memory processes, Current Opinion in Neurobiology, 54, 20, 10.1016/j.conb.2018.08.006 Perry, 2002, A novel neurotrophic property of glucagon-like peptide 1: a promoter of nerve growth factor-mediated differentiation in PC12 cells, Journal of Pharmacology and Experimental Therapeutics, 300, 958, 10.1124/jpet.300.3.958 Perry, 2002, Protection and reversal of excitotoxic neuronal damage by glucagon-like peptide-1 and exendin-4, Journal of Pharmacology and Experimental Therapeutics, 302, 881, 10.1124/jpet.102.037481 Perry, 2002, The glucagon-like peptides: a new genre in therapeutic targets for intervention in Alzheimer's disease, Journal of Alzheimer's Disease, 4, 487, 10.3233/JAD-2002-4605 Warby, 2009, CAG expansion in the Huntington disease gene is associated with a specific and targetable predisposing haplogroup, The American Journal of Human Genetics, 84, 351, 10.1016/j.ajhg.2009.02.003 Vidoni, 2016, Dopamine exacerbates mutant Huntingtin toxicity via oxidative-mediated inhibition of autophagy in SH-SY5Y neuroblastoma cells: Beneficial effects of anti-oxidant therapeutics, Neurochemistry International, 101, 132, 10.1016/j.neuint.2016.11.003 Lalic, 2008, Glucose homeostasis in Huntington disease: abnormalities in insulin sensitivity and early-phase insulin secretion, Archives of Neurology, 65, 476, 10.1001/archneur.65.4.476 Chang, 2018, GLP-1 analogue liraglutide attenuates mutant huntingtin-induced neurotoxicity by restoration of neuronal insulin signaling, International Journal of Molecular Sciences, 19, 10.3390/ijms19092505 Qi, 2016, Subcutaneous administration of liraglutide ameliorates learning and memory impairment by modulating tau hyperphosphorylation via the glycogen synthase kinase-3beta pathway in an amyloid beta protein induced alzheimer disease mouse model, European Journal of Pharmacology, 783, 23, 10.1016/j.ejphar.2016.04.052 Wang, 2010, Val8-glucagon-like peptide-1 protects against Abeta1-40-induced impairment of hippocampal late-phase long-term potentiation and spatial learning in rats, Neuroscience, 170, 1239, 10.1016/j.neuroscience.2010.08.028 Chen, 2017, Liraglutide improves water maze learning and memory performance while reduces hyperphosphorylation of tau and neurofilaments in APP/PS1/Tau triple transgenic mice, Neurochemical Research, 42, 2326, 10.1007/s11064-017-2250-8 Hansen, 2015, The GLP-1 receptor agonist liraglutide improves memory function and increases hippocampal CA1 neuronal numbers in a senescence-accelerated mouse model of Alzheimer's disease, Journal of Alzheimer's Disease, 46, 877, 10.3233/JAD-143090 McClean, 2011, The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer's disease, Journal of Neuroscience, 31, 6587, 10.1523/JNEUROSCI.0529-11.2011 Gejl, 2017, Blood-brain glucose transfer in Alzheimer's disease: Effect of GLP-1 analog treatment, Scientific Reports, 7, 17490, 10.1038/s41598-017-17718-y Watson, 2019, Neural correlates of liraglutide effects in persons at risk for Alzheimer's disease, Behavioural Brain Research, 356, 271, 10.1016/j.bbr.2018.08.006 Femminella, 2019, Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer's disease: study protocol for a randomised controlled trial (ELAD study), Trials, 20, 191, 10.1186/s13063-019-3259-x Burns, 1983, A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Proceedings of the National Academy of Sciences of the United States of America, 80, 4546, 10.1073/pnas.80.14.4546 Chiueh, 1984, Neurochemical and behavioral effects of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) in rat, guinea pig, and monkey, Psychopharmacology Bulletin, 20, 548 Heikkila, 