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Alteration of de novo glucose production contributes to fasting hypoglycaemia in fyn deficient mice
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Tarabra, Elena, Yang, Yingjuan, Yang, Gong-She, Vaitheesvaran, Bhavapriya, Palacios, Gustavo, Kurland, Irwin J., Pessin, Jeffrey E. and Bastie, Claire C. (2013) Alteration of de novo glucose production contributes to fasting hypoglycaemia in fyn deficient mice. PLoS One, Volume 8 (Number 11). Article number e81866. doi:10.1371/journal.pone.0081866
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WRAP_Bastie_pone.0081866_.pdf - Published Version Available under License Creative Commons Attribution. Download (754Kb) | Preview |
Official URL: http://dx.doi.org/10.1371/journal.pone.0081866
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.
| Item Type: | Journal Article | ||||
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| Subjects: | R Medicine > R Medicine (General) | ||||
| Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine > Metabolic and Vascular Health (- until July 2016) Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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| Library of Congress Subject Headings (LCSH): | Hypoglycemia, Blood sugar -- Analysis, Insulin | ||||
| Journal or Publication Title: | PLoS One | ||||
| Publisher: | Public Library of Science | ||||
| ISSN: | 1932-6203 | ||||
| Official Date: | 28 November 2013 | ||||
| Dates: |
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| Volume: | Volume 8 | ||||
| Number: | Number 11 | ||||
| Page Range: | Article number e81866 | ||||
| DOI: | 10.1371/journal.pone.0081866 | ||||
| Status: | Peer Reviewed | ||||
| Publication Status: | Published | ||||
| Access rights to Published version: | Open Access | ||||
| Funder: | National Institutes of Health (U.S.) (NIH), Ellison Medical Foundation, China. Guo jia ke xue ji shu bu [Ministry of Science and Technology], Albert Einstein College of Medicine | ||||
| Grant number: | DK81412, DK020541, DK033823, DK58132, P60DK020541 (NIH) ; 2012CB124705 (MST) |
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