Hepatic carbon flux after re-feeding in the glycogen-storage-disease (gsd/gsd) rat

Abstract

In this study we utilized the phosphorylase b kinase-deficient (gsd/gsd) rat as a model of hepatic substrate utilization where there is a constraint on glycogenesis imposed by the maintenance of high glycogen concentrations. Glucose re-feeding of 48 h-starved gsd/gsd rats led to suppression of hepatic glucose output. In contrast with the situation in normal rats, activation of the pyruvate dehydrogenase complex and lipogenesis was observed. It is suggested that impeding glycogenic flux may divert substrate into lipogenesis, possibly via activation of the pyruvate dehydrogenase complex.

Prolonged Inhibition of Glycogen Phosphorylase in Livers of Zucker Diabetic Fatty Rats Models Human Glycogen Storage Diseases

“…The resultant hepatomegaly in this rat is also associated with increased hepatic lipids, illustrative of the diversion of glucose into lipogenesis in the event of impeded glycogenesis (Clark et al 1980;Haynes, Hall, and Clark 1983;Holness, Palmer, and Sugden 1987). Furthermore, a similar phenotype has also been reported in rats administered FIGURE 6.-Liver sections from control animals (A) and those treated with GPi921 for twenty-eight days (B, C, and D) stained with hematoxylin and eosin stain.…”

“…Instances of GSD-like conditions have also been described in animal species, including laboratory animals such as the rat and the dog (Walvoort 1983). Glycogen storage disease has been described in the phosphorylase β kinase-deficient ( gsd/gsd ) rat, in which hepatocytes contain more than twice as much free glycogen and visible lipid in comparison to controls, indicating that a mechanism may exist that diverts glucose into lipogenesis following an impediment to normal glycogenesis (Clark et al 1980; Haynes, Hall, and Clark 1983; Holness, Palmer, and Sugden 1987).…”

The relative importance of kinetic mechanisms and variable enzyme abundances for the regulation of hepatic glucose metabolism – insights from mathematical modeling

“…The simulation was repeated 50 times with uniformly sampled protein abundances from the observed range for each enzyme (Table 1 ). Due to conflicting experimental data regarding the amount of glycogen synthase (GS) and glycogen phosphorylase (GP) in diabetic hepatocytes, we set up three different scenarios: increased activity of GS by 70 % and diminished activity of GP by 50 % [ 29 ] (top trace – solid line); increased activity of GS by 70 % and decreased activity of GP by 50 % and reduced total glycogen storage capacity to 75 % [ 57 ] (bottom trace – dashed line); and decreased GS activity by 50 % and unchanged GP activity [ 58 ] (middle trace – dash-dotted line) …”

Fuel selection and carbon flux during the starved-to-fed transition

“…However, although hyperinsulinaemia inhibits hepatic glucose production in the fed and post-absorptive states [50,51], a role for an increased insulin concentration as the sole factor in suppression of glucose output after refeeding can be excluded as it can be observed in rats treated with anti-insulin serum [29]. Suppression of glucose output is observed in the absence of increased glycogen synthesis in glycogen-storage-disease rats [52], and is therefore not a simple consequence of the preferential utilization of hexose monophosphate for glycogenesis [29].…”