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Wagner, R. ; Kaiser, G.* ; Gerst, F. ; Christiansen, E.* ; Due-Hansen, M.E.* ; Grundmann, M.* ; Machicao, F. ; Peter, A. ; Kostenis, E.* ; Ulven, T.* ; Fritsche, A. ; Häring, H.-U. ; Ullrich, S.

Reevaluation of fatty acid receptor 1 as a drug target for the stimulation of insulin secretion in humans.

Diabetes 62, 2106-2111 (2013)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Beta-cell Function ; Adme Properties ; Potent ; Gpr40 ; Discovery ; Elevation ; Agonists
ISSN (print) / ISBN 0012-1797
e-ISSN 1939-327X
Journal Diabetes
Quellenangaben Volume: 62, Issue: 6, Pages: 2106-2111 Article Number: , Supplement: ,
Publisher American Diabetes Association
Publishing Place Alexandria, VA.
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes Research and Metabolic Diseases (IDM)