The brain is as an important regulator of appetite and metabolism. Glucokinase (GK) is a key component of glucose sensing, and is expressed in many glucose sensitive neurones (Rosario et al., 2016, Pocai et al., 2005b). Two regions where glucokinase is expressed are the arcuate nucleus and the paraventricular nucleus of the hypothalamus (Jetton et al., 1994b). Using viral techniques to specifically alter glucokinase expression, I show that upregulation of glucokinase in these nuclei individually, significantly improves glucose tolerance and increases insulin secretion. Conversely down regulation significantly worsens glucose tolerance and reduces insulin secretion. Interestingly the incretin effect is negligible within the arcuate nucleus but within the paraventricular nucleus, glucagon like peptide-1 (GLP-1) secretion is blunted when glucokinase expression is reduced. GLP-1 secretion has been believed to be entirely regulated by the enteroendocrine L-cells of the small intestine however these results suggest that the brain may play a role. The pathway of action of both the arcuate and paraventricular GK appears to be via ATP-sensitive potassium channels (KATP) channels (Maekawa et al., 2000, Hussain et al., 2015b, Ma et al., 2018a). These results suggest an important role for arcuate and paraventricular nuclei glucokinase in glucose homeostasis via KATP channels.