{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T11:20:50Z","timestamp":1793532050266,"version":"4.5.0"},"reference-count":107,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T00:00:00Z","timestamp":1778025600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:00:00Z","timestamp":1782777600000},"content-version":"vor","delay-in-days":55,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nutr. Diabetes"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Incretin hormones, specifically glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), serve as crucial mediators of postprandial glucose homeostasis by primarily enhancing glucose-stimulated insulin secretion. Research indicates that the incretin effect accounts for approximately 50% of insulin secretion in individuals without diabetes, which is significantly reduced to 30% or less in those with Type 2 Diabetes Mellitus (T2DM). The mechanisms underlying this incretin resistance have emerged as critical causes of postprandial hyperglycemia. Incretin-based therapies, including GLP-1 receptor agonists (GLP-1RAs) and DPP-4 inhibitors, have demonstrated efficacy in managing T2DM; however, intrinsic resistance mechanisms may limit their effectiveness. Understanding the processes by which T2DM affects incretin action, from hormone secretion to the modulation of signal transduction, is essential for optimizing current therapies and developing new interventions to enhance \u03b2-cell responsiveness and improve glycemic control. The concept of incretin resistance has a well-established history in literature, dating back to at least the early 1990\u2009s. It is used to describe a reduced insulinotropic responsiveness to incretin hormones in individuals diagnosed with T2DM. This review examines how hyperglycemia, chronic inflammation, and genetic susceptibility collectively inhibit incretin signaling through distinct yet interconnected molecular pathways. This impairment exacerbates postprandial hyperglycemia and accelerates \u03b2-cell dysfunction. We propose novel hypotheses regarding selective \u03b2-arrestin signaling, enhancers, epigenetic regulation, interactions between gut microbiota and incretins, inflammation-induced endoplasmic reticulum (ER) stress, and genotype-specific therapeutic responses. The hypotheses presented in this review serve as a framework for future research and therapeutic development to combat the phenomenon of incretin resistance and improve the clinical management of T2DM.<\/jats:p>","DOI":"10.1038\/s41387-026-00426-w","type":"journal-article","created":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T17:35:10Z","timestamp":1778088910000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The molecular mechanisms of incretin resistance in Type 2 Diabetes Mellitus (T2DM)"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4940-1994","authenticated-orcid":false,"given":"Rawayh Muslim","family":"Albaghlany","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abbas Ali","family":"Mansour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,6]]},"reference":[{"key":"426_CR1","doi-asserted-by":"publisher","first-page":"883","DOI":"10.3390\/nu13030883","volume":"13","author":"VB Lu","year":"2021","unstructured":"Lu VB, Gribble FM, Reimann F. Nutrient-induced cellular mechanisms of gut hormone secretion. Nutrients. 2021;13:883.","journal-title":"Nutrients"},{"key":"426_CR2","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1210\/jcem-63-2-492","volume":"63","author":"MA Nauck","year":"1986","unstructured":"Nauck MA, Homberger E, Siegel EG, Allen RC, Eaton RP, Ebert R, et al. Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab. 1986;63:492\u20138.","journal-title":"J Clin Endocrinol Metab"},{"key":"426_CR3","doi-asserted-by":"publisher","unstructured":"Kuhre RE, Deacon CF, Holst JJ, Petersen N. What is an L-cell and how do we study the secretory mechanisms of the L-cell? Front Endocrinol. 2021;12. https:\/\/doi.org\/10.3389\/fendo.2021.694284.","DOI":"10.3389\/fendo.2021.694284"},{"key":"426_CR4","doi-asserted-by":"crossref","unstructured":"Maselli DB, Camilleri M. Effects of GLP-1 and its analogs on gastric physiology in diabetes mellitus and obesity. In: Islam MDS, editor. Diabetes: from research to clinical practice: Volume 4. Springer International Publishing: Cham, 2021, p. 171\u201392.","DOI":"10.1007\/5584_2020_496"},{"key":"426_CR5","doi-asserted-by":"publisher","first-page":"2092","DOI":"10.1210\/clinem\/dgac213","volume":"107","author":"E Grespan","year":"2022","unstructured":"Grespan E, Guolo A, Muscelli E, Ferrannini E, Mari A. Loss of the incretin effect in type 2 diabetes: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2022;107:2092\u20132100.","journal-title":"J Clin Endocrinol Metab"},{"key":"426_CR6","doi-asserted-by":"crossref","unstructured":"Holst J. From the incretin concept and the discovery of GLP-1 to today\u2019s diabetes therapy. Front. Endocrinol. 2019;10:260.","DOI":"10.3389\/fendo.2019.00260"},{"key":"426_CR7","doi-asserted-by":"publisher","first-page":"e2314493","DOI":"10.1001\/jamanetworkopen.2023.14493","volume":"6","author":"AR Saxena","year":"2023","unstructured":"Saxena AR, Frias JP, Brown LS, Gorman DN, Vasas S, Tsamandouras N, et al. Efficacy and safety of oral small molecule glucagon-like peptide 1 receptor agonist danuglipron for glycemic control among patients with type 2 diabetes: a randomized clinical trial. JAMA Netw Open. 2023;6:e2314493.","journal-title":"JAMA Netw Open"},{"key":"426_CR8","doi-asserted-by":"publisher","unstructured":"Lisco G, De Tullio A, Disoteo O, De Geronimo V, Piazzolla G, De Pergola G, et al. Basal insulin intensification with GLP-1RA and dual GIP and GLP-1RA in patients with uncontrolled type 2 diabetes mellitus: a rapid review of randomized controlled trials and meta-analysis. Front Endocrinol. 