{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T05:56:44Z","timestamp":1788415004530,"version":"build-2803163510"},"reference-count":133,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2024,11,7]],"date-time":"2024-11-07T00:00:00Z","timestamp":1730937600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Recent clinical trials using synthetic incretin hormones, glucagon-like peptide 1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists have demonstrated that these treatments ameliorated many complications related to obesity, emphasizing the significant impact of body weight on overall health. Incretins are enteroendocrine hormones secreted by gut endothelial cells triggered by nutrient ingestion. The phenomenon that oral ingestion of glucose elicits a much higher insulin secretion than intra-venous injection of equimolar glucose is known as the incretin effect. This also alludes to the thesis that food intake is the root cause of insulin resistance. Synthetic GLP-1 and GIP agonists have demonstrated unprecedented glucoregulation and body weight reduction. Also, randomized trials have shown their ability to prevent complications of obesity, including development of diabetes from prediabetes, reducing cardiovascular disease risks and renal complications in diabetic patients. Moreover, the benefits of these agonists persist among the patients who are already on metformin or insulin. The ultimate question is \u201cAre these benefits of incretin agonism sustainable?\u201d Chronic agonism of pancreatic \u03b2-cells may decrease the number of receptors and cause \u03b2-cell exhaustion, leading to \u03b2-cell failure. Unfortunately, the long-term effects of these drugs are unknown at the present because the longest duration in randomized trials is 3 years. Additionally, manipulation of the neurohormonal axis to control satiety and food intake may hinder the long-term sustainability of these treatments. In this review, we will discuss the incretins\u2019 mechanism of action, challenges, and future directions. We will briefly review other molecules involved in glucose homeostasis such as amylin and glucagon. Amylin is co-expressed with insulin from the pancreas \u03b2-cells but does not have insulinotropic function. Amylin suppresses glucagon secretion, slowing gastric emptying and suppressing the reward center in the central nervous system, leading to weight loss. However, amylin can self-aggregate and cause serious cytotoxicity and may cause \u03b2-cell apoptosis. Glucagon is secreted by pancreatic \u03b1-cells and participates in glucose homeostasis in a glucose-dependent manner. In hypoglycemia, glucagon increases the blood glucose level by glycogenolysis and gluconeogenesis and inhibits glycogenesis in the liver. Several triple agonists, in combination with dual incretins and glucagon, are being developed.<\/jats:p>","DOI":"10.3390\/cells13221842","type":"journal-article","created":{"date-parts":[[2024,11,7]],"date-time":"2024-11-07T04:22:56Z","timestamp":1730953376000},"page":"1842","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Does Incretin Agonism Have Sustainable Efficacy?"],"prefix":"10.3390","volume":"13","author":[{"given":"Sok-Ja","family":"Janket","sequence":"first","affiliation":[{"name":"Retired Research Associate Professor, Boston University Goldman School of Dental Medicine, Boston, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5864-8315","authenticated-orcid":false,"given":"Miyo K.","family":"Chatanaka","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorsa","family":"Sohaei","sequence":"additional","affiliation":[{"name":"M.D., C.M. Candidate 2026, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H4A QT2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faleh","family":"Tamimi","sequence":"additional","affiliation":[{"name":"Department of Restorative Dentistry, College of Dental Medicine, Qatar University, Doha P.O. Box 2713, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6702-6836","authenticated-orcid":false,"given":"Jukka H.","family":"Meurman","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Diseases, Helsinki University Hospital and University of Helsinki, FI-00290 Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleftherios P.","family":"Diamandis","sequence":"additional","affiliation":[{"name":"Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5T 3L9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,7]]},"reference":[{"key":"ref_1","first-page":"620","article-title":"Sur les possibilities d\u2019un traitement du diabete par. L\u2019incretine","volume":"12","author":"Barre","year":"1932","journal-title":"Bull. Acad. R. Med. Belg."},{"key":"ref_2","unstructured":"Gupta, K., and Raja, A. (2024). Physiology, Gastric Inhibitory Peptide, StatPearls Publishing."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1409","DOI":"10.1152\/physrev.00034.2006","article-title":"The physiology of glucagon-like peptide 1","volume":"87","author":"Holst","year":"2007","journal-title":"Physiol. