Ding Hanying, Zhang Yan, Xu Chen, Hou Dongxia, Li Jing, Zhang Yujing, Peng Wei, Zen Ke, Zhang Chen-Yu, Jiang Xiaohong
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 210093, Nanjing, Jiangsu, People's Republic of China.
Diabetologia. 2014 Oct;57(10):2145-54. doi: 10.1007/s00125-014-3315-8. Epub 2014 Jul 2.
AIM/HYPOTHESIS: Protein tyrosine phosphatase 1B (PTP1B) negatively regulates insulin signalling. PTP1B deficiency improves obesity-induced insulin resistance and consequently improves type 2 diabetes in mice. Here, the small molecule norathyriol reversed obesity- and high-fat-diet-induced insulin resistance by inhibiting PTP1B.
The inhibitory mode of PTP1B was evaluated by using the double-reciprocal substrate in the presence of norathyriol. Primary cultured hepatocytes, myoblasts and white adipocytes were used to investigate the effect of norathyriol on insulin signalling. Glucose homeostasis and insulin sensitivity were characterised by glucose and insulin tolerance tests.
Norathyriol was identified as a competitive inhibitor of PTP1B, with an IC50 of 9.59 ± 0.39 μmol/l. In cultured hepatocytes and myoblasts, norathyriol treatment blocked the PTP1B-mediated dephosphorylation of the insulin receptor. Intraperitoneal injection of norathyriol inhibited liver and muscle PTP1B activity in mice, thus contributing to the improved glucose homeostasis and insulin sensitivity. However, these beneficial effects were abolished in PTP1B-deficient mice. Notably, oral administration of norathyriol protected mice from diet-induced obesity and insulin resistance through inhibition of hypothalamic PTP1B activity.
CONCLUSIONS/INTERPRETATION: Our results indicate that the small molecule norathyriol is a potent PTP1B inhibitor with good cell permeability and oral availability.
目的/假设：蛋白酪氨酸磷酸酶1B（PTP1B）对胰岛素信号传导起负调节作用。PTP1B缺乏可改善肥胖诱导的胰岛素抵抗，进而改善小鼠的2型糖尿病。在此，小分子诺拉替罗通过抑制PTP1B逆转肥胖和高脂饮食诱导的胰岛素抵抗。
在诺拉替罗存在的情况下，使用双倒数底物评估PTP1B的抑制模式。原代培养的肝细胞、成肌细胞和白色脂肪细胞用于研究诺拉替罗对胰岛素信号传导的影响。通过葡萄糖和胰岛素耐量试验来表征葡萄糖稳态和胰岛素敏感性。
诺拉替罗被鉴定为PTP1B的竞争性抑制剂，IC50为9.59±0.39μmol/l。在培养的肝细胞和成肌细胞中，诺拉替罗处理可阻断PTP1B介导的胰岛素受体去磷酸化。腹腔注射诺拉替罗可抑制小鼠肝脏和肌肉中的PTP1B活性，从而有助于改善葡萄糖稳态和胰岛素敏感性。然而，在PTP1B缺陷小鼠中，这些有益作用消失。值得注意的是，口服诺拉替罗通过抑制下丘脑PTP1B活性，保护小鼠免受饮食诱导的肥胖和胰岛素抵抗。
结论/解读：我们的结果表明，小分子诺拉替罗是一种有效的PTP1B抑制剂，具有良好的细胞通透性和口服可用性。
