{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T00:21:20Z","timestamp":1790295680122,"version":"4.1.0"},"reference-count":141,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T00:00:00Z","timestamp":1630454400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Type 2 Diabetes Mellitus (T2DM) is one of the most prevalent chronic metabolic disorders, and insulin has been placed at the epicentre of its pathophysiological basis. However, the involvement of impaired alpha (\u03b1) cell function has been recognized as playing an essential role in several diseases, since hyperglucagonemia has been evidenced in both Type 1 and T2DM. This phenomenon has been attributed to intra-islet defects, like modifications in pancreatic \u03b1 cell mass or dysfunction in glucagon\u2019s secretion. Emerging evidence has shown that chronic hyperglycaemia provokes changes in the Langerhans\u2019 islets cytoarchitecture, including \u03b1 cell hyperplasia, pancreatic beta (\u03b2) cell dedifferentiation into glucagon-positive producing cells, and loss of paracrine and endocrine regulation due to \u03b2 cell mass loss. Other abnormalities like \u03b1 cell insulin resistance, sensor machinery dysfunction, or paradoxical ATP-sensitive potassium channels (KATP) opening have also been linked to glucagon hypersecretion. Recent clinical trials in phases 1 or 2 have shown new molecules with glucagon-antagonist properties with considerable effectiveness and acceptable safety profiles. Glucagon-like peptide-1 (GLP-1) agonists and Dipeptidyl Peptidase-4 inhibitors (DPP-4 inhibitors) have been shown to decrease glucagon secretion in T2DM, and their possible therapeutic role in T1DM means they are attractive as an insulin-adjuvant therapy.<\/jats:p>","DOI":"10.3390\/ijms22179504","type":"journal-article","created":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T11:39:03Z","timestamp":1630496343000},"page":"9504","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["The Role of the \u03b1 Cell in the Pathogenesis of Diabetes: A World beyond the Mirror"],"prefix":"10.3390","volume":"22","author":[{"given":"Mar\u00eda Sof\u00eda","family":"Mart\u00ednez","sequence":"first","affiliation":[{"name":"MedStar Health Internal Medicine, Georgetown University Affiliated, Baltimore, MD 21218-2829, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6652-8834","authenticated-orcid":false,"given":"Alexander","family":"Manzano","sequence":"additional","affiliation":[{"name":"Endocrine and Metabolic Diseases Research Center, School of Medicine, Universidad del Zulia, Maracaibo 4002, Venezuela"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9325-6376","authenticated-orcid":false,"given":"Luis Carlos","family":"Olivar","sequence":"additional","affiliation":[{"name":"Endocrine and Metabolic Diseases Research Center, School of Medicine, Universidad del Zulia, Maracaibo 4002, Venezuela"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9769-1693","authenticated-orcid":false,"given":"Manuel","family":"Nava","sequence":"additional","affiliation":[{"name":"Endocrine and Metabolic Diseases Research Center, School of Medicine, Universidad del Zulia, Maracaibo 4002, Venezuela"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Salazar","sequence":"additional","affiliation":[{"name":"Endocrine and Metabolic Diseases Research Center, School of Medicine, Universidad del Zulia, Maracaibo 4002, Venezuela"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0148-891X","authenticated-orcid":false,"given":"Luis","family":"D\u2019Marco","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Hospital Clinico Universitario de Valencia, INCLIVA, University of Valencia, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rina","family":"Ortiz","sequence":"additional","affiliation":[{"name":"Facultad de Medicina, Universidad Cat\u00f3lica de Cuenca, Ciudad de Cuenca, Azuay 010105, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maricarmen","family":"Chac\u00edn","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias de la Salud, Universidad Sim\u00f3n Bol\u00edvar, Barranquilla 080022, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion","family":"Guerrero-Wyss","sequence":"additional","affiliation":[{"name":"Escuela de Nutrici\u00f3n y Diet\u00e9tica, Facultad de Ciencias Para el Cuidado de la Salud, Universidad San Sebasti\u00e1n, Valdivia 5090000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayela","family":"Cabrera de Bravo","sequence":"additional","affiliation":[{"name":"City of Houston Health Department, Houston, TX 77054, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cl\u00edmaco","family":"Cano","sequence":"additional","affiliation":[{"name":"Endocrine and Metabolic Diseases Research Center, School of Medicine, Universidad del Zulia, Maracaibo 4002, Venezuela"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1880-8887","authenticated-orcid":false,"given":"Valmore","family":"Berm\u00fadez","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias de la Salud, Universidad Sim\u00f3n Bol\u00edvar, Barranquilla 080022, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7860-5112","authenticated-orcid":false,"given":"Lisse","family":"Angarita","sequence":"additional","affiliation":[{"name":"Escuela de Nutrici\u00f3n y Diet\u00e9tica, Facultad de Medicina, Universidad Andres Bello, Sede Concepci\u00f3n 4260000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,1]]},"reference":[{"key":"ref_1","unstructured":"(2021, March 21). Noncommunicable Diseases Progress Monitor 2017. Available online: https:\/\/www.who.int\/publications-detail-redirect\/9789241513029."