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1530\/JOE-15-0247","article-title":"GLP1- and GIP-producing cells rarely overlap and differ by bombesin receptor-2 expression and responsiveness","volume":"228","author":"Svendsen","year":"2016","journal-title":"J. Endocrinol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3501","DOI":"10.1111\/dom.15693","article-title":"Glucagon agonism in the treatment of metabolic diseases including type 2 diabetes mellitus and obesity","volume":"26","author":"Winther","year":"2024","journal-title":"Diabetes Obes. Metab."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1016\/j.cmet.2019.07.013","article-title":"Glucose-Dependent Insulinotropic Polypeptide Receptor-Expressing Cells in the Hypothalamus Regulate Food Intake","volume":"30","author":"Adriaenssens","year":"2019","journal-title":"Cell Metab."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2075","DOI":"10.1038\/s42255-023-00931-7","article-title":"Glucose-dependent insulinotropic polypeptide regulates body weight and food intake via GABAergic neurons in mice","volume":"5","author":"Liskiewicz","year":"2023","journal-title":"Nat. Metab."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1646","DOI":"10.1016\/j.cub.2024.02.074","article-title":"A brainstem to hypothalamic arcuate nucleus GABAergic circuit drives feeding","volume":"34","author":"Gonzalez","year":"2024","journal-title":"Curr. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"E614","DOI":"10.1152\/ajpendo.00639.2009","article-title":"On the role of glucose-dependent insulintropic polypeptide in postprandial metabolism in humans","volume":"298","author":"Asmar","year":"2010","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"E621","DOI":"10.1152\/ajpendo.00499.2003","article-title":"Gastric inhibitory polypeptide does not inhibit gastric emptying in humans","volume":"286","author":"Meier","year":"2004","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1007\/s00125-018-4810-0","article-title":"Effects of combined GIP and GLP-1 infusion on energy intake, appetite and energy expenditure in overweight\/obese individuals: A randomised, crossover study","volume":"62","author":"Bergmann","year":"2019","journal-title":"Diabetologia"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1414","DOI":"10.1001\/jama.2021.3224","article-title":"Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial","volume":"325","author":"Rubino","year":"2021","journal-title":"JAMA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1001\/jama.2021.23619","article-title":"Effect of Weekly Subcutaneous Semaglutide vs. Daily Liraglutide on Body Weight in Adults With Overweight or Obesity Without Diabetes: The STEP 8 Randomized Clinical Trial","volume":"327","author":"Rubino","year":"2022","journal-title":"JAMA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"765","DOI":"10.2337\/dc20-1473","article-title":"Efficacy and Safety of Dulaglutide 3.0 mg and 4.5 mg Versus Dulaglutide 1.5 mg in Metformin-Treated Patients With Type 2 Diabetes in a Randomized Controlled Trial (AWARD-11)","volume":"44","author":"Frias","year":"2021","journal-title":"Diabetes Care"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1016\/S0140-6736(17)30069-7","article-title":"3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: A randomised, double-blind trial","volume":"389","author":"Astrup","year":"2017","journal-title":"Lancet"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1056\/NEJMoa1901118","article-title":"Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes","volume":"381","author":"Husain","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1016\/S2213-8587(22)00243-1","article-title":"Effects of tirzepatide versus insulin glargine on kidney outcomes in type 2 diabetes in the SURPASS-4 trial: Post-hoc analysis of an open-label, randomised, phase 3 trial","volume":"10","author":"Heerspink","year":"2022","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1056\/NEJMoa2107519","article-title":"Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes","volume":"385","author":"Davies","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/S0140-6736(23)01053-X","article-title":"Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: A randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA","volume":"402","author":"Rosenstock","year":"2023","journal-title":"Lancet"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/S0140-6736(21)01324-6","article-title":"Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): A double-blind, randomised, phase 3 trial","volume":"398","author":"Rosenstock","year":"2021","journal-title":"Lancet"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1056\/NEJMoa2206038","article-title":"Tirzepatide Once Weekly for the Treatment of Obesity","volume":"387","author":"Jastreboff","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1056\/NEJMoa2301972","article-title":"Triple-Hormone-Receptor Agonist Retatrutide for Obesity\u2014A Phase 2 