2022;13. https:\/\/doi.org\/10.3389\/fendo.2022.920541.","DOI":"10.3389\/fendo.2022.920541"},{"key":"426_CR9","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1172\/JCI116186","volume":"91","author":"MA Nauck","year":"1993","unstructured":"Nauck MA, Heimesaat MM, Orskov C, Holst JJ, Ebert R, Creutzfeldt W. Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest. 1993;91:301\u20137.","journal-title":"J Clin Invest"},{"key":"426_CR10","doi-asserted-by":"publisher","first-page":"767","DOI":"10.1146\/annurev-biochem-072909-095555","volume":"81","author":"SH Back","year":"2012","unstructured":"Back SH, Kaufman RJ. Endoplasmic reticulum stress and type 2 diabetes. Annu Rev Biochem. 2012;81:767\u201393.","journal-title":"Annu Rev Biochem"},{"key":"426_CR11","doi-asserted-by":"publisher","first-page":"3346","DOI":"10.2337\/dc13-0465","volume":"36","author":"S Calanna","year":"2013","unstructured":"Calanna S, Christensen M, Holst JJ, Laferr\u00e8re B, Gluud LL, Vilsb\u00f8ll T, et al. Secretion of glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes. Diab Care. 2013;36:3346\u201352.","journal-title":"Diab Care"},{"key":"426_CR12","doi-asserted-by":"publisher","first-page":"351","DOI":"10.3390\/nu13020351","volume":"13","author":"J Micha\u0142owska","year":"2021","unstructured":"Micha\u0142owska J, Miller-Kasprzak E, Bogda\u0144ski P. Incretin hormones in obesity and related cardiometabolic disorders: the clinical perspective. Nutrients. 2021;13:351.","journal-title":"Nutrients"},{"key":"426_CR13","doi-asserted-by":"publisher","first-page":"609","DOI":"10.2337\/diabetes.50.3.609","volume":"50","author":"T Vilsb\u00f8ll","year":"2001","unstructured":"Vilsb\u00f8ll T, Krarup T, Deacon CF, Madsbad S, Holst JJ. Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes. 2001;50:609\u201313.","journal-title":"Diabetes"},{"key":"426_CR14","doi-asserted-by":"publisher","first-page":"G424","DOI":"10.1152\/ajpgi.2002.282.3.G424","volume":"282","author":"S Delgado-Aros","year":"2002","unstructured":"Delgado-Aros S, Kim DY, Burton DD, Thomforde GM, Stephens D, Brinkmann BH, et al. Effect of GLP-1 on gastric volume, emptying, maximum volume ingested, and postprandial symptoms in humans. Am J Physiol-Gastrointest Liver Physiol. 2002;282:G424\u2013G431.","journal-title":"Am J Physiol-Gastrointest Liver Physiol"},{"key":"426_CR15","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1111\/j.1467-789X.2012.01011.x","volume":"13","author":"EE Blaak","year":"2012","unstructured":"Blaak EE, Antoine JM, Benton D, Bj\u00f6rck I, Bozzetto L, Brouns F, et al. Impact of postprandial glycaemia on health and prevention of disease. Obes Rev. 2012;13:923\u201384.","journal-title":"Obes Rev"},{"key":"426_CR16","doi-asserted-by":"publisher","first-page":"584","DOI":"10.1111\/bph.15603","volume":"179","author":"DI Brierley","year":"2022","unstructured":"Brierley DI, de Lartigue G. Reappraising the role of the vagus nerve in GLP-1-mediated regulation of eating. Br J Pharmacol. 2022;179:584\u201399.","journal-title":"Br J Pharmacol"},{"key":"426_CR17","doi-asserted-by":"publisher","first-page":"1330","DOI":"10.2337\/db09-1253","volume":"59","author":"M Salehi","year":"2010","unstructured":"Salehi M, Aulinger B, Prigeon RL, D\u2019Alessio DA. Effect of endogenous GLP-1 on insulin secretion in type 2 diabetes. Diabetes. 2010;59:1330\u20137.","journal-title":"Diabetes"},{"key":"426_CR18","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1530\/eje.0.1350425","volume":"135","author":"AA Vaag","year":"1996","unstructured":"Vaag AA, Holst JJ, V\u00f8lund A, Beck-Nielsen HB. Gut incretin hormones in identical twins discordant for non-insulin-dependent diabetes mellitus (NIDDM)-evidence for decreased glucagon-like peptide 1 secretion during oral glucose ingestion in NIDDM twins. Eur J Endocrinol. 1996;135:425\u201332.","journal-title":"Eur J Endocrinol"},{"key":"426_CR19","doi-asserted-by":"publisher","first-page":"965","DOI":"10.1007\/s00125-013-2841-0","volume":"56","author":"S Calanna","year":"2013","unstructured":"Calanna S, Christensen M, Holst JJ, Laferr\u00e8re B, Gluud LL, Vilsb\u00f8ll T, et al. Secretion of glucagon-like peptide-1 in patients with type 2 diabetes mellitus: systematic review and meta-analyses of clinical studies. Diabetologia. 2013;56:965\u201372.","journal-title":"Diabetologia"},{"key":"426_CR20","doi-asserted-by":"publisher","unstructured":"Masse KE, Lu VB. Short-chain fatty acids, secondary bile acids and indoles: gut microbial metabolites with effects on enteroendocrine cell function and their potential as therapies for metabolic disease. Front Endocrinol. 2023;14. https:\/\/doi.org\/10.3389\/fendo.2023.1169624.","DOI":"10.3389\/fendo.2023.1169624"},{"key":"426_CR21","doi-asserted-by":"publisher","first-page":"1744","DOI":"10.1136\/gutjnl-2014-307913","volume":"64","author":"ES Chambers","year":"2015","unstructured":"Chambers ES, Viardot A, Psichas A, Morrison DJ, Murphy KG, Zac-Varghese SEK, et al. Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance and adiposity in overweight adults. Gut. 2015;64:1744\u201354.","journal-title":"Gut"},{"key":"426_CR22","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1016\/j.tem.2023.02.001","volume":"34","author":"G Di Giuseppe","year":"2023","unstructured":"Di Giuseppe G, Ciccarelli G, Soldovieri L, Capece U, Cefalo CMA, Moffa S, et al. First-phase insulin secretion: can its evaluation direct therapeutic approaches? Trends Endocrinol Metab. 2023;34:216\u201330.","journal-title":"Trends Endocrinol Metab"},{"key":"426_CR23","doi-asserted-by":"publisher","first-page":"2389","DOI":"10.2337\/db18-0279","volume":"67","author":"T Mezza","year":"2018","unstructured":"Mezza T, Ferraro PM, Sun VA, Moffa S, Cefalo CMA, Quero G, et al. Increased \u03b2-cell workload modulates proinsulin-to-insulin ratio in humans. Diabetes. 2018;67:2389\u201396.","journal-title":"Diabetes"},{"key":"426_CR24","doi-asserted-by":"publisher","first-page":"2431","DOI":"10.2337\/dbi20-0033","volume":"70","author":"RB Sharma","year":"2021","unstructured":"Sharma RB, Landa-Galv\u00e1n HV, Alonso LC. Living dangerously: protective and harmful ER stress responses in pancreatic \u03b2-cells. Diabetes. 2021;70:2431\u201343.","journal-title":"Diabetes"},{"key":"426_CR25","doi-asserted-by":"publisher","first-page":"3305","DOI":"10.1172\/JCI65390","volume":"123","author":"S Guo","year":"2013","unstructured":"Guo S, Dai C, Guo M, Taylor B, Harmon JS, Sander M, et al. Inactivation of specific \u03b2 cell transcription factors in type 2 diabetes. J Clin Invest. 2013;123:3305\u201316.","journal-title":"J Clin Invest"},{"key":"426_CR26","doi-asserted-by":"publisher","first-page":"3353","DOI":"10.1111\/bph.16478","volume":"182","author":"LS Gasbjerg","year":"2025","unstructured":"Gasbjerg LS, Rasmussen RS, Dragan A, Lindquist P, Melchiorsen JU, Stepniewski TM, et al. Altered desensitization and internalization patterns of rodent versus human glucose-dependent insulinotropic polypeptide (GIP) receptors. An important drug discovery challenge. Br J Pharm. 2025;182:3353\u201370.","journal-title":"Br J Pharm"},{"key":"426_CR27","doi-asserted-by":"publisher","unstructured":"G X, H K, Dr L, Vf D-K, N T, K S, et al. Downregulation of GLP-1 and GIP receptor expression by hyperglycemia: possible contribution to impaired incretin effects in diabetes. Diabetes. 2007;56. https:\/\/doi.org\/10.2337\/db06-1033.","DOI":"10.2337\/db06-1033"},{"key":"426_CR28","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2350-14-76","volume":"14","author":"E Hall","year":"2013","unstructured":"Hall E, Dayeh T, Kirkpatrick CL, Wollheim CB, Dekker Nitert M, Ling C. DNA methylation of the glucagon-like peptide 1 receptor (GLP1R) in human pancreatic islets. BMC Med Genet. 2013;14:76.","journal-title":"BMC Med Genet"},{"key":"426_CR29","doi-asserted-by":"publisher","first-page":"11529","DOI":"10.1074\/jbc.RA120.014368","volume":"295","author":"SM Gray","year":"2020","unstructured":"Gray SM, Xin Y, Ross EC, Chazotte BM, Capozzi ME, El K, et al. Discordance between GLP-1R gene and protein expression in mouse pancreatic islet cells. J Biol Chem. 2020;295:11529\u201341.","journal-title":"J Biol Chem"},{"key":"426_CR30","doi-asserted-by":"publisher","first-page":"256","DOI":"10.2337\/db17-0506","volume":"67","author":"S Jo","year":"2018","unstructured":"Jo S, Chen J, Xu G, Grayson TB, Thielen LA, Shalev A. miR-204 controls glucagon-like peptide 1 receptor expression and agonist function. Diabetes. 2018;67:256\u201364.","journal-title":"Diabetes"},{"key":"426_CR31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/S0031-6997(24)01478-9","volume":"53","author":"SS Ferguson","year":"2001","unstructured":"Ferguson SS. Evolving concepts in G protein-coupled receptor endocytosis: the role in receptor desensitization and signaling. Pharm Rev. 2001;53:1\u201324.","journal-title":"Pharm Rev"},{"key":"426_CR32","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1016\/j.molmet.2015.01.010","volume":"4","author":"S Rajan","year":"2015","unstructured":"Rajan S, Dickson LM, Mathew E, Orr CMO, Ellenbroek JH, Philipson LH, et al. Chronic hyperglycemia downregulates GLP-1 receptor signaling in pancreatic \u03b2-cells via protein kinase A. Mol Metab. 2015;4:265\u201376.","journal-title":"Mol Metab"},{"key":"426_CR33","first-page":"E661","volume":"270","author":"CC Tseng","year":"1996","unstructured":"Tseng CC, Boylan MO, Jarboe LA, Usdin TB, Wolfe MM. Chronic desensitization of the glucose-dependent insulinotropic polypeptide receptor in diabetic rats. Am J Physiol. 1996;270:E661\u201366.","journal-title":"Am J Physiol"},{"key":"426_CR34","doi-asserted-by":"publisher","first-page":"G820","DOI":"10.1152\/ajpgi.00063.2010","volume":"298","author":"MA McGuckin","year":"2010","unstructured":"McGuckin MA, Eri RD, Das I, Lourie R, Florin TH. ER stress and the unfolded protein response in intestinal inflammation. Am J Physiol Gastrointest Liver Physiol. 2010;298:G820\u201332.","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"426_CR35","unstructured":"Mayer F. Stimulation of substance P release from sensory nerves by incretin hormones. 2019. https:\/\/escholarship.org\/uc\/item\/95z8b1r1. Accessed 21 Mar 2025."},{"key":"426_CR36","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1007\/164_2015_32","volume":"233","author":"K Ravnskjaer","year":"2016","unstructured":"Ravnskjaer K, Madiraju A, Montminy M. Role of the cAMP pathway in glucose and lipid metabolism. Handb Exp Pharm. 