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  • Glucagon regulates the transition from hepatic glucose

    2022-09-21

    Glucagon regulates the transition from hepatic glucose utilisation in the absorptive state to glucagon production in the post-absorptive state by acute stimulation of glycogenolysis and inhibition of glycolysis [1]. An important component of this response is Azimilide the phosphorylation of liver PFK2/FBPase2 at Ser-32 [25], [29], which increases the bisphosphatase to kinase ratio of the bifunctional enzyme leading to depletion of fructose 2,6-bisphosphate and inhibition of glycolysis and elevation in gluconeogenesis [25]. Here we show that the phosphorylated form of PFK2/FBPase2 is found in the nucleus as well as the Azimilide and that glucagon alters the amount of phosphorylated PFK2/FBPase2 in the nucleus. This implicates a potential role for PFK2/FBPase2 in the glucagon-induced changes in the subcellular location of glucokinase. We propose the following model: glucagon via cAMP/PKA-dependent signalling alters the glucokinase–PFK2/FBPase2 interaction by a mechanism that may involve phosphorylation of PFK2/FBPase2 at Ser-32. These changes enable movement of glucokinase to the nuclear compartment, either in complex with PFK2/FBPase2 or GKRP or both proteins. The BiFC data supports the existence of a multi-protein complex since the cAMP analogue significantly attenuated but did not block the formation of the glucokinase–PFK2/FBPase2 complex. The BiFC assay is carried out in a heterologous cell system lacking GKRP and thus measures the interaction of glucokinase and PFK2/FBPase2 independently of GKRP, which is essential for translocation and sequestration of glucokinase to the nucleus in hepatocytes [47], [48]. The failure of the cAMP analogue to block the interaction of glucokinase with PFK2/FBPase2 in the BiFC assay indicates that phosphorylation does not prevent formation of the complex. One possibility that remains to be tested is that phosphorylation may favour formation of a multi-protein complex with GKRP enabling translocation of glucokinase to the nucleus. Further work testing for a trimer complex is required to investigate this possibility. Several studies have reported that translocation of glucokinase in response to glucose is impaired in animal models of type 2 diabetes [25], [37], [38], [49], [50]. The present evidence that glucagon antagonises the action of elevated glucose on translocation of glucokinase from the nucleus and binding to PFK2/FBPase2 in the cytoplasm adds a new perspective to the acute control of glucokinase activity and shows that absolute or relative glucagon excess as occurs in diabetes [3] is most likely a contributing factor to the defective glucokinase translocation in animal models of diabetes [25], [37], [38], [49], [50]. The following are the supplementary data related to this article.
    Acknowledgements C.A. is an RD Lawrence Research Fellow funded by Diabetes UK (07/0003674). This work received additional support from the European Foundation for the Study of Diabetes (Albert Renolds travel grant), European Molecular Biology Organisation (short-term travel fellowship ASTF 171.00-2007), Diabetes UK (equipment grant 08/0003772), the Royal Society (project grant RG080223), the Medical Research Council (project grant G0501543) and an Invest NI Proof of Concept 106 grant. No potential conflicts of interest relevant to this article were reported.
    Introduction Incretin hormones (glucagon-like peptide-1, GLP-1, and glucose-dependent insulinotropic polypeptide, GIP) exert multiple biological effects such as enhancement of glucose-induced insulin secretion, affect glucagon and somatostatin secretion, increment of β-cell mass, delay of gastric emptying and appetite inhibition [6]. Regarding their glucagon effect, while GLP-1 inhibits GIP stimulates its secretion [7]. The significant decrease of all these pleiotropic effects present in people with Type 2 diabetes (T2DM), has been mainly ascribed to a glucotoxic-induced down regulation of incretin-receptors rather than to a decrease in their circulating levels [6], [21], [30]. Currently, many of these people are treated with either GLP-1 and its analogs, or specific inhibitors of their degrading enzyme dipeptidyl peptidase IV (DPP-IV) [6], [25], [29].