Lipid receptors and islet function: therapeutic implications?
G-protein coupled receptors (GPCRs) are targets of approximately 30% of currently marketed drugs. Over the last few years, a number of GPCRs expressed in pancreatic beta-cells and activated by lipids have been discovered. GPR40 was shown to be activated by medium- to long-chain fatty acids (FAs). It has since been shown that GPR40 contributes to FA amplification of glucose-induced insulin secretion. Although some controversy still exists as to whether GPR40 agonists or antagonists should be designed as novel type 2 diabetes drugs, data obtained in our laboratory and others strongly suggest that GPR40 agonism might represent a valuable therapeutic approach. GPR119 is expressed in pancreatic beta-cells and enteroendocrine L-cells, and augments circulating insulin levels both through its direct insulinotropic action on beta-cells and through FA stimulation of glucagon-like peptide 1 (GLP-1) secretion. GPR120 is expressed in L-cells and was also shown to mediate FA-stimulated GLP-1 release. Finally, GPR41 and GPR43 are receptors for short-chain FAs and may indirectly regulate beta-cell function via adipokine secretion. Although the discovery of these various lipid receptors opens new and exciting avenues of research for drug development, a number of questions regarding their mechanisms of action and physiological roles remain to be answered.
Kebede
M A
MA
Montréal Diabetes Research Center, CRCHUM, QC, Canada.
Alquier
T
T
Latour
M G
MG
Poitout
V
V
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D015870:Gene Expression; D052216:Glucagon-Like Peptide 1 / Q000502:physiology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000378:metabolism / Q000502:physiology*
D005230:Fatty Acids, Nonesterified; C473036:Ffar1 protein, mouse; D007004:Hypoglycemic Agents; D007328:Insulin; D043562:Receptors, G-Protein-Coupled; D052216:Glucagon-Like Peptide 1