2016;233:29\u201349.","journal-title":"Handb Exp Pharm"},{"key":"426_CR37","unstructured":"Qi Y. Leptin\u2019s Potential Interactions with Counter-Regulatory Hormones and Glucocorticoid Receptor Signaling in Type 1 Diabetic Rats. 2019. https:\/\/etd.auburn.edu\/\/handle\/10415\/7025. Accessed 21 Mar 2025."},{"issue":"Suppl 1","key":"426_CR38","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1111\/dom.12993","volume":"19","author":"A Tengholm","year":"2017","unstructured":"Tengholm A, Gylfe E. cAMP signalling in insulin and glucagon secretion. Diab Obes Metab. 2017;19(Suppl 1):42\u201353.","journal-title":"Diab Obes Metab"},{"key":"426_CR39","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.113326","volume":"42","author":"N Za\u00efmia","year":"2023","unstructured":"Za\u00efmia N, Obeid J, Varrault A, Sabatier J, Broca C, Gilon P, et al. GLP-1 and GIP receptors signal through distinct \u03b2-arrestin 2-dependent pathways to regulate pancreatic \u03b2 cell function. Cell Rep. 2023;42:113326.","journal-title":"Cell Rep"},{"key":"426_CR40","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/j.mce.2010.04.022","volume":"325","author":"\u00d6 Erdogdu","year":"2010","unstructured":"Erdogdu \u00d6, Nathanson D, Sj\u00f6holm \u00c5, Nystr\u00f6m T, Zhang Q. Exendin-4 stimulates proliferation of human coronary artery endothelial cells through eNOS-, PKA- and PI3K\/Akt-dependent pathways and requires GLP-1 receptor. Mol Cell Endocrinol. 2010;325:26\u201335.","journal-title":"Mol Cell Endocrinol"},{"key":"426_CR41","doi-asserted-by":"publisher","DOI":"10.1002\/mco2.283","volume":"4","author":"R Cao","year":"2023","unstructured":"Cao R, Tian H, Zhang Y, Liu G, Xu H, Rao G, et al. Signaling pathways and intervention for therapy of type 2 diabetes mellitus. MedComm. 2023;4:e283.","journal-title":"MedComm"},{"key":"426_CR42","doi-asserted-by":"publisher","first-page":"1839","DOI":"10.1172\/JCI200216857","volume":"110","author":"T Kitamura","year":"2002","unstructured":"Kitamura T, Nakae J, Kitamura Y, Kido Y, Biggs WH, Wright CVE, et al. The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic beta cell growth. J Clin Invest. 2002;110:1839\u201347.","journal-title":"J Clin Invest"},{"key":"426_CR43","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1016\/j.cmet.2006.10.001","volume":"4","author":"B Yusta","year":"2006","unstructured":"Yusta B, Baggio LL, Estall JL, Koehler JA, Holland DP, Li H, et al. GLP-1 receptor activation improves \u03b2 cell function and survival following induction of endoplasmic reticulum stress. Cell Metab. 2006;4:391\u2013406.","journal-title":"Cell Metab"},{"key":"426_CR44","doi-asserted-by":"publisher","first-page":"42","DOI":"10.3389\/fphar.2015.00042","volume":"6","author":"JG Partridge","year":"2015","unstructured":"Partridge JG. Utilizing GCaMP transgenic mice to monitor endogenous Gq\/11-coupled receptors. Front Pharm. 2015;6:42.","journal-title":"Front Pharm"},{"key":"426_CR45","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2024.111311","volume":"122","author":"D Chen","year":"2024","unstructured":"Chen D, Wang J, Cao J, Zhu G. cAMP-PKA signaling pathway and anxiety: Where do we go next? Cell Signal. 2024;122:111311.","journal-title":"Cell Signal"},{"key":"426_CR46","doi-asserted-by":"publisher","first-page":"S3","DOI":"10.1016\/j.amjmed.2010.11.002","volume":"124","author":"MA Nauck","year":"2011","unstructured":"Nauck MA. Incretin-based therapies for type 2 diabetes mellitus: properties, functions, and clinical implications. Am J Med. 2011;124:S3\u2013S18.","journal-title":"Am J Med"},{"key":"426_CR47","doi-asserted-by":"publisher","first-page":"851","DOI":"10.1172\/JCI200215318","volume":"110","author":"K Maedler","year":"2002","unstructured":"Maedler K, Sergeev P, Ris F, Oberholzer J, Joller-Jemelka HI, Spinas GA, et al. Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets. J Clin Invest. 2002;110:851\u201360.","journal-title":"J Clin Invest"},{"key":"426_CR48","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.smrv.2017.01.001","volume":"37","author":"NJ Saner","year":"2018","unstructured":"Saner NJ, Bishop DJ, Bartlett JD. Is exercise a viable therapeutic intervention to mitigate mitochondrial dysfunction and insulin resistance induced by sleep loss? Sleep Med Rev. 2018;37:60\u201368.","journal-title":"Sleep Med Rev"},{"key":"426_CR49","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1210\/er.2007-0023","volume":"29","author":"V Poitout","year":"2008","unstructured":"Poitout V, Robertson RP. Glucolipotoxicity: fuel excess and beta-cell dysfunction. Endocr Rev. 2008;29:351\u201366.","journal-title":"Endocr Rev"},{"key":"426_CR50","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1007\/s00424-010-0862-9","volume":"460","author":"G Drews","year":"2010","unstructured":"Drews G, Krippeit-Drews P, D\u00fcfer M. Oxidative stress and beta-cell dysfunction. Pflug Arch - Eur J Physiol. 2010;460:703\u201318.","journal-title":"Pflug Arch - Eur J Physiol"},{"key":"426_CR51","doi-asserted-by":"publisher","first-page":"706","DOI":"10.3390\/cells9030706","volume":"9","author":"JHM Yung","year":"2020","unstructured":"Yung JHM, Giacca A. Role of c-Jun N-terminal kinase (JNK) in obesity and type 2 diabetes. Cells. 