title: Alteration of de novo glucose production contributes to fasting hypoglycaemia in Fyn deficient mice.
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.
authors: Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, People's Republic of China ; Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors: Yingjuan
authors: Y
authors: Yang
authors: Elena
authors: E
authors: Tarabra
authors: Gong-She
authors: GS
authors: Yang
authors: Bhavapriya
authors: B
authors: Vaitheesvaran
authors: Gustavo
authors: G
authors: Palacios
authors: Irwin J
authors: IJ
authors: Kurland
authors: Jeffrey E
authors: JE
authors: Pessin
authors: Claire C
authors: CC
authors: Bastie
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D005215:Fasting; D005947:Glucose / Q000096:biosynthesis*; D022781:Hepatocytes / Q000201:enzymology / Q000378:metabolism; D007003:Hypoglycemia / Q000209:etiology*; D051379:Mice; D018345:Mice, Knockout; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics / Q000502:physiology*
chemical_list: C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; D019764:Phosphoenolpyruvate Carboxykinase (ATP); D005947:Glucose