1985, Dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) in the mouse: relationships between monoamine oxidase, MPTP metabolism and neurotoxicity, Life Sciences, 36, 231, 10.1016/0024-3205(85)90064-5 Li, 2009, GLP-1 receptor stimulation preserves primary cortical and dopaminergic neurons in cellular and rodent models of stroke and Parkinsonism, Proceedings of the National Academy of Sciences of the United States of America, 106, 1285, 10.1073/pnas.0806720106 Abuirmeileh, 2012, Exendin-4 treatment enhances L-DOPA evoked release of striatal dopamine and decreases dyskinetic movements in the 6-hydoxydopamine lesioned rat, Journal of Pharmacy and Pharmacology, 64, 637, 10.1111/j.2042-7158.2011.01394.x Harkavyi, 2008, Glucagon-like peptide 1 receptor stimulation reverses key deficits in distinct rodent models of Parkinson's disease, Journal of Neuroinflammation, 5, 19, 10.1186/1742-2094-5-19 Kim, 2009, Exendin-4 protects dopaminergic neurons by inhibition of microglial activation and matrix metalloproteinase-3 expression in an animal model of Parkinson's disease, Journal of Endocrinology, 202, 431, 10.1677/JOE-09-0132 Liu, 2015, Neuroprotective effects of lixisenatide and liraglutide in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease, Neuroscience, 303, 42, 10.1016/j.neuroscience.2015.06.054 Rampersaud, 2012, Exendin-4 reverts behavioural and neurochemical dysfunction in a pre-motor rodent model of Parkinson's disease with noradrenergic deficit, British Journal of Pharmacology, 167, 1467, 10.1111/j.1476-5381.2012.02100.x Rampersaud, 2012, Exendin-4 reverses biochemical and behavioral deficits in a pre-motor rodent model of Parkinson's disease with combined noradrenergic and serotonergic lesions, Neuropeptides, 46, 183, 10.1016/j.npep.2012.07.004 Athauda, 2017, Exenatide once weekly versus placebo in Parkinson's disease: a randomised, double-blind, placebo-controlled trial, Lancet, 390, 1664, 10.1016/S0140-6736(17)31585-4 Aviles-Olmos, 2013, Exenatide and the treatment of patients with Parkinson's disease, Journal of Clinical Investigation, 123, 2730, 10.1172/JCI68295 Aviles-Olmos, 2014, Motor and cognitive advantages persist 12 months after exenatide exposure in Parkinson's disease, Journal of Parkinson's Disease, 4, 337, 10.3233/JPD-140364 Foltynie, 2014, Exenatide as a potential treatment for patients with Parkinson's disease: first steps into the clinic, Alzheimers Dementia, 10, S38, 10.1016/j.jalz.2013.12.005 Yamada, 2008, The murine glucagon-like peptide-1 receptor is essential for control of bone resorption, Endocrinology, 149, 574, 10.1210/en.2007-1292 Hegedus, 2011, GLP-1 and calcitonin concentration in humans: lack of evidence of calcitonin release from sequential screening in over 5000 subjects with type 2 diabetes or nondiabetic obese subjects treated with the human GLP-1 analog, liraglutide, The Journal of Cinical Endocrinology and Metabolism, 96, 853, 10.1210/jc.2010-2318 Bjerre Knudsen, 2010, Glucagon-like Peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation, Endocrinology, 151, 1473, 10.1210/en.2009-1272 Mabilleau, 2013, Optimal bone mechanical and material properties require a functional glucagon-like peptide-1 receptor, Journal of Endocrinology, 219, 59, 10.1530/JOE-13-0146 Mieczkowska, 2013, Glucose-dependent insulinotropic polypeptide (GIP) receptor deletion leads to reduced bone strength and quality, Bone, 56, 337, 10.1016/j.bone.2013.07.003 Gaudin-Audrain, 2013, Glucose-dependent insulinotropic polypeptide receptor deficiency leads to modifications of trabecular bone volume and quality in mice, Bone, 53, 221, 10.1016/j.bone.2012.11.039 