2020;9:706.","journal-title":"Cells"},{"key":"426_CR52","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1210\/er.2007-0015","volume":"29","author":"DL Eizirik","year":"2008","unstructured":"Eizirik DL, Cardozo AK, Cnop M. The role for endoplasmic reticulum stress in diabetes mellitus. Endocr Rev. 2008;29:42\u201361.","journal-title":"Endocr Rev"},{"key":"426_CR53","doi-asserted-by":"publisher","DOI":"10.1155\/2021\/7297419","volume":"2021","author":"TV Velikova","year":"2021","unstructured":"Velikova TV, Kabakchieva PP, Assyov YS, Georgiev T\u0410. Targeting inflammatory cytokines to improve type 2 diabetes control. Biomed Res Int. 2021;2021:7297419.","journal-title":"Biomed Res Int"},{"key":"426_CR54","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1038\/414813a","volume":"414","author":"M Brownlee","year":"2001","unstructured":"Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414:813\u201320.","journal-title":"Nature"},{"key":"426_CR55","doi-asserted-by":"publisher","first-page":"26","DOI":"10.3390\/ijms19010026","volume":"19","author":"YS Oh","year":"2017","unstructured":"Oh YS, Jun HS. Effects of glucagon-like peptide-1 on oxidative stress and Nrf2 signaling. Int J Mol Sci. 2017;19:26.","journal-title":"Int J Mol Sci"},{"key":"426_CR56","doi-asserted-by":"publisher","unstructured":"Zatterale F, Longo M, Naderi J, Raciti GA, Desiderio A, Miele C, et al. Chronic adipose tissue inflammation linking obesity to insulin resistance and type 2 diabetes. Front Physiol. 2020;10. https:\/\/doi.org\/10.3389\/fphys.2019.01607.","DOI":"10.3389\/fphys.2019.01607"},{"key":"426_CR57","doi-asserted-by":"publisher","first-page":"18408","DOI":"10.1007\/s11356-022-18534-2","volume":"29","author":"NE Nasr","year":"2022","unstructured":"Nasr NE, Sadek KM. Role and mechanism(s) of incretin-dependent therapies for treating diabetes mellitus. Environ Sci Pollut Res. 2022;29:18408\u201322.","journal-title":"Environ Sci Pollut Res"},{"key":"426_CR58","doi-asserted-by":"publisher","first-page":"1185","DOI":"10.1111\/j.1464-5491.2009.02847.x","volume":"26","author":"S Del Prato","year":"2009","unstructured":"Del Prato S. Role of glucotoxicity and lipotoxicity in the pathophysiology of Type 2 diabetes mellitus and emerging treatment strategies. Diabet Med. 2009;26:1185\u201392.","journal-title":"Diabet Med"},{"key":"426_CR59","doi-asserted-by":"publisher","first-page":"1483","DOI":"10.3390\/molecules23061483","volume":"23","author":"P Je\u017eek","year":"2018","unstructured":"Je\u017eek P, Jab\u016frek M, Holendov\u00e1 B, Plecit\u00e1-Hlavat\u00e1 L. Fatty acid-stimulated insulin secretion vs. lipotoxicity. Molecules. 2018;23:1483.","journal-title":"Molecules"},{"key":"426_CR60","doi-asserted-by":"publisher","first-page":"S264","DOI":"10.2337\/dc11-s223","volume":"34","author":"S Cernea","year":"2011","unstructured":"Cernea S, Raz I. Therapy in the early stage: incretins. Diab Care. 2011;34:S264\u2013S271.","journal-title":"Diab Care"},{"key":"426_CR61","doi-asserted-by":"publisher","first-page":"S19","DOI":"10.1016\/j.amjmed.2009.12.006","volume":"123","author":"S Mudaliar","year":"2010","unstructured":"Mudaliar S, Henry RR. Effects of incretin hormones on \u03b2-cell mass and function, body weight, and hepatic and myocardial function. Am J Med. 2010;123:S19\u2013S27.","journal-title":"Am J Med"},{"key":"426_CR62","doi-asserted-by":"publisher","first-page":"S258","DOI":"10.2337\/dc11-s230","volume":"34","author":"AJ Garber","year":"2011","unstructured":"Garber AJ. Incretin effects on \u03b2-cell function, replication, and mass. Diab Care. 2011;34:S258\u2013S263.","journal-title":"Diab Care"},{"key":"426_CR63","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1016\/j.ando.2012.06.002","volume":"74","author":"AJ Scheen","year":"2013","unstructured":"Scheen AJ. GLP-1 receptor agonists or DPP-4 inhibitors: how to guide the clinician? Ann Endocrinol. 2013;74:515\u201322.","journal-title":"Ann Endocrinol"},{"key":"426_CR64","doi-asserted-by":"publisher","first-page":"29","DOI":"10.3390\/life12010029","volume":"12","author":"MC Pelle","year":"2022","unstructured":"Pelle MC, Provenzano M, Zaffina I, Pujia R, Giofr\u00e8 F, Luc\u00e0 S, et al. Role of a dual glucose-dependent insulinotropic peptide (GIP)\/glucagon-like peptide-1 receptor agonist (twincretin) in glycemic control: from pathophysiology to treatment. Life. 2022;12:29.","journal-title":"Life"},{"key":"426_CR65","doi-asserted-by":"publisher","first-page":"1723","DOI":"10.2337\/db07-1472","volume":"57","author":"S Han","year":"2008","unstructured":"Han S, Hagan DL, Taylor JR, Xin L, Meng W, Biller SA, et al. Dapagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats. Diabetes. 2008;57:1723\u20139.","journal-title":"Diabetes"},{"key":"426_CR66","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-03941-2","volume":"9","author":"B Jones","year":"2018","unstructured":"Jones B, Buenaventura T, Kanda N, Chabosseau P, Owen BM, Scott R, et al. Targeting GLP-1 receptor trafficking to improve agonist efficacy. Nat Commun. 2018;9:1602.","journal-title":"Nat Commun"},{"key":"426_CR67","doi-asserted-by":"publisher","first-page":"1220","DOI":"10.2337\/db20-0573","volume":"70","author":"L del Bosque-Plata","year":"2021","unstructured":"del Bosque-Plata L, Mart\u00ednez-Mart\u00ednez E, Espinoza-Camacho M\u00c1, Gragnoli C. The role of TCF7L2 in type 2 diabetes. Diabetes. 