},{"key":"ref_2","unstructured":"(2021, March 21). IDF Diabetes Atlas 9th Edition 2019. Available online: https:\/\/www.diabetesatlas.org\/en\/."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1007\/s11886-016-0755-4","article-title":"Genetics of Insulin Resistance and the Metabolic Syndrome","volume":"18","author":"Brown","year":"2016","journal-title":"Curr. Cardiol. Rep."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2133","DOI":"10.1152\/physrev.00063.2017","article-title":"Mechanisms of Insulin Action and Insulin Resistance","volume":"98","author":"Petersen","year":"2018","journal-title":"Physiol. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Cantley, J., and Ashcroft, F.M. (2015). Q&A: Insulin secretion and type 2 diabetes: Why do \u03b2-cells fail?. BMC Biol., 13.","DOI":"10.1186\/s12915-015-0140-6"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/S0140-6736(75)92375-2","article-title":"The essential role of glucagon in the pathogenesis of diabetes mellitus","volume":"305","author":"Unger","year":"1975","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1210\/jcem-64-1-106","article-title":"Documentation of hyperglucagonemia throughout the day in nonobese and obese patients with noninsulin-dependent diabetes mellitus","volume":"64","author":"Reaven","year":"1987","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"28","DOI":"10.2174\/1874104501408010028","article-title":"Recent Progress in the Use of Glucagon and Glucagon Receptor Antagonists in the Treatment of Diabetes Mellitus","volume":"8","author":"Lotfy","year":"2014","journal-title":"Open Med. Chem. J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1152\/physrev.00013.2014","article-title":"Physiology of proglucagon peptides: Role of glucagon and GLP-1 in health and disease","volume":"95","author":"Sandoval","year":"2015","journal-title":"Physiol. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.semcdb.2020.01.006","article-title":"Pancreatic \u03b1-cells\u2014The unsung heroes in islet function","volume":"103","author":"Wendt","year":"2020","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1111\/j.1463-1326.2011.01440.x","article-title":"Transcriptional regulation of \u03b1-cell differentiation","volume":"13","author":"Bramswig","year":"2011","journal-title":"Diabetes Obes. Metab."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1016\/j.cmet.2019.09.013","article-title":"The Long Noncoding RNA Paupar Modulates PAX6 Regulatory Activities to Promote Alpha Cell Development and Function","volume":"30","author":"Singer","year":"2019","journal-title":"Cell Metab."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1016\/S0140-6736(75)92078-4","article-title":"Functional subdivision of islets of Langerhans and possible role of D cells","volume":"2","author":"Orci","year":"1975","journal-title":"Lancet"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.2337\/db09-1177","article-title":"Unique arrangement of alpha- and beta-cells in human islets of Langerhans","volume":"59","author":"Bosco","year":"2010","journal-title":"Diabetes"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2218","DOI":"10.1007\/s00125-015-3699-0","article-title":"New insights into the architecture of the islet of Langerhans: A focused cross-species assessment","volume":"58","author":"Ali","year":"2015","journal-title":"Diabetologia"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1896","DOI":"10.1038\/s41467-020-15717-8","article-title":"Paracrine control of \u03b1-cell glucagon exocytosis is compromised in human type-2 diabetes","volume":"11","author":"Lund","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1210\/er.2006-0007","article-title":"Alpha-cells of the endocrine pancreas: 35 years of research but the enigma remains","volume":"28","author":"Gromada","year":"2007","journal-title":"Endocr. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"E597","DOI":"10.1152\/ajpendo.00415.2015","article-title":"Paracrine regulation of glucagon secretion: The \u03b2\/\u03b1\/\u03b4 model","volume":"310","author":"Watts","year":"2016","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"120","DOI":"10.3109\/03009734.2016.1154905","article-title":"Glucose control of glucagon secretion\u2014\u2018There\u2019s a brand-new gimmick every year\u2019","volume":"121","author":"Gylfe","year":"2016","journal-title":"Ups. J. Med. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/j.cmet.2018.01.015","article-title":"Paracrine Interactions within the Pancreatic Islet Determine the Glycemic Set Point","volume":"27","author":"Molano","year":"2018","journal-title":"Cell Metab."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.semcdb.2012.09.007","article-title":"Paracrine and autocrine interactions in the human islet: More than meets the eye","volume":"24","author":"Caicedo","year":"2013","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/j.cmet.2009.02.007","article-title":"Insulin signaling in alpha cells modulates glucagon secretion in vivo","volume":"9","author":"Kawamori","year":"2009","journal-title":"Cell Metab."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1111\/j.1463-1326.2011.01442.x","article-title":"Growth factor signalling in the regulation of \u03b1-cell fate","volume":"13","author":"Kawamori","year":"2011","journal-title":"Diabetes Obes. Metab."