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

Abstract

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 ␤-endorphin-like immunoreactivity (BER). Mediation of opioid -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 -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 ␤-endorphin secretion from adrenal glands to stimulate opioid -receptor linkage, leading to an increase of GLUT-4 gene expression and an attenuation of hepatic PEPCK gene expression in STZinduced diabetic rats. Diabetes 55:819 -825, 2006

Metabolic Effects of Tulbaghia Violacea Harv. In a Diabetic Model.

“…Others have alluded to the ability of metformin to attenuate oxidative stress (Nasri et al, 2013;Piwkowska et al, 2010) but this function in the clinical setting still needs to be investigated. It is also of great interest, that metformin apart from its insulin dependent functions, is able to lower glucose via novel mechanisms such as the GLUT 4 genetic expression, via the B endorphin secretion from the adrenal glands (Cheng et al, 2006). This may have particular relevance to type 1 diabetes and account for our findings in this model STZ-induced diabetes.…”

The Effect of Nrf2 on Diabetic Complications

“…The antioxidant response provided by the NFE2L2 and Keap1-NFE2L2/ARE signaling pathways protects the pulmonary, hepatic, digestive, neural and cardiovascular systems, and Nrf2 is considered a promising target against diabetic complications such as cardiovascular diseases and diabetic nephropathy [7][8][9].…”

“…Research has revealed that the expressions of Nrf2-mediated anti-oxidative enzymes, including HO-1, NQO-1, and GPx-1, were signiicantly increased in the diabetic kidney when treated with salvianolic acid A (SAA) alone or in combination with metformin (MET). SAA is a polyphenol derivative extracted from the root of Salvia miltiorrhiza, which is known to show a variety of pharmacological activities including antioxidant, anti-inlammatory, and antiplatelet properties [8,9].…”

“…The MET is an oral hypoglycemic agent, which is widely used in patients with type 2 diabetes. MET decreases blood glucose levels by decreasing hepatic glucose production, decreasing intestinal absorption of glucose, and improving insulin sensitivity by increasing peripheral glucose uptake and utilization [8][9][10].…”

UPLCMS Method Development and Validation of Tablet Dosage form Containing Glimepiride, Metformin and Pioglitazone Using Internal Standard

“…Diabetes and its abnormalities constitute a major health problem in the modern society [1]. It is characterized by disrupted insulin production, leading to high blood glucose concentration and other complications such as renal dysfunction, neuropathy and cardiopathy [2].…”