1. Diabetes. 2006 Mar;55(3):819-25.
Novel mechanism for plasma glucose-lowering action of metformin in
streptozotocin-induced diabetic rats.
Cheng JT, Huang CC, Liu IM, Tzeng TF, Chang CJ.
Department of Pharmacology, College of Medicine, National Cheng Kung University,
Tainan City, Taiwan 70101, ROC.
[email protected]
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.
PMID: 16505249 [PubMed - indexed for MEDLINE]