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"E130","DOI":"10.1152\/ajpendo.00344.2014","article-title":"Somatostatin and insulin mediate glucose-inhibited glucagon secretion in the pancreatic \u03b1-cell by lowering cAMP","volume":"308","author":"Elliott","year":"2015","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1126\/science.6126003","article-title":"Quantitative electron microscopic autoradiography of insulin, glucagon, and somatostatin binding sites on islets","volume":"217","author":"Patel","year":"1982","journal-title":"Science"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1535","DOI":"10.2337\/db10-1087","article-title":"Glucose- and hormone-induced cAMP oscillations in \u03b1- and \u03b2-cells within intact pancreatic islets","volume":"60","author":"Tian","year":"2011","journal-title":"Diabetes"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2155","DOI":"10.1210\/en.2005-1249","article-title":"Insulin regulates islet alpha-cell function by reducing KATP channel sensitivity to adenosine 5\u2032-triphosphate inhibition","volume":"147","author":"Leung","year":"2006","journal-title":"Endocrinology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.cmet.2005.11.015","article-title":"Intra-islet insulin suppresses glucagon release via GABA-GABAA receptor system","volume":"3","author":"Xu","year":"2006","journal-title":"Cell Metab."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4197","DOI":"10.2337\/db14-0153","article-title":"GABA promotes human \u03b2-cell proliferation and modulates glucose homeostasis","volume":"63","author":"Purwana","year":"2014","journal-title":"Diabetes"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1007\/s00125-017-4239-x","article-title":"Paracrine GABA and insulin regulate pancreatic alpha cell proliferation in a mouse model of type 1 diabetes","volume":"60","author":"Feng","year":"2017","journal-title":"Diabetologia"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Katsura, T., Kawamori, D., Aida, E., Matsuoka, T.-A., and Shimomura, I. (2017). Glucotoxicity induces abnormal glucagon secretion through impaired insulin signaling in InR1G cells. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0176271"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3760","DOI":"10.2337\/db13-0931","article-title":"\u03b3-Aminobutyric acid regulates both the survival and replication of human \u03b2-cells","volume":"62","author":"Tian","year":"2013","journal-title":"Diabetes"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3172","DOI":"10.2337\/db15-0039","article-title":"Novel Observations From Next-Generation RNA Sequencing of Highly Purified Human Adult and Fetal Islet Cell Subsets","volume":"64","author":"Blodgett","year":"2015","journal-title":"Diabetes"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3379","DOI":"10.1096\/fj.14-265918","article-title":"Submembrane ATP and Ca2+ kinetics in \u03b1-cells: Unexpected signaling for glucagon secretion","volume":"29","author":"Li","year":"2015","journal-title":"FASEB J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3281","DOI":"10.1016\/j.celrep.2016.11.072","article-title":"Human Beta Cells Produce and Release Serotonin to Inhibit Glucagon Secretion from Alpha Cells","volume":"17","author":"Molina","year":"2016","journal-title":"Cell Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1111\/dom.12993","article-title":"cAMP signalling in insulin and glucagon secretion","volume":"19","author":"Tengholm","year":"2017","journal-title":"Diabetes Obes. Metab."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"E1107","DOI":"10.1152\/ajpendo.00207.2012","article-title":"SSTR2 is the functionally dominant somatostatin receptor in human pancreatic \u03b2- and \u03b1-cells","volume":"303","author":"Kailey","year":"2012","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1113\/JP274581","article-title":"\u03b4-cells and \u03b2-cells are electrically coupled and regulate \u03b1-cell activity via somatostatin","volume":"596","author":"Briant","year":"2018","journal-title":"J. Physiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.molmet.2018.01.016","article-title":"TALK-1 reduces delta-cell endoplasmic reticulum and cytoplasmic calcium levels limiting somatostatin secretion","volume":"9","author":"Vierra","year":"2018","journal-title":"Mol. Metab."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"20925","DOI":"10.1073\/pnas.1212870110","article-title":"Glucagon regulates its own synthesis by autocrine signaling","volume":"109","author":"Leibiger","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1124\/jpet.108.147009","article-title":"Fully human monoclonal antibodies antagonizing the glucagon receptor improve glucose homeostasis in mice and monkeys","volume":"329","author":"Yan","year":"2009","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1042\/CS20070040","article-title":"Targeting glucagon receptor signalling in treating metabolic syndrome and renal injury in Type 2 diabetes: Theory versus promise","volume":"113","author":"Li","year":"2007","journal-title":"Clin. