title: Reevaluation of fatty acid receptor 1 as a drug target for the stimulation of insulin secretion in humans.
abstract: 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 β-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 β-cell function, but variation in FFAR1 influences NEFA effects on insulin secretion and therefore could affect therapeutic efficacy of FFAR1 agonists.
authors: University of Tübingen, Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, Tübingen, Germany.
authors: Robert
authors: R
authors: Wagner
authors: Gabriele
authors: G
authors: Kaiser
authors: Felicia
authors: F
authors: Gerst
authors: Elisabeth
authors: E
authors: Christiansen
authors: Maria E
authors: ME
authors: Due-Hansen
authors: Manuel
authors: M
authors: Grundmann
authors: Fausto
authors: F
authors: Machicao
authors: Andreas
authors: A
authors: Peter
authors: Evi
authors: E
authors: Kostenis
authors: Trond
authors: T
authors: Ulven
authors: Andreas
authors: A
authors: Fritsche
authors: Hans-Ulrich
authors: HU
authors: Häring
authors: Susanne
authors: S
authors: Ullrich
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005838:Genotype; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D010168:Palmitates / Q000494:pharmacology; D010666:Phenylpropionates / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000235:genetics / Q000378:metabolism*
chemical_list: D000814:Aniline Compounds; C473034:FFAR1 protein, human; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D010168:Palmitates; D010666:Phenylpropionates; D043562:Receptors, G-Protein-Coupled; C000589451:TUG-469
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