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

TY - JOUR

T1 - Reevaluation of Fatty acid receptor 1 (FFAR1/GPR40) as drug target for the stimulation of insulin secretion in humans

AU - Wagner, Robert

AU - Kaiser, Gabriele

AU - Gerst, Felicia

AU - Christiansen, Elisabeth

AU - Due-Hansen, Maria Elisabeth

AU - Grundmann, Manuel

AU - Machicao, Fausto

AU - Peter, Andreas

AU - Kostenis, Evi

AU - Ulven, Trond

AU - Fritsche, Andreas

AU - Häring, Hans-Ulrich

AU - Ullrich, Susanne

PY - 2013/6

Y1 - 2013/6

N2 - 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, genomewide 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 effi cacy of FFAR1 agonists.

AB - 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, genomewide 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 effi cacy of FFAR1 agonists.

U2 - 10.2337/db12-1249

DO - 10.2337/db12-1249

M3 - Journal article

SN - 0046-0192

VL - 62

SP - 2106

EP - 2111

JO - Diabetes

JF - Diabetes

IS - 6

ER -