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2018","DOI":"10.1007\/s001250100006","article-title":"Effects of a novel glucagon receptor antagonist (Bay 27-9955) on glucagon-stimulated glucose production in humans","volume":"44","author":"Petersen","year":"2001","journal-title":"Diabetologia"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1210\/me.2004-0059","article-title":"Glucagon stimulates exocytosis in mouse and rat pancreatic alpha-cells by binding to glucagon receptors","volume":"19","author":"Ma","year":"2005","journal-title":"Mol. Endocrinol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Liu, Z., Kim, W., Chen, Z., Shin, Y.-K., Carlson, O.D., Fiori, J.L., Xin, L., Napora, J.K., Short, R., and Odetunde, J.O. (2011). Insulin and glucagon regulate pancreatic \u03b1-cell proliferation. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0016096"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3725","DOI":"10.1038\/s41598-018-21751-w","article-title":"Pancreatic alpha cells in diabetic rats express active GLP-1 receptor: Endosomal co-localization of GLP-1\/GLP-1R complex functioning through intra-islet paracrine mechanism","volume":"8","author":"Nakashima","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1016\/j.cmet.2008.03.004","article-title":"Glutamate is a positive autocrine signal for glucagon release","volume":"7","author":"Cabrera","year":"2008","journal-title":"Cell Metab."},{"key":"ref_48","first-page":"485","article-title":"Intra-islet glucagon secretion and action in the regulation of glucose homeostasis","volume":"3","author":"Wang","year":"2012","journal-title":"Front. Physiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"552","DOI":"10.5483\/BMBRep.2014.47.10.216","article-title":"Type 3 muscarinic acetylcholine receptor stimulation is a determinant of endothelial barrier function and adherens junctions integrity: Role of protein-tyrosine phosphatase 1B","volume":"47","author":"Jiao","year":"2014","journal-title":"BMB Rep."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3413","DOI":"10.1113\/jphysiol.2013.269910","article-title":"Neurotransmitters act as paracrine signals to regulate insulin secretion from the human pancreatic islet","volume":"592","author":"Menegaz","year":"2014","journal-title":"J. Physiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3839","DOI":"10.2337\/db15-0488","article-title":"EphA4 Receptor Forward Signaling Inhibits Glucagon Secretion From \u03b1-Cells","volume":"64","author":"Hutchens","year":"2015","journal-title":"Diabetes"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.ebiom.2019.11.018","article-title":"Abnormal regulation of glucagon secretion by human islet alpha cells in the absence of beta cells","volume":"50","author":"Liu","year":"2019","journal-title":"EBioMedicine"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"960","DOI":"10.2337\/db16-1291","article-title":"Reestablishment of Glucose Inhibition of Glucagon Secretion in Small Pseudoislets","volume":"66","author":"Reissaus","year":"2017","journal-title":"Diabetes"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1038\/nrm.2015.16","article-title":"Mechanisms of ephrin\u2013Eph signalling in development, physiology and disease","volume":"17","author":"Kania","year":"2016","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.3389\/fimmu.2019.01473","article-title":"Emerging Roles for Eph Receptors and Ephrin Ligands in Immunity","volume":"10","author":"Darling","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1016\/j.jmb.2020.01.004","article-title":"The Role of \u03b1-Cells in Islet Function and Glucose Homeostasis in Health and Type 2 Diabetes","volume":"432","author":"Gilon","year":"2020","journal-title":"J. Mol. Biol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1111\/dom.13381","article-title":"Regulation of islet glucagon secretion: Beyond calcium","volume":"20","author":"Hughes","year":"2018","journal-title":"Diabetes Obes. Metab."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"248a","DOI":"10.1016\/j.bpj.2019.11.1454","article-title":"RhoA Mediated Juxtacrine Regulation of Glucagon Secretion","volume":"118","author":"Chung","year":"2020","journal-title":"Biophys. J."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1002\/bdrc.21064","article-title":"Role of cilia in normal pancreas function and in diseased states","volume":"102","author":"DiIorio","year":"2014","journal-title":"Birth Defects Res. C Embryo Today"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1002\/bdrc.21063","article-title":"Primary cilia in pancreatic development and disease","volume":"102","author":"Lodh","year":"2014","journal-title":"Birth Defects Res. C Embryo Today"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"5308","DOI":"10.1038\/ncomms6308","article-title":"Ciliary dysfunction impairs beta-cell insulin secretion and promotes development of type 2 diabetes in rodents","volume":"5","author":"Gerdes","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"9601801","DOI":"10.1155\/2018\/9601801","article-title":"Pancreatic Beta Cell Death: Novel Potential Mechanisms in Diabetes Therapy","volume":"2018","author":"Rojas","year":"2018","journal-title":"J. Diabetes Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1966","DOI":"10.2337\/dc13-2018","article-title":"Involvement of oxidative stress-induced DNA damage, endoplasmic reticulum stress, and autophagy deficits in the decline of \u03b2-cell mass in Japanese type 2 diabetic patients","volume":"37","author":"Mizukami","year":"2014","journal-title":"Diabetes Care"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"13163","DOI":"10.1073\/pnas.0801059105","article-title":"Interleukin-6 