Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/10671
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dc.contributor.authorVisinoni, Sherleyen
dc.contributor.authorFam, Barbara Cen
dc.contributor.authorBlair, Amy Ren
dc.contributor.authorRantzau, Christianen
dc.contributor.authorLamont, Benjamin Jen
dc.contributor.authorBouwman, Russellen
dc.contributor.authorWatt, Matthew Jen
dc.contributor.authorProietto, Josephen
dc.contributor.authorFavaloro, Jenny Men
dc.contributor.authorAndrikopoulos, Sofianosen
dc.date.accessioned2015-05-16T00:11:58Z
dc.date.available2015-05-16T00:11:58Z
dc.date.issued2008-09-09en
dc.identifier.citationAmerican Journal of Physiology. Endocrinology and Metabolism 2008; 295(5): E1132-41en
dc.identifier.govdoc18780768en
dc.identifier.otherPUBMEDen
dc.identifier.urihttp://ahro.austin.org.au/austinjspui/handle/1/10671en
dc.description.abstractIncreased endogenous glucose production (EGP) predominantly from the liver is a characteristic feature of type 2 diabetes, which positively correlates with fasting hyperglycemia. Gluconeogenesis is the biochemical pathway shown to significantly contribute to increased EGP in diabetes. Fructose-1,6-bisphosphatase (FBPase) is a regulated enzyme in gluconeogenesis that is increased in animal models of obesity and insulin resistance. However, whether a specific increase in liver FBPase can result in increased EGP has not been shown. The objective of this study was to determine the role of upregulated liver FBPase in glucose homeostasis. To achieve this goal, we generated human liver FBPase transgenic mice under the control of the transthyretin promoter, using insulator sequences to flank the transgene and protect it from site-of-integration effects. This resulted in a liver-specific model, as transgene expression was not detected in other tissues. Mice were studied under the following conditions: 1) at two ages (24 wk and 1 yr old), 2) after a 60% high-fat diet, and 3) when bred to homozygosity. Hemizygous transgenic mice had an approximately threefold increase in total liver FBPase mRNA with concomitant increases in FBPase protein and enzyme activity levels. After high-fat feeding, hemizygous transgenics were glucose intolerant compared with negative littermates (P < 0.02). Furthermore, when bred to homozygosity, chow-fed transgenic mice showed a 5.5-fold increase in liver FBPase levels and were glucose intolerant compared with negative littermates, with a significantly higher rate of EGP (P < 0.006). This is the first study to show that FBPase regulates EGP and whole body glucose homeostasis in a liver-specific transgenic model. Our homozygous transgenic model may be useful for testing human FBPase inhibitor compounds with the potential to treat patients with type 2 diabetes.en
dc.language.isoenen
dc.subject.otherAnimalsen
dc.subject.otherBlood Glucose.metabolismen
dc.subject.otherBody Weight.drug effectsen
dc.subject.otherDietary Fats.administration & dosage.pharmacologyen
dc.subject.otherEating.drug effectsen
dc.subject.otherFructose-Bisphosphatase.genetics.metabolismen
dc.subject.otherGene Expressionen
dc.subject.otherGlucose.metabolismen
dc.subject.otherGlucose Intoleranceen
dc.subject.otherGlucose-6-Phosphatase.metabolismen
dc.subject.otherHomozygoteen
dc.subject.otherHumansen
dc.subject.otherHypothalamus.drug effects.metabolismen
dc.subject.otherInsulin.blooden
dc.subject.otherInsulin Resistanceen
dc.subject.otherLiver.drug effects.metabolismen
dc.subject.otherMiceen
dc.subject.otherMice, Inbred C57BLen
dc.subject.otherMice, Transgenicen
dc.subject.otherPhosphoenolpyruvate Carboxykinase (GTP).metabolismen
dc.subject.otherPyruvic Acid.metabolismen
dc.titleIncreased glucose production in mice overexpressing human fructose-1,6-bisphosphatase in the liver.en
dc.typeJournal Articleen
dc.identifier.journaltitleAmerican journal of physiology. Endocrinology and metabolismen
dc.identifier.affiliationDepartment of Medicine, Austin Health and Northern Health, University of Melbourne, Heidelberg Heights, Australiaen
dc.identifier.doi10.1152/ajpendo.90552.2008en
dc.description.pagesE1132-41en
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pubmed/18780768en
Appears in Collections:Journal articles

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