Liver GlucokinaseA456V Induces Potent Hypoglycemia without Dyslipidemia through a Paradoxical Induction of the Catalytic Subunit of Glucose-6-Phosphatase
Recent reports point out the importance of the complex GK-GKRP in controlling glucose and lipid homeostasis. Several GK mutations affect GKRP binding, resulting in permanent activation of the enzyme. We hypothesize that hepatic overexpression of a mutated form of GK, GKA456V, described in a patient...
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doaj-c70250b757ab48f0bf0ce4e04dce12c42020-11-24T23:50:11ZengHindawi LimitedInternational Journal of Endocrinology1687-83371687-83452011-01-01201110.1155/2011/707928707928Liver GlucokinaseA456V Induces Potent Hypoglycemia without Dyslipidemia through a Paradoxical Induction of the Catalytic Subunit of Glucose-6-PhosphataseAnna Vidal-Alabró0Alícia G. Gómez-Valadés1Andrés Méndez-Lucas2Jordi Llorens3Ramon Bartrons4Jordi Bermúdez5Jose C. Perales6Biophysics Unit, Department of Physiological Sciences II, IDIBELL-University of Barcelona, Campus de Bellvitge, 08907 L'Hospitalet de Llobregat, SpainBiophysics Unit, Department of Physiological Sciences II, IDIBELL-University of Barcelona, Campus de Bellvitge, 08907 L'Hospitalet de Llobregat, SpainBiophysics Unit, Department of Physiological Sciences II, IDIBELL-University of Barcelona, Campus de Bellvitge, 08907 L'Hospitalet de Llobregat, SpainBiophysics Unit, Department of Physiological Sciences II, IDIBELL-University of Barcelona, Campus de Bellvitge, 08907 L'Hospitalet de Llobregat, SpainBiophysics Unit, Department of Physiological Sciences II, IDIBELL-University of Barcelona, Campus de Bellvitge, 08907 L'Hospitalet de Llobregat, SpainBiophysics Unit, Department of Physiological Sciences II, IDIBELL-University of Barcelona, Campus de Bellvitge, 08907 L'Hospitalet de Llobregat, SpainBiophysics Unit, Department of Physiological Sciences II, IDIBELL-University of Barcelona, Campus de Bellvitge, 08907 L'Hospitalet de Llobregat, SpainRecent reports point out the importance of the complex GK-GKRP in controlling glucose and lipid homeostasis. Several GK mutations affect GKRP binding, resulting in permanent activation of the enzyme. We hypothesize that hepatic overexpression of a mutated form of GK, GKA456V, described in a patient with persistent hyperinsulinemic hypoglycemia of infancy (PHHI) and could provide a model to study the consequences of GK-GKRP deregulation in vivo. GKA456V was overexpressed in the liver of streptozotocin diabetic mice. Metabolite profiling in serum and liver extracts, together with changes in key components of glucose and lipid homeostasis, were analyzed and compared to GK wild-type transfected livers. Cell compartmentalization of the mutant but not the wild-type GK was clearly affected in vivo, demonstrating impaired GKRP regulation. GKA456V overexpression markedly reduced blood glucose in the absence of dyslipidemia, in contrast to wild-type GK-overexpressing mice. Evidence in glucose utilization did not correlate with increased glycogen nor lactate levels in the liver. PEPCK mRNA was not affected, whereas the mRNA for the catalytic subunit of glucose-6-phosphatase was upregulated ~4 folds in the liver of GKA456V-treated animals, suggesting that glucose cycling was stimulated. Our results provide new insights into the complex GK regulatory network and validate liver-specific GK activation as a strategy for diabetes therapy.http://dx.doi.org/10.1155/2011/707928 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Anna Vidal-Alabró Alícia G. Gómez-Valadés Andrés Méndez-Lucas Jordi Llorens Ramon Bartrons Jordi Bermúdez Jose C. Perales |
spellingShingle |
Anna Vidal-Alabró Alícia G. Gómez-Valadés Andrés Méndez-Lucas Jordi Llorens Ramon Bartrons Jordi Bermúdez Jose C. Perales Liver GlucokinaseA456V Induces Potent Hypoglycemia without Dyslipidemia through a Paradoxical Induction of the Catalytic Subunit of Glucose-6-Phosphatase International Journal of Endocrinology |
author_facet |
Anna Vidal-Alabró Alícia G. Gómez-Valadés Andrés Méndez-Lucas Jordi Llorens Ramon Bartrons Jordi Bermúdez Jose C. Perales |
author_sort |
Anna Vidal-Alabró |
title |
Liver GlucokinaseA456V Induces Potent Hypoglycemia without Dyslipidemia through a Paradoxical Induction of the Catalytic Subunit of Glucose-6-Phosphatase |
title_short |
Liver GlucokinaseA456V Induces Potent Hypoglycemia without Dyslipidemia through a Paradoxical Induction of the Catalytic Subunit of Glucose-6-Phosphatase |
title_full |
Liver GlucokinaseA456V Induces Potent Hypoglycemia without Dyslipidemia through a Paradoxical Induction of the Catalytic Subunit of Glucose-6-Phosphatase |
title_fullStr |
Liver GlucokinaseA456V Induces Potent Hypoglycemia without Dyslipidemia through a Paradoxical Induction of the Catalytic Subunit of Glucose-6-Phosphatase |
title_full_unstemmed |
Liver GlucokinaseA456V Induces Potent Hypoglycemia without Dyslipidemia through a Paradoxical Induction of the Catalytic Subunit of Glucose-6-Phosphatase |
title_sort |
liver glucokinasea456v induces potent hypoglycemia without dyslipidemia through a paradoxical induction of the catalytic subunit of glucose-6-phosphatase |
publisher |
Hindawi Limited |
series |
International Journal of Endocrinology |
issn |
1687-8337 1687-8345 |
publishDate |
2011-01-01 |
description |
Recent reports point out the importance of the complex GK-GKRP in controlling glucose and lipid homeostasis. Several GK mutations affect GKRP binding, resulting in permanent activation of the enzyme. We hypothesize that hepatic overexpression of a mutated form of GK, GKA456V, described in a patient with persistent hyperinsulinemic hypoglycemia of infancy (PHHI) and could provide a model to study the consequences of GK-GKRP deregulation in vivo.
GKA456V was overexpressed in the liver of streptozotocin diabetic mice. Metabolite profiling in serum and liver extracts, together with changes in key components of glucose and lipid homeostasis, were analyzed and compared to GK wild-type transfected livers. Cell compartmentalization of the mutant but not the wild-type GK was clearly affected in vivo, demonstrating impaired GKRP regulation.
GKA456V overexpression markedly reduced blood glucose in the absence of dyslipidemia, in contrast to wild-type GK-overexpressing mice. Evidence in glucose utilization did not correlate with increased glycogen nor lactate levels in the liver. PEPCK mRNA was not affected, whereas the mRNA for the catalytic subunit of glucose-6-phosphatase was upregulated ~4 folds in the liver of GKA456V-treated animals, suggesting that glucose cycling was stimulated. Our results provide new insights into the complex GK regulatory network and validate liver-specific GK activation as a strategy for diabetes therapy. |
url |
http://dx.doi.org/10.1155/2011/707928 |
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