Activation of Imidazoline I-2B Receptor by Metformin to Increase Glucose Uptake in Skeletal Muscle

Metformin (dimethylbiguanide) belongs to guanidinium-derivative and is widely used for treatment of diabetic disorders in clinic. Metformin lowers blood glucose in diabetic animals through increase of glucose uptake into skeletal muscle. Recent evidence indicates that activation of imidazoline I(2B) receptor (I(2B)R) by guanidinium-derivatives also increased glucose uptake; however, the effect of metformin on I(2B)R is still unknown. The blood glucose levels were determined by a glucose kit. The ability of glucose uptake into isolated skeletal muscle or cultured C(2)C(12) cells was determined using 2-[(14)C]-deoxyglucose as tracer. The expressions of 5' AMP-activated protein kinase (AMPK) and glucose transporter 4 (GLUT-4) were identified by Western blotting analysis. The metformin-induced blood glucose-lowering action was dose-dependently blocked by BU224, a specific I(2)R antagonist, in Wistar rats. Also, similar reversion by BU224 was observed in isolated skeletal muscle regarding the metformin-induced glucose uptake. Moreover, AMPK phosphorylation by metformin was concentration-dependently reduced by BU224 in isolated skeletal muscle. In addition, signals for metformin increased glucose uptake were identified via I2R/PI3K/PKC/AMPK dependent pathway in C(2)C(12) cells. Thus, we suggest that metformin can activate I(2B)R to increase glucose uptake and I(2B)R will be a new target for diabetic therapy.