GPR40 Modulators: New Kid on the Block
- Autores: Ananda Basu, Yogish C Kudva, Rita Basu
- Localización: Diabetes care, ISSN-e 0149-5992, Vol. 36, Nº. 2, 2013, págs. 185-187
- Idioma: inglés
- Texto completo no disponible (Saber más ...)
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Resumen
Impairments in insulin secretion and action are the pathophysiological hallmarks of type 2 diabetes (1,2). Pharmacological approaches to restore ß-cell function have led to the use of insulin secretagogues that include sulphonylureas, glinides, and glucagon-like peptide-1�based therapies. Of these, the latter hold particular clinical advantage because glucagon-like peptide-1�modulated insulin secretion is glucose dependent (3,4), thereby minimizing the risk for hypoglycemia�the bane of clinicians managing diabetes across the world.
Fatty acids have long been known (5) to modulate human ß-cell function. While acutely fatty acids amplify glucose-stimulated insulin secretion, chronic elevation of free fatty acid (FFA) levels has been thought to inhibit insulin secretion through the phenomenon of �lipotoxicity� (6,7). The cellular/molecular intermediates that are involved in this complex modulation, elegantly summarized in ref. 5, include malonyl CoA/long-chain acyl-CoA, triglyceride/FFA cycling through diacylglycerol, G-protein�coupled receptor 40 (GPR40) and phospholipase A2.
G-protein�coupled receptors have recently emerged as novel therapeutic targets because they appear to be closely involved in the pathology of various metabolic disorders including obesity, dyslipidemia, and type 2 diabetes (8). Since the seminal article (9) in 2003 about the role of GPR40 (also known as FFA1R: free fatty acid 1 receptor) in long-chain fatty acid�mediated glucose-stimulated insulin secretion from rodent and human ß-cells, there have been over 60 publications investigating the properties and modulators of this receptor as yet another potential therapeutic approach for the management of type 2 diabetes. GPR40 is expressed most abundantly in humans in pancreatic ß-cells �
