Glucokinase as a Glucose Sensor in Hypothalamus - Regulation by Orexigenic and Anorexigenic Peptides

Abstract

Glucose homeostasis requires hormonal and neural mechanisms in an attempt to get a normal functioning of the brain and of peripheral tissues. Blood glucose levels must be maintained within a physiological range depending of feeding and hormonal status, having the alterations of normoglycemic levels deleterious consequences. Hypothalamus plays a major role on feeding behaviour and energy homeostasis. It contains the called satiety centre and hunger centre located in ventromedial (VMH) and lateral hypothalamus (LH) respectively. These brain areas, besides others, may be altered by metabolic signals, such as changes in the electrical activity of neurons by direct application of glucose or by modifications of blood glucose levels. In this regard, glucose activates or inhibits neuronal activity, and both responses suggest the presence of glucose sensors in these brain areas. Glucose sensors are molecular designs responsible for detecting and measuring glucose concentrations in the extracellular space. Thus, glucose sensor are presents in gut, endocrine pancreatic cells, portal vein, central nervous system and rare neuroendocrine cells, and they are responsible to avoid marked blood glucose oscillations, which permit to maintain glucose homeostasis. First evidence of the existence of a glucose sensor system was reported in pancreatic betacells (Matschinsky 1990), constituted by glucokinase (GK). GK catalyses glucose phosphorylation with low afffinity and it is not inhibited by its product (glucose-6phosphate), which allows increased glucose utilization as its concentration rises. Due to GK properties, the glucose catabolism rate is proportional to glucose levels in the extracellular space and for that reason GK is the major contributor to glucose sense, since catalyses the rate-limiting step of glucose catabolism. Interestingly, glucose transporter isoform 2 (GLUT2) also with a high Km for glucose transport, has a different role since glucose transport occurs in both directions of the beta-cell membrane and glucose transport is 100-fold higher that the rates of glucose metabolism. Our previous findings (Alvarez et al., 1996; Navarro et al., 1996) indicating the presence of GK together with GLUT-2 and glucagon-like peptide-1 receptor (GLP-1R) in the same cells