Abstract
Previous studies have demonstrated that glucose disposal is increased in the Fyn knockout (FynKO) mice due to increased insulin sensitivity. FynKO mice also display fasting hypoglycaemia despite decreased insulin levels, which suggested that hepatic glucose production was unable to compensate for the increased basal glucose utilization. The present study investigates the basis for the reduction in plasma glucose levels and the reduced ability for the liver to produce glucose in response to gluconeogenic substrates. FynKO mice had a 5-fold reduction in phosphoenolpyruvate carboxykinase (PEPCK) gene and protein expression and a marked reduction in pyruvate, pyruvate/lactate-stimulated glucose output. Remarkably, de novo glucose production was also blunted using gluconeogenic substrates that bypass the PEPCK step. Impaired conversion of glycerol to glucose was observed in both glycerol tolerance test and determination of the conversion of 13C-glycerol to glucose in the fasted state. α-glycerol phosphate levels were reduced but glycerol kinase protein expression levels were not changed. Fructose-driven glucose production was also diminished without alteration of fructokinase expression levels. The normal levels of dihydroxyacetone phosphate and glyceraldehyde-3-phosphate observed in the FynKO liver extracts suggested normal triose kinase function. Fructose-bisphosphate aldolase (aldolase) mRNA or protein levels were normal in the Fyn-deficient livers, however, there was a large reduction in liver fructose-6-phosphate (30-fold) and fructose-1,6-bisphosphate (7-fold) levels as well as a reduction in glucose-6-phosphate (2-fold) levels. These data suggest a mechanistic defect in the allosteric regulation of aldolase activity.
Highlights
The regulation of glucose homeostasis is a complex integrative response between multiple tissues that dynamically respond to metabolic and nutritional states
We reported that Fyn knockout (FynKO) mice have reduced adiposity, increased energy expenditure and insulin sensitivity that correlated with increased activation of AMP-dependent protein kinase (AMPK) as well as increased fatty acid oxidation in skeletal muscle and adipose tissue but not in the liver [8]
Fasting glucose levels typically reflect the relative contribution of hepatic glucose output and not peripheral tissue insulin sensitivity, as insulin levels are low and glucagon levels are high in the fasted state
Summary
The regulation of glucose homeostasis is a complex integrative response between multiple tissues that dynamically respond to metabolic and nutritional states. To ensure that glucose production matches the whole-body requirements, gluconeogenesis must be tightly regulated This physiologic regulation fails in diabetes and obesity states with concomitant exacerbation of glucagon responsiveness and defective insulin-driven suppression of hepatic glucose output [3,4,5]. For this reason, mechanisms by which de novo glucose production is controlled have been intensively investigated and numerous studies have focused on the transcriptional control of genes mediating liver glucose metabolism. This suggests a defect in the fructose-bisphosphate aldolase, the enzyme responsible for the reversible condensation of dihydroxyacetone phosphate (DHAP) with glyceraldehyde-3phosphate (G-3P) into fructose-1,6-bisphosphate
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