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Mediation of β-endorphin in andrographolide-induced plasma glucose-lowering action in type I diabetes-like animals

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Abstract

In the present study, we investigated the mechanism(s) for glucose-lowering action of andrographolide in streptozotocin-induced diabetic rats (STZ-diabetic rats). Andrographolide lowered plasma glucose concentrations in a dose-dependent manner and increased plasma β-endorphin-like immunoreactivity (BER) dose-dependently in diabetic rats. Both of these responses to andrographolide were abolished by the pretreatment of animals with prazosin or N-(2 -(2-cyclopropylmethoxy) ethyl) 5-choro-α-dimethyl-1H-indole-3-thylamine (RS17053) at doses sufficient to block α1-adrenoceptors (ARs). Also, andrographolide enhanced BER release from isolated rat adrenal medulla in a concentration-related manner that could be abolished by α1-ARs antagonists. Bilateral adrenalectomy in STZ-diabetic rats eliminated the activities of andrographolide, including the plasma glucose-lowering effect and the plasma BER-elevating effect. Andrographolide failed to lower plasma glucose in the presence of opioid μ-receptor antagonists and in the opioid μ-receptor knockout diabetic mice. Treatment of STZ-diabetic rats with andrographolide resulted in the reduced expression of phosphoenolpyruvate carboxykinase (PEPCK) in liver and an increased expression of the glucose transporter subtype 4 (GLUT 4) in soleus muscle. These effects were also blocked by opioid μ-receptor antagonists. In conclusion, our results suggest that andrographolide may activate α1-ARs to enhance the secretion of β-endorphin which can stimulate the opioid μ-receptors to reduce hepatic gluconeogenesis and to enhance the glucose uptake in soleus muscle, resulting in a decrease of plasma glucose in STZ-diabetic rats. However, the roles of other endogenous opioid peptides or the mixture of several opioid peptides in the activation of opioid μ-receptors associated with the plasma glucose-lowering action of andrographolide, should be considered and need more investigation in the future.

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Acknowledgements

We are grateful to Professor H.H. Loh (Department of Pharmacology, University of Minnesota Medical School. Minneapolis, MN, USA) for the kind supply of opioid μ-receptor knockout mice and wild-type mice. Thanks are also due to Professor C. Makepeace (Department of Cell Biology and Physiology, School of Medicine, Washington University, St. Louis, MO, USA) and Professor S.S. Liu (Department of Microbiology and Immunology, National Cheng Kung University, Tainan City, Taiwan, ROC) for kindly providing us with the plasmid containing cDNAs. Furthermore, the kind donation of antibodies specific to PEPCK by Professor D.K. Granner (Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA) is respectfully acknowledged. Also, we appreciated Professor I.M. Liu (Department of Pharmacy, Tajen University of Technology, Ping-Tong, Taiwan) for kindly editing the manuscript. The present study was supported in part by a grant from the National Science Council (NSC93-2320-B006-010) of the Republic of China.

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Correspondence to Juei Tang Cheng.

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Yu, B.C., Chang, C.K., Su, C.F. et al. Mediation of β-endorphin in andrographolide-induced plasma glucose-lowering action in type I diabetes-like animals. Naunyn-Schmied Arch Pharmacol 377, 529–540 (2008). https://doi.org/10.1007/s00210-007-0240-0

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