2021;70:1220\u20138.","journal-title":"Diabetes"},{"key":"426_CR68","doi-asserted-by":"publisher","first-page":"S251","DOI":"10.2337\/dc11-s227","volume":"34","author":"JJ Holst","year":"2011","unstructured":"Holst JJ, Knop FK, Vilsb\u00f8ll T, Krarup T, Madsbad S. Loss of incretin effect is a specific, important, and early characteristic of type 2 diabetes. Diab Care. 2011;34:S251\u2013S257.","journal-title":"Diab Care"},{"key":"426_CR69","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1007\/s42000-018-0047-z","volume":"17","author":"K Katsoulis","year":"2018","unstructured":"Katsoulis K, Paschou SA, Hatzi E, Tigas S, Georgiou I, Tsatsoulis A. TCF7L2 gene variants predispose to the development of type 2 diabetes mellitus among individuals with metabolic syndrome. Hormones. 2018;17:359\u201365.","journal-title":"Hormones"},{"key":"426_CR70","doi-asserted-by":"publisher","first-page":"1298","DOI":"10.1007\/s00125-009-1307-x","volume":"52","author":"K Pilgaard","year":"2009","unstructured":"Pilgaard K, Jensen CB, Schou JH, Lyssenko V, Wegner L, Br\u00f8ns C, et al. The T allele of rs7903146 TCF7L2 is associated with impaired insulinotropic action of incretin hormones, reduced 24 h profiles of plasma insulin and glucagon, and increased hepatic glucose production in young healthy men. Diabetologia. 2009;52:1298\u2013307.","journal-title":"Diabetologia"},{"key":"426_CR71","doi-asserted-by":"publisher","first-page":"2388","DOI":"10.1093\/hmg\/ddp178","volume":"18","author":"L Shu","year":"2009","unstructured":"Shu L, Matveyenko AV, Kerr-Conte J, Cho JH, McIntosh CHS, Maedler K. Decreased TCF7L2 protein levels in type 2 diabetes mellitus correlate with downregulation of GIP- and GLP-1 receptors and impaired beta-cell function. Hum Mol Genet. 2009;18:2388\u201399.","journal-title":"Hum Mol Genet"},{"key":"426_CR72","doi-asserted-by":"publisher","first-page":"E538","DOI":"10.1152\/ajpendo.00070.2007","volume":"293","author":"J Zhou","year":"2007","unstructured":"Zhou J, Livak MFA, Bernier M, Muller DC, Carlson OD, Elahi D, et al. Ubiquitination is involved in glucose-mediated downregulation of GIP receptors in islets. Am J Physiol-Endocrinol Metab. 2007;293:E538\u2013E547.","journal-title":"Am J Physiol-Endocrinol Metab"},{"key":"426_CR73","doi-asserted-by":"publisher","first-page":"2553","DOI":"10.2337\/dc20-0445","volume":"43","author":"A Galderisi","year":"2020","unstructured":"Galderisi A, Tric\u00f2 D, Pierpont B, Shabanova V, Samuels S, Dalla Man C, et al. A reduced incretin effect mediated by the rs7903146 variant in the TCF7L2 gene is an early marker of \u03b2-cell dysfunction in obese youth. Diab Care. 2020;43:2553\u201363.","journal-title":"Diab Care"},{"key":"426_CR74","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1016\/j.diabres.2014.03.019","volume":"105","author":"M Wegner","year":"2014","unstructured":"Wegner M, Neddermann D, Piorunska-Stolzmann M, Jagodzinski PP. Role of epigenetic mechanisms in the development of chronic complications of diabetes. Diab Res Clin Pract. 2014;105:164\u201375.","journal-title":"Diab Res Clin Pract"},{"key":"426_CR75","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1186\/s13148-020-00896-4","volume":"12","author":"SAH Ahmed","year":"2020","unstructured":"Ahmed SAH, Ansari SA, Mensah-Brown EPK, Emerald BS. The role of DNA methylation in the pathogenesis of type 2 diabetes mellitus. Clin Epigenet. 2020;12:104.","journal-title":"Clin Epigenet"},{"key":"426_CR76","doi-asserted-by":"publisher","first-page":"2207","DOI":"10.3390\/genes14122207","volume":"14","author":"H Seo","year":"2023","unstructured":"Seo H, Park JH, Hwang JT, Choi HK, Park SH, Lee J. Epigenetic profiling of type 2 diabetes mellitus: an epigenome-wide association study of DNA methylation in the Korean Genome and Epidemiology Study. Genes. 2023;14:2207.","journal-title":"Genes"},{"key":"426_CR77","doi-asserted-by":"publisher","first-page":"695","DOI":"10.3390\/ijms23020695","volume":"23","author":"A Dimas","year":"2022","unstructured":"Dimas A, Politi A, Papaioannou G, Barber TM, Weickert MO, Grammatopoulos DK, et al. The gestational effects of maternal appetite axis molecules on fetal growth, metabolism and long-term metabolic health: a systematic review. Int J Mol Sci. 2022;23:695.","journal-title":"Int J Mol Sci"},{"key":"426_CR78","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1380476","volume":"15","author":"J Kopczy\u0144ska","year":"2024","unstructured":"Kopczy\u0144ska J, Kowalczyk M. The potential of short-chain fatty acid epigenetic regulation in chronic low-grade inflammation and obesity. Front Immunol. 2024;15:1380476.","journal-title":"Front Immunol"},{"key":"426_CR79","doi-asserted-by":"publisher","first-page":"2589","DOI":"10.2337\/db20-0262","volume":"69","author":"SE Martchenko","year":"2020","unstructured":"Martchenko SE, Martchenko A, Cox BJ, Naismith K, Waller A, Gurges P, et al. Circadian GLP-1 secretion in mice is dependent on the intestinal microbiome for maintenance of diurnal metabolic homeostasis. Diabetes. 2020;69:2589\u2013602.","journal-title":"Diabetes"},{"key":"426_CR80","doi-asserted-by":"publisher","first-page":"1816","DOI":"10.1016\/j.apsb.2025.03.008","volume":"15","author":"D Qian","year":"2025","unstructured":"Qian D, Xu P, Wang X, Du C, Zhao X, Xu J. Bacterial extracellular vesicles for gut microbiome\u2013host communication and drug development. Acta Pharm Sin B. 2025;15:1816\u201340.","journal-title":"Acta Pharm Sin B"},{"key":"426_CR81","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1002\/jat.4658","volume":"45","author":"P Potdar","year":"2025","unstructured":"Potdar P, Kharat A, Sanap A, Kheur S, Bhonde R. Pancreatic \u03b2 cell models for screening insulin secretagogues and cytotoxicity. J Appl Toxicol. 