AbstractHypoglycaemia is the major complication associated with insulin therapy in type 1 diabetes. Repeated exposure to hypoglycaemia leads to suppression of normal counter regulatory responses (CRR) to subsequent hypoglycaemia, which increases the risk of severe episodes of hypoglycaemia. Studies have demonstrated the important role the brain plays in the regulation of whole body glucose homeostasis, including a vital role in mounting the CRR. Detection of hypoglycaemia by specialised glucose-sensing neurons of the hypothalamus is critical for initiating the associated CRR. It is believed that defective CRRs are mediated by brain adaptations leading to impaired central glucose sensing, although the mechanisms by which these occur remain unknown. Hypoglycaemia evokes a significant systemic and central stress response with an increase in inflammatory mediators including interleukin-6 (IL-6). The aim of the current study was to investigate whether IL-6 played a role in the regulation of central glucose sensing. This was addressed by examining the effects of IL-6 exposure on electrophysiological and biochemical responses in hypothalamic glucose-excited GT1-7 neurons. Antecedent exposure to IL-6 induced defective glucose sensing of subsequent hypoglycaemia, with a role for the exchange protein activated by cAMP (EPAC) implicated in this observation. The results obtained suggest that EPAC may mediate this effect by enhancing the sensitivity of ATP-sensitive potassium (KATP) channels to ATP-mediated inhibition following IL-6 exposure. The current results identify IL-6 and EPAC2 as novel mediators of defective hypothalamic glucose sensing, suggesting they may contribute to the development of blunted CRR observed with recurrent hypoglycaemia exposure.
|Date of Award||2015|
|Add any sponsors of the thesis research||Juvenile Diabetes Research Foundation|
|Supervisor||Rory McCrimmon (Supervisor) & Michael Ashford (Supervisor)|
The Role of Interleukin-6 in the Regulation of Glucose Sensing in Hypothalamic GT1-7 Neurons
Denwood, G. T. (Author). 2015
Student thesis: Doctoral Thesis › Doctor of Philosophy