Trial","volume":"389","author":"Jastreboff","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1016\/S0140-6736(21)01443-4","article-title":"Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): A randomised, open-label, parallel-group, phase 3 trial","volume":"398","author":"Ludvik","year":"2021","journal-title":"Lancet"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1811","DOI":"10.1016\/S0140-6736(21)02188-7","article-title":"Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): A randomised, open-label, parallel-group, multicentre, phase 3 trial","volume":"398","author":"Kahn","year":"2021","journal-title":"Lancet"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1111\/dom.14725","article-title":"Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension","volume":"24","author":"Wilding","year":"2022","journal-title":"Diabetes Obes. Metab."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1001\/jama.2022.0078","article-title":"Effect of Subcutaneous Tirzepatide vs Placebo Added to Titrated Insulin Glargine on Glycemic Control in Patients With Type 2 Diabetes: The SURPASS-5 Randomized Clinical Trial","volume":"327","author":"Dahl","year":"2022","journal-title":"JAMA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2221","DOI":"10.1056\/NEJMoa2307563","article-title":"Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes","volume":"389","author":"Lincoff","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1001\/jama.2023.24945","article-title":"Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial","volume":"331","author":"Aronne","year":"2024","journal-title":"JAMA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1056\/NEJMoa2401943","article-title":"Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis","volume":"391","author":"Loomba","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1056\/NEJMoa2401755","article-title":"A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis","volume":"391","author":"Sanyal","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2037","DOI":"10.1038\/s41591-024-03018-2","article-title":"Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: A randomized phase 2a trial","volume":"30","author":"Sanyal","year":"2024","journal-title":"Nat. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1186\/s12933-023-01800-z","article-title":"Time-dependent effect of GLP-1 receptor agonists on cardiovascular benefits: A real-world study","volume":"22","author":"Piccini","year":"2023","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"897","DOI":"10.2337\/dbi19-0005","article-title":"GIP and GLP-1: Stepsiblings Rather Than Monozygotic Twins Within the Incretin Family","volume":"68","author":"Nauck","year":"2019","journal-title":"Diabetes"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1016\/S2213-8587(15)00482-9","article-title":"The incretin effect in healthy individuals and those with type 2 diabetes: Physiology, pathophysiology, and response to therapeutic interventions","volume":"4","author":"Nauck","year":"2016","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"170213","DOI":"10.1016\/j.peptides.2019.170213","article-title":"The role of GIP in \u03b1-cells and glucagon secretion","volume":"125","author":"El","year":"2020","journal-title":"Peptides"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3316","DOI":"10.2337\/db13-0822","article-title":"Incretin action in the pancreas: Potential promise, possible perils, and pathological pitfalls","volume":"62","author":"Drucker","year":"2013","journal-title":"Diabetes"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1886","DOI":"10.1111\/dom.14110","article-title":"The novel dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist tirzepatide transiently delays gastric emptying similarly to selective long-acting GLP-1 receptor agonists","volume":"22","author":"Urva","year":"2020","journal-title":"Diabetes Obes. Metab."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1956","DOI":"10.2337\/dbi21-0004","article-title":"The Role of GIP in the Regulation of GLP-1 Satiety and Nausea","volume":"70","author":"Hayes","year":"2021","journal-title":"Diabetes"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1146\/annurev-nutr-071812-161201","article-title":"Incretins and amylin: Neuroendocrine communication between the gut, pancreas, and brain in control of food intake and blood glucose","volume":"34","author":"Hayes","year":"2014","journal-title":"Annu. Rev. Nutr."