Muscarinic M1, M3 receptors function in the brainstem of streptozotocin induced diabetic rats: Their role in insulin secretion from the pancreatic islets as a function of age

In the present study, we have investigated acetylcholine esterase (AM) activity and muscarinic M-1, M-3 receptors kinetics in the brainstem of both young and old streptozotocin induced and insulin treated diabetic rats (D + 1). Also, the functional role of acetylcholine and muscarinic receptors in insulin secretion from the pancreatic islets was studied in vitro. 90 week old control rats showed decreased V-max (P<0.001) for AChE compared to 7 week old control rats. V-max was decreased (P<0.001) in 7 week diabetic groups whereas 90 week old diabetic groups showed increased (P<0.001) V-max when compared to their respective controls. Binding studies using [H-3]QNB and [H-3]DAMP of 90 week old control showed significant increase in the B-max (P<0.001) and K-d (P<0.01) of muscarinic M-1 receptors whereas M-3 receptor number was decreased significantly (P<0.001) with no change in affinity when compared to 7 week old control respectively. M-1 receptor number was decreased significantly (P<0.001) whereas M-3 receptor number was increased significantly (P<0.001) in both 7 week and 90 week old diabetic rat groups compared to their respective controls. The competition curve for [H-3]QNB fitted for two sited model in 7 week old groups whereas fitted for one sited model in 90 week old groups. [H-3]DAMP was fitted for two sited model in both 7 week and 90 week old groups. Insulin treatment significantly reversed (P<0.001) the binding parameters to near control level. In vitro studies showed that acetylcholine through muscarinic M-1 and M-3 receptors stimulated insulin secretion from the pancreatic islets. Thus our studies suggest that both brainstem and pancreatic muscarinic M-1, M-3 receptors differentially regulate the cholinergic activity and insulin secretion which will have clinical significance in the management of diabetes and insulin treatment as a function of age. (c) 2009 Elsevier B.V. All rights reserved.