Coskun T, Sloop KW, Loghin C, 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;18:3–14. https://doi.org/10.1016/j.molmet.2018.09.009.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Mounjaro, Prescribing Information. Lilly USA, LLC. 2022.

Zepbound. Prescribing information. Lilly USA, LLC. 2023.

Zepbound. Prescribing information. Lilly USA, LLC. 2024.

Loomba R, Hartman ML, Lawitz EJ, et al. Tirzepatide for metabolic dysfunction-associated steatohepatitis with liver fibrosis. N Engl J Med. 2024;391(4):299–310. https://doi.org/10.1056/NEJMoa2401943.

Article  CAS  PubMed  Google Scholar 

Packer M, Zile MR, Kramer CM, et al. Tirzepatide for heart failure with preserved ejection fraction and obesity. N Engl J Med. 2025;392(5):427–37. https://doi.org/10.1056/NEJMoa2410027.

Article  CAS  PubMed  Google Scholar 

Newswire Press. Lilly’s Mounjaro (tirzepatide), a GIP/GLP-1 dual agonist, demonstrated cardiovascular protection in landmark head-to-head trial, reinforcing its benefit in patients with type 2 diabetes and heart disease 2025 [Press release]. Available from: https://www.prnewswire.com/news-releases/lillys-mounjaro-tirzepatide-a-gipglp-1-dual-agonist-demonstrated-cardiovascular-protection-in-landmark-head-to-head-trial-reinforcing-its-benefit-in-patients-with-type-2-diabetes-and-heart-disease-302517872.html. Last Accessed 28 August 2025.

Nauck MA, Quast DR, Wefers J, Pfeiffer AFH. The evolving story of incretins (GIP and GLP-1) in metabolic and cardiovascular disease: a pathophysiological update. Diabetes Obes Metab. 2021;23(Suppl 3):5–29. https://doi.org/10.1111/dom.14496.

Article  CAS  PubMed  Google Scholar 

Kanoski SE, Hayes MR, Skibicka KP. GLP-1 and weight loss: unraveling the diverse neural circuitry. Am J Physiol Regul Integr Comp Physiol. 2016;310(10):R885–95. https://doi.org/10.1152/ajpregu.00520.2015.

Article  PubMed  PubMed Central  Google Scholar 

Tschöp M, Nogueiras R, Ahrén B. Gut hormone-based pharmacology: novel formulations and future possibilities for metabolic disease therapy. Diabetologia. 2023;66(10):1796–808. https://doi.org/10.1007/s00125-023-05929-0.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Holst JJ, Ørskov C, Vagn Nielsen O, Schwartz TW. Truncated glucagon-like peptide I, an insulin-releasing hormone from the distal gut. FEBS Lett. 1987;211(2):169–74. https://doi.org/10.1016/0014-5793(87)81430-8.

Article  CAS  PubMed  Google Scholar 

Kreymann B, Williams G, Ghatei MA, Bloom SR. Glucagon-like peptide-1 7-36: a physiological incretin in man. Lancet. 1987;2(8571):1300–94. https://doi.org/10.1016/s0140-6736(87)91194-9.

Article  CAS  PubMed  Google Scholar 

Schirra J, Leicht P, Hildebrand P, et al. Mechanisms of the antidiabetic action of subcutaneous glucagon-like peptide-1(7–36)amide in non-insulin dependent diabetes mellitus. J Endocrinol. 1998;156(1):177–86. https://doi.org/10.1677/joe.0.1560177.

Article  CAS  PubMed  Google Scholar 

I˙meryüz N, Yeğen BÇ, Bozkurt A, Coşkun T, Villanueva-Peñacarrillo ML, Ulusoy NB. Glucagon-like peptide-1 inhibits gastric emptying via vagal afferent-mediated central mechanisms. Am J Physiol. 1997;273(4):G920–7. https://doi.org/10.1152/ajpgi.1997.273.4.G920.