regulates pancreatic alpha-cell mass expansion","volume":"105","author":"Ellingsgaard","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"3067","DOI":"10.1210\/en.2008-0475","article-title":"Impaired insulin exocytosis in neural cell adhesion molecule\u2212\/\u2212 mice due to defective reorganization of the submembrane F-actin network","volume":"150","author":"Olofsson","year":"2009","journal-title":"Endocrinology"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1210\/jc.2010-2435","article-title":"Impaired regulation of the incretin effect in patients with type 2 diabetes","volume":"96","author":"Bagger","year":"2011","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Piro, S., Mascali, L.G., Urbano, F., Filippello, A., Malaguarnera, R., Calanna, S., Rabuazzo, A.M., and Purrello, F. (2014). Chronic exposure to GLP-1 increases GLP-1 synthesis and release in a pancreatic alpha cell line (\u03b1-TC1): Evidence of a direct effect of GLP-1 on pancreatic alpha cells. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0090093"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1111\/j.1463-1326.2011.01452.x","article-title":"Regulation of glucagon secretion by incretins","volume":"13","author":"Holst","year":"2011","journal-title":"Diabetes Obes. Metab."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1111\/dom.12879","article-title":"Immunohistochemical assessment of glucagon-like peptide 1 receptor (GLP-1R) expression in the pancreas of patients with type 2 diabetes","volume":"19","author":"Kirk","year":"2017","journal-title":"Diabetes Obes. Metab."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1007\/s00125-017-4315-2","article-title":"The role of somatostatin in GLP-1-induced inhibition of glucagon secretion in mice","volume":"60","author":"Holst","year":"2017","journal-title":"Diabetologia"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"e13852","DOI":"10.14814\/phy2.13852","article-title":"GLP-1 suppresses glucagon secretion in human pancreatic alpha-cells by inhibition of P\/Q-type Ca2+ channels","volume":"6","author":"Ramracheya","year":"2018","journal-title":"Physiol. Rep."},{"key":"ref_72","first-page":"45","article-title":"Pulsatile Secretion of Glucagon-Like Peptide-1(GLP-1) from Pancreatic Alpha Cells: Evidence for Independent Mechanism from Intestinal GLP-1 Secretion in Rodents","volume":"56","author":"Nakashima","year":"2013","journal-title":"Diabetologia"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"188","DOI":"10.4161\/isl.20500","article-title":"\u03b1-cell role in \u03b2-cell generation and regeneration","volume":"4","author":"Habener","year":"2012","journal-title":"Islets"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Patarr\u00e3o, R.S., Lautt, W.W., and Macedo, M.P. (2015). Acute glucagon induces postprandial peripheral insulin resistance. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0127221"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4093\/dmj.2015.39.1.1","article-title":"Pancreatic \u03b1-Cell Dysfunction in Type 2 Diabetes: Old Kids on the Block","volume":"39","author":"Moon","year":"2015","journal-title":"Diabetes Metab. J."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1111\/j.1463-1326.2011.01449.x","article-title":"The role of dysregulated glucagon secretion in type 2 diabetes","volume":"13","year":"2011","journal-title":"Diabetes Obes. Metab."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"644826","DOI":"10.3389\/fendo.2021.644826","article-title":"Pancreas Optical Clearing and 3-D Microscopy in Health and Diabetes","volume":"12","author":"Tang","year":"2021","journal-title":"Front. Endocrinol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"e2894","DOI":"10.1002\/dmrr.2894","article-title":"Ultrastructural alterations of pancreatic beta cells in human diabetes mellitus","volume":"33","author":"Masini","year":"2017","journal-title":"Diabetes Metab. Res. Rev."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1007\/7651_2015_287","article-title":"Histology of Type 1 Diabetes Pancreas","volume":"Volume 1433","author":"Gillespie","year":"2015","journal-title":"Type-1 Diabetes"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"602519","DOI":"10.3389\/fendo.2020.602519","article-title":"Functional Characterization of the Human Islet Microvasculature Using Living Pancreas Slices","volume":"11","year":"2021","journal-title":"Front. Endocrinol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1007\/s00125-014-3242-8","article-title":"IL-6-dependent proliferation of alpha cells in mice with partial pancreatic-duct ligation","volume":"57","author":"Cai","year":"2014","journal-title":"Diabetologia"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"674","DOI":"10.2337\/db17-1114","article-title":"Highly Proliferative \u03b1-Cell-Related Islet Endocrine Cells in Human Pancreata","volume":"67","author":"Lam","year":"2018","journal-title":"Diabetes"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1111\/jdi.12862","article-title":"Dysregulated plasma glucagon levels in Japanese young adult type 1 diabetes patients","volume":"10","author":"Kawamori","year":"2019","journal-title":"J. Diabetes Investig."