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.
Highlights
Hypoglycemic brain injury is a common and serious complication of insulin therapy in diabetic individuals [1,2]
Enhanced Muscarinic M1, M3 receptor binding in the Cerebellum of Diabetic, Diabetic + IIH and Control + IIH Rats Scatchard analysis of [3H] Quinuclidinyl benzilate (QNB) Binding against Pirenzepine to study muscarinic M1 receptor binding parameters showed a significant increase in Bmax in the cerebellum of hypoglycemic (P < 0.001) and diabetic (P < 0.001) rats when compared to control
Hypoglycemia impose alterations upon both the central (CNS) and peripheral (PNS) nervous systems which leads to brain damage and long-term cognitive impairment
Summary
Hypoglycemic brain injury is a common and serious complication of insulin therapy in diabetic individuals [1,2]. Studies suggest that acute or chronic hypoglycemia leads to neurological dysfunction and injury. Altered neurotransmitter action appears to play a role in hypoglycemic brain dysfunction [7,8,9]. Muscarinic acetylcholine receptors play important roles in many fundamental central functions including higher cognitive processes and modulation of extrapyramidal motor activity. In terms of the contribution of cholinergic cerebellar abnormalities to mental function, early reports of cerebellar abnormalities in autism [10] and of intellectual and behavioural abnormalities in patients with cerebellar damage [11] originally suggested a cognitive role for the cerebellum. Many studies have confirmed that the cerebellum contributes to cognitive and other non-motor functions. Alterations in glucose utilization are known to occur in the important regions of brain connected with learning and memory [14,15]
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