Expression of glucose transporter isoform GLUT‐2 and glucokinase genes in human brain

Abstract

The glucose transporter isoform-2 (GLUT-2) and glucokinase are considered to be components of a glucose sensor system controlling several key processes, and hence may modulate feeding behaviour. We have found GLUT-2 and glucokinase mRNAs in several brain regions, including the ventromedial and arcuate nuclei of the hypothalamus. GLUT-2, glucokinase and glucokinase regulatory protein mRNAs and proteins were present in these areas as determined by biochemical approaches. In addition, glucose-phosphorylating activity with a high apparent K m for glucose that displayed no product inhibition by glucose-6-phosphate was observed. Increased glycaemia after meals may be recognized by specific hypothalamic neurones due to the high K m of GLUT-2 and glucokinase. This enzyme is considered to be the true glucose sensor because it catalyses the rate-limiting step of glucose catabolism its activity being regulated by interaction with glucokinase regulatory protein, that functions as a metabolic sensor. Keywords: GLUT-2, glucokinase, glucokinase regulatory protein, glucose sensing, human brain. Glucose homeostasis requires hormone and neural mechanisms to provide a continuous glucose supply to the CNS and to face the metabolic needs of peripheral tissues. Glucose is required as an energy substrate, but also functions as a signalling molecule in primary processes. Indeed, alterations of normoglycaemic levels have deleterious consequences that increase morbidity and mortality rates. Glucose sensors, molecular systems that accurately detect glucose concentrations in the extracellular space, contribute to maintaining glucose homeostasis by controlling several key processes. The first glucose sensor was described in the pancreatic b-cell (Matschinsky 1990) and is constituted by GLUT-2 and glucokinase (GK). These proteins are involved in high-K m glucose transport and high-K m phosphorylation of glucose, respectively, which allows increased glucose utilization as its concentration rises. Pancreatic b-cells appear to sense glucose concentrations through its catabolic products, such that the glucose catabolism rate must be proportional to glucose levels in the extracellular space. Glucose sensing does not directly depend on GLUT-2 activity. This glucose transporter plays a more permissive role in glucose catabolism, as glucose transport in b-cells is 100-fold higher than the rates of glucose metabolism. In contrast, GK catalyses the rate-limiting step of glucose catabolism, thus acting as a true glucose sensor. GK activity controls glucose oxidation and adenosine triphosphate (ATP) formation, and the resulting increase in the ATP/ADP (adenosine diphosphate) ratio favours the closure of ATP-sensitive potassium channels and the depolarization of b-cells, which in turn causes voltagesensitive calcium channels to open. This then promotes an

Glucokinase and hexokinase expression and activities in rainbow trout tissues: changes with food deprivation and refeeding

“…In fish, GK expression was described in rainbow trout whole brain (22) but not carp whole brain (4,22). In mammals, high GK expression is reported in the hypothalamus (9,14,15,26) with measurable expression noted in other regions, including the thalamus, olfactory nucleus, preoptic area, mesencephalon, and cortex (14,15,26). The absence of GK expression in the other trout tissues examined is consistent with previous fish studies (22).…”

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

“…It is noteworthy that in the brain, GLP-1 contributes to reducing food intake (Navarro et al, 1996;Turton et al, 1996), and the co-localization of those three components in hypothalamic neurons suggests that a glucose sensor system may be involved in the transduction of signals required to produce a state of satiety. As we previously cited, GK activity may also be regulated by GKRP, acting in accordance with the metabolic needs of the cells (Van Schaftingen et al, 1984;Shiota et al, 1999;Roncero et al, 2004). Interestingly, we reported the coexpression of GK and GKRP in both rat and human brains Alvarez et al, 2002;Roncero et al, 2004), as well as GKRP interacting with GK in the presence of fructose-6-phosphate, which suggests that both are active and both may participate in the glucosensing process in the central nervous system (Alvarez et al, 2002).…”

“…As we previously cited, GK activity may also be regulated by GKRP, acting in accordance with the metabolic needs of the cells (Van Schaftingen et al, 1984;Shiota et al, 1999;Roncero et al, 2004). Interestingly, we reported the coexpression of GK and GKRP in both rat and human brains Alvarez et al, 2002;Roncero et al, 2004), as well as GKRP interacting with GK in the presence of fructose-6-phosphate, which suggests that both are active and both may participate in the glucosensing process in the central nervous system (Alvarez et al, 2002). GK and GKRP have been found in foetal pancreas and liver (Vandercammen & Van Schaftingen 1993;Garcia-Flores et al, 2002).…”

Effects of glucose and insulin on glucokinase activity in rat hypothalamus

“…In previous reports, we described the presence of GK mRNA and protein in rat (Navarro et al 1996, Roncero et al 2000 and human (Roncero et al 2004) brains, with similar kinetic properties as the enzyme from liver and pancreatic islets. In this work, we present experimental evidence of the existence of GK protein and activities in VMH and LH areas, which permits comparative analyses between different hypothalamic areas, such as we observed in the VMH and LH in response to glucose.…”