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"45","DOI":"10.15277\/bjdvd.2014.014","article-title":"Alpha cell function in type 1 diabetes","volume":"14","author":"Hughes","year":"2014","journal-title":"Br. J. Diabetes"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"13972","DOI":"10.1038\/s41598-018-32351-z","article-title":"SIRT1 activation attenuates \u03b1 cell hyperplasia, hyperglucagonaemia and hyperglycaemia in STZ-diabetic mice","volume":"8","author":"Zhang","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"737586","DOI":"10.1155\/2015\/737586","article-title":"Moderate Intensity Training Impact on the Inflammatory Status and Glycemic Profiles in NOD Mice","volume":"2015","author":"Codella","year":"2015","journal-title":"J. Diabetes Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"4639","DOI":"10.1038\/ncomms5639","article-title":"Reversible changes in pancreatic islet structure and function produced by elevated blood glucose","volume":"5","author":"Brereton","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.stem.2014.11.001","article-title":"Plasticity and dedifferentiation within the pancreas: Development, homeostasis, and disease","volume":"16","author":"Puri","year":"2015","journal-title":"Cell Stem Cell"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"489","DOI":"10.5966\/sctm.2013-0078","article-title":"Prospectively isolated NGN3-expressing progenitors from human embryonic stem cells give rise to pancreatic endocrine cells","volume":"3","author":"Cai","year":"2014","journal-title":"Stem Cells Transl. Med."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1007\/s00125-011-2344-9","article-title":"Immunohistochemical characterisation of cells co-producing insulin and glucagon in the developing human pancreas","volume":"55","author":"Riedel","year":"2012","journal-title":"Diabetologia"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"2471","DOI":"10.2337\/db12-1001","article-title":"Conversion of mature human \u03b2-cells into glucagon-producing \u03b1-cells","volume":"62","author":"Spijker","year":"2013","journal-title":"Diabetes"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"2928","DOI":"10.2337\/db14-1752","article-title":"Loss of \u03b2-Cell Identity Occurs in Type 2 Diabetes and Is Associated with Islet Amyloid Deposits","volume":"64","author":"Spijker","year":"2015","journal-title":"Diabetes"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1111\/jdi.12841","article-title":"Human pancreatic \u03b1- to \u03b2-cell area ratio increases after type 2 diabetes onset","volume":"9","author":"Fujita","year":"2018","journal-title":"J. Diabetes Investig."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1016\/j.cell.2012.07.029","article-title":"Pancreatic \u03b2 Cell Dedifferentiation as a Mechanism of Diabetic \u03b2 Cell Failure","volume":"150","author":"Talchai","year":"2012","journal-title":"Cell"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1016\/j.cmet.2014.03.010","article-title":"Pancreatic \u03b2 cell dedifferentiation in diabetes and redifferentiation following insulin therapy","volume":"19","author":"Wang","year":"2014","journal-title":"Cell Metab."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"6285","DOI":"10.1038\/s41598-017-06731-w","article-title":"The Role of Inflammation in \u03b2-cell Dedifferentiation","volume":"7","author":"Nordmann","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1186\/s13287-017-0694-z","article-title":"PDX1, Neurogenin-3, and MAFA: Critical transcription regulators for beta cell development and regeneration","volume":"8","author":"Zhu","year":"2017","journal-title":"Stem Cell Res. Ther."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1210\/jc.2015-2860","article-title":"Evidence of \u03b2-Cell Dedifferentiation in Human Type 2 Diabetes","volume":"101","author":"Cinti","year":"2016","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"12631","DOI":"10.1038\/ncomms12631","article-title":"Aldehyde dehydrogenase 1a3 defines a subset of failing pancreatic \u03b2 cells in diabetic mice","volume":"7","author":"Fan","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.cmet.2013.12.002","article-title":"Pdx1 maintains \u03b2 cell identity and function by repressing an \u03b1 cell program","volume":"19","author":"Gao","year":"2014","journal-title":"Cell Metab."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.molmet.2018.05.019","article-title":"Secretagogin protects Pdx1 from proteasomal degradation to control a transcriptional program required for \u03b2 cell specification","volume":"14","author":"Malenczyk","year":"2018","journal-title":"Mol. Metab."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"21","DOI":"10.3389\/fgene.2017.00021","article-title":"Metabolic Stress and Compromised Identity of Pancreatic Beta Cells","volume":"8","author":"Swisa","year":"2017","journal-title":"Front. Genet."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"2874","DOI":"10.1210\/jc.2016-1374","article-title":"Effects of Obesity and Diabetes on \u03b1- and \u03b2-Cell Mass in Surgically Resected Human Pancreas","volume":"101","author":"Inaishi","year":"2016","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"6864","DOI":"10.1038\/s41598-018-25126-z","article-title":"Effect of the sodium-glucose cotransporter 2 inhibitor luseogliflozin on pancreatic beta cell mass in db\/db mice of different ages","volume":"8","author":"Takahashi","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"2092","DOI":"10.2337\/db16-1213","article-title":"Pair Feeding, but Not Insulin, Phloridzin, or Rosiglitazone Treatment, Curtails Markers of \u03b2-Cell Dedifferentiation in db\/db Mice","volume":"66","author":"Ishida","year":"2017","journal-title":"Diabetes"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.2337\/db17-1102","article-title":"Adrenaline Stimulates Glucagon Secretion by Tpc2-Dependent Ca2+ Mobilization from Acidic Stores in Pancreatic \u03b1-Cells","volume":"67","author":"Hamilton","year":"2018","journal-title":"Diabetes"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1016\/j.cmet.2013.10.014","article-title":"Role of KATP channels in glucose-regulated glucagon secretion and impaired counterregulation in type 2 diabetes","volume":"18","author":"Zhang","year":"2013","journal-title":"Cell Metab."