Identification of a small molecular insulin receptor agonist with potent antidiabetes activity.
Identification of a small molecular insulin receptor agonist with potent antidiabetes activity.
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作者：
Qiang G;Xue S;Yang JJ;Du G;Pang X;Li X;Goswami D;Griffin PR;Ortlund EA;Chan CB;Ye K
胰岛素替代疗法是所有1型糖尿病患者和部分2型糖尿病患者广泛采用的治疗方法。然而，注射胰岛素存在组织刺激、脓肿、不适和不便等问题。因此，口服生物活性胰岛素模拟物的使用是一种理想的治疗选择。在这里，我们展示了一种毛色胺衍生物（4548-G05）作为一种新的非肽基胰岛素模拟物。4548-G05选择性激活胰岛素受体（IR），但不激活胰岛素样生长因子受体i或其他酪氨酸激酶受体。通过结合IR的胞外结构域，4548-G05诱导受体激活，启动下游Akt和胞外信号相关激酶通路，触发C2C12肌管的葡萄糖摄取。此外，在正常、1型糖尿病和2型糖尿病小鼠模型中口服时，它显示出强有力的降血糖作用。因此，4548-G05可能是一种新的抗糖尿病药物。
Insulin replacement therapy is a widely adopted treatment for all patients with type 1 diabetes and some with type 2 diabetes. However, injection of insulin has suffered from problems such as tissue irritation, abscesses, discomfort, and inconvenience. The use of orally bioactive insulin mimetics thus represents an ideal treatment alternative. Here we show that a chaetochromin derivative (4548-G05) acts as a new nonpeptidyl insulin mimetic. 4548-G05 selectively activates an insulin receptor (IR) but not insulin-like growth factor receptor-I or other receptor tyrosine kinases. Through binding to the extracellular domain of the IR, 4548-G05 induces activation of the receptor and initiates the downstream Akt and extracellular signal–related kinase pathways to trigger glucose uptake in C2C12 myotubes. Moreover, it displays a potent blood glucose-lowering effect when administrated orally in normal, type 1 diabetic, and type 2 diabetic mice models. Therefore, 4548-G05 may represent a novel pharmacological agent for antidiabetes drug development.
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影响因子：
2
作者：
Ishii, R;Horie, M;Kitanaka, S
通讯作者：
Kitanaka, S
影响因子：
2.9
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Huang, Yun;Zhou, Yubin;Castiblanco, Adriana;Yang, Wei;Brown, Edward M.;Yang, Jenny J.
通讯作者：
Yang, Jenny J.
影响因子：
7.3
作者：
Liu, K;Xu, LB;Jones, AB
通讯作者：
Jones, AB
影响因子：
4.8
作者：
LEVYTOLEDANO, R;CARO, LHP;TAYLOR, SI
通讯作者：
TAYLOR, SI
影响因子：
16.8
作者：
Musille, Paul M.;Pathak, Manish C.;Lauer, Janelle L.;Hudson, William H.;Griffin, Patrick R.;Ortlund, Eric A.
通讯作者：
Ortlund, Eric A.