PMID- 32730231 OWN - NLM STAT- MEDLINE DCOM- 20210616 LR - 20240214 IS - 2379-3708 (Electronic) IS - 2379-3708 (Linking) VI - 5 IP - 17 DP - 2020 Sep 3 TI - Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. LID - 140532 [pii] LID - 10.1172/jci.insight.140532 [doi] LID - e140532 AB - Tirzepatide (LY3298176) is a dual GIP and GLP-1 receptor agonist under development for the treatment of type 2 diabetes mellitus (T2DM), obesity, and nonalcoholic steatohepatitis. Early phase trials in T2DM indicate that tirzepatide improves clinical outcomes beyond those achieved by a selective GLP-1 receptor agonist. Therefore, we hypothesized that the integrated potency and signaling properties of tirzepatide provide a unique pharmacological profile tailored for improving broad metabolic control. Here, we establish methodology for calculating occupancy of each receptor for clinically efficacious doses of the drug. This analysis reveals a greater degree of engagement of tirzepatide for the GIP receptor than the GLP-1 receptor, corroborating an imbalanced mechanism of action. Pharmacologically, signaling studies demonstrate that tirzepatide mimics the actions of native GIP at the GIP receptor but shows bias at the GLP-1 receptor to favor cAMP generation over beta-arrestin recruitment, coincident with a weaker ability to drive GLP-1 receptor internalization compared with GLP-1. Experiments in primary islets reveal beta-arrestin1 limits the insulin response to GLP-1, but not GIP or tirzepatide, suggesting that the biased agonism of tirzepatide enhances insulin secretion. Imbalance toward GIP receptor, combined with distinct signaling properties at the GLP-1 receptor, together may account for the promising efficacy of this investigational agent. FAU - Willard, Francis S AU - Willard FS AD - Quantitative Biology, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA. FAU - Douros, Jonathan D AU - Douros JD AD - Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA. FAU - Gabe, Maria Bn AU - Gabe MB AD - Department of Biomedical Sciences and NNF Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark. FAU - Showalter, Aaron D AU - Showalter AD AD - Diabetes and Complications, and. FAU - Wainscott, David B AU - Wainscott DB AD - Quantitative Biology, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA. FAU - Suter, Todd M AU - Suter TM AD - Diabetes and Complications, and. FAU - Capozzi, Megan E AU - Capozzi ME AD - Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA. FAU - van der Velden, Wijnand Jc AU - van der Velden WJ AD - Department of Biomedical Sciences and NNF Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark. FAU - Stutsman, Cynthia AU - Stutsman C AD - Diabetes and Complications, and. FAU - Cardona, Guemalli R AU - Cardona GR AD - Quantitative Biology, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA. FAU - Urva, Shweta AU - Urva S AD - PK/PD & Pharmacometrics, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA. FAU - Emmerson, Paul J AU - Emmerson PJ AD - Diabetes and Complications, and. FAU - Holst, Jens J AU - Holst JJ AD - Department of Biomedical Sciences and NNF Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark. FAU - D'Alessio, David A AU - D'Alessio DA AD - Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA. FAU - Coghlan, Matthew P AU - Coghlan MP AD - Diabetes and Complications, and. FAU - Rosenkilde, Mette M AU - Rosenkilde MM AD - Department of Biomedical Sciences and NNF Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark. FAU - Campbell, Jonathan E AU - Campbell JE AD - Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA. FAU - Sloop, Kyle W AU - Sloop KW AD - Diabetes and Complications, and. LA - eng GR - F32 DK116542/DK/NIDDK NIH HHS/United States GR - T32 DK007012/DK/NIDDK NIH HHS/United States GR - F32 DK115031/DK/NIDDK NIH HHS/United States GR - R01 DK101991/DK/NIDDK NIH HHS/United States GR - R01 DK123075/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20200903 PL - United States TA - JCI Insight JT - JCI insight JID - 101676073 RN - 0 (Arrb1 protein, mouse) RN - 0 (Blood Glucose) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Hypoglycemic Agents) RN - 0 (Insulin) RN - 0 (Receptors, Gastrointestinal Hormone) RN - 0 (beta-Arrestin 1) RN - 59392-49-3 (Gastric Inhibitory Polypeptide) RN - D6H00MV7K8 (gastric inhibitory polypeptide receptor) RN - OYN3CCI6QE (tirzepatide) SB - IM MH - Animals MH - Blood Glucose/*metabolism MH - Gastric Inhibitory Polypeptide/*pharmacology MH - Glucagon-Like Peptide-1 Receptor/*agonists MH - Hypoglycemic Agents/*pharmacology MH - Insulin/*metabolism MH - Islets of Langerhans/*drug effects/metabolism/pathology MH - Male MH - Mice MH - Mice, Knockout MH - Receptors, Gastrointestinal Hormone/*agonists MH - beta-Arrestin 1/physiology PMC - PMC7526454 OTO - NOTNLM OT - Diabetes OT - Therapeutics COIS- Conflict of interest: FSW, ADS, DBW, TMS, CS, GRC, SU, PJE, MPC, and KWS are employees of Eli Lilly and Company and may own company stock. JEC and DAD receive research support from Eli Lilly and Company. DAD participates on the Diabetes Advisory Board for Eli Lilly and Company and the steering committee for the tirzepatide CVOT. MMR is a minority shareholder of and consultant for Antag Therapeutics, Bainan Biotech, and Synklino and is a coinventor on patents covering GIPR ligands and dual-acting GIP/GLP-2 agonists. JJH is a minority shareholder and board member of Antag Therapeutics and Bainan Biotech and has been a consultant for, has served on scientific advisory panels of, and has been speaker honoraria for Novo Nordisk and MSD/Merck. JJH is a coinventor on patents covering GIPR ligands and dual-acting GIP/GLP-2 agonists. EDAT- 2020/07/31 06:00 MHDA- 2021/06/17 06:00 PMCR- 2020/09/03 CRDT- 2020/07/31 06:00 PHST- 2020/05/26 00:00 [received] PHST- 2020/07/22 00:00 [accepted] PHST- 2020/07/31 06:00 [pubmed] PHST- 2021/06/17 06:00 [medline] PHST- 2020/07/31 06:00 [entrez] PHST- 2020/09/03 00:00 [pmc-release] AID - 140532 [pii] AID - 10.1172/jci.insight.140532 [doi] PST - epublish SO - JCI Insight. 2020 Sep 3;5(17):e140532. doi: 10.1172/jci.insight.140532.