title: GPR40 Agonists for the Treatment of Type 2 Diabetes Mellitus: Benefits and Challenges.
abstract: Apart from functioning as an energy source and important structural components of biological membranes, Free Fatty acids (FFAs) play a key role in the regulation of metabolic homeostasis. FFAs activate specific G-protein coupled receptors (GPCRs) in pancreatic β-cells, immune cells adipose, and intestine. GPR40 (also known as FFA receptor 1) is primarily expressed in pancreatic .-cells and is activated by medium-chain and long-chain FFAs. GPR40 has been shown to augment glucose dependent insulin secretion (GDIS) from pancreatic .-cells and is widely studied drug discovery target for the treatment of type 2 diabetes mellitus (T2DM) and other metabolic diseases. Several synthetic agonists of GPR40 augment insulin secretion from pancreatic β- cells and consequently improve glucose tolerance and restore metabolic homeostasis in various rodent models of T2DM. GPR40 agonists TAK-875 and AMG 837 have reached clinical trials and TAK 875 was shown to improve glycemic control in Type 2 diabetic patients. However, phase III clinical trials involving TAK-875 were recently terminated due to signs of liver toxicity in patients. Despite this setback, therapies based on GPR40 agonism provide an attractive alternative in the discovery of new anti-diabetic drugs. This review summarizes our current understanding of the physiological functions of GPR40, benefits and future prospects of GPR40 agonists to treat patients with T2DM.
authors.affiliation: Experimental Medicine, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), Ministry of National Guard Health Affairs (NGHA), Riyadh, Saudi Arabia. mohammadsa1@ngha.med.sa.
authors.forename: Sameer
authors.initials: S
authors.lastname: Mohammad
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000009:adverse effects / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000009:adverse effects / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000503:physiopathology; D015195:Drug Design; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D013450:Sulfones / Q000009:adverse effects / Q000494:pharmacology; D000480:Alkynes; D010666:Phenylpropionates
chemical_list: D001572:Benzofurans; D001713:Biphenyl Compounds; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D007328:Insulin; D043562:Receptors, G-Protein-Coupled; D013450:Sulfones; C473034:FFAR1 protein, human; C557331:TAK-875; C557933:AMG-837; D000480:Alkynes; D010666:Phenylpropionates