Glucokinase and molecular aspects of liver glycogen metabolism

Abstract

Conversion of glucose into glycogen is a major pathway that contributes to the removal of glucose from the portal vein by the liver in the postprandial state. It is regulated in part by the increase in blood-glucose concentration in the portal vein, which activates glucokinase, the first enzyme in the pathway, causing an increase in the concentration of glucose 6-P (glucose 6-phosphate), which modulates the phosphorylation state of downstream enzymes by acting synergistically with other allosteric effectors. Glucokinase is regulated by a hierarchy of transcriptional and post-transcriptional mechanisms that are only partially understood. In the fasted state, glucokinase is in part sequestered in the nucleus in an inactive state, complexed to a specific regulatory protein, GKRP (glucokinase regulatory protein). This reserve pool is rapidly mobilized to the cytoplasm in the postprandial state in response to an elevated concentration of glucose. The translocation of glucokinase between the nucleus and cytoplasm is modulated by various metabolic and hormonal conditions. The elevated glucose 6-P concentration, consequent to glucokinase activation, has a synergistic effect with glucose in promoting dephosphorylation (inactivation) of glycogen phosphorylase and inducing dephosphorylation (activation) of glycogen synthase. The latter involves both a direct ligand-induced conformational change and depletion of the phosphorylated form of glycogen phosphorylase, which is a potent allosteric inhibitor of glycogen synthase phosphatase activity associated with the glycogen-targeting protein, GL [hepatic glycogen-targeting subunit of PP-1 (protein phosphatase-1) encoded by PPP1R3B]. Defects in both the activation of glucokinase and in the dephosphorylation of glycogen phosphorylase are potential contributing factors to the dysregulation of hepatic glucose metabolism in Type 2 diabetes.

Evolution of glucose utilization: Glucokinase and glucokinase regulator protein

“…Loss of glucokinase activity in humans and mice leads to diabetes (Printz et al, 1993b;Postic et al, 2001;Agius, 2008;Iynedjian, 2009); however, this does not appear to be the case for all vertebrate species. Several mammals, and other vertebrate species, have been reported to be deficient in liver glucokinase activity (reviewed in Ureta, 1982).…”

“…Glucokinase is expressed in the liver, pancreatic islets, and select cells in the gut and the brain. In the liver glucokinase functions to regulate glucose metabolism, while in the pancreatic islets, intestinal cells and neurons it functions as a glucose sensor (Iynedjian, 1993(Iynedjian, , 2009Postic et al, 2001;Agius, 2008). As a key component of the glucose sensor in pancreatic islet beta-cells, glucokinase regulates the release on insulin in response to blood glucose levels (Postic et al, 2001;Agius, 2008).…”

“…In contrast, the liver-specific promoter is transcriptionally regulated, yielding glucokinase activity when blood glucose levels are elevated (Postic et al, 2001;Iynedjian, 1993Iynedjian, , 2009). However, since changes in blood glucose levels can occur rapidly, at rates more rapid than can be addressed by transcriptional regulation, changes in glucokinase activity levels is also regulated at the post-translational level (van Schaftingen et al, 1997;Agius, 2008;Iynedjian, 2009). …”

“…Glucokinase is essential for sensing blood glucose levels, thus controls metabolism (Iynedjian, 1993(Iynedjian, , 2009Postic et al, 2001;Agius, 2008). Loss of glucokinase activity in humans and mice leads to diabetes (Printz et al, 1993b;Postic et al, 2001;Agius, 2008;Iynedjian, 2009); however, this does not appear to be the case for all vertebrate species.…”

“…The liver only needs glucokinase activity if blood glucose levels can exceed the preferred level, and glucose levels would only exceed this level if too much is made by gluconeogenesis or if too much is absorbed from the diet. Since gluconeogenesis is a regulated process (Postic et al, 2001;Agius, 2008), this should not cause excess blood glucose levels. Acquiring glucose from the diet is not a regulated process, therefore it can lead to elevated blood glucose levels, but only if the diet is high in carbohydrate as they are broken down to sugars in the digestive tract.…”