Investigation of KATP channel function in response to metabolic and pharmacological manipulation, in the hypothalamic GT1-7 cell line

Animal and human studies have consistently demonstrated that recurrent hypoglycaemia (RH) blunts both hormonal and behavioral counter regulatory responses (CRR) to further episodes of hypoglycaemia. It is now well established that the brain is involved in regulating whole-body glucose homeostasis, including the CRR to hypoglycaemia. The aim of the current study was to investigate if adaptations occur, following RH, which are intrinsic to glucose-sensing neurons in the absence of synaptic/glial inputs or signals from the periphery. Utilising the GT1-7 hypothalamic mouse cell line as an in vitro model of homogenous glucose-excited neurons, the current study has demonstrated that recurrent low glucose exposure reprograms intracellular metabolism towards a “hypometabolic state”. This result occurs in conjunction with an attenuated ability of the cells to hyperpolarise in response to low glucose and a reduction in the sensitivity of the KATP channel to activation by MgADP. In an attempt to reverse the changes observed in KATP channel activity, the SUR1-selective KATP channel opener, NN414, was applied chronically to GT1-7 cells. However, chronic KATP channel activation severely reduced channel conductance and sensitivity to activation by MgADP and further NN414 application. These results suggest that chronic activation of the KATP channel leads to the induction of a negative feedback mechanism to reduce channel activity. This may be in an attempt to maintain neuronal membrane potential within a physiological range. These results also suggest activation of central KATP channels during RH may be driving the resulting defective CRR. However, adaptations in metabolism following RH may also be altering the function of central KATP channels.

Name dc:type.qualificationname

Doctor of Philosophy

Level dc:type.qualificationlevel

Doctoral Thesis

Grantor dc:publisher.institution

University of Dundee

Year dc:date.issued

2014

Author dc:creator

• Haythorne, Elizabeth

Advisors dc:contributor.advisor

• Ashford, Michael
• McCrimmon, Rory

• Glucose-sensing
• Type 1 diabetes
• Hypoglycaemia
• KATP channel
• Metabolism
• Hypothalamus

Language dc:language

eng

Identifier

oai:discovery.dundee.ac.uk:studenttheses/419b0b9f-3596-4724-a4b4-01254bfcc44c

OAI identifier oai:identifier

oai:discovery.dundee.ac.uk:studenttheses/419b0b9f-3596-4724-a4b4-01254bfcc44c