Mieczkowska, 2015, Double incretin receptor knock-out (DIRKO) mice present with alterations of trabecular and cortical micromorphology and bone strength, Osteoporosis International, 26, 209, 10.1007/s00198-014-2845-8 Meng, 2016, Activation of GLP-1 Receptor Promotes Bone Marrow Stromal Cell Osteogenic Differentiation through beta-Catenin, Stem Cell Reports, 6, 633, 10.1016/j.stemcr.2016.03.010 Mansur, 2015, Stable Incretin Mimetics Counter Rapid Deterioration of Bone Quality in Type 1 Diabetes Mellitus, Journal of Cellular Physiology, 230, 3009, 10.1002/jcp.25033 Pereira, 2017, Exenatide Improves Bone Quality in a Murine Model of Genetically Inherited Type 2 Diabetes Mellitus, Frontiers in Endocrinology (Lausanne), 8, 327, 10.3389/fendo.2017.00327 Mansur, 2019, The GLP-1 receptor agonist exenatide ameliorates bone composition and tissue material properties in high fat fed diabetic mice, Frontiers in Endocrinology (Lausanne), 10, 51, 10.3389/fendo.2019.00051 Mansur, 2016, A new stable GIP-Oxyntomodulin hybrid peptide improved bone strength both at the organ and tissue levels in genetically-inherited type 2 diabetes mellitus, Bone, 87, 102, 10.1016/j.bone.2016.04.001 Mabilleau, 2018, Efficacy of targeting bone-specific GIP receptor in ovariectomy-induced bone loss, Journal of Endocrinology, 10.1530/JOE-18-0214 Mabilleau, 2014, Beneficial effects of a N-terminally modified GIP agonist on tissue-level bone material properties, Bone, 63, 61, 10.1016/j.bone.2014.02.013 Mansur, 2019, Sitagliptin Alters Bone Composition in High-Fat-Fed Mice, Calcified Tissue International, 104, 437, 10.1007/s00223-018-0507-0 Henriksen, 2003, Role of gastrointestinal hormones in postprandial reduction of bone resorption, Journal of Bone and Mineral Research, 18, 2180, 10.1359/jbmr.2003.18.12.2180 Eriksson, 2018, Bone Status in Obese, Non-diabetic, Antipsychotic-Treated Patients, and Effects of the Glucagon-Like Peptide-1 Receptor Agonist Exenatide on Bone Turnover Markers and Bone Mineral Density, Frontiers in Psychiatry, 9, 781, 10.3389/fpsyt.2018.00781 Iepsen, 2015, GLP-1 receptor agonist treatment increases bone formation and prevents bone loss in weight-reduced obese women, The Journal of Cinical Endocrinology and Metabolism, 100, 2909, 10.1210/jc.2015-1176 Mabilleau, 2014, Use of glucagon-like peptide-1 receptor agonists and bone fractures: a meta-analysis of randomized clinical trials, Journal of Diabetes, 6, 260, 10.1111/1753-0407.12102 Driessen, 2015, Bone fracture risk is not associated with the use of glucagon-like peptide-1 receptor agonists: a population-based cohort analysis, Calcified Tissue International, 97, 104, 10.1007/s00223-015-9993-5 Cheng, 2019, Glucagon-like peptide-1 receptor agonists and risk of bone fracture in patients with type 2 diabetes mellitus: a meta-analysis of randomized controlled trials, Diabetes Metabolism in Research Review, e3168, 10.1002/dmrr.3168 Banting, 1922, Pancreatic Extracts in the Treatment of Diabetes Mellitus, Canadian Medical Association Journal, 12, 141 Vilsboll, 2003, Similar elimination rates of glucagon-like peptide-1 in obese type 2 diabetic patients and healthy subjects, The Journal of Cinical Endocrinology and Metabolism, 88, 220, 10.1210/jc.2002-021053 Peters, 2013, Liraglutide for the treatment of type 2 diabetes: a clinical update, American Journal of Therapeutics, 20, 178, 10.1097/MJT.0b013e3182204c16 Muller, 2018, Anti-Obesity Therapy: from Rainbow Pills to Polyagonists, Pharmacological Reviews, 70, 712, 10.1124/pr.117.014803 Eng, 1992, Exendin peptides, Mount Sinai Journal of Medicine A Journal of Translational and