Investigation of mechanistic processes that regulate hypothalamic response to glucose and oxygen variability

Abstract

The hypothalamus is a central regulator of neuroendocrine responses. It plays a pivotal role in maintaining adequate levels of glucose and oxygen, both of which are essential parameters for the brain’s homeostatic function. Thereby, hypothalamic dysfunction is associated with severe neuroendocrine consequences such as diabetes mellitus (DM), where the latter is mainly characterized by hyperglycaemia. A major disadvantage of treatment against hyperglycaemia is recurrent hypoglycaemia that leads to hypoglycaemia unawareness (HU), the pathogenesis of which remains to be elucidated. Moreover, DM-associated neurological dysfunction manifests as diabetic neuropathy, the implications of which remain to be fully characterized. This thesis investigates the mechanistic processes governing hypothalamic responses to glucose and oxygen variability, focusing on hypoglycaemia-induced neuropathy. Various in-vitro studies have been employed to decipher the molecular and translational mechanisms behind hypothalamic dysfunction subjected to variable glucose and oxygen concentrations. Since hypoxia-inducible factor-1α is a key regulator of both oxygen homeostasis and glucose metabolism, it was hypothesized to mediate the hypothalamic response to glucose and oxygen variability under the physiological oxygen concentration of the brain. Intriguing findings from primary and immortalized microglial cells debunked the proposed hypothesis. They revealed the NF-κB pathway as potential regulator of these responses, suggesting novel avenues for targeting hypoglycaemia-induced neuroinflammation. Furthermore, analysing hypothalamic neuronal responses to glucose variability implicated autophagy in the pathogenesis of hypoglycaemia-associated autonomic failure and revealed FOS as a potential regulator of these responses. The unique upregulation of angiotensin 1 converting enzyme-2 in hypothalamic neurons under glucose variability provided critical insights into the neurological manifestations of COVID-19 and its susceptibility to patients with DM, emphasizing the need for strict glycaemic control in this population. Collectively, these outcomes have achieved the primary purpose of advancing the current understanding of glucose and oxygen-induced neurological impairments, whilst offering novel insights into neuroendocrine regulation governed by the hypothalamus.