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Kiriyama, Y., and Nochi, H. (2018). Role and Cytotoxicity of Amylin and Protection of Pancreatic Islet \u03b2-Cells from Amylin Cytotoxicity. Cells, 7.","DOI":"10.3390\/cells7080095"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1566","DOI":"10.1038\/oby.2012.67","article-title":"The glucagon receptor is involved in mediating the body weight-lowering effects of oxyntomodulin","volume":"20","author":"Kosinski","year":"2012","journal-title":"Obesity"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"R1","DOI":"10.1530\/JOE-16-0513","article-title":"Hepatic lipid accumulation: Cause and consequence of dysregulated glucoregulatory hormones","volume":"234","author":"Geisler","year":"2017","journal-title":"J. Endocrinol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"32246","DOI":"10.1038\/srep32246","article-title":"Glucagon regulates hepatic lipid metabolism via cAMP and Insig-2 signaling: Implication for the pathogenesis of hypertriglyceridemia and hepatic steatosis","volume":"6","author":"Wang","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3103","DOI":"10.2337\/db11-0979","article-title":"Glucose-dependent insulinotropic polypeptide: A bifunctional glucose-dependent regulator of glucagon and insulin secretion in humans","volume":"60","author":"Christensen","year":"2011","journal-title":"Diabetes"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"119s","DOI":"10.1177\/0022034515580795","article-title":"Oral Infections, Metabolic Inflammation, Genetics, and Cardiometabolic Diseases","volume":"94","author":"Janket","year":"2015","journal-title":"J. Dent. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"111663","DOI":"10.1016\/j.diabres.2024.111663","article-title":"Tissue-specific inflammation and insulin sensitivity in subjects with obesity","volume":"211","author":"Oussaada","year":"2024","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1111\/dom.14280","article-title":"The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity","volume":"23","author":"Friedrichsen","year":"2021","journal-title":"Diabetes Obes. Metab."},{"key":"ref_48","first-page":"327","article-title":"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","volume":"81","author":"Willms","year":"1996","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"407","DOI":"10.2337\/db13-1764","article-title":"Give the receptor a brake: Slowing gastric emptying by GLP-1","volume":"63","author":"Tong","year":"2014","journal-title":"Diabetes"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"5670","DOI":"10.1210\/en.2008-0336","article-title":"The glucagon-like peptide-1 receptor agonist oxyntomodulin enhances beta-cell function but does not inhibit gastric emptying in mice","volume":"149","author":"Maida","year":"2008","journal-title":"Endocrinology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1111\/dom.15325","article-title":"Impact on glycated haemoglobin and body weight changes after stopping tirzepatide for 4\u2009weeks in the SURPASS-1 monotherapy trial","volume":"26","author":"Rosenstock","year":"2024","journal-title":"Diabetes Obes. Metab."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"eaaw9996","DOI":"10.1126\/scitranslmed.aaw9996","article-title":"GLP-1 receptor agonists synergize with DYRK1A inhibitors to potentiate functional human \u03b2 cell regeneration","volume":"12","author":"Ackeifi","year":"2020","journal-title":"Sci. Transl. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e3168","DOI":"10.1002\/dmrr.3168","article-title":"Glucagon-like peptide-1 receptor agonists and risk of bone fracture in patients with type 2 diabetes: A meta-analysis of randomized controlled trials","volume":"35","author":"Cheng","year":"2019","journal-title":"Diabetes Metab. Res. Rev."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"e2416775","DOI":"10.1001\/jamanetworkopen.2024.16775","article-title":"Bone Health After Exercise Alone, GLP-1 Receptor Agonist Treatment, or Combination Treatment: A Secondary Analysis of a Randomized Clinical Trial","volume":"7","author":"Jensen","year":"2024","journal-title":"JAMA Netw. Open."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1111\/dom.12900","article-title":"Effect of exercise combined with glucagon-like peptide-1 receptor agonist treatment on cardiac function: A randomized double-blind placebo-controlled clinical trial","volume":"19","author":"Jensen","year":"2017","journal-title":"Diabetes Obes. Metab."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1210\/er.2006-0026","article-title":"The role of alpha-cell dysregulation in fasting and postprandial hyperglycemia in type 2 diabetes and therapeutic implications","volume":"28","author":"Dunning","year":"2007","journal-title":"Endocr. Rev."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1186\/s12933-018-0791-z","article-title":"Does glucagon have a positive inotropic effect in the human heart?","volume":"17","year":"2018","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1093\/cvr\/cvae150","article-title":"New insights into the effects of glucagon-like peptide-1 on heart rate and sinoatrial node function","volume":"120","author":"Kaur","year":"2024","journal-title":"Cardiovasc. Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1093\/cvr\/cvae120","article-title":"GLP-1 increases heart rate by a direct action on the sinus node","volume":"120","author":"Lubberding","year":"2024","journal-title":"Cardiovasc. Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e016828","DOI":"10.1161\/JAHA.120.016828","article-title":"High-Dose Glucagon Has Hemodynamic Effects Regardless of Cardiac Beta-Adrenoceptor Blockade: A Randomized Clinical Trial","volume":"9","author":"Petersen","year":"2020","journal-title":"J. Am. Heart Assoc."