Personalized Medicine, 59, 147 Neidigh, 2001, Exendin-4 and glucagon-like-peptide-1: NMR structural comparisons in the solution and micelle-associated states, Biochemistry, 40, 13188, 10.1021/bi010902s Barnett, 2007, Tolerability and efficacy of exenatide and titrated insulin glargine in adult patients with type 2 diabetes previously uncontrolled with metformin or a sulfonylurea: a multinational, randomized, open-label, two-period, crossover noninferiority trial, Clinical Therapeutics, 29, 2333, 10.1016/j.clinthera.2007.11.006 DeFronzo, 2005, Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes, Diabetes Care, 28, 1092, 10.2337/diacare.28.5.1092 Kolterman, 2003, Synthetic exendin-4 (exenatide) significantly reduces postprandial and fasting plasma glucose in subjects with type 2 diabetes, The Journal of Cinical Endocrinology and Metabolism, 88, 3082, 10.1210/jc.2002-021545 Poon, 2005, Exenatide improves glycemic control and reduces body weight in subjects with type 2 diabetes: a dose-ranging study, Diabetes Technology and Therapeutics, 7, 467, 10.1089/dia.2005.7.467 Edwards, 2001, Exendin-4 reduces fasting and postprandial glucose and decreases energy intake in healthy volunteers, American Journal of Physiology Endocrinology and Metabolism, 281, E155, 10.1152/ajpendo.2001.281.1.E155 Ratner, 2006, Long-term effects of exenatide therapy over 82 weeks on glycaemic control and weight in over-weight metformin-treated patients with type 2 diabetes mellitus, Diabetes Obesity and Metabolism, 8, 419, 10.1111/j.1463-1326.2006.00589.x Toft-Nielsen, 1999, Continuous subcutaneous infusion of glucagon-like peptide 1 lowers plasma glucose and reduces appetite in type 2 diabetic patients, Diabetes Care, 22, 1137, 10.2337/diacare.22.7.1137 Aroda, 2011, Clinical implications of exenatide as a twice-daily or once-weekly therapy for type 2 diabetes, Postgraduate Medicine, 123, 228, 10.3810/pgm.2011.09.2479 Thorkildsen, 2003, Glucagon-like peptide 1 receptor agonist ZP10A increases insulin mRNA expression and prevents diabetic progression in db/db mice, Journal of Pharmacology and Experimental Therapeutics, 307, 490, 10.1124/jpet.103.051987 McCarty, 2017, Lixisenatide: a new daily GLP-1 Agonist for type 2 diabetes management, The Annals of Pharmacotherapy, 51, 401, 10.1177/1060028017689878 Finan, 2015, Emerging opportunities for the treatment of metabolic diseases: Glucagon-like peptide-1 based multi-agonists, Molecular and Cellular Endocrinology, 418, 42, 10.1016/j.mce.2015.07.003 Ratner, 2010, Dose-dependent effects of the once-daily GLP-1 receptor agonist lixisenatide in patients with Type 2 diabetes inadequately controlled with metformin: a randomized, double-blind, placebo-controlled trial, Diabetic Medicine, 27, 1024, 10.1111/j.1464-5491.2010.03020.x Jacobsen, 2016, Liraglutide in Type 2 Diabetes Mellitus: Clinical Pharmacokinetics and Pharmacodynamics, Clinical Pharmacokinetics, 55, 657, 10.1007/s40262-015-0343-6 Agerso, 2002, The pharmacokinetics, pharmacodynamics, safety and tolerability of NN2211, a new long-acting GLP-1 derivative, in healthy men, Diabetologia, 45, 195, 10.1007/s00125-001-0719-z O'Neil, 2018, Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial, Lancet, 392, 637, 10.1016/S0140-6736(18)31773-2 Lau, 2015, Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide, Journal of Medicinal Chemistry, 58, 7370, 10.1021/acs.jmedchem.5b00726 Gotfredsen, 2014, The human GLP-1 analogs liraglutide and semaglutide: absence of histopathological effects on the pancreas in nonhuman primates, Diabetes, 63, 2486, 10.2337/db13-1087 Pratley, 