题名：Reevaluation of Fatty Acid receptor 1 as a drug target for the stimulation of insulin secretion in humans.
作者：WAGNER R; KAISER G; GERST F; CHRISTIANSEN E; DUE-HANSEN ME; GRUNDMANN M; MACHICAO F; PETER A; KOSTENIS E; ULVEN T; FRITSCHE A; HARING HU; ULLRICH S;
来源：Diabetes. 2013 Jun;62(6):2106-11. doi: 10.2337/db12-1249. Epub 2013 Feb 1. [ IF= 8.29 ] ]
摘要：The role of free fatty acid receptor 1 (FFAR1/GPR40) in glucose homeostasis is
still incompletely understood. Small receptor agonists stimulating insulin
secretion are undergoing investigation for the treatment of type 2 diabetes.
Surprisingly, genome-wide association studies did not discover diabetes risk
variants in FFAR1. We reevaluated the role of FFAR1 in insulin secretion using a
specific agonist, FFAR1-knockout mice and human islets. Nondiabetic individuals
were metabolically phenotyped and genotyped. In vitro experiments indicated that
palmitate and a specific FFAR1 agonist, TUG-469, stimulate glucose-induced
insulin secretion through FFAR1. The proapoptotic effect of chronic exposure of
beta-cells to palmitate was independent of FFAR1. TUG-469 was protective, whereas
inhibition of FFAR1 promoted apoptosis. In accordance with the proapoptotic
effect of palmitate, in vivo cross-sectional observations demonstrated a negative
association between fasting free fatty acids (NEFAs) and insulin secretion.
Because NEFAs stimulate secretion through FFAR1, we examined the interaction of
genetic variation in FFAR1 with NEFA and insulin secretion. The inverse
association of NEFA and secretion was modulated by rs1573611 and became steeper
for carriers of the minor allele. In conclusion, FFAR1 agonists support beta-cell
function, but variation in FFAR1 influences NEFA effects on insulin secretion and
therefore could affect therapeutic efficacy of FFAR1 agonists.