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1007\/s11606-021-07105-9","article-title":"The Longer-Term Benefits and Harms of Glucagon-Like Peptide-1 Receptor Agonists: A Systematic Review and Meta-Analysis","volume":"37","author":"Alexander","year":"2022","journal-title":"J. Gen. Intern. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.jdiacomp.2018.11.012","article-title":"Efficacy and tolerability of exenatide once weekly over 7 years in patients with type 2 diabetes: An open-label extension of the DURATION-1 study","volume":"33","author":"Wysham","year":"2019","journal-title":"J. Diabetes Complicat."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"e8668","DOI":"10.1136\/bmj.e8668","article-title":"Differential dropout and bias in randomised controlled trials: When it matters and when it may not","volume":"346","author":"Bell","year":"2013","journal-title":"BMJ"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"102661","DOI":"10.1016\/j.eclinm.2024.102661","article-title":"GLP-1 receptor agonists for weight reduction in people living with obesity but without diabetes: A living benefit-harm modelling study","volume":"73","author":"Moll","year":"2024","journal-title":"EClinicalMedicine"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1149328","DOI":"10.3389\/fendo.2023.1149328","article-title":"GLP-1RAs caused gastrointestinal adverse reactions of drug withdrawal: A system review and network meta-analysis","volume":"14","author":"Zhang","year":"2023","journal-title":"Front. Endocrinol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.cmet.2017.09.021","article-title":"Overlapping Brain Circuits for Homeostatic and Hedonic Feeding","volume":"27","author":"Rossi","year":"2018","journal-title":"Cell Metab."},{"key":"ref_67","first-page":"T1","article-title":"Effects of glucagon-like peptide 1 on appetite and body weight: Focus on the CNS","volume":"221","author":"Ijzerman","year":"2014","journal-title":"J. Endocrinol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"103","DOI":"10.3389\/fendo.2013.00103","article-title":"Glutamate and GABA in Appetite Regulation","volume":"4","author":"Delgado","year":"2013","journal-title":"Front. Endocrinol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"6449","DOI":"10.1523\/JNEUROSCI.3193-18.2019","article-title":"GABAergic Inputs to POMC Neurons Originating from the Dorsomedial Hypothalamus Are Regulated by Energy State","volume":"39","author":"Rau","year":"2019","journal-title":"J. Neurosci."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1146\/annurev-physiol-022516-034110","article-title":"POMC Neurons: From Birth to Death","volume":"79","author":"Toda","year":"2017","journal-title":"Annu. Rev. Physiol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1016\/j.neuron.2011.06.012","article-title":"Serotonin 2C receptor activates a distinct population of arcuate pro-opiomelanocortin neurons via TRPC channels","volume":"71","author":"Sohn","year":"2011","journal-title":"Neuron"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2472","DOI":"10.1523\/JNEUROSCI.3118-09.2010","article-title":"Segregation of acute leptin and insulin effects in distinct populations of arcuate proopiomelanocortin neurons","volume":"30","author":"Williams","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.neuron.2011.05.028","article-title":"Leptin action on GABAergic neurons prevents obesity and reduces inhibitory tone to POMC neurons","volume":"71","author":"Vong","year":"2011","journal-title":"Neuron"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"4473","DOI":"10.1172\/JCI75276","article-title":"The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss","volume":"124","author":"Secher","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1098\/rstb.2006.1855","article-title":"Neuropeptide Y in normal eating and in genetic and dietary-induced obesity","volume":"361","author":"Beck","year":"2006","journal-title":"Philos. Trans. R. Soc. Lond. B Biol. Sci."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1111\/bph.15535","article-title":"The diverse effects of brain glucagon-like peptide 1 receptors on ingestive behaviour","volume":"179","author":"Williams","year":"2022","journal-title":"Br. J. Pharmacol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"100133","DOI":"10.1074\/jbc.RA120.016334","article-title":"Genetic and biased agonist-mediated reductions in \u03b2-arrestin recruitment prolong cAMP signaling at glucagon family receptors","volume":"296","author":"Jones","year":"2021","journal-title":"J. Biol. Chem."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"eadf7737","DOI":"10.1126\/sciadv.adf7737","article-title":"Divergent acute versus prolonged pharmacological GLP-1R responses in adult \u03b2 cell-specific \u03b2-arrestin 2 knockout mice","volume":"9","author":"Bitsi","year":"2023","journal-title":"Sci. Adv."