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Alteration of De Novo Glucose Production Contributes to Fasting Hypoglycaemia in Fyn Deficient Mice

Authors :
Jeffrey E. Pessin
Claire C. Bastie
Bhavapriya Vaitheesvaran
Elena Tarabra
Gong She Yang
Irwin J. Kurland
Gustavo Palacios
Yingjuan Yang
Source :
PLoS ONE, Vol 8, Iss 11, p e81866 (2013), PLoS ONE
Publication Year :
2013
Publisher :
Public Library of Science (PLoS), 2013.

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 (13)C-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.

Details

ISSN :
19326203
Volume :
8
Database :
OpenAIRE
Journal :
PLoS ONE
Accession number :
edsair.doi.dedup.....c5c3b5b3a221e73b01c4c0fdc0882e30
Full Text :
https://doi.org/10.1371/journal.pone.0081866