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

Diabetologia. 2005 Apr;48(4):767-75. doi: 10.1007/s00125-005-1698-2. Epub 2005 Mar 9.


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 beta-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 beta-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 I(1)-imidazoline receptors and/or alpha2-adrenoceptors in this effect of agmatine was thus unlikely. The lowering of plasma glucose and increase of plasma beta-endorphin-like immunoreactivity by agmatine were abolished by pretreating the rats with BU-224 at a dose sufficient to block I(2)-imidazoline receptors. Both effects of agmatine were also abolished in adrenalectomised STZ-diabetic rats. Moreover, agmatine enhanced beta-endorphin-like immunoreactivity release from the isolated adrenal medulla of STZ-diabetic rats, an effect also blocked by BU-224. Release of beta-endorphin from the adrenal glands by I(2)-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 mu-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 I(2)-imidazoline receptors in the adrenal gland. This enhances secretion of beta-endorphin, which can activate opioid mu-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Glands / drug effects*
  • Adrenal Glands / metabolism
  • Adrenal Medulla / drug effects
  • Adrenal Medulla / metabolism
  • Adrenalectomy
  • Agmatine / administration & dosage
  • Agmatine / pharmacology
  • Animals
  • Blood Glucose / metabolism*
  • Blood Pressure / drug effects
  • Clonidine / pharmacology
  • Diabetes Mellitus, Experimental / blood
  • Diabetes Mellitus, Experimental / drug therapy*
  • Diabetes Mellitus, Experimental / metabolism
  • Gene Expression / drug effects
  • Glucose Transporter Type 4
  • Imidazoles / pharmacology
  • Imidazoline Receptors
  • Male
  • Monosaccharide Transport Proteins / genetics
  • Muscle Proteins / genetics
  • Phosphoenolpyruvate Carboxykinase (GTP) / genetics
  • Rats
  • Rats, Wistar
  • Receptors, Drug / agonists*
  • Receptors, Drug / antagonists & inhibitors
  • Receptors, Opioid, mu / antagonists & inhibitors
  • beta-Endorphin / blood


  • BU 224
  • Blood Glucose
  • Glucose Transporter Type 4
  • Imidazoles
  • Imidazoline Receptors
  • Monosaccharide Transport Proteins
  • Muscle Proteins
  • Receptors, Drug
  • Receptors, Opioid, mu
  • Slc2a4 protein, rat
  • imidazoline receptor 2
  • beta-Endorphin
  • Agmatine
  • Phosphoenolpyruvate Carboxykinase (GTP)
  • Clonidine