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Although insulin and metformin formulations have long constituted the foundation of diabetes care, a paradigm shift in T2D management has been observed with the advent of novel pharmacotherapies. Gut peptide analogues are at the forefront of this transformation. The emergence of glucagon-like peptide-1 (GLP-1) receptor agonists represents a watershed moment, fundamentally reshaping the therapeutic landscape for both T2D and obesity due to multifaceted metabolic benefits. The clinical success of GLP-1-based therapies has stimulated pharmaceutical interest in other metabolic peptides. Gut-pancreatic peptides such as glucose-dependent insulinotropic polypeptide, glucagon, amylin, and peptide YY are of particular interest due to their distinct pharmacological benefits and therapeutic promise in metabolic disorders. The present review aims to provide a comprehensive and current overview of non-insulin gut-pancreatic peptide signalling-based therapies that are either clinically approved or under clinical investigation, with a focus on the emerging therapeutic convergence between T2D, obesity, and associated liver disease. The review critically narrates their mechanisms of action, therapeutic efficacy, limitations, current development status, and positioning in the treatment landscape. Furthermore, the review delineates the emerging avenues in the development of novel peptide-based pharmacotherapies, offering insights into their future potential and acquainting the reader with developments in non-insulin gut-pancreatic peptide signalling-based therapies for metabolic disorders.<\/jats:p>","DOI":"10.1042\/bsr20250114","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T12:23:37Z","timestamp":1781699017000},"update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The evolving therapeutic landscape of gut-pancreatic peptide signalling in metabolic disorders: from mono- to multi-agonist therapies"],"prefix":"10.1042","volume":"46","author":[{"given":"Mohan","family":"Patil","sequence":"first","affiliation":[{"name":"1Molecular Endocrinology and Pharmacology, Harry Perkins Institute of Medical Research and Centre for Medical Research, The University of Western Australia, Nedlands, WA, Australia"},{"name":"2School of Biomedical Sciences, The University of Western Australia, Nedlands, WA, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Piccinini","sequence":"additional","affiliation":[{"name":"3Department of Medicine and Surgery, University of Parma, Parma 43125, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth\u00a0K.M.","family":"Johnstone","sequence":"additional","affiliation":[{"name":"1Molecular Endocrinology and Pharmacology, Harry Perkins Institute of Medical Research and Centre for Medical Research, The University of Western Australia, Nedlands, WA, Australia"},{"name":"2School of Biomedical Sciences, The University of Western Australia, Nedlands, WA, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Casari","sequence":"additional","affiliation":[{"name":"3Department of Medicine and Surgery, University of Parma, Parma 43125, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9801-7235","authenticated-orcid":false,"given":"Marco","family":"Falasca","sequence":"additional","affiliation":[{"name":"1Molecular Endocrinology and Pharmacology, Harry Perkins Institute of Medical Research and Centre for Medical Research, The University of Western Australia, Nedlands, WA, Australia"},{"name":"2School of Biomedical Sciences, The University of Western Australia, Nedlands, WA, Australia"},{"name":"3Department of Medicine and Surgery, University of Parma, Parma 43125, Italy"},{"name":"4Lipovexa SRL, Via Giuseppe Mangionello, 12, 73024 Maglie (LE), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2026,7,16]]},"reference":[{"key":"2026071605414228800_B1","doi-asserted-by":"publisher","first-page":"9084","DOI":"10.3390\/cimb45110570","article-title":"The interconnection between hepatic insulin resistance and metabolic dysfunction-associated steatotic liver disease\u2014the transition from an adipocentric to liver-centric approach","volume":"45","author":"Veskovi\u0107","year":"2023","journal-title":"Curr. 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