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1016\/j.cmet.2018.10.003","article-title":"Dysregulation of Glucagon Secretion by Hyperglycemia-Induced Sodium-Dependent Reduction of ATP Production","volume":"29","author":"Knudsen","year":"2019","journal-title":"Cell Metab."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"3135","DOI":"10.1016\/j.celrep.2017.08.093","article-title":"Fumarate Hydratase Deletion in Pancreatic \u03b2 Cells Leads to Progressive Diabetes","volume":"20","author":"Adam","year":"2017","journal-title":"Cell Rep."},{"key":"ref_110","first-page":"1800","article-title":"Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes","volume":"375","author":"Pareek","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"2117","DOI":"10.1056\/NEJMoa1504720","article-title":"Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes","volume":"373","author":"Zinman","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1038\/s41467-018-03034-0","article-title":"\u03b1-cell glucokinase suppresses glucose-regulated glucagon secretion","volume":"9","author":"Basco","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_113","first-page":"1","article-title":"Effects of a Novel Glucokinase Activator, HMS5552, on Glucose Metabolism in a Rat Model of Type 2 Diabetes Mellitus","volume":"2017","author":"Wang","year":"2017","journal-title":"J. Diabetes Res."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1080\/13543784.2017.1395020","article-title":"Investigational glucagon receptor antagonists in Phase I and II clinical trials for diabetes","volume":"26","author":"Scheen","year":"2017","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"2183","DOI":"10.1194\/jlr.M060897","article-title":"Glucagon receptor antagonism induces increased cholesterol absorption","volume":"56","author":"Guan","year":"2015","journal-title":"J. Lipid Res."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1111\/dom.12958","article-title":"Treatment with LY2409021, a glucagon receptor antagonist, increases liver fat in patients with type 2 diabetes: Guzman et al","volume":"19","author":"Guzman","year":"2017","journal-title":"Diabetes Obes. Metab."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.2337\/dci15-0033","article-title":"Clinical Trials, Triumphs, and Tribulations of Glucagon Receptor Antagonists","volume":"39","author":"Pearson","year":"2016","journal-title":"Dia Care"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"585","DOI":"10.2337\/dc18-1343","article-title":"Antisense Inhibition of Glucagon Receptor by IONIS-GCGRRx Improves Type 2 Diabetes without Increase in Hepatic Glycogen Content in Patients with Type 2 Diabetes on Stable Metformin Therapy","volume":"42","author":"Morgan","year":"2019","journal-title":"Diabetes Care"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1016\/j.endonu.2012.06.006","article-title":"Glucagon receptor is required for long-term survival: A natural history study of the Mahvash disease in a murine model","volume":"59","author":"Yu","year":"2012","journal-title":"Endocrinol. Nutr."},{"key":"ref_120","first-page":"46","article-title":"The first pediatric case of glucagon receptor defect due to biallelic mutations in GCGR is identified by newborn screening of elevated arginine","volume":"17","author":"Li","year":"2018","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"3119","DOI":"10.1210\/jc.2018-01074","article-title":"Hypercalcemia in Glucagon Cell Hyperplasia and Neoplasia (Mahvash Syndrome): A New Association","volume":"103","author":"Gild","year":"2018","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"68","DOI":"10.3164\/jcbn.13-14","article-title":"Effects of liraglutide on postprandial insulin and glucagon responses in Japanese patients with type 2 diabetes","volume":"53","author":"Matsumoto","year":"2013","journal-title":"J. Clin. Biochem. Nutr."},{"key":"ref_123","first-page":"33","article-title":"Effect of liraglutide on glucagon secretion in obese type 2 diabetic patients","volume":"58","author":"Sun","year":"2019","journal-title":"Zhonghua Nei Ke Za Zhi"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"617","DOI":"10.2337\/dc15-2383","article-title":"GLP-1 Restores Altered Insulin and Glucagon Secretion in Posttransplantation Diabetes","volume":"39","author":"Halden","year":"2016","journal-title":"Diabetes Care"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1007\/s00125-012-2738-3","article-title":"Direct effect of GLP-1 infusion on endogenous glucose production in humans","volume":"56","author":"Seghieri","year":"2013","journal-title":"Diabetologia"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"1765","DOI":"10.2337\/db09-1414","article-title":"The Glucagonostatic and Insulinotropic