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Reevaluation of Fatty acid receptor 1 (FFAR1/GPR40) as drug target for the stimulation of insulin secretion in humans

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Robert Wagner, Gabriele Kaiser, Felicia Gerst, Elisabeth Christiansen, Maria Elisabeth Due-Hansen, Manuel Grundmann, Fausto Machicao, Andreas Peter, Evi Kostenis, Trond Ulven, Andreas Fritsche, Hans-Ulrich Häring, Susanne Ullrich

The role of free fatty acid receptor 1 (FFAR1/GPR40) in glucose homeostasis is still incompletely understood. Small receptor agonists stimulating insulin secretion are under 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 pro-apoptotic effect of chronic exposure of beta-cells to palmitate was independent of FFAR1. TUG-469 was protective, while inhibition of FFAR1 promoted apoptosis. In accordance with the pro-apoptotic effect of palmitate, in vivo crosssectional observations demonstrated a negative association between fasting free fatty acids (NEFA) and insulin secretion. As NEFA 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 could, therefore, affect therapeutic efficacy of FFAR1-agonists.
Original languageEnglish
Issue number6
Pages (from-to)2106-2111
Number of pages6
StatePublished - 1 Feb 2013

ID: 189158148