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  • br Acknowledgments br The authors would like to acknowledge


    The authors would like to acknowledge the technical assistance of J. Lee. This work was supported by the U.S. National Institute of Health grant HL111206 (to R.A.H.) the Italian Ministry for University and Research (MIUR 2010329EKE).
    Introduction The liver plays a vital role in blood glucose homeostasis by production of glucose in the fasted state and efficient removal of glucose in the post-prandial state in response to portal hyperglycaemia for storage of glucose as glycogen or conversion to triacylglycerol [1]. Central to this process is the responsiveness of the liver to Melittin the hormone glucagon [1], [2], [3]. In normal physiology, glucagon is elevated in the post-absorptive state and acts on the liver to stimulate glucose production via glycogenolysis and gluconeogenesis to maintain blood glucose homeostasis [1], [2], [4]. After a carbohydrate-containing meal, the elevation in insulin suppresses glucagon secretion and thereby hepatic glucose production. However, in type 2 diabetes the deficiency in insulin secretion results in post-prandial hyperglucagonaemic and inadequate suppression of glucose production [2], [3]. Whilst the mechanisms involved in the regulation of glycogenolysis and gluconeogenesis by glucagon have been well characterised, the effects of glucagon excess on glucose utilisation have not been fully elucidated. Glucose metabolism by the liver is critically dependent on the activity of glucokinase, which catalyses the first-step in glucose metabolism [5], [6]. Two major mechanisms are involved in the regulation of glucokinase activity: transcriptional mechanisms which account for chronic changes in protein expression [6], [7] and translocation from the nucleus to the Melittin in response to portal hyperglycaemia or low concentrations of fructose, which accounts for the acute changes in postprandial glucose disposal [5], [8]. Sequestration of glucokinase in the hepatocyte nucleus at basal glucose concentrations is regulated by binding to its inhibitory protein (GKRP) [8], [9], [10]. Stimulation with elevated concentrations of glucose (>10mM) or micromolar concentrations of fructose or other precursors of fructose 1-phosphate causes the dissociation of the glucokinase–GKRP complex, allowing translocation of glucokinase from the nucleus to the cytoplasm, with consequent activation and stimulation of glycogen synthesis [5], [6], [8]. Various lines of evidence implicate a potential role for phosphofructo 2-kinase/fructose 2,6-bisphosphate (PFK2/FBPase2) as a cytoplasmic binding partner of glucokinase [11], [12]. Whilst a role for glucose in regulating glucose translocation is well established [5], [6], the role of hormones on glucokinase translocation and its interaction with PFK2/FBPase2 remains unsettled [6], [13]. Compelling evidence for an over-riding role for glucagon excess in the pathogenesis of diabetes [3], [14] and development of non-invasive methods for estimating glucokinase activity in man based on the assumption that glucokinase activity responds to glucose but not to hormones [15], [16], calls for a critical re-evaluation of the effect of glucagon on glucokinase translocation and activity. The aims of this study were to investigate whether glucagon acutely regulates glucokinase translocation and binding to its binding partners GKRP and PFK2/FBPase2.
    Materials and methods
    Discussion The importance of glucokinase translocation in determining the rate of hepatic glucose disposal [5] and also the effect of glucose concentration on glucokinase translocation are well established from studies in vitro or in vivo from several independent laboratories [13], [22], [23], [24], [26], [36], [37], [38]. However, the question whether this translocation mechanism is regulated by hormones and specifically by glucagon has been less widely investigated and remains contentious [6], [13], [22], [25]. This question is timely in view of the recognised role of hyperglucagonaemic in human diabetes [3], the potential therapeutic benefit of glucagon antagonists for glycaemic control in diabetes [39], and current methods for assessment of glucokinase activity based on the assumption of exclusive control by glucose as opposed to hormones [15], [16].