Doshi Lalit S, Brahma Manoja K, Sayyed Sufyan G, Dixit Amol V, Chandak Prakash G, Pamidiboina Venu, Motiwala Hashim F, Sharma Somesh D, Nemmani Kumar V S
Piramal Life Sciences Limited, Nirlon Complex, Goregaon (E), Mumbai-400 063, India.
Metabolism. 2009 Mar;58(3):333-43. doi: 10.1016/j.metabol.2008.10.005.
Recently, several in vitro studies have shown that GPR40 receptor activation by free fatty acids (FFAs) results in glucose-dependent insulin secretion. However, whether GPR40 receptor activation results in glucose-dependent insulin secretion in vivo in rats is not known. Therefore, we evaluated the effect of synthetic GPR40 receptor agonist (compound 1) on glucose tolerance test (GTT) in fed, fasted, and insulin-resistant rats. In oral GTT, intraperitoneal GTT, and intravenous GTT, GPR40 receptor agonist improved glucose tolerance, which was associated with increase in plasma insulin level. Interestingly, in GTTs, the rise in insulin levels in agonist-treated group was directly proportional to the rate of rise and peak levels of glucose in control group. Although glibenclamide, a widely used insulin secretagogue, improved glucose tolerance in all GTTs, it did not display insulin release in intraperitoneal GTT or intravenous GTT. In the absence of glucose load, GPR40 receptor agonist did not significantly change the plasma insulin concentration, but did decrease the plasma glucose concentration. Fasted rats exhibited impaired glucose-stimulated insulin secretion (GSIS) as compared with fed rats. Compound 1 potentiated GSIS in fasted state but failed to do so in fed state. Suspecting differential pharmacokinetics, a detailed pharmacokinetic evaluation was performed, which revealed the low plasma concentration of compound 1 in fed state. Consequently, we examined the absorption profile of compound 1 at higher doses in fed state; and at a dose at which its absorption was comparable with that in fasted state, we observed significant potentiation of GSIS. Chronic high-fructose (60%) diet feeding resulted in impaired glucose tolerance, which was improved by GPR40 receptor agonist. Therefore, our results demonstrate for the first time that acute GPR40 receptor activation leads to potentiation of GSIS in vivo and improves glucose tolerance even in insulin-resistant condition in rats. Taken together, these results suggest that GPR40 receptor agonists could be potential therapeutic alternatives to sulfonylureas.
最近，多项体外研究表明，游离脂肪酸（FFA）激活GPR40受体可导致葡萄糖依赖性胰岛素分泌。然而，GPR40受体激活在大鼠体内是否会导致葡萄糖依赖性胰岛素分泌尚不清楚。因此，我们评估了合成GPR40受体激动剂（化合物1）对喂食、禁食和胰岛素抵抗大鼠葡萄糖耐量试验（GTT）的影响。在口服GTT、腹腔注射GTT和静脉注射GTT中，GPR40受体激动剂改善了葡萄糖耐量，这与血浆胰岛素水平升高有关。有趣的是，在GTT中，激动剂治疗组胰岛素水平的升高与对照组葡萄糖升高速率和峰值水平成正比。尽管广泛使用的胰岛素促分泌剂格列本脲在所有GTT中均改善了葡萄糖耐量，但在腹腔注射GTT或静脉注射GTT中它并未表现出胰岛素释放。在没有葡萄糖负荷的情况下，GPR40受体激动剂并未显著改变血浆胰岛素浓度，但确实降低了血浆葡萄糖浓度。与喂食大鼠相比，禁食大鼠表现出葡萄糖刺激的胰岛素分泌（GSIS）受损。化合物1在禁食状态下增强了GSIS，但在喂食状态下未能如此。由于怀疑存在不同的药代动力学，我们进行了详细的药代动力学评估，结果显示喂食状态下化合物1的血浆浓度较低。因此，我们研究了喂食状态下较高剂量化合物1的吸收情况；在其吸收与禁食状态相当的剂量下，我们观察到GSIS有显著增强。长期高果糖（60%）饮食喂养导致葡萄糖耐量受损，而GPR40受体激动剂可改善这种情况。因此，我们的结果首次证明，急性激活GPR40受体可在体内增强GSIS，甚至在大鼠胰岛素抵抗状态下也能改善葡萄糖耐量。综上所述，这些结果表明GPR40受体激动剂可能是磺脲类药物潜在的治疗替代品。
