Journal Article

G protein-coupled receptors as targets for anti-diabetic therapeutics

Olefsky, Jerrold M., Oh, Da Young

2016

Overview

Key Points G protein-coupled receptors (GPCRs) can affect insulin action, insulin secretion and β-cell expansion, and certain GPCRs have emerged as potential drug targets for the development of anti-diabetic therapeutics. Decreased insulin sensitivity is a major metabolic defect in the great majority of individualswith type 2 diabetes (T2D), and one of the key mechanisms underlying insulin resistance is chronic tissue inflammation. Leukotriene B4 (LTB4) receptor 1 (LTB4R1) inhibitors may be anti-diabetic insulin sensitizers, as they inhibit inflammation and directly block the capacity of LTB4 to impair cellular insulin signalling in hepatocytes and myocytes. The long-chain fatty acid receptors, free fatty acid receptor 1 (FFAR1, also known as GPR40) and FFAR4 (also known as GPR120), mediate beneficial effects by promoting glucose-induced insulin secretion or by inhibiting inflammatory signalling in immune cells, respectively. The stimulation of β-cell glucose-dependent insulinotropic receptor (GPR119) leads directly to an increase in insulin secretion, and agonism of GPR119 on enteroendocrine cells promotes both glucagon-like peptide 1 (GLP1) and gastric inhibitory polypeptide (GIP) release. Therefore, GPR119 could be an important anti-diabetic drug target to promote insulin secretion. Administration of exogenous CX3C-chemokine ligand 1 (CX3CL1, also known as fractalkine) to mice strikingly improves glucose tolerance and enhances β-cell insulin secretion. CX3CL1 and its receptor, CX3CR1, could be new targets used to positively influence β-cell function, and CX3CL1-based reagents might be future therapeutic approaches to anti-diabetes therapy. Modulators of glucagon-like peptide 1 (GLP1) and the resulting G protein-coupled receptor (GPCR) signalling have recently come to the fore of the treatment of type 2 diabetes. In this Opinion article, Oh and Olefsky discuss the potential for intervention with other GPCRs for the treatment of this disease, highlighting GPCR-mediated effects on insulin secretion, insulin sensitivity and inflammation. The prevalence of obesity and type 2 diabetes (T2D) is increasing worldwide, and these two metabolic disorders are closely linked. Lifestyle modification, including weight loss and exercise, are effective treatments for T2D, but, unfortunately, most patients are unsuccessful at maintaining durable weight reduction and recidivism is all too common. Therefore, safe and efficacious drugs are required for the successful treatment of T2D in a large proportion of patients. Targeting G protein-coupled receptors (GPCRs) in metabolic tissues — such as adipose tissue, liver, muscle, pancreatic islets, immune cells and the central nervous system — has emerged as a key target for current and future anti-diabetic compounds. This Opinion focuses on the potential of GPCRs as targets for the discovery of new drugs to successfully treat T2D.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/154 / 631/45/612/194 / 692/699/2743/137/773 / Animals / Biomedicine / Biotechnology / Cancer Research / Diabetes Mellitus, Type 2 - drug therapy / Diabetes Mellitus, Type 2 - metabolism / Drug Delivery Systems - methods / Drug therapy / G proteins / Humans / Hypoglycemic Agents - administration & dosage / Hypoglycemic Agents - metabolism / Insulin Resistance - physiology / Medicinal Chemistry / Methods / Molecular Medicine / Molecular targeted therapy / Obesity - drug therapy / Obesity - metabolism / opinion-2 / Pharmacology/Toxicology / Properties / Receptors, G-Protein-Coupled - metabolism / Type 2 diabetes