2025;45:89\u2013106.","journal-title":"J Appl Toxicol"},{"key":"426_CR82","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1016\/j.ejphar.2015.10.028","volume":"767","author":"L Sun","year":"2015","unstructured":"Sun L, Wang C, Dai Y, Chu Y, Han J, Zhou J, et al. Coumaglutide, a novel long-acting GLP-1 analog, inhibits \u03b2-cell apoptosis in vitro and invokes sustained glycemic control in vivo. Eur J Pharmacol. 2015;767:211\u20139.","journal-title":"Eur J Pharmacol"},{"key":"426_CR83","doi-asserted-by":"publisher","first-page":"693","DOI":"10.3390\/pharmaceutics16060693","volume":"16","author":"A Lymperopoulos","year":"2024","unstructured":"Lymperopoulos A, Borges JI, Stoicovy RA. Cyclic adenosine monophosphate in cardiac and sympathoadrenal GLP-1 receptor signaling: focus on anti-inflammatory effects. Pharmaceutics. 2024;16:693.","journal-title":"Pharmaceutics"},{"key":"426_CR84","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1038\/nrm908","volume":"3","author":"KL Pierce","year":"2002","unstructured":"Pierce KL, Premont RT, Lefkowitz RJ. Seven-transmembrane receptors. Nat Rev Mol Cell Biol. 2002;3:639\u201350.","journal-title":"Nat Rev Mol Cell Biol"},{"key":"426_CR85","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1385\/JMN:26:2-3:253","volume":"26","author":"LM Luttrell","year":"2005","unstructured":"Luttrell LM. Composition and function of g protein-coupled receptor signalsomes controlling mitogen-activated protein kinase activity. J Mol Neurosci. 2005;26:253\u201364.","journal-title":"J Mol Neurosci"},{"key":"426_CR86","doi-asserted-by":"publisher","first-page":"8582","DOI":"10.3390\/ijms23158582","volume":"23","author":"FF Jubaidi","year":"2022","unstructured":"Jubaidi FF, Zainalabidin S, Taib IS, Abdul Hamid Z, Mohamad Anuar NN, Jalil J, et al. The role of PKC-MAPK signalling pathways in the development of hyperglycemia-induced cardiovascular complications. Int J Mol Sci. 2022;23:8582.","journal-title":"Int J Mol Sci"},{"key":"426_CR87","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1016\/j.biopha.2018.02.084","volume":"101","author":"PC Chao","year":"2018","unstructured":"Chao PC, Li Y, Chang CH, Shieh JP, Cheng JT, Cheng KC. Investigation of insulin resistance in the popularly used four rat models of type-2 diabetes. Biomed Pharmacother. 2018;101:155\u201361.","journal-title":"Biomed Pharmacother"},{"key":"426_CR88","doi-asserted-by":"publisher","first-page":"1037","DOI":"10.1172\/JCI113157","volume":"80","author":"L Rossetti","year":"1987","unstructured":"Rossetti L, Shulman GI, Zawalich W, DeFronzo RA. Effect of chronic hyperglycemia on in vivo insulin secretion in partially pancreatectomized rats. J Clin Invest. 1987;80:1037\u201344.","journal-title":"J Clin Invest"},{"key":"426_CR89","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3803\/EnM.2023.103","volume":"38","author":"CH Ahn","year":"2023","unstructured":"Ahn CH, Oh TJ, Min SH, Cho YM. Incretin and pancreatic \u03b2-cell function in patients with type 2 diabetes. Endocrinol Metab. 2023;38:1\u20139.","journal-title":"Endocrinol Metab"},{"key":"426_CR90","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1016\/j.regpep.2004.07.019","volume":"128","author":"T Hansotia","year":"2005","unstructured":"Hansotia T, Drucker DJ. GIP and GLP-1 as incretin hormones: lessons from single and double incretin receptor knockout mice. Regul Pept. 2005;128:125\u201334.","journal-title":"Regul Pept"},{"key":"426_CR91","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2020.101090","volume":"46","author":"LL Baggio","year":"2021","unstructured":"Baggio LL, Drucker DJ. Glucagon-like peptide-1 receptor co-agonists for treating metabolic disease. Mol Metab. 2021;46:101090.","journal-title":"Mol Metab"},{"key":"426_CR92","doi-asserted-by":"publisher","first-page":"473","DOI":"10.3390\/biomedicines12030473","volume":"12","author":"BA Covington","year":"2024","unstructured":"Covington BA, Chen W. Animal models for understanding the mechanisms of beta cell death during type 2 diabetes pathogenesis. Biomedicines. 2024;12:473.","journal-title":"Biomedicines"},{"key":"426_CR93","doi-asserted-by":"publisher","first-page":"1341","DOI":"10.2337\/db19-1130","volume":"69","author":"L Plecit\u00e1-Hlavat\u00e1","year":"2020","unstructured":"Plecit\u00e1-Hlavat\u00e1 L, Jab\u016frek M, Holendov\u00e1 B, Tauber J, Pavluch V, Berkov\u00e1 Z, et al. Glucose-stimulated insulin secretion fundamentally requires H2O2 signaling by NADPH oxidase 4. Diabetes. 2020;69:1341\u201354.","journal-title":"Diabetes"},{"key":"426_CR94","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.molmet.2018.09.009","volume":"18","author":"T Coskun","year":"2018","unstructured":"Coskun T, Sloop KW, Loghin C, Alsina-Fernandez J, Urva S, Bokvist KB, et al. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept. Mol Metab. 2018;18:3\u201314.","journal-title":"Mol Metab"},{"key":"426_CR95","doi-asserted-by":"publisher","first-page":"E1038","DOI":"10.1152\/ajpendo.00665.2010","volume":"300","author":"A Lund","year":"2011","unstructured":"Lund A, Vilsb\u00f8ll T, Bagger JI, Holst JJ, Knop FK. The separate and combined impact of the intestinal hormones, GIP, GLP-1, and GLP-2, on glucagon secretion in type 2 diabetes. Am J Physiol-Endocrinol Metab. 