Hypoglycemia causes dysregulation of Neuregulin 1, ErbB receptors, Ki67 in cerebellum and brainstem during diabetes: Implications in motor function

Abstract

Hypoglycemia induced brain injury poses a major setback to optimal blood glucose regulation during diabetes. It causes irreversible injury in several brain regions culminating in improper function. Neuregulin 1 and ErbB receptors are involved in regeneration during adulthood as well as in glucose homeostasis. We intended to understand the influence of extreme discrepancies in glycemic levels on Neuregulin 1, ErbB receptor subtypes and Ki67 expression in relation to motor deficits as a consequence of cellular dysfunction/degeneration in the cerebellum and brainstem during diabetes. Elevated oxidative stress and compromised antioxidant system havocs cerebellum and brainstem related function. Cellular alteration of Purkinje neurons in the cerebellum and presence of axonal spheroids in the brainstem are suggestive of impairment to neural circuits involved in motor function. Down regulation of Neuregulin 1, ErbB 2, ErbB 3, ErbB 4 and Ki67 expression observed during diabetes and hypoglycemia may critically cause regenerative deficiency in cerebellum. The coincident up regulation of Neuregulin 1, ErbB 2, ErbB 3 and ErbB 4 in brainstem during diabetes is an attempt to maintain regenerative homeostasis to ensure its function. However, hypoglycemic insults results in down regulation of Neuregulin 1, ErbB 4 expression that severely compromises their role in brainstem. Grid walking test confirmed motor impairment during diabetes that showed further deterioration due to hypoglycemic stress. Thus altered expression of Neuregulin 1, ErbB receptor subtypes and Ki67 during diabetes and hypoglycemia contributes to reduced cellular proliferation and deficits in motor function.