Glutamate Cysteine Ligase—Modulatory Subunit Knockout Mouse Shows Normal Insulin Sensitivity but Reduced Liver Glycogen Storage

Handle URI:
http://hdl.handle.net/10754/610552
Title:
Glutamate Cysteine Ligase—Modulatory Subunit Knockout Mouse Shows Normal Insulin Sensitivity but Reduced Liver Glycogen Storage
Authors:
Lavoie, Suzie; Steullet, Pascal; Kulak, Anita; Preitner, Frederic; Do, Kim Q.; Magistretti, Pierre J. ( 0000-0002-6678-320X )
Abstract:
Glutathione (GSH) deficits have been observed in several mental or degenerative illness, and so has the metabolic syndrome. The impact of a decreased glucose metabolism on the GSH system is well-known, but the effect of decreased GSH levels on the energy metabolism is unclear. The aim of the present study was to investigate the sensitivity to insulin in the mouse knockout (KO) for the modulatory subunit of the glutamate cysteine ligase (GCLM), the rate-limiting enzyme of GSH synthesis. Compared to wildtype (WT) mice, GCLM-KO mice presented with reduced basal plasma glucose and insulin levels. During an insulin tolerance test, GCLM-KO mice showed a normal fall in glycemia, indicating normal insulin secretion. However, during the recovery phase, plasma glucose levels remained lower for longer in KO mice despite normal plasma glucagon levels. This is consistent with a normal counterregulatory hormonal response but impaired mobilization of glucose from endogenous stores. Following a resident-intruder stress, during which stress hormones mobilize glucose from hepatic glycogen stores, KO mice showed a lower hyperglycemic level despite higher plasma cortisol levels when compared to WT mice. The lower hepatic glycogen levels observed in GCLM-KO mice could explain the impaired glycogen mobilization following induced hypoglycemia. Altogether, our results indicate that reduced liver glycogen availability, as observed in GCLM-KO mice, could be at the origin of their lower basal and challenged glycemia. Further studies will be necessary to understand how a GSH deficit, typically observed in GCLM-KO mice, leads to a deficit in liver glycogen storage.
KAUST Department:
Biological and Environmental Sciences and Engineering (BESE) Division
Citation:
Glutamate Cysteine Ligase—Modulatory Subunit Knockout Mouse Shows Normal Insulin Sensitivity but Reduced Liver Glycogen Storage 2016, 7 Frontiers in Physiology
Publisher:
Frontiers Media SA
Journal:
Frontiers in Physiology
Issue Date:
21-Apr-2016
DOI:
10.3389/fphys.2016.00142
PubMed ID:
27148080
Type:
Article
ISSN:
1664-042X
Sponsors:
The authors would like to thank Anabela Pimentel from the Mouse Metabolic Evaluation Facility of the University of Lausanne for her implication in the ITTs. We would also like to acknowledge Dr Igor Allaman and Dr Jean-Marie Petit for their critical comments on the manuscript. The authors are also grateful to Adeline Cottier and Joel Gyger for their technical assistance.
Additional Links:
http://journal.frontiersin.org/Article/10.3389/fphys.2016.00142/abstract
Appears in Collections:
Articles; Biological and Environmental Sciences and Engineering (BESE) Division

Full metadata record

DC FieldValue Language
dc.contributor.authorLavoie, Suzieen
dc.contributor.authorSteullet, Pascalen
dc.contributor.authorKulak, Anitaen
dc.contributor.