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Novel Mechanism for Plasma Glucose–Lowering Action of Metformin in Streptozotocin-Induced Diabetic Rats

¹ Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan City, Taiwan, R.O.C
² Department of Pharmacy, Tajen University, Yen-Pou, Ping Tung Shien, Taiwan, R.O.C
³ Department of Internal Medicine, Pao Chien Hospital, Ping Tung City, Taiwan, R.O.C
⁴ Department of Family Medicine, College of Medicine, National Cheng Kung University, Tainan City, Taiwan, R.O.C

Address correspondence and reprint requests to Prof. Juei-Tang Cheng, PhD, FCP, Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan City, Taiwan 70101, R.O.C. E-mail: jtcheng{at}mail.ncku.edu.tw

Abbreviations: AMPK, 5'AMP-activated protein kinase; BER, ß-endorphin–like immunoreactivity; PKC, protein kinase C; STZ, streptozotocin

To better understand the insulin-independent plasma glucose–lowering action of metformin, we used streptozotocin (STZ)-induced diabetic rats to investigate the possible mechanisms. Oral intake of metformin decreased the plasma glucose of STZ-induced diabetic rats with a parallel increase of plasma ß-endorphin–like immunoreactivity (BER). Mediation of opioid µ-receptors in the action of metformin was identified by the blockade of receptors with antagonist in STZ-induced diabetic rats and the failure of action in opioid µ-receptor knockout diabetic mice. Release of BER from adrenal glands by metformin was characterized, using bilateral adrenalectomy and the release of BER from isolated adrenal medulla of STZ-induced diabetic rats. Repeated treatment with metformin in STZ-induced diabetic rats increased the mRNA and protein levels of GLUT-4 in soleus muscle that was blocked by naloxonazine. Reduction of the mRNA or protein levels of hepatic PEPCK was also impeded in the same group of STZ-induced diabetic rats. In conclusion, our results provide novel mechanisms for the plasma glucose–lowering action of metformin, via an increase of ß-endorphin secretion from adrenal glands to stimulate opioid µ-receptor linkage, leading to an increase of GLUT-4 gene expression and an attenuation of hepatic PEPCK gene expression in STZ-induced diabetic rats.

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