2018, Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): a randomised, open-label, phase 3b trial, Lancet Diabetes Endocrinology, 6, 275, 10.1016/S2213-8587(18)30024-X Marso, 2016, Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes, New England Journal of Medicine, 375, 1834, 10.1056/NEJMoa1607141 Glaesner, 2010, Engineering and characterization of the long-acting glucagon-like peptide-1 analogue LY2189265, an Fc fusion protein, Diabetes Metabolism in Research Review, 26, 287, 10.1002/dmrr.1080 Barrington, 2011, LY2189265, a long-acting glucagon-like peptide-1 analogue, showed a dose-dependent effect on insulin secretion in healthy subjects, Diabetes Obesity and Metabolism, 13, 434, 10.1111/j.1463-1326.2011.01365.x Dungan, 2014, Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 diabetes (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial, Lancet, 384, 1349, 10.1016/S0140-6736(14)60976-4 Bush, 2009, Safety, tolerability, pharmacodynamics and pharmacokinetics of albiglutide, a long-acting glucagon-like peptide-1 mimetic, in healthy subjects, Diabetes Obesity and Metabolism, 11, 498, 10.1111/j.1463-1326.2008.00992.x Alfaris, 2015, Combination phentermine and topiramate extended release in the management of obesity, Expert Opinion on Pharmacotherapy, 16, 1263, 10.1517/14656566.2015.1041505 Gadde, 2011, Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial, Lancet, 377, 1341, 10.1016/S0140-6736(11)60205-5 Diamant, 2014, Glucagon-like peptide 1 receptor agonist or bolus insulin with optimized basal insulin in type 2 diabetes, Diabetes Care, 37, 2763, 10.2337/dc14-0876 Eng, 2014, Glucagon-like peptide-1 receptor agonist and basal insulin combination treatment for the management of type 2 diabetes: a systematic review and meta-analysis, Lancet, 384, 2228, 10.1016/S0140-6736(14)61335-0 Goldenberg, 2018, Adding prandial GLP-1 receptor agonists to basal insulin: a promising option for type 2 diabetes therapy, Current Medical Research and Opinion, 34, 1, 10.1080/03007995.2017.1372118 Yang, 2018, Addition of dipeptidyl peptidase-4 inhibitors to insulin treatment in type 2 diabetes patients: A meta-analysis, Journal of Diabetes Investigation, 9, 813, 10.1111/jdi.12764 Nauck, 2017, Addition of a dipeptidyl peptidase-4 inhibitor, sitagliptin, to ongoing therapy with the glucagon-like peptide-1 receptor agonist liraglutide: A randomized controlled trial in patients with type 2 diabetes, Diabetes Obesity and Metabolism, 19, 200, 10.1111/dom.12802 Violante, 2012, A randomized non-inferiority study comparing the addition of exenatide twice daily to sitagliptin or switching from sitagliptin to exenatide twice daily in patients with type 2 diabetes experiencing inadequate glycaemic control on metformin and sitagliptin, Diabetic Medicine, 29, e417, 10.1111/j.1464-5491.2012.03624.x Kanoski, 2015, Liraglutide, leptin and their combined effects on feeding: additive intake reduction through common intracellular signalling mechanisms, Diabetes Obesity and Metabolism, 17, 285, 10.1111/dom.12423 Muller, 2012, Restoration of leptin responsiveness in diet-induced obese mice using an optimized leptin analog in combination with exendin-4 or FGF21, Journal of Peptide Science, 18, 383, 10.1002/psc.2408 Bello, 2010, Dose combinations of exendin-4 and salmon calcitonin produce additive and synergistic reductions in food intake in nonhuman primates, American Journal of Physiology Regulatory Integrative and Comparative Physiology, 299, R945, 10.1152/ajpregu.00275.2010 Neary, 2005, Peptide YY3-36 and glucagon-like peptide-17-36 inhibit food intake additively, Endocrinology, 146, 5120, 10.1210/en.2005-0237 