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Agonists which bind and stimulate multiple receptors have shown particular promise. However, off\u2010target effects remain a complication of using these agents, and modified versions with optimised pharmacological profiles and\/or biased signalling are sought.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and Methods<\/jats:title>\n                    <jats:p>\n                      Ligand synthesis was achieved using standard solid\u2010phase techniques. Assessments of GLP\u20101R\u2010binding 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\n                      <jats:italic>db\/db<\/jats:italic>\n                      mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We describe the synthesis and properties of a molecule which binds to both glucagon\u2010like peptide\u20101 (GLP\u20101) and glucose\u2010dependent insulinotropic polypeptide (GIP) receptors (GLP\u20101R and GIPR) to enhance insulin secretion. HISHS\u20102001 shows increased affinity at the GLP\u20101R, as well as a tendency towards reduced internalisation and recycling at this receptor versus FDA\u2010approved dual GLP\u20101R\/GIPR agonist tirzepatide. HISHS\u20102001 also displayed significantly greater bias towards cAMP generation versus \u03b2\u2010arrestin 2 recruitment compared to tirzepatide. In contrast, G\n                      <jats:sub>\u03b1<\/jats:sub>\n                      s recruitment was lower versus tirzepatide at the GLP\u20101R, but unchanged at the GIPR. Administered to obese hyperglycaemic\n                      <jats:italic>db\/db<\/jats:italic>\n                      mice, HISHS\u20102001 increased circulating insulin whilst lowering body weight and HbA1c with similar efficacy to tirzepatide at substantially lower doses.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>HISHS\u20102001 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/dom.16652","type":"journal-article","created":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T07:26:36Z","timestamp":1755674796000},"page":"5938-5949","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Binding kinetics, bias, receptor internalization and effects on insulin secretion in vitro and in vivo of a novel\n                    <scp>GLP<\/scp>\n                    \u2010\n                    <scp>1R<\/scp>\n                    \/\n                    <scp>GIPR<\/scp>\n                    dual agonist,\n                    <scp>HISHS<\/scp>\n                    \u20102001"],"prefix":"10.1111","volume":"27","author":[{"given":"Yusman","family":"Manchanda","sequence":"first","affiliation":[{"name":"Section of Cell Biology and Functional Genomics, 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