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"113326","DOI":"10.1016\/j.celrep.2023.113326","article-title":"GLP-1 and GIP receptors signal through distinct \u03b2-arrestin 2-dependent pathways to regulate pancreatic \u03b2 cell function","volume":"42","author":"Obeid","year":"2023","journal-title":"Cell Rep."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1097\/FJC.0000000000000482","article-title":"G Protein-Coupled Receptor Signaling Through \u03b2-Arrestin-Dependent Mechanisms","volume":"70","author":"Kaur","year":"2017","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1124\/pr.116.013367","article-title":"The Diverse Roles of Arrestin Scaffolds in G Protein-Coupled Receptor Signaling","volume":"69","author":"Peterson","year":"2017","journal-title":"Pharmacol. Rev."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"e140532","DOI":"10.1172\/jci.insight.140532","article-title":"Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist","volume":"5","author":"Willard","year":"2020","journal-title":"JCI Insight"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1740","DOI":"10.1073\/pnas.262789099","article-title":"Desensitization, internalization, and signaling functions of beta-arrestins demonstrated by RNA interference","volume":"100","author":"Ahn","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1093\/bja\/aer291","article-title":"Antinociceptive potentiation and attenuation of tolerance by intrathecal \u03b2-arrestin 2 small interfering RNA in rats","volume":"107","author":"Yang","year":"2011","journal-title":"Br. J. Anaesth."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"15054","DOI":"10.1038\/ncomms15054","article-title":"A new inhibitor of the \u03b2-arrestin\/AP2 endocytic complex reveals interplay between GPCR internalization and signalling","volume":"8","author":"Beautrait","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"eaal3395","DOI":"10.1126\/scisignal.aal3395","article-title":"Genetic evidence that \u03b2-arrestins are dispensable for the initiation of \u03b2(2)-adrenergic receptor signaling to ERK","volume":"10","author":"Eichel","year":"2017","journal-title":"Sci. Signal."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1038\/s41580-020-00317-7","article-title":"Mechanisms controlling pancreatic islet cell function in insulin secretion","volume":"22","author":"Campbell","year":"2021","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1007\/s00125-008-0930-2","article-title":"Too much of a good thing: Why it is bad to stimulate the beta cell to secrete insulin","volume":"51","author":"Proietto","year":"2008","journal-title":"Diabetologia"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"4981","DOI":"10.1038\/s41467-020-18751-8","article-title":"Chronic glucose-dependent insulinotropic polypeptide receptor (GIPR) agonism desensitizes adipocyte GIPR activity mimicking functional GIPR antagonism","volume":"11","author":"Killion","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"101139","DOI":"10.1016\/j.molmet.2020.101139","article-title":"Targeting the GIPR for obesity: To agonize or antagonize? Potential mechanisms","volume":"46","author":"Campbell","year":"2021","journal-title":"Mol. Metab."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"S122","DOI":"10.2337\/diabetes.50.2007.S122","article-title":"Overstimulation and beta-cell function","volume":"50","author":"Grill","year":"2001","journal-title":"Diabetes"},{"key":"ref_92","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_93","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1186\/s12916-020-01688-6","article-title":"Insulin: Too much of a good thing is bad","volume":"18","author":"Kolb","year":"2020","journal-title":"BMC Med."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"S225","DOI":"10.2337\/dc11-s225","article-title":"Insulin: Potential negative consequences of early routine use in patients with type 2 diabetes","volume":"34","author":"Lebovitz","year":"2011","journal-title":"Diabetes Care."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.ejim.2013.01.009","article-title":"Incretin-based therapies in the treatment of type 2 diabetes--more than meets the eye?","volume":"24","author":"Labuzek","year":"2013","journal-title":"Eur. J. Intern. Med."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"378","DOI":"10.3389\/fendo.2020.00378","article-title":"Reducing Glucokinase Activity to Enhance Insulin Secretion: A Counterintuitive Theory to Preserve Cellular Function and Glucose Homeostasis","volume":"11","author":"Whitticar","year":"2020","journal-title":"Front. Endocrinol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1007\/s11892-013-0363-2","article-title":"Interventions to preserve beta-cell function in the management and prevention of type 2 diabetes","volume":"13","author":"Page","year":"2013","journal-title":"Curr. Diab Rep."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1001\/jamainternmed.2013.2720","article-title":"Glucagonlike peptide 1-based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus: A population-based matched case-control study","volume":"173","author":"Singh","year":"2013","journal-title":"JAMA Intern. Med."