{"doi":"10.1111/dom.16652","title":"Binding kinetics, bias, receptor internalization and effects on insulin secretion in vitro and in vivo of a novel <scp>GLP</scp> ‐ <scp>1R</scp> / <scp>GIPR</scp> dual agonist, <scp>HISHS</scp> ‐2001","abstract":"Abstract Aims The use of incretin analogues has emerged as an effective approach to achieve both enhanced insulin secretion and weight loss in Type 2 diabetes (T2D) patients. Agonists which bind and stimulate multiple receptors have shown particular promise. However, off‐target effects remain a complication of using these agents, and modified versions with optimised pharmacological profiles and/or biased signalling are sought. Materials and Methods Ligand synthesis was achieved using standard solid‐phase techniques. Assessments of GLP‐1R‐binding kinetics, G protein recruitment and receptor internalisation were performed using biochemical and imaging approaches. Insulin secretion was measured in purified mouse and human islets, and drug efficacy was assessed in hyperglycaemic db/db mice. Results We describe the synthesis and properties of a molecule which binds to both glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP) receptors (GLP‐1R and GIPR) to enhance insulin secretion. HISHS‐2001 shows increased affinity at the GLP‐1R, as well as a tendency towards reduced internalisation and recycling at this receptor versus FDA‐approved dual GLP‐1R/GIPR agonist tirzepatide. HISHS‐2001 also displayed significantly greater bias towards cAMP generation versus β‐arrestin 2 recruitment compared to tirzepatide. In contrast, G α s recruitment was lower versus tirzepatide at the GLP‐1R, but unchanged at the GIPR. Administered to obese hyperglycaemic db/db mice, HISHS‐2001 increased circulating insulin whilst lowering body weight and HbA1c with similar efficacy to tirzepatide at substantially lower doses. Conclusion HISHS‐2001 represents a novel dual receptor agonist with a promising pharmacological profile and actions. Future clinical studies will be needed to assess the safety and efficacy of this molecule in humans.","journal":"Diabetes Obesity and Metabolism","year":2025,"id":553915,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9562,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":260262,"name":"Ben Jones","orcid":"0000-0003-0461-2584","position":1,"is_corresponding":false},{"id":483198,"name":"Gaëlle Carrat","orcid":"0000-0003-1189-3441","position":2,"is_corresponding":false},{"id":1450799,"name":"Zenouska Ramchunder","orcid":"0009-0008-0194-2311","position":3,"is_corresponding":false},{"id":262816,"name":"Piero Marchetti","orcid":"0000-0003-4907-0635","position":4,"is_corresponding":false},{"id":350919,"name":"Isabelle Leclerc","orcid":"0000-0003-0044-7921","position":5,"is_corresponding":false},{"id":1451243,"name":"Rajamannar Thennati","orcid":null,"position":6,"is_corresponding":false},{"id":1450800,"name":"Vinod Burade","orcid":"0009-0008-3710-3667","position":7,"is_corresponding":false},{"id":1451244,"name":"Muthukumaran Natarajan","orcid":null,"position":8,"is_corresponding":false},{"id":1451245,"name":"Pradeep Shahi","orcid":null,"position":9,"is_corresponding":false},{"id":260266,"name":"Alejandra Tomás","orcid":"0000-0002-2290-8453","position":10,"is_corresponding":false},{"id":350920,"name":"Guy A. Rutter","orcid":"0000-0001-6360-0343","position":11,"is_corresponding":false},{"id":1450798,"name":"Yusman Manchanda","orcid":"0000-0002-2874-5608","position":0,"is_corresponding":true}],"reference_count":33,"raw_metadata":null,"created_at":"2026-07-19T02:54:45.872391Z","pmid":"40831316","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}