AbstractInsulin induced hypoglycaemia is a significant cause of morbidity and mortality in people with diabetes, and commonly limits tight glycaemic control. An additional challenge is the loss of the normal counterregulatory response to hypoglycaemia over time in many patients, which reduces their ability to sense and respond to hypoglycaemia and can result in more frequent/severe hypoglycaemia. In addition, failure of the counterregulatory response is accelerated by recurrent hypoglycaemia. The mechanisms underlying this phenomenon remain incompletely understood, but one contributor is reduction of sympatho-adrenal responses to hypoglycaemia, originating in the central nervous system.
Novel techniques including the use of genetically modified mice now allow more detailed investigation of neuronal subtype connectivity and responses to hypoglycaemia. This thesis uses a mouse expressing Cre recombinase under the control of the corticotrophin releasing hormone (CRH) promoter to investigate the role of CRH PVN neurons in more detail. CRH neurons of the PVN are well placed to influence responses to hypoglycaemia, as they receive inputs from multiple central and peripheral centres providing information on glycaemic and overall metabolic state, and have outputs via the pituitary and (as shown in this thesis) the sympathetic outflow centres of the brainstem and spinal cord. In addition, data shown here presents the first evidence that a subset of CRH PVN neurons are able to directly sense changes in local glucose levels in the PVN, becoming activated when glucose levels fall. This represents a novel glucose sensing population of the CNS, which may have an important role to play in modulating the counterregulatory response to hypoglycaemia. Finally, data is presented of a model of recurrent hypoglycaemia resulting in an expansion of this glucose sensing CRH PVN population, which could represent a means by which these cells contribute to the development of counterregulatory failure following recurrent episodes of hypoglycaemia.
|Date of Award||23 Jan 2019|
|Supervisor||Anthony Edward Pickering (Supervisor) & Nina Balthasar (Supervisor)|