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Impaired glycogen synthesis in hepatocytes from Zucker fatty fa/fa rats: The role of increased phosphorylase activity

Lookup NU author(s): Dr Susan Aiston, Professor Loranne Agius

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Abstract

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.


Publication metadata

Author(s): Aiston S, Peak M, Agius L

Publication type: Article

Publication status: Published

Journal: Diabetologia

Year: 2000

Volume: 43

Issue: 5

Pages: 589-597

ISSN (print): 0012-186X

ISSN (electronic): 1432-0428

Publisher: Springer

URL: http://dx.doi.org/10.1007/s001250051348

DOI: 10.1007/s001250051348

PubMed id: 10855534


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