Chronically high circulating glucose levels can lead to metabolic problems such as Type II Diabetes Mellitus (T2DM). Plasma glucose levels are constantly monitored by a process named glucose-sensing. Glucokinase (GK) is a key glucose-sensing enzyme and is expressed in various areas of the brain associated with the control of energy homeostasis. It has been detected in the nucleus tractus solitarius (NTS) and the paraventricular nucleus (PVN) but its physiological role in these nuclei in the regulation of energy homeostasis is unclear.
GK’s function in the NTS and PVN was determined by both down-regulating and up-regulating its expression in these nuclei using a viral vector encoding glucokinase antisense or sense, respectively. Feeding studies demonstrated that GK knockdown had no effect on food intake. GK knockdown in both the NTS and PVN impaired glucose tolerance and disrupted glucose-stimulated insulin secretion. PVN GK knockdown also reduced glucose-stimulated glucagon-like peptide 1 (GLP-1) release. On the other hand, up-regulating GK expression in the PVN had the opposite effect and improved glucose tolerance by stimulating insulin and GLP-1 release. These effects were reproduced by iPVN injection of KATP channel modulators during an oral GTT.
Evidence presented in this thesis suggests that NTS and PVN GK play an important role in glucose homeostasis by regulating insulin and GLP-1 (7-36) secretion during the initial insulin response to hyperglycaemia. GK in both the NTS and PVN appears important in restoring euglycaemia following a glucose challenge. In the PVN, this seems to be mediated by the inhibition of KATP channels. This study sheds light on the previously unexplored function of GK in the NTS and PVN. A role of PVN and NTS GK in modulating insulin and GLP-1 (7-36) release in the regulation of glucose homeostasis has not been suggested before.