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

2005; Springer Science+Business Media; Volume: 48; Issue: 4 Linguagem: Inglês

10.1007/s00125-005-1698-2

1432-0428

Shiuh‐Lin Hwang, I‐Min Liu, T. F. Tzeng, Juei‐Tang Cheng,

Adipose Tissue and Metabolism

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). 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. 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. 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.