Qin Zhaohong, Pandey Nihar R, Zhou Xun, Stewart Chloe A, Hari Aswin, Huang Hua, Stewart Alexandre F R, Brunel Jean Michel, Chen Hsiao-Huei
Ottawa Hospital Research Institute, Canada.
Ottawa Hospital Research Institute, Canada; University of Ottawa, Canada.
Biochem Biophys Res Commun. 2015 Feb 27;458(1):21-7. doi: 10.1016/j.bbrc.2015.01.040. Epub 2015 Jan 24.
Protein tyrosine phosphatase 1B (PTP1B) inhibits insulin signaling, interfering with its control of glucose homeostasis and metabolism. PTP1B activity is elevated in obesity and type 2 diabetes and is a major cause of insulin resistance. Trodusquemine (MSI-1436) is a "first-in-class" highly selective inhibitor of PTP1B that can cross the blood-brain barrier to suppress feeding and promote insulin sensitivity and glycemic control. Trodusquemine is a naturally occurring cholestane that can be purified from the liver of the dogfish shark, Squalus acanthias, but it can also be manufactured synthetically by a fairly laborious process that requires several weeks. Here, we tested a novel easily and rapidly (2 days) synthesized polyaminosteroid derivative (Claramine) containing a spermino group similar to Trodusquemine for its ability to inhibit PTP1B. Like Trodusquemine, Claramine displayed selective inhibition of PTP1B but not its closest related phosphatase TC-PTP. In cultured neuronal cells, Claramine and Trodusquemine both activated key components of insulin signaling, with increased phosphorylation of insulin receptor-β (IRβ), Akt and GSK3β. Intraperitoneal administration of Claramine or Trodusquemine effectively restored glycemic control in diabetic mice as determined by glucose and insulin tolerance tests. A single intraperitoneal dose of Claramine, like an equivalent dose of Trodusquemine, suppressed feeding and caused weight loss without increasing energy expenditure. In summary, Claramine is an alternative more easily manufactured compound for the treatment of type II diabetes.
蛋白酪氨酸磷酸酶1B（PTP1B）抑制胰岛素信号传导，干扰其对葡萄糖稳态和代谢的控制。在肥胖症和2型糖尿病中，PTP1B的活性升高，这是胰岛素抵抗的主要原因。曲度喹明（MSI-1436）是一种“一流的”PTP1B高度选择性抑制剂，它可以穿过血脑屏障，抑制进食，提高胰岛素敏感性并控制血糖。曲度喹明是一种天然存在的胆甾烷，可以从白斑角鲨（Squalus acanthias）的肝脏中提纯，但也可以通过一个相当繁琐的过程进行合成，该过程需要数周时间。在此，我们测试了一种新型的、易于快速（2天）合成的、含有与曲度喹明类似的亚精胺基团的多氨基甾体衍生物（克拉拉明）抑制PTP1B的能力。与曲度喹明一样，克拉拉明对PTP1B具有选择性抑制作用，但对与其最相关的磷酸酶TC-PTP则无抑制作用。在培养的神经元细胞中，克拉拉明和曲度喹明均激活了胰岛素信号传导的关键成分，胰岛素受体-β（IRβ）、Akt和GSK3β的磷酸化增加。通过葡萄糖和胰岛素耐量试验测定，腹腔注射克拉拉明或曲度喹明可有效恢复糖尿病小鼠的血糖控制。单次腹腔注射克拉拉明，与等量的曲度喹明一样，可抑制进食并导致体重减轻，而不会增加能量消耗。总之，克拉拉明是一种更易于制造的治疗II型糖尿病的替代化合物。