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1016\/j.therap.2020.02.024","article-title":"Incretin-based drugs and intestinal obstruction: A pharmacovigilance study","volume":"75","author":"Gudin","year":"2020","journal-title":"Therapie"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"23247096211051919","DOI":"10.1177\/23247096211051919","article-title":"Medication-Induced Gastroparesis: A Case Report","volume":"9","author":"Kalas","year":"2021","journal-title":"J. Investig. Med. High. Impact Case Rep."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1111\/dom.12926","article-title":"Safety issues with glucagon-like peptide-1 receptor agonists (pancreatitis, pancreatic cancer and cholelithiasis): Data from randomized controlled trials","volume":"19","author":"Monami","year":"2017","journal-title":"Diabetes Obes. Metab."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1111\/dom.15382","article-title":"Glucagon-like peptide-1 receptor agonists and risk of thyroid cancer: A systematic review and meta-analysis of randomized controlled trials","volume":"26","author":"Silverii","year":"2024","journal-title":"Diabetes Obes. Metab."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.1001\/jama.2023.19574","article-title":"Risk of Gastrointestinal Adverse Events Associated With Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss","volume":"330","author":"Sodhi","year":"2023","journal-title":"JAMA"},{"key":"ref_104","first-page":"G984","article-title":"Glucagon-like peptide-1 inhibits gastropancreatic function by inhibiting central parasympathetic outflow","volume":"275","author":"Wettergren","year":"1998","journal-title":"Am. J. Physiol."},{"key":"ref_105","first-page":"e43773","article-title":"Acute Pancreatitis in a Patient Taking Semaglutide","volume":"15","author":"Patel","year":"2023","journal-title":"Cureus"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1364110","DOI":"10.3389\/fphar.2024.1364110","article-title":"Pancreatitis with use of new diabetic medications: A real-world data study using the post-marketing FDA adverse event reporting system (FAERS) database","volume":"15","author":"Alenzi","year":"2024","journal-title":"Front. Pharmacol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"2148","DOI":"10.2337\/db09-0626","article-title":"Glucagon-like peptide-1 receptor activation modulates pancreatitis-associated gene expression but does not modify the susceptibility to experimental pancreatitis in mice","volume":"58","author":"Koehler","year":"2009","journal-title":"Diabetes"},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Valente, R., Coppola, A., Scandavini, C.M., Halimi, A., Magnusson, A., Lauro, A., Sotirova, I., Arnelo, U., and Franklin, O. (2024). Interactions between the Exocrine and the Endocrine Pancreas. J. Clin. Med., 13.","DOI":"10.3390\/jcm13041179"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"2291","DOI":"10.1016\/j.apsb.2023.02.020","article-title":"A potentially serious adverse effect of GLP-1 receptor agonists","volume":"13","author":"Lu","year":"2023","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"S68","DOI":"10.1016\/j.eprac.2024.03.258","article-title":"A Case of Fatal Fulminant Necrotizing Pancreatitis in a Patient with Recent Tirzepatide Initiation","volume":"30","author":"Grennan","year":"2024","journal-title":"Endocr. Pract."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1080\/03007995.2024.2386047","article-title":"The first report of leukocytoclastic vasculitis induced by once-weekly subcutaneous semaglutide","volume":"40","author":"Pinheiro","year":"2024","journal-title":"Curr. Med. Res. Opin."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/s12933-016-0490-6","article-title":"Differential effects of glucagon-like peptide-1 receptor agonists on heart rate","volume":"16","author":"Lorenz","year":"2017","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"e22","DOI":"10.2337\/dc15-1437","article-title":"Effects of GLP-1 Receptor Agonists on Heart Rate and the Autonomic Nervous System Using Holter Electrocardiography and Power Spectrum Analysis of Heart Rate Variability","volume":"39","author":"Nakatani","year":"2016","journal-title":"Diabetes Care."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1210\/endo-121-1-323","article-title":"Sympathetic nerve stimulation versus pancreatic norepinephrine infusion in the dog: 1). Effects on basal release of insulin and glucagon","volume":"121","author":"Veith","year":"1987","journal-title":"Endocrinology"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1016\/0031-9384(86)90286-6","article-title":"Central glucagon-induced hyperglycemia is mediated by combined activation of the adrenal medulla and sympathetic nerve endings","volume":"37","author":"Amir","year":"1986","journal-title":"Physiol. Behav."