Article  PubMed  Google Scholar 

Urva S, Coskun T, Loghin C, et al. 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. Diabetes Obes Metab. 2020;22(10):1886–91. https://doi.org/10.1111/dom.14110.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Jalleh RJ, Plummer MP, Marathe CS, et al. Clinical consequences of delayed gastric emptying with GLP-1 receptor agonists and tirzepatide. J Clin Endocrinol Metab. 2024;110(1):1–15. https://doi.org/10.1210/clinem/dgae719.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Knop FK, Urva S, Rettiganti M, et al. A long-acting glucose-dependent insulinotropic polypeptide receptor agonist improves the gastrointestinal tolerability of glucagon-like peptide-1 receptor agonist therapy. Diabetes Obes Metab. 2024;26(11):5474–8. https://doi.org/10.1111/dom.15875.

Article  CAS  PubMed  Google Scholar 

Schulz C, Vezzani C, Kroemer NB. How gut hormones shape reward: a systematic review of the role of ghrelin and GLP-1 in human fMRI. Physiol Behav. 2023;263:114111. https://doi.org/10.1016/j.physbeh.2023.114111.

Article  CAS  PubMed  Google Scholar 

Sisley S, Gutierrez-Aguilar R, Scott M, D’Alessio DA, Sandoval DA, Seeley RJ. Neuronal GLP1R mediates liraglutide’s anorectic but not glucose-lowering effect. J Clin Invest. 2014;124(6):2456–63. https://doi.org/10.1172/JCI72434.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Secher A, Jelsing J, Baquero AF, et al. The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss. J Clin Invest. 2014;124(10):4473–88. https://doi.org/10.1172/JCI75276.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Liskiewicz A, Khalil A, Liskiewicz D, et al. Glucose-dependent insulinotropic polypeptide regulates body weight and food intake via GABAergic neurons in mice. Nat Metab. 2023;5(12):2075–85. https://doi.org/10.1038/s42255-023-00931-7.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Huang K-P, Acosta AA, Ghidewon MY, et al. Dissociable hindbrain GLP1R circuits for satiety and aversion. Nature. 2024;632(8025):585–93. https://doi.org/10.1038/s41586-024-07685-6.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Turton MD, O’Shea D, Gunn I, et al. A role for glucagon-like peptide-1 in the central regulation of feeding. Nature. 1996;379(6560):69–72. https://doi.org/10.1038/379069a0.

Article  CAS  PubMed  Google Scholar 

Nyberg J, Jacobsson C, Anderson MF, Eriksson PS. Immunohistochemical distribution of glucose-dependent insulinotropic polypeptide in the adult rat brain. J Neurosci Res. 2007;85(10):2099–119. https://doi.org/10.1002/jnr.21349.

Article  CAS  PubMed  Google Scholar 

Adriaenssens AE, Biggs EK, Darwish T, et al. Glucose-dependent insulinotropic polypeptide receptor-expressing cells in the hypothalamus regulate food intake. Cell Metabol. 2019;30(5):987-996.e6. https://doi.org/10.1016/j.cmet.2019.07.013.

Article  CAS  Google Scholar 

Samms RJ, Sloop KW, Gribble FM, Reimann F, Adriaenssens AE. GIPR function in the central nervous system: implications and novel perspectives for GIP-based therapies in treating metabolic disorders. Diabetes. 2021;70(9):1938–44. https://doi.org/10.2337/dbi21-0002.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Zhang Q, Delessa CT, Augustin R, et al. The glucose-dependent insulinotropic polypeptide (GIP) regulates body weight and food intake via CNS-GIPR signaling. Cell Metab. 2021;33(4):833-844.e5. https://doi.org/10.1016/j.cmet.2021.01.015.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Wean J, Kowalsky AH, Laker R, et al. Specific loss of GIPR signaling in GABAergic neurons enhances GLP-1R agonist-induced body weight loss. Mol Metab. 2025;95:102074. https://doi.org/10.1016/j.molmet.2024.102074.

Article  CAS  PubMed  Google Scholar 

Yip RGC, Boylan MO, Kieffer TJ, Wolfe MM. Functional GIP receptors are present on adipocytes. Endocrinology. 1998;139(9):4004–7. https://doi.org/10.1210/endo.139.9.6288.

Article  CAS  PubMed  Google Scholar 

Song DH, Getty-Kaushik L, Tseng E, Simon J, Corkey BE, Wolfe MM. Glucose-dependent insulinotropic polypeptide enhances adipocyte development and glucose uptake in part through Akt activation. Gastroenterology. 2007;133(6):1796–805. https://doi.org/10.1053/j.gastro.2007.09.005.

Article