2011;300:E1038\u2013E1046.","journal-title":"Am J Physiol-Endocrinol Metab"},{"key":"426_CR96","doi-asserted-by":"publisher","first-page":"30","DOI":"10.2337\/dc07-1616","volume":"31","author":"J Rosenstock","year":"2008","unstructured":"Rosenstock J, Foley JE, Rendell M, Landin-Olsson M, Holst JJ, Deacon CF, et al. Effects of the dipeptidyl peptidase-IV inhibitor vildagliptin on incretin hormones, islet function, and postprandial glycemia in subjects with impaired glucose tolerance. Diab Care. 2008;31:30\u201335.","journal-title":"Diab Care"},{"key":"426_CR97","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1007\/s00125-017-4500-3","volume":"61","author":"M Solimena","year":"2018","unstructured":"Solimena M, Schulte AM, Marselli L, Ehehalt F, Richter D, Kleeberg M, et al. Systems biology of the IMIDIA biobank from organ donors and pancreatectomised patients defines a novel transcriptomic signature of islets from individuals with type 2 diabetes. Diabetologia. 2018;61:641\u201357.","journal-title":"Diabetologia"},{"key":"426_CR98","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-020-02006-2","volume":"21","author":"B Marquina-Sanchez","year":"2020","unstructured":"Marquina-Sanchez B, Fortelny N, Farlik M, Vieira A, Collombat P, Bock C, et al. Single-cell RNA-seq with spike-in cells enables accurate quantification of cell-specific drug effects in pancreatic islets. Genome Biol. 2020;21:106.","journal-title":"Genome Biol"},{"key":"426_CR99","doi-asserted-by":"publisher","first-page":"e230404","DOI":"10.1530\/JOE-23-0404","volume":"262","author":"X Huang","year":"2024","unstructured":"Huang X, Liu J, Peng G, Lu M, Zhou Z, Jiang N, et al. Gut hormone multi-agonists for the treatment of type 2 diabetes and obesity: advances and challenges. J Endocrinol. 2024;262:e230404.","journal-title":"J Endocrinol"},{"key":"426_CR100","doi-asserted-by":"publisher","first-page":"199","DOI":"10.7326\/ANNALS-24-01590","volume":"178","author":"A Moiz","year":"2025","unstructured":"Moiz A, Filion KB, Toutounchi H, Tsoukas MA, Yu OHY, Peters TM, et al. Efficacy and safety of glucagon-like peptide-1 receptor agonists for weight loss among adults without diabetes: a systematic review of randomized controlled trials. Ann Intern Med. 2025;178:199\u2013217.","journal-title":"Ann Intern Med"},{"key":"426_CR101","doi-asserted-by":"publisher","unstructured":"Saini K, Sharma S, Khan Y. DPP-4 inhibitors for treating T2DM - hype or hope? an analysis based on the current literature. Front Mol Biosci. 2023;10. https:\/\/doi.org\/10.3389\/fmolb.2023.1130625.","DOI":"10.3389\/fmolb.2023.1130625"},{"key":"426_CR102","doi-asserted-by":"publisher","first-page":"1793","DOI":"10.3390\/medicina60111793","volume":"60","author":"F Epelde","year":"2024","unstructured":"Epelde F. Transforming diabetes care: the expanding role of DPP-4 inhibitors in cardiovascular and renal protection. Medicina. 2024;60:1793.","journal-title":"Medicina"},{"key":"426_CR103","first-page":"21","volume":"20","author":"M Nauck","year":"2018","unstructured":"Nauck M, Meier J. Incretin hormones: their role in health and disease. Diabetes. 2018;20:21\u20135.","journal-title":"Diabetes"},{"key":"426_CR104","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1038\/s41392-024-01931-z","volume":"9","author":"Z Zheng","year":"2024","unstructured":"Zheng Z, Zong Y, Ma Y, Tian Y, Pang Y, Zhang C, et al. Glucagon-like peptide-1 receptor: mechanisms and advances in therapy. Sig Transduct Target Ther. 2024;9:234.","journal-title":"Sig Transduct Target Ther"},{"key":"426_CR105","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1038\/nrneph.2016.170","volume":"13","author":"RA DeFronzo","year":"2017","unstructured":"DeFronzo RA, Norton L, Abdul-Ghani M. Renal, metabolic and cardiovascular considerations of SGLT2 inhibition. Nat Rev Nephrol. 2017;13:11\u201326.","journal-title":"Nat Rev Nephrol"},{"key":"426_CR106","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1056\/NEJMoa2107519","volume":"385","author":"JP Fr\u00edas","year":"2021","unstructured":"Fr\u00edas JP, Davies MJ, Rosenstock J, Manghi FCP, Land\u00f3 LF, Bergman BK, et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med. 2021;385:503\u201315.","journal-title":"N Engl J Med"},{"key":"426_CR107","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1016\/j.cmet.2013.04.008","volume":"17","author":"JE Campbell","year":"2013","unstructured":"Campbell JE, Drucker DJ. Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metab. 2013;17:819\u201337.","journal-title":"Cell Metab"}],"container-title":["Nutrition &amp; Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41387-026-00426-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41387-026-00426-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41387-026-00426-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:02:44Z","timestamp":1782777764000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41387-026-00426-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,6]]},"references-count":107,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["426"],"URL":"https:\/\/doi.org\/10.1038\/s41387-026-00426-w","relation":{},"ISSN":["2044-4052"],"issn-type":[{"value":"2044-4052","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,6]]},"assertion":[{"value":"5 May 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 April 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 April 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 May 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"19"}}