Curcumin pretreatment mediates antidiabetogenesis via functional regulation of adrenergic receptor subtypes in the pancreas of multiple low-dose streptozotocin-induced diabetic rats.

Lifestyle modification pivoting on nutritional management holds tremendous potential to meet the challenge of management of diabetes. The current study hypothesizes that regular uptake of curcumin lowers the incidence of diabetes by functional regulation of pancreatic adrenergic receptor subtypes. The specific objective of the study was to identify the regulatory pathways implicated in the antidiabetogenesis effect of curcumin in multiple low-dose streptozotocin (MLD-STZ)-induced diabetic Wistar rats. Administration of MLD-STZ to curcumin-pretreated rats induced a prediabetic condition. Scatchard analysis, real-time polymerase chain reaction, and confocal microscopic studies confirmed a significant increase in α2-adrenergic receptor expression in the pancreas of diabetic rats. Pretreatment with curcumin significantly decreased α2-adrenergic receptor expression. The diabetic group showed a significant decrease in the expression of ß-adrenergic receptors when compared with control. Pretreatment significantly increased ß-adrenergic receptor expression to near control. When compared with the diabetic rats, a significant up-regulation of CREB, phospholipase C, insulin receptor, and glucose transporter 2 were observed in the pretreated group. Curcumin pretreatment was also able to maintain near control levels of cyclic adenosine monophosphate, cyclic guanosine monophosphate, and inositol triphosphate. These results indicate that a marked decline in α2-adrenergic receptor function relents sympathetic inhibition of insulin release. It also follows that escalated signaling through ß-adrenergic receptors mediates neuronal stimulation of hyperglycemia-induced ß-cell compensatory response. Curcumin-mediated functional regulation of adrenergic receptors and modulation of key cell signaling molecules improve pancreatic glucose sensing, insulin gene expression, and insulin secretion.

The effects of abnormalities of glucose homeostasis on the expression and binding of muscarinic receptors in cerebral cortex of rats.

Glucose homeostasis in humans is an important factor for the functioning of nervous system. Both hypo and hyperglycemia contributes to neuronal functional deficit. In the present study, effect of insulin induced hypoglycemia and streptozotocin induced diabetes on muscarinic receptor binding, cholinergic enzymes; AChE, ChAT expression and GLUT3 in the cerebral cortex of experimental rats were analysed. Total muscarinic, muscarinic M(1) receptor showed a significant decrease and muscarinic M(3) receptor subtype showed a significant increased binding in the cerebral cortex of hypoglycemic rats compared to diabetic and control. Real-Time PCR analysis of muscarinic M(1), M(3) receptor subtypes confirmed the receptor binding studies. Immunohistochemistry of muscarinic M(1), M(3) receptors using specific antibodies were also carried out. AChE and GLUT3 expression up regulated and ChAT expression down regulated in hypoglycemic rats compared to diabetic and control rats. Our results showed that hypo/hyperglycemia caused impaired glucose transport in neuronal cells as shown by altered expression of GLUT3. Increased AChE and decreased ChAT expression is suggested to alter cortical acetylcholine metabolism in experimental rats along with altered muscarinic receptor binding in hypo/hyperglycemic rats, impair cholinergic transmission, which subsequently lead to cholinergic dysfunction thereby causing learning and memory deficits. We observed a prominent cholinergic functional disturbance in hypoglycemic condition than in hyperglycemia. Hypoglycemia exacerbated the neurochemical changes in cerebral cortex induced by hyperglycemia. These findings have implications for both therapy and identification of causes contributing to neuronal dysfunction in diabetes.

Vitamin D3 restores altered cholinergic and insulin receptor expression in the cerebral cortex and muscarinic M3 receptor expression in pancreatic islets of streptozotocin induced diabetic rats.

Nutritional therapy is a challenging but necessary dimension in the management of diabetes and neurodegenerative changes associated with it. The study evaluates the effect of vitamin D(3) in preventing the altered function of cholinergic, insulin receptors and GLUT3 in the cerebral cortex of diabetic rats. Muscarinic M3 acetylcholine receptors in pancreas control insulin secretion. Vitamin D(3) treatment in M3 receptor regulation in the pancreatic islets was also studied. Radioreceptor binding assays and gene expression was done in the cerebral cortex of male Wistar rats. Immunocytochemistry of muscarinic M3 receptor was studied in the pancreatic islets using specific antibodies. Y-maze was used to evaluate the exploratory and spatial memory. Diabetes induced a decrease in muscarinic M1, insulin and vitamin D receptor expression and an increase in muscarinic M3, α7 nicotinic acetylcholine receptor, acetylcholine esterase and GLUT3 expression. Vitamin D(3) and insulin treatment reversed diabetes-induced alterations to near control. Diabetic rats showed a decreased Y-maze performance while vitamin D(3) supplementation improved the behavioural deficit. In conclusion, vitamin D(3) shows a potential therapeutic effect in normalizing diabetes-induced alterations in cholinergic, insulin and vitamin D receptor and maintains a normal glucose transport and utilisation in the cortex. In addition vitamin D(3) modulated muscarinic M3 receptors activity in pancreas and plays a pivotal role in controlling insulin secretion. Hence our findings proved, vitamin D(3) supplementation as a potential nutritional therapy in ameliorating diabetes mediated cortical dysfunctions and suggest an interaction between vitamin D(3) and muscarinic M3 receptors in regulating insulin secretion from pancreas.

Muscarinic M1, M3 receptor modulation in the corpus striatum of streptozotocin induced diabetic rats as a function of age.

OBJECTIVES: In this study we have investigated muscarinic M1, M3 receptor kinetics and the functional role of IP3 and cGMP in the corpus striatum of both young and old diabetic and insulin-treated diabetic rats. METHODS: Radioreceptor binding assays was done in the corpus striatum using specific antagonists QNB and DAMP. IP3 and cGMP assay using [3H]IP3 and [3H]cGMP Biotrak assay system kits. KEY FINDINGS: M1 receptor increased and M3 receptor decreased in control old rats when compared with young control rats. In young diabetic groups M1 receptor increased and M3 receptor decreased. Old diabetic groups showed reversed M1 and M3 receptors compared with their controls. IP3 and cGMP content increased in old control rats compared with young control rats. IP3 content increased in young diabetic rats and decreased in old diabetic rats. cGMP content was increased significantly in both young and old diabetic groups. Insulin treatment reversed these altered parameters near to control. CONCLUSIONS: Our studies showed that M1 and M3 receptors, IP3 and cGMP were functionally regulated during diabetes as function of age, which will have immense clinical significance.

Opioid system functional regulation in neurological disease management.

There is increasing evidence to suggest a role for the opioid system in the control of pathophysiology of neurological disorders (Alzheimer's, Parkinson's, and Huntington's diseases, spinal cord injury, epilepsy, hypoxia, and autism). Resuscitation of the altered expression of the opioid system in various neurological disorders is of therapeutic importance. Such treatment may be beneficial in ameliorating the clinical symptoms of the disorder. This Mini-Review provides a brief update on opioid system regulation in neurological disorders and focuses on the opioids' pharmacological importance.