Trevaskis, 2015, Synergistic metabolic benefits of an exenatide analogue and cholecystokinin in diet-induced obese and leptin-deficient rodents, Diabetes Obesity and Metabolism, 17, 61, 10.1111/dom.12390 Baruah, 2012, The novel use of GLP-1 analogue and insulin combination in type 2 diabetes mellitus, Recent Patents on Endocrine Metabolic and Immune Drug Discovery, 6, 129, 10.2174/187221412800604563 Bech, 2019, Adrenomedullin and glucagon-like peptide-1 have additive effects on food intake in mice, Biomedicine and Pharmacotherapy, 109, 167, 10.1016/j.biopha.2018.10.040 Decara, 2018, Cooperative role of the glucagon-like peptide-1 receptor and beta3-adrenergic-mediated signalling on fat mass reduction through the downregulation of PKA/AKT/AMPK signalling in the adipose tissue and muscle of rats, Acta Physiologica (Oxford), 222, 10.1111/apha.13008 Bojanowska, 2011, Combined stimulation of glucagon-like peptide-1 receptor and inhibition of cannabinoid CB1 receptor act synergistically to reduce food intake and body weight in the rat, Journal of Physiology and Pharmacology, 62, 395 Jouihan, 2017, Superior reductions in hepatic steatosis and fibrosis with co-administration of a glucagon-like peptide-1 receptor agonist and obeticholic acid in mice, Molecular Metabolism, 6, 1360, 10.1016/j.molmet.2017.09.001 Day, 2009, A new glucagon and GLP-1 co-agonist eliminates obesity in rodents, Nature Chemical Biology, 5, 749, 10.1038/nchembio.209 Pocai, 2009, Glucagon-like peptide 1/glucagon receptor dual agonism reverses obesity in mice, Diabetes, 58, 2258, 10.2337/db09-0278 Evers, 2017, Design of novel exendin-based dual glucagon-like peptide 1 (GLP-1)/glucagon receptor agonists, Journal of Medicinal Chemistry, 60, 4293, 10.1021/acs.jmedchem.7b00174 Clemmensen, 2019, Emerging hormonal-based combination pharmacotherapies for the treatment of metabolic diseases, Nature Reviews Endocrinology, 15, 90, 10.1038/s41574-018-0118-x Ambery, 2018, 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, 10.1016/S0140-6736(18)30726-8 Tillner, 2019, A novel dual glucagon-like peptide and glucagon receptor agonist SAR425899: Results of randomized, placebo-controlled first-in-human and first-in-patient trials, Diabetes Obesity and Metabolism, 21, 120, 10.1111/dom.13494 Nauck, 1993, 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, The Journal of Cinical Endocrinology and Metabolism, 76, 912 Finan, 2016, Reappraisal of GIP pharmacology for metabolic diseases, Trends in Molecular Medicine, 22, 359, 10.1016/j.molmed.2016.03.005 Irwin, 2009, Therapeutic potential for GIP receptor agonists and antagonists, Best Practice and Research Clinical Endocrinology and Metabolism, 23, 499, 10.1016/j.beem.2009.03.001 Irwin, 2010, Therapeutic potential of the original incretin hormone glucose-dependent insulinotropic polypeptide: diabetes, obesity, osteoporosis and Alzheimer's disease?, Expert Opinion on Investigational Drugs, 19, 1039, 10.1517/13543784.2010.513381 Mroz, 2019, Optimized GIP analogs promote body weight lowering in mice through GIPR agonism not antagonism, Molecular Metabolism, 20, 51, 10.1016/j.molmet.2018.12.001 Killion, 2018, Anti-obesity effects of GIPR antagonists alone and in combination with GLP-1R agonists in preclinical models, Science Translational Medicine, 10, 10.1126/scitranslmed.aat3392 Pathak, 2015, Antagonism of gastric inhibitory polypeptide (GIP) by palmitoylation of GIP analogues with N- and C-terminal modifications improves obesity and metabolic control in high fat fed mice, Molecular and Cellular Endocrinology, 401, 120, 10.1016/j.mce.2014.10.025 Norregaard, 2018, A