caa a22 4500 475772849 CHVBK 20180406123622.0 cr unu---uuuuu 170329e20000501xx s 000 0 eng 10.1007/s001250051348 doi (NATIONALLICENCE)springer-10.1007/s001250051348 Impaired glycogen synthesis in hepatocytes from Zucker fatty fa/fa rats: the role of increased phosphorylase activity [Elektronische Daten] [S. Aiston, M. Peak, L. Agius] Aims/hypothesis. The Zucker fatty fa/fa rat develops hyperinsulinaemia, insulin-resistance and severe obesity as a result of a homozygous mutation in the leptin receptor gene. The aim was to characterise the metabolic defect(s) in hepatocytes from fa/fa rats. Methods. Glucose metabolism and key regulatory enzymes were investigated in hepatocytes from fa/fa and Fa/? rats after short-term culture in the absence of insulin. Results. Hepatocytes from fa/fa rats have higher glucokinase activity and expression of the glucokinase regulatory protein and higher rates of glycolysis and lipogenesis, but lower rates of glycogen synthesis than hepatocytes from Fa/? controls. Insulin caused a similar stimulation of glycogen synthesis in hepatocytes from fa/fa rats as in controls ( > twofold) but did not restore the impaired glycogen synthesis in cells from fa/fa rats. Adenovirus-mediated glucokinase overexpression stimulated glycogen synthesis and glycolysis but aggravated rather than abolished the relative impairment of glycogen synthesis in cells from fa/fa rats. Inhibition of glycolysis with 2,5-anhydromannitol, an inhibitor of glycolysis and gluconeogenesis, increased glucose 6-phosphate concentrations and glycogen synthesis in hepatocytes from Fa/? and fa/fa rats but did not restore the impaired glycogen synthesis in cells from fa/fa rats. Hepatocytes from fa/fa rats had a higher activity of phosphorylase a in the basal state and after incubation with insulin or glucagon and higher total phosphorylase. Conclusion/interpretation. The increased activity of phosphorylase is a major contributing factor to the impaired glycogen synthesis in hepatocytes from fa/fa rats and could contribute to the lipogenic state by a glycogenolytic-glycolytic-lipogenic pathway. [Diabetologia (2000) 43: 589-597] Springer-Verlag Berlin Heidelberg, 2000 Keywords Zucker nationallicence fa/fa rat nationallicence leptin nationallicence insulin nationallicence phosphorylase nationallicence glycogen synthesis nationallicence glucokinase nationallicence Aiston S. Department of Diabetes and Metabolism, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, UK, GB aut Peak M. Department of Diabetes and Metabolism, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, UK, GB aut Agius L. Department of Diabetes and Metabolism, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, UK, GB aut https://doi.org/10.1007/s001250051348 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s001250051348 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Aiston S. Department of Diabetes and Metabolism, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, UK, GB aut NATIONALLICENCE 700 1- Peak M. Department of Diabetes and Metabolism, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, UK, GB aut NATIONALLICENCE 700 1- Agius L. Department of Diabetes and Metabolism, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, UK, GB aut Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer