Wellcome Trust PhD Programme for Clinicians at Imperial College London: Investigating the physiological role of hypothalamic glucose-sensing neurones in glucose homeostasis. (360G-Wellcome-090792_Z_09_A)

Until recently it was thought that day to day blood glucose is regulated by peripheral factors, principally insulin. Recent data suggests glucose sensing in the brain is important for the regulation of whole body glucose homeostasis. These effects are thought to be mediated by a complex network of specialised glucose sensing neurones. Glucokinase is the body's glucose sensor and is expressed within these neurones. Glucose sensing neurones have been identified in the ARC and PVN of the hypothalamus. My pilot data provides evidence that overexpression of glucokinase in the ARC using recombinant adeno-associated virus (rAAV) results in increased glucose disposal during a glucose tolerance test. Despite recent advances there is little evidence linking neuronal glucose sensing directly to the in vivo day to day regulation of glucose homeostasis. To further test the hypothesis that hypothalamic glucokinase is the key neuronal regulator of glucose control I will use virally mediated gene transfer to increase or decrease glucokinase expression specifically in the ARC and PVN of the hypothalamus and determine the effect on glucose homeostasis. These studies will determine the physiological role of glucokinase in the hypothalamus and may lead to the identification of new therapeutic targets to treat diabetes.