Reevaluation of fatty acid receptor 1 as a drug target for the stimulation of insulin secretion in humans.
Reevaluation of fatty acid receptor 1 as a drug target for the stimulation of insulin secretion in humans.
复制标题
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;Häring HU;Ullrich S
游离脂肪酸受体1（FFAR 1/GPR 40）在葡萄糖稳态中的作用仍不完全清楚。刺激胰岛素分泌的小受体激动剂正在研究用于治疗2型糖尿病。令人惊讶的是，全基因组关联研究没有发现FFAR 1中的糖尿病风险变异。我们使用一种特异性激动剂、FFAR 1基因敲除小鼠和人类胰岛重新评估了FFAR 1在胰岛素分泌中的作用。非糖尿病个体进行代谢表型和基因分型。体外实验表明，棕榈酸酯和特异性FFAR 1激动剂TUG-469通过FFAR 1刺激葡萄糖诱导的胰岛素分泌。β细胞长期暴露于棕榈酸酯的促凋亡作用不依赖于FFAR 1。TUG-469是保护性的，而FFAR 1的抑制促进细胞凋亡。根据棕榈酸酯的促凋亡作用，体内横截面观察表明空腹游离脂肪酸（NEFAs）和胰岛素分泌之间存在负相关。由于NEFA通过FFAR 1刺激分泌，我们研究了FFAR 1的遗传变异与NEFA和胰岛素分泌的相互作用。NEFA和分泌的反向关联由rs 1573611调节，并且对于次要等位基因的携带者变得更陡峭。总之，FFAR 1激动剂支持β细胞功能，但FFAR 1的变化影响NEFA对胰岛素分泌的作用，因此可能影响FFAR 1激动剂的治疗效果。
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.
登录
查看更多内容
影响因子：
4.5
作者：
Sargsyan E;Bergsten P
通讯作者：
Bergsten P
影响因子：
3.5
作者：
Zhang, Ying;Xu, Mingtong;Cheng, Hua
通讯作者：
Cheng, Hua
新的遗传基因座涉及禁食葡萄糖稳态及其对2型糖尿病风险的影响。
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
4.2
作者：
Christiansen, Elisabeth;Due-Hansen, Maria E.;Ulven, Trond
通讯作者：
Ulven, Trond
影响因子：
3.7
作者：
Herzberg-Schäfer SA;Staiger H;Heni M;Ketterer C;Guthoff M;Kantartzis K;Machicao F;Stefan N;Häring HU;Fritsche A
通讯作者：
Fritsche A