GLP-1 and GIP receptor signaling in beta cells – A review of receptor interactions and co-stimulation

Jan 22, 2022Peptides

How GLP-1 and GIP Receptors Work Together to Stimulate Insulin-Producing Beta Cells

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Abstract

GLP-1R and GIPR activation in pancreatic beta cells leads to increased cyclic adenosine monophosphate (cAMP) and glucose-dependent insulin secretion.

GLP-1R and GIPR are stimulated by the hormones GLP-1 and GIP, respectively.
Marketed GLP-1R agonists may provide benefits for individuals with type 2 diabetes and obesity.
Tirzepatide, a GLP-1R-GIPR co-agonist, shows potential for improved glycemic control and weight loss.
The mechanisms of action for tirzepatide involve biased signaling of GLP-1R and potent GIPR signaling.
Understanding the pharmacodynamic mechanisms and signaling pathways of GLP-1R-GIPR co-agonists remains incomplete.

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Glucagon-like peptide 1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) are two class B1 G protein-coupled receptors, which are stimulated by the gastrointestinal hormones GLP-1 and GIP, respectively. In the pancreatic beta cells, activation of both receptors lead to increased cyclic adenosine monophosphate (cAMP) and glucose-dependent insulin secretion. Marketed GLP-1R agonists such as dulaglutide, liraglutide, exenatide and semaglutide constitute an expanding drug class with beneficial effects for persons suffering from type 2 diabetes and/or obesity. In recent years another drug class, the GLP-1R-GIPR co-agonists, has emerged. Especially the peptide-based, co-agonist tirzepatide is a promising candidate for a better treatment of type 2 diabetes by improving glycemic control and weight reduction. The mechanism of action for tirzepatide include biased signaling of the GLP-1R as well as potent GIPR signaling. Since the implications of co-targeting these closely related receptors concomitantly are challenging to study in vivo, the pharmacodynamic mechanisms and downstream signaling pathways of the GLP-1R-GIPR co-agonists in general, are not fully elucidated. In this review, we present the individual signaling pathways for GLP-1R and GIPR in the pancreatic beta cell with a focus on the shared signaling pathways of the two receptors and interpret the implications of GLP-1R-GIPR co-activation in the light of recent co-activating therapeutic compounds.

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GLP-1 and GIP receptor signaling in beta cells – A review of receptor interactions and co-stimulation

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