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1007\/s13181-022-00923-1","article-title":"Does Glucagon Really Work for Beta Blocker Overdose?","volume":"19","author":"Routsolias","year":"2023","journal-title":"J. Med. Toxicol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"1229086","DOI":"10.1080\/23312025.2016.1229086","article-title":"The physiological role of the brain GLP-1 system in stress","volume":"2","author":"Holt","year":"2016","journal-title":"Cogent Biol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1016\/j.neuroscience.2014.10.043","article-title":"Spinally projecting preproglucagon axons preferentially innervate sympathetic preganglionic neurons","volume":"284","author":"Marina","year":"2015","journal-title":"Neuroscience"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"e2032232024","DOI":"10.1523\/JNEUROSCI.2032-23.2024","article-title":"GLP-1 in the Hypothalamic Paraventricular Nucleus Promotes Sympathetic Activation and Hypertension","volume":"44","author":"Xu","year":"2024","journal-title":"J. Neurosci."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"R77","DOI":"10.1530\/JOE-16-0118","article-title":"Stressing diabetes? The hidden links between insulinotropic peptides and the HPA axis","volume":"230","author":"Toba","year":"2016","journal-title":"J. Endocrinol."},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Diz-Chaves, Y., Herrera-P\u00e9rez, S., Gonz\u00e1lez-Mat\u00edas, L.C., Lamas, J.A., and Mallo, F. (2020). Glucagon-Like Peptide-1 (GLP-1) in the Integration of Neural and Endocrine Responses to Stress. Nutrients, 12.","DOI":"10.3390\/nu12113304"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"2629","DOI":"10.1210\/en.2009-0915","article-title":"GLP-1(7-36)-amide and Exendin-4 stimulate the HPA axis in rodents and humans","volume":"151","author":"Fernandez","year":"2010","journal-title":"Endocrinology"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"e13539","DOI":"10.1111\/obr.13539","article-title":"Glucocorticoids, stress and eating: The mediating role of appetite-regulating hormones","volume":"24","author":"Kuckuck","year":"2023","journal-title":"Obes. Rev."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"e006740","DOI":"10.1161\/CIRCEP.118.006740","article-title":"Modulation of Cardiac Ventricular Excitability by GLP-1 (Glucagon-Like Peptide-1)","volume":"11","author":"Ang","year":"2018","journal-title":"Circ. Arrhythm. Electrophysiol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1016\/S2213-8587(19)30249-9","article-title":"Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: A systematic review and meta-analysis of cardiovascular outcome trials","volume":"7","author":"Kristensen","year":"2019","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1016\/S2213-8587(21)00203-5","article-title":"Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: A systematic review and meta-analysis of randomised trials","volume":"9","author":"Sattar","year":"2021","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"q53","DOI":"10.1136\/bmj.q53","article-title":"Semaglutide reduces the absolute risk of major cardiovascular events by 1.5","volume":"384","author":"Phizackerley","year":"2024","journal-title":"BMJ"},{"key":"ref_128","first-page":"S42","article-title":"Cardiovascular Outcomes with Once-Weekly GLP-1 RAs: Clinical and Economic Implications","volume":"24","author":"Heile","year":"2018","journal-title":"J. Manag. Care Spec. Pharm."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1001\/jama.2024.2252","article-title":"GLP-1 Agonists for Obesity-A New Recipe for Success?","volume":"331","author":"Mozaffarian","year":"2024","journal-title":"JAMA"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"e806","DOI":"10.1016\/S2468-2667(22)00235-3","article-title":"Long-term maintenance of weight loss","volume":"7","year":"2022","journal-title":"Lancet Public Health"},{"key":"ref_131","unstructured":"O\u2019Neil, P., and Adams, H. (2023). The-Upsides-and-Downsides-of-Blockbuster-Weight-Loss-Drugs, Medical University of South Carolina."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1097\/MCO.0000000000000110","article-title":"Functional foods to promote weight loss and satiety","volume":"17","author":"Rebello","year":"2014","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care."},{"key":"ref_133","unstructured":"Seier, S., Larsen, K.S., Pedersen, J., Biccler, J., and Gudbergsen, H. (2024, January 12\u201315). Tapering semaglutide to the most effective dose: Real-world evidence from a digital weight management programme (TAILGATE). Proceedings of the 31st European Congress on Obesity, Venice, Italy."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/22\/1842\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:27:54Z","timestamp":1760113674000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/22\/1842"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,7]]},"references-count":133,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2024,11]]}},"alternative-id":["cells13221842"],"URL":"https:\/\/doi.org\/10.3390\/cells13221842","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,7]]}}}