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  • Review Article
  • Published:

Islet G protein-coupled receptors as potential targets for treatment of type 2 diabetes

A Corrigendum to this article was published on 01 August 2009

A Corrigendum to this article was published on 01 June 2009

Key Points

  • Islet dysfunction underlies the pathophysiology of type 2 diabetes and is characterized by defective insulin secretion, inappropriately high glucagon secretion and reduced b-cell mass.

  • Several guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) are expressed in islet β-cells and contribute to the regulation of islet function, thereby representing potential therapeutic targets.

  • The most important islet incretin hormone GPCRs are glucagon-like peptide 1 (GLP1) receptors and glucose-dependent insulinotropic peptide receptors, which both signal potentiation of glucose-stimulated insulin secretion.

  • GLP1 mimetics and dipeptidyl peptidase 4 inhibitors promote activation of the GLP1 receptors and are currently applied in the treatment of type 2 diabetes.

  • GPR40 and GPR119 are islet lipid GPCRs that signal the potentiation of glucose-stimulated insulin secretion. They are currently being explored as therapeutic targets, particularly because GPR40 and GPR119 agonists also stimulate the release of GLP1 from the gut.

  • Although currently less successful than incretin hormone and lipid GPCRs, other islet GPCRs that are of potential interest as therapeutic targets include the islet pleiotropic GPCRs (glucagon receptors, receptors for pituitary adenylate cyclase activating polypeptide and vasoactive intestinal polypeptide, neuropeptide Y receptors, ghrelin receptors and GPR54); the biogenic amine receptors (adrenergic and melatonin receptors); and the muscarinic, endocannabinoid and purinergic receptors.

  • This Review summarizes islet GPCRs expression, signalling and function, and highlights their individual potential as targets for the future treatment of type 2 diabetes.

Abstract

Islet dysfunction — characterized by a combination of defective insulin secretion, inappropriately high glucagon secretion and reduced β-cell mass — has a central role in the pathophysiology of type 2 diabetes. Several G protein-coupled receptors (GPCRs) expressed in islet β-cells are known to be involved in the regulation of islet function, and therefore are potential therapeutic targets. This is evident from the recent success of glucagon-like peptide 1 (GLP1) mimetics and dipeptidyl peptidase 4 (DPP4) inhibitors, which promote activation of the GLP1 receptor to stimulate insulin secretion and inhibit glucagon secretion, and also have the potential to increase β-cell mass. Other islet β-cell GPCRs that are involved in the regulation of islet function include the glucose-dependent insulinotropic peptide (GIP) receptor, lipid GPCRs, pleiotropic peptide GPCRs and islet biogenic amine GPCRs. This Review summarizes islet GPCR expression, signalling and function, and highlights their potential as targets for the treatment of type 2 diabetes.

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Figure 1: Schematic view of the control of prandial circulating glucose levels.
Figure 2: Schematic overview of the cellular processes that are involved in stimulating insulin secretion from pancreatic β-cells.
Figure 3: Schematic role of glucagon-like peptide 1 (GLP1) as an anti-diabetic agent.

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DATABASES

OMIM

type 2 diabetes

Glossary

Glycated haemoglobin A1c

A measure of blood glucose concentration.

Tachyphylaxis (desensitization)

Diminution or waning of response upon repeated or sustained stimulation of a receptor by a ligand.

Orthosteric binding

Binding of a ligand to a receptor.

Allosteric binding

Binding of more than one ligand at different sites on a receptor, resulting in complex action.

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Ahrén, B. Islet G protein-coupled receptors as potential targets for treatment of type 2 diabetes. Nat Rev Drug Discov 8, 369–385 (2009). https://doi.org/10.1038/nrd2782

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