Activation of imidazoline receptors in adrenal gland to lower plasma glucose in streptozotocin-induced diabetic rats

Abstract

Aims/hypothesis: The present study investigated the effect of agmatine, an endogenous ligand of imidazoline receptors, on plasma glucose in streptozotocin-induced diabetic rats (STZ-diabetic rats). Methods: Plasma glucose was assessed by the glucose oxidase method. Plasma insulin and β-endorphin-like immunoreactivity in plasma or adrenal medulla were measured by enzyme-linked immunosorbent assay. Systolic blood pressure was determined by the tail-cuff method. The mRNA levels of glucose transporter subtype 4 (GLUT4) in soleus muscle and phosphoenolpyruvate carboxykinase (PEPCK) in liver were detected by northern blotting. Protein levels of GLUT4 in soleus muscle and hepatic PEPCK were estimated using western blotting analysis. Results: After intravenous injection into fasting STZ-diabetic rats for 30 min, agmatine decreased plasma glucose in a dose-dependent manner without changing systolic blood pressure. At the same time, plasma β-endorphin-like immunoreactivity also increased in STZ-diabetic rats receiving the same treatment. Plasma glucose was significantly elevated in STZ-diabetic rats by an intravenous injection of clonidine at a dose sufficient to decrease systolic blood pressure. Involvement of I1-imidazoline receptors and/or α2-adrenoceptors in this effect of agmatine was thus unlikely. The lowering of plasma glucose and increase of plasma β-endorphin-like immunoreactivity by agmatine were abolished by pretreating the rats with BU-224 at a dose sufficient to block I2-imidazoline receptors. Both effects of agmatine were also abolished in adrenalectomised STZ-diabetic rats. Moreover, agmatine enhanced β-endorphin-like immunoreactivity release from the isolated adrenal medulla of STZ-diabetic rats, an effect also blocked by BU-224. Release of β-endorphin from the adrenal glands by I2- imidazoline receptor activation seems responsible for the plasma glucose-lowering action of agmatine. This was supported by the fact that intravenous injection of naloxone or naloxonazine at doses sufficient to block opioid μ-receptors inhibited the action of agmatine. In addition to lowering plasma glucose, repeated intravenous injection of agmatine into STZ-diabetic rats for 4 days also increased mRNA and protein levels of GLUT4 in soleus muscle. The same treatment also reversed the higher mRNA and protein levels of PEPCK in liver of STZ-diabetic rats. Conclusions/interpretation: Our results suggest that agmatine may activate I2-imidazoline receptors in the adrenal gland. This enhances secretion of β-endorphin, which can activate opioid μ-receptors to increase GLUT4 gene expression and/or suppress hepatic PEPCK gene expression, resulting in a lowering of plasma glucose in diabetic rats lacking insulin. The results provide a potential new target for intervention in type 1 diabetes. © Springer-Verlag 2005.