Tang Ran-qi, Zhang Xiao-lin, Tian Jin-ying, Kong Si-ming, Zhou Ying, Zhang Pei, Yang Hong-kun, Wu Song, Zhang Ying, Ye Fei
Yao Xue Xue Bao. 2015 Jun;50(6):682-9.
To investigate the effects of 2-(4-methoxycarbonyl-2-tetradecyloxyphenyl)carbamoylbenzoic acid (CX09040) on protecting pancreatic β cells, the β cell dysfunction model mice were induced by injection of alloxan into the caudal vein of ICR mice, and were treated with compound CX09040. Liraglutide was used as the positive control drug. The amount and the size of islets observed in pathological sections were calculated to evaluate the β cell mass; the glucose stimulated insulin secretion (GSIS) test was applied to estimate the β cell secretary function; the oral glucose tolerance test (OGTT) was taken to observe the glucose metabolism in mice; the expressions of protein in pancreas were detected by Western blotting. The effects on the target protein tyrosine phosphatase 1B (PTP1B) were assessed by the PTP1B activities of both recombinant protein and the intracellular enzyme, and by the PTP1B expression in the pancreas of mice, separately. As the results, with the treatment of CX09040 in alloxan-induced β cell dysfunction mice, the islet amount (P<0.05) and size (P<0.05) increased significantly, the changes of serum insulin in GSIS (P<0.01) and the values of acute insulin response (AIR, P<0.01) were enhanced, compared to those in model group; the impaired glucose tolerance was also ameliorated by CX09040 with the decrease of the values of area under curve (AUC, P<0.01). The activation of the signaling pathways related to β cell proliferation was enhanced by increasing the levels of p-Akt/Akt (P<0.01), p-FoxO1/FoxOl (P<0.001) and PDX-1 (P<0.01). The effects of CX09040 on PTP1B were observed by inhibiting the recombinant hPTP1B activity with IC50 value of 2.78x 10(-7) mol.L-1, reducing the intracellular PTP1B activity of 72.8% (P<0.001), suppressing the PTP1B expression (P<0.001) and up-regulating p-IRβ/IRβ (P<0.01) in pancreas of the β cell dysfunction mice, separately. In conclusion, compound CX09040 showed significant protection effects against the dysfunction of β cell of mice by enlarging the pancreatic β cell mass and increasing the glucose-induced insulin secretion; its major mechanism may be the inhibition on target PTP1B and the succedent up-regulation of β cell proliferation.
为研究2-(4-甲氧羰基-2-十四烷氧基苯基)氨基甲酰苯甲酸（CX09040）对胰腺β细胞的保护作用，通过向ICR小鼠尾静脉注射四氧嘧啶诱导建立β细胞功能障碍模型小鼠，并给予化合物CX09040进行治疗。利拉鲁肽用作阳性对照药物。计算病理切片中观察到的胰岛数量和大小以评估β细胞量；应用葡萄糖刺激胰岛素分泌（GSIS）试验评估β细胞分泌功能；进行口服葡萄糖耐量试验（OGTT）观察小鼠的葡萄糖代谢情况；通过蛋白质免疫印迹法检测胰腺中蛋白质的表达。分别通过重组蛋白和细胞内酶的蛋白酪氨酸磷酸酶1B（PTP1B）活性以及小鼠胰腺中PTP1B的表达来评估对靶蛋白PTP1B的影响。结果显示，在四氧嘧啶诱导的β细胞功能障碍小鼠中给予CX09040治疗后，与模型组相比，胰岛数量（P<0.05）和大小（P<0.05）显著增加，GSIS中血清胰岛素变化（P<0.01）和急性胰岛素反应值（AIR，P<0.01）增强；CX09040还改善了糖耐量受损情况，曲线下面积值（AUC，P<0.01）降低。通过提高p-Akt/Akt（P<0.01）、p-FoxO1/FoxO1（P<0.001）和PDX-1（P<0.01）水平增强了与β细胞增殖相关的信号通路激活。通过抑制重组hPTP1B活性（IC50值为2.78×10⁻⁷mol·L⁻¹）、降低细胞内PTP1B活性72.8%（P<0.001）、抑制PTP1B表达（P<0.001）以及上调β细胞功能障碍小鼠胰腺中p-IRβ/IRβ（P<0.01），分别观察到CX09040对PTP1B的影响。综上所述，化合物CX09040通过扩大胰腺β细胞量和增加葡萄糖诱导的胰岛素分泌，对小鼠β细胞功能障碍显示出显著的保护作用；其主要机制可能是抑制靶标PTP1B以及随后上调β细胞增殖。
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