Activation of imidazoline receptors in adrenal gland to lower plasma glucose in streptozotocin-induced diabetic rats.
OBJECTIVE
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
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.
Hwang
S-L
SL
Division of Neurosurgery, Kaohsiung Medical University Hospital, 100 Shih Chuan 1st Road, Kaohsiung City, Taiwan.
Liu
I-M
IM
Tzeng
T-F
TF
Cheng
J-T
JT
D000311:Adrenal Glands / Q000187:drug effects* / Q000378:metabolism; D000313:Adrenal Medulla / Q000187:drug effects / Q000378:metabolism; D000315:Adrenalectomy; D000376:Agmatine / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D001794:Blood Pressure / Q000187:drug effects; D003000:Clonidine / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D051275:Glucose Transporter Type 4; D007093:Imidazoles / Q000494:pharmacology; D054755:Imidazoline Receptors; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000235:genetics; D009124:Muscle Proteins / Q000235:genetics; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D011955:Receptors, Drug / Q000819:agonists* / Q000037:antagonists & inhibitors; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors; D001615:beta-Endorphin / Q000097:blood
C105826:BU 224; D001786:Blood Glucose; D051275:Glucose Transporter Type 4; D007093:Imidazoles; D054755:Imidazoline Receptors; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D011955:Receptors, Drug; D017450:Receptors, Opioid, mu; C495694:Slc2a4 protein, rat; C487767:imidazoline receptor 2; D001615:beta-Endorphin; D000376:Agmatine; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D003000:Clonidine