novel GIP analogue, ZP4165, enhances glucagon-like peptide-1-induced body weight loss and improves glycaemic control in rodents, Diabetes Obesity and Metabolism, 20, 60, 10.1111/dom.13034 Irwin, 2015, New perspectives on exploitation of incretin peptides for the treatment of diabetes and related disorders, World Journal of Diabetes, 6, 1285, 10.4239/wjd.v6.i15.1285 Pathak, 2018, Novel dual incretin agonist peptide with antidiabetic and neuroprotective potential, Biochemical Pharmacology, 155, 264, 10.1016/j.bcp.2018.07.021 Coskun, 2018, LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept, Molecular Metabolism, 18, 3, 10.1016/j.molmet.2018.09.009 Frias, 2018, 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, 10.1016/S0140-6736(18)32260-8 Cassidy, 2008, Effects of gastric inhibitory polypeptide (GIP) and related analogues on glucagon release at normo- and hyperglycaemia in Wistar rats and isolated islets, Biological Chemistry, 389, 189, 10.1515/BC.2008.019 Gault, 2013, A novel glucagon-like peptide-1 (GLP-1)/glucagon hybrid peptide with triple-acting agonist activity at glucose-dependent insulinotropic polypeptide, GLP-1, and glucagon receptors and therapeutic potential in high fat-fed mice, Journal of Biological Chemistry, 288, 35581, 10.1074/jbc.M113.512046 Fosgerau, 2013, The novel GLP-1-gastrin dual agonist, ZP3022, increases beta-cell mass and prevents diabetes in db/db mice, Diabetes Obesity and Metabolism, 15, 62, 10.1111/j.1463-1326.2012.01676.x Hasib, 2019, Exendin-4(Lys(27) PAL)/gastrin/xenin-8-Gln: A novel acylated GLP-1/gastrin/xenin hybrid peptide that improves metabolic status in obese-diabetic (ob/ob) mice, Diabetes Metabolism in Research Review, 35, e3106, 10.1002/dmrr.3106 Hasib, 2018, Characterisation and antidiabetic utility of a novel hybrid peptide, exendin-4/gastrin/xenin-8-Gln, European Journal of Pharmacology, 834, 126, 10.1016/j.ejphar.2018.07.027 Trevaskis, 2013, Improved glucose control and reduced body weight in rodents with dual mechanism of action peptide hybrids, PLoS One, 8, 10.1371/journal.pone.0078154 Hornigold, 2018, A GLP-1:CCK fusion peptide harnesses the synergistic effects on metabolism of CCK-1 and GLP-1 receptor agonism in mice, Appetite, 127, 334, 10.1016/j.appet.2018.05.131 Irwin, 2015, A Novel CCK-8/GLP-1 hybrid peptide exhibiting prominent insulinotropic, glucose-lowering, and satiety actions with significant therapeutic potential in high-fat-fed mice, Diabetes, 64, 2996, 10.2337/db15-0220 Talukdar, 2016, A long-acting FGF21 molecule, PF-05231023, decreases body weight and improves lipid profile in non-human primates and type 2 diabetic subjects, Cell Metabolism, 23, 427, 10.1016/j.cmet.2016.02.001 Chodorge, 2018, Engineering of a GLP-1 analogue peptide/anti-PCSK9 antibody fusion for type 2 diabetes treatment, Scientific Reports, 8, 17545, 10.1038/s41598-018-35869-4 Jain, 2019, Randomised, phase 1, dose-finding study of MEDI4166, a PCSK9 antibody and GLP-1 analogue fusion molecule, in overweight or obese patients with type 2 diabetes mellitus, Diabetologia, 62, 373, 10.1007/s00125-018-4789-6 Ammala, 2018, Targeted delivery of antisense oligonucleotides to pancreatic beta-cells, Science Advances, 4, eaat3386, 10.1126/sciadv.aat3386 Schwenk, 2015, GLP-1-oestrogen attenuates hyperphagia and protects from beta cell failure in diabetes-prone New Zealand obese (NZO) mice, Diabetologia, 58, 604, 10.1007/s00125-014-3478-3 Tiano, 2015, Effect of targeted estrogen delivery using glucagon-like peptide-1 on insulin secretion, insulin sensitivity and glucose homeostasis, Scientific Reports, 5, 10211, 10.1038/srep10211