Corosolic acid stimulates glucose uptake via enhancing insulin receptor phosphorylation

Corosolic acid, a triterpenoid compound widely existing in many traditional Chinese medicinal herbs, has been proved to have antidiabetic effects on animal experiments and clinical trials. However, the underlying mechanisms remain unknown. Here, we investigate its cellular effects and related signaling pathway. We demonstrate that it enhances glucose uptake in L6 myotubes and facilitates glucose transporter isoform 4 translocation in CHO/hIR cells. These actions are mediated by insulin pathway activation and can be blocked by phosphatidylinositol 3-kinase (PI3 Kinase) inhibitor Wortmannin. Furthermore, Corosolic acid inhibits the enzymatic activities of several diabetes-related non-receptor protein tyrosine phosphatases (PTPs) in vitro, such as PTP1B, T-cell-PTP, src homology phosphatase-1 and src homology phosphatase-2.

Type 2 diabetes mellitus or non-insulin-dependent diabetes mellitus is a widespread syndrome characterized by fasting and post-prandial hyperglycemia affecting increasing number of the world population Despite considerable progress in the management of diabetes mellitus with synthetic drugs, the search for indigenous natural antidiabetic agents is ongoing. With the distinctive traditional medical opinions and natural medicines mainly originated in herbs, the traditional Chinese medicine performed a good clinical practice and is showing a bright future in the therapy of diabetes mellitus and its complications. Based on a large number of chemical and pharmacological research work, numerous bioactive compounds have been found in Chinese medicinal plants for diabetes.
Corosolic acid , a triterpenoid named 2α-hydric ursolic acid, has been discovered in many Chinese medicinal herbs, such as the Lagerstroemia speciosa L (Fukushima et al., 2006), banaba leaves (Yamaguchi et al., 2006), Tiarella polyphylla (Park et al., 2002), etc. Recently, it has been reported to have antidiabetic activity in some animal experiments and clinical trials. Miura T reported that Corosolic acid reduced the blood glucose levels and significantly lowered plasma insulin levels in KK-Ay mice 2 weeks after a single oral dose of 2 mg/ kg. Furthermore, blood glucose in KK-Ay mice treated with Corosolic acid significantly decreased in an insulin tolerance test (Miura et al., 2006). The muscle GLUT4 translocation from low-density microsomal membrane to plasma membrane was significantly increased in the orally Corosolic acid-treated mice when compared with that of the controls Fukushima M demonstrated that Corosolic acid has an effect on lowering postchallenge plasma glucose levels in vivo in human. Corosolic acid treatment subjects showed lower glucose levels from 60 min until 120 min and reached statistical significance at 90 min Although Corosolic acid was suggested to be a promising lead compound for diabetes, its underlying mechanisms remain unknown.
The aim of this study is to gain the insight into the cellular effects of Corosolic acid on glucose metabolism and related signaling pathway.

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