Regulation of insulin signal transduction pathway by a small-molecule insulin receptor activator
Regulation of insulin signal transduction pathway by a small-molecule insulin receptor activator
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DOI：
10.1042/bj20020708
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发表时间：
2002-10-01
影响因子：
4.1
通讯作者：
Zhang, BB
中科院分区：
文献类型：
--
作者：
Ding, VDH;Qureshi, SA;Zhang, BB
胰岛素通过激活胰岛素受体 (IR) 来调节细胞代谢和生长。我们最近鉴定了一种非肽小分子 IR 激活剂（化合物 2），它可以在表达人 IR 的中国仓鼠卵巢细胞中诱导人 IR 酪氨酸激酶活性 [Qureshi, Ding, Li, Szalkowski, Biazzo-Ashnault, Xie, Saperstein, Brady, Huskey, Shen 等人。 (2000) J.Biol。化学。 275、36590-36595]。用这种化合物口服治疗可以纠正几种糖尿病啮齿动物模型中的高血糖、高三酰甘油血症和高胰岛素血症。在本研究中，我们发现该化合物可增加原代大鼠脂肪细胞中 IR β 亚基和 IR 底物 1 的酪氨酸磷酸化，并诱导表达人 IR 的中国仓鼠卵巢细胞中 Akt、70 kDa 核糖体蛋白 S6 激酶和糖原合酶 3 的磷酸化（失活）。与胰岛素相似，化合物 2 刺激葡萄糖摄取、糖原合成并抑制脂肪细胞中异丙肾上腺素刺激的脂肪分解。结构相关的类似物（化合物 3）缺乏上述活性，表明化合物 2 的活性是由靶向 IR 激活特异性介导的。化合物 2 对刺激葡萄糖摄取、糖原合成和抑制脂肪分解的作用被渥曼青霉素阻断，这与磷酸肌醇 3-激酶依赖性途径的参与一致。此外，化合物2而非化合物3在大鼠脂肪细胞中与次最大浓度的胰岛素表现出相加或协同作用。因此，IR激活剂能够激活原代脂肪细胞中胰岛素介导的信号传导和代谢途径。这些结果表明，IR 激活剂对 I 型和 II 型糖尿病新治疗方法的未来开发具有重要意义。
Insulin regulates cellular metabolism and growth through activation of insulin receptors (IRs). We recently identified a nonpeptide small-molecule IR activator (compound 2), which induced human IR tyrosine kinase activity in Chinese-hamster ovary cells expressing human IR [Qureshi, Ding, Li, Szalkowski, Biazzo-Ashnault, Xie, Saperstein, Brady, Huskey, Shen et al. (2000) J. Biol. Chem. 275, 36590-36595]. Oral treatment with this compound resulted in correction of hyperglycaemia, hypertriacylglycerolaemia and hyperinsulinaemia in several rodent models of diabetes. In the present study, we have found that this compound increased tyrosine phosphorylation of the IR beta-subunit and IR substrate 1 in primary rat adipocytes as well as induced phosphorylation of Akt, the 70 kDa ribosomal protein S6 kinase and glycogen synthase-3 (deactivation) in Chinese-hamster ovary cells expressing human IR. Similar to insulin, compound 2 stimulated glucose uptake, glycogen synthesis and inhibited isoprenaline-stimulated lipolysis in adipocytes. A structurally related analogue (compound 3) was devoid of the above activities suggesting that the activity of compound 2 is specifically mediated by targeted IR activation. The effects of compound 2 on stimulation of glucose uptake, glycogen synthesis and inhibition of lipolysis were blocked by wortmannin, consistent with the involvement of a phosphoinositide 3-kinase-dependent pathway. In addition, compound 2, but not compound 3, exhibited additive or synergistic effects with sub-maximal concentrations of insulin in rat adipocytes. Thus the IR activator was capable of activating insulin-mediated signalling and metabolic pathways in primary adipocytes. These results demonstrate that IR activators have implications for the future development of new therapeutic approaches to Type I and Type II diabetes.