Molecular and pathophysiological basis of the brain glucose sensing ability

Abstract

The presence of the messenger RNA for GLP-1 receptor (GLP-1R), GLUT-2 (isoform 2 of glucose transporter ) and GK (glucokinase) in brain areas might be related to the glucose sensing process that was recently described in pancreatic β cells. GLUT-2, GK and the regulatory protein of GK (GKRP) were identified in both human and rat brains. The GK gene expression generates a 52 kDa protein, identified by biochemical and immunochemical methods; it shows a high Km for glucose and a high capacity to phosphorylate glucose in the hypothalamus and in the brain cortex. Its physiological importance is related to its activation secondary to an increase in glycaemia related to food ingestion. GK and GKRP modulate the enzymatic activity according to the metabolic needs of the cells. This is necessary for the sensing process that is controlled by GK and GKRP, and could also contribute to a sensation of satiety. It would be interesting to know if mutations in the genes codifying the mentioned proteins can produce pathological alterations, or whether changes in the feeding behavior are related to the brain glucose sensing process. Until now, our work has focused on the role of hypothalamic glucokinase as a glucose sensor related to food behavior, but we cannot forget that this enzyme is widely expressed in the brain cortex, where it could also carry out other important functions. These observations, together with the anorexigenic activity of GLP-1 (glucagon-like peptide-1), suggest a combined role of these peptides on food intake control.