Novel mechanism for plasma glucose-lowering action of metformin in streptozotocin-induced diabetic rats.
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 beta-endorphin-like immunoreactivity (BER). Mediation of opioid mu-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 mu-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 beta-endorphin secretion from adrenal glands to stimulate opioid mu-receptor linkage, leading to an increase of GLUT-4 gene expression and an attenuation of hepatic PEPCK gene expression in STZ-induced diabetic rats.
Cheng
Juei-Tang
JT
Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan City, Taiwan 70101, ROC. jtcheng@mail.ncku.edu.tw
Huang
Ching-Chiu
CC
Liu
I-Min
IM
Tzeng
Thing-Fong
TF
Chang
Chih Jen
CJ
D000315:Adrenalectomy; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy*; D051275:Glucose Transporter Type 4 / Q000032:analysis / Q000235:genetics; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D008687:Metformin / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D009270:Naloxone / Q000031:analogs & derivatives / Q000494:pharmacology; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000032:analysis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin; D001615:beta-Endorphin / Q000097:blood
D001786:Blood Glucose; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D009270:Naloxone; D013311:Streptozocin; D001615:beta-Endorphin; C034643:naloxonazine; D008687:Metformin; D010729:Phosphoenolpyruvate Carboxykinase (GTP)