Hypoglycemia induced changes in cholinergic receptor expression in the cerebellum of diabetic rats

Abstract

Glucose homeostasis in humans is an important factor for the functioning of nervous system. Hypoglycemia and hyperglycemia is found to be associated with central and peripheral nerve system dysfunction. Changes in acetylcholine receptors have been implicated in the pathophysiology of many major diseases of the central nervous system (CNS). In the present study we showed the effects of insulin induced hypoglycemia and streptozotocin induced diabetes on the cerebellar cholinergic receptors, GLUT3 and muscle cholinergic activity. Results showed enhanced binding parameters and gene expression of Muscarinic M1, M3 receptor subtypes in cerebellum of diabetic (D) and hypoglycemic group (D + IIH and C + IIH). α7nAchR gene expression showed a significant upregulation in diabetic group and showed further upregulated expression in both D + IIH and C + IIH group. AchE expression significantly upregulated in hypoglycemic and diabetic group. ChAT showed downregulation and GLUT3 expression showed a significant upregulation in D + IIH and C + IIH and diabetic group. AchE activity enhanced in the muscle of hypoglycemic and diabetic rats. Our studies demonstrated a functional disturbance in the neuronal glucose transporter GLUT3 in the cerebellum during insulin induced hypoglycemia in diabetic rats. Altered expression of muscarinic M1, M3 and α7nAchR and increased muscle AchE activity in hypoglycemic rats in cerebellum is suggested to cause cognitive and motor dysfunction. Hypoglycemia induced changes in ChAT and AchE gene expression is suggested to cause impaired acetycholine metabolism in the cerebellum. Cerebellar dysfunction is associated with seizure generation, motor deficits and memory impairment. The results shows that cerebellar cholinergic neurotransmission is impaired during hyperglycemia and hypoglycemia and the hypoglycemia is causing more prominent imbalance in cholinergic neurotransmission which is suggested to be a cause of cerebellar dysfunction associated with hypoglycemia.

Analysis of diabetes-related cerebellar changes in streptozotocin-induced diabetic rats

“…Dopamine D1 receptor expression was downregulated in accordance with the total dopamine receptor decline. However, dopamine D2 receptor expression of cortex and cerebellum were upregulated (2,9).…”

“…Four groups, classified as control, diabetic, insulin-induced hypoglycemic diabetic, and insulininduced hypoglycemic control rats, were compared. Increased gene expression in the cerebellums of the diabetic hypoglycemic group showed that cerebellar glucose transport impairment is maximal during insulininduced hypoglycemia, leading to neuronal dysfunction (2).…”

“…However, all these studies are not specific to the cerebellum. Research studies related to the cerebellum are very few to our knowledge (1,2,4,7,8).…”

“…Muscarinic receptor-binding assays using specific antagonists in the cerebellum showed cerebellar cholinergic receptor dysfunction due to impaired neuronal glucose transport in the cerebellum during recurrent hypoglycemia in diabetic rats (2).…”

Hormonal Signaling Systems of the Brain in Diabetes Mellitus

“…The prolonged influence of mild hypoglycemia on the brain leads to deregulation of many processes in CNS, which underlines the importance of scrupulously avoiding even mild hypoglycemic episodes in patients with DM. Hypoglycemia induces progressive reduction in cerebral glycogen and glucose, which is due to an increase in gene expression of GLUT3, the glucose transporter rather abundant in the brain (Antony et al, 2010b). Alteration of expression of GLUT3 in the cerebral cortex in hypoglycemia is the evidence for impairment of neuronal glucose transport during glucose deprivation.…”