Effects of Glucagon-Like Peptide 1 Contribute Equally to Its Glucose-Lowering Action","volume":"59","author":"Hare","year":"2010","journal-title":"Diabetes"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.2337\/dc15-1136","article-title":"Addition of Liraglutide to Insulin in Patients with Type 1 Diabetes: A Randomized Placebo-Controlled Clinical Trial of 12 Weeks","volume":"39","author":"Kuhadiya","year":"2016","journal-title":"Diabetes Care"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1210\/jc.2017-02265","article-title":"Pramlintide but Not Liraglutide Suppresses Meal-Stimulated Glucagon Responses in Type 1 Diabetes","volume":"103","author":"Galderisi","year":"2018","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1111\/dom.12473","article-title":"Counter-regulatory hormone responses to hypoglycaemia in people with type 1 diabetes after 4 weeks of treatment with liraglutide adjunct to insulin: A randomized, placebo-controlled, double-blind, crossover trial","volume":"17","author":"Pieber","year":"2015","journal-title":"Diabetes Obes. Metab."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"2818","DOI":"10.1210\/jc.2012-1205","article-title":"Mechanisms for the Antihyperglycemic Effect of Sitagliptin in Patients with Type 2 Diabetes","volume":"97","author":"Muscelli","year":"2012","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1530\/EJE-13-0639","article-title":"The effect of alogliptin and pioglitazone combination therapy on various aspects of \u03b2-cell function in patients with recent-onset type 2 diabetes","volume":"170","author":"Eliasson","year":"2014","journal-title":"Eur. J. Endocrinol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.4158\/EP14489.OR","article-title":"Postprandial Dynamics of Plasma Glucose, Insulin, and Glucagon in Patients with Type 2 Diabetes Treated with Saxagliptin Plus Dapagliflozin Add-On to Metformin Therapy","volume":"20","author":"Hansen","year":"2014","journal-title":"Endocr. Pract."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"2756","DOI":"10.2337\/dc12-2072","article-title":"Mechanisms of Glucose Lowering of Dipeptidyl Peptidase-4 Inhibitor Sitagliptin When Used Alone or with Metformin in Type 2 Diabetes: A double-tracer study","volume":"36","author":"Triplitt","year":"2013","journal-title":"Diabetes Care"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"730","DOI":"10.2337\/dc09-1867","article-title":"Changes in Prandial Glucagon Levels After a 2-Year Treatment with Vildagliptin or Glimepiride in Patients with Type 2 Diabetes Inadequately Controlled with Metformin Monotherapy","volume":"33","author":"Ahren","year":"2010","journal-title":"Diabetes Care"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1007\/s13300-017-0299-7","article-title":"Possible Long-Term Efficacy of Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor, for Slowly Progressive Type 1 Diabetes (SPIDDM) in the Stage of Non-Insulin-Dependency: An Open-Label Randomized Controlled Pilot Trial (SPAN-S)","volume":"8","author":"Awata","year":"2017","journal-title":"Diabetes Ther."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1177\/1932296817699847","article-title":"Use of Sitagliptin with Closed-Loop Technology to Decrease Postprandial Blood Glucose in Type 1 Diabetes","volume":"11","author":"Underland","year":"2017","journal-title":"J. Diabetes Sci. Technol."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"19","DOI":"10.4158\/EP12100.OR","article-title":"Effect of Sitagliptin on Post-Prandial Glucagon and GLP-1 Levels in Patients with Type 1 Diabetes: Investigator-Initiated, Double-Blind, Randomized, Placebo-Controlled Trial","volume":"19","author":"Garg","year":"2013","journal-title":"Endocr. Pract."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"2325","DOI":"10.1111\/bcp.13688","article-title":"MEDI0382, a GLP-1\/glucagon receptor dual agonist, meets safety and tolerability endpoints in a single-dose, healthy-subject, randomized, Phase 1 study: Single-dose MEDI0382 in healthy subjects","volume":"84","author":"Ambery","year":"2018","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"649","DOI":"10.3389\/fendo.2018.00649","article-title":"Future Perspectives on GLP-1 Receptor Agonists and GLP-1\/glucagon Receptor Co-agonists in the Treatment of NAFLD","volume":"9","author":"Seghieri","year":"2018","journal-title":"Front. Endocrinol."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"35","DOI":"10.2174\/1871525716666180118152158","article-title":"Coagonist of GLP-1 and Glucagon Receptor Ameliorates Development of Non-Alcoholic Fatty Liver Disease","volume":"16","author":"Patel","year":"2018","journal-title":"Cardiovasc. Hematol. Agents Med. Chem."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"1851","DOI":"10.1007\/s00125-017-4354-8","article-title":"GLP-1\/glucagon receptor co-agonism for treatment of obesity","volume":"60","author":"Brandt","year":"2017","journal-title":"Diabetologia"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/17\/9504\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:54:09Z","timestamp":1760165649000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/17\/9504"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,1]]},"references-count":141,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["ijms22179504"],"URL":"https:\/\/doi.org\/10.3390\/ijms22179504","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,1]]}}}