title: Mediation of beta-endorphin in andrographolide-induced plasma glucose-lowering action in type I diabetes-like animals.
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 beta-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-alpha-dimethyl-1H-indole-3-thylamine (RS17053) at doses sufficient to block alpha1-adrenoceptors (ARs). Also, andrographolide enhanced BER release from isolated rat adrenal medulla in a concentration-related manner that could be abolished by alpha1-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 micro-receptor antagonists and in the opioid micro-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 micro-receptor antagonists. In conclusion, our results suggest that andrographolide may activate alpha1-ARs to enhance the secretion of beta-endorphin which can stimulate the opioid micro-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 micro-receptors associated with the plasma glucose-lowering action of andrographolide, should be considered and need more investigation in the future.
authors: Institute of Basic Medical Science, and Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan City, Taiwan, 70101, Republic of China.
authors: Bu Chin
authors: BC
authors: Yu
authors: Cheng Kuei
authors: CK
authors: Chang
authors: Chih Fen
authors: CF
authors: Su
authors: Juei Tang
authors: JT
authors: Cheng
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000503:physiopathology; D004224:Diterpenes / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D051275:Glucose Transporter Type 4 / Q000235:genetics; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism; D013311:Streptozocin; D001615:beta-Endorphin / Q000187:drug effects / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D004224:Diterpenes; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D017450:Receptors, Opioid, mu; C030419:andrographolide; D013311:Streptozocin; D001615:beta-Endorphin