Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist.
JCI Insight
; 5(17)2020 09 03.
Article
em En
| MEDLINE
| ID: mdl-32730231
ABSTRACT
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 ß-arrestin recruitment, coincident with a weaker ability to drive GLP-1 receptor internalization compared with GLP-1. Experiments in primary islets reveal ß-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.
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Base de dados:
MEDLINE
Assunto principal:
Glicemia
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Receptores dos Hormônios Gastrointestinais
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Polipeptídeo Inibidor Gástrico
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Ilhotas Pancreáticas
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Receptor do Peptídeo Semelhante ao Glucagon 1
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Hipoglicemiantes
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Insulina
Limite:
Animals
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article