Xelaglifam,开发为GPR40/FFAR1激动剂,诱导葡萄糖依赖性胰岛素分泌并降低2型糖尿病治疗的循环葡萄糖水平。这项研究调查了Xelaglifam与Fasiglifam相比对体外/体内抗糖尿病功效和选择性的影响。和机械基础。在表达GPR40的细胞中进行了Xelaglifam下游靶标的体外研究。Xelaglifam治疗表现出剂量依赖性效应,增加肌醇磷酸-1,Ca2+动员,和β-抑制蛋白募集(EC50:0.76nM,20nM,68nM),支持其在Gq蛋白依赖性和G蛋白非依赖性机制中的作用。尽管cAMP通路缺乏变化,在高糖条件下,与Fasiglifam相比,Xelaglifam治疗组HIT-T15β细胞的胰岛素分泌增加.高剂量的Xelaglifam(<30mg/kg)不会在Sprague-Dawley大鼠中引起低血糖。此外,Xelaglifam在糖尿病大鼠模型中降低葡萄糖并增加胰岛素水平(GK,ZDF,OLETF)。在GK大鼠中,在连续葡萄糖挑战后,1mg/kg的Xelaglifam改善了葡萄糖耐量(1和5小时分别为33.4%和15.6%)。此外,在ZDF和OLETF大鼠中重复给药导致优异的葡萄糖耐量(ZDF和OLETF中34%和35.1%),在较低剂量下降低空腹高血糖症(ZDF和OLETF为18.3%和30%);Xelaglifam表现出更持久的作用,对β细胞的作用更大,包括增加3.8倍的胰岛素分泌。Xelaglifam与SGLT-2抑制剂的共治疗显示出累加或协同作用。总的来说,这些结果证明了Xelaglifam对GPR40的治疗效果和选择性,支持了其治疗2型糖尿病的潜力。
Xelaglifam, developed as a GPR40/FFAR1 agonist, induces glucose-dependent insulin secretion and reduces circulating glucose levels for Type 2 diabetes treatment. This study investigated the effects of Xelaglifam in comparison with Fasiglifam on the in vitro/in vivo anti-diabetic efficacy and selectivity, and the mechanistic basis. In vitro studies on downstream targets of Xelaglifam were performed in GPR40-expressing cells. Xelaglifam treatment exhibited dose-dependent effects, increasing inositol phosphate-1, Ca2+ mobilization, and β-arrestin recruitment (EC50: 0.76 nM, 20 nM, 68 nM), supporting its role in Gq protein-dependent and G-protein-independent mechanisms. Despite a lack of change in the cAMP pathway, the Xelaglifam-treated group demonstrated increased insulin secretion compared to Fasiglifam in HIT-T15 β cells under high glucose conditions. High doses of Xelaglifam (<30 mg/kg) did not induce hypoglycemia in Sprague-Dawley rats. In addition, Xelaglifam lowered glucose and increased insulin levels in diabetic rat models (GK, ZDF, OLETF). In GK rats, 1 mg/kg of Xelaglifam improved glucose tolerance (33.4 % and 15.6 % for the 1 and 5 h) after consecutive glucose challenges. Moreover, repeated dosing in ZDF and OLETF rats resulted in superior glucose tolerance (34 % and 35.1 % in ZDF and OLETF), reducing fasting hyperglycemia (18.3 % and 30 % in ZDF and OLETF) at lower doses; Xelaglifam demonstrated a longer-lasting effect with a greater effect on β-cells including 3.8-fold enhanced insulin secretion. Co-treatment of Xelaglifam with SGLT-2 inhibitors showed additive or synergistic effects. Collectively, these results demonstrate the therapeutic efficacy and selectivity of Xelaglifam on GPR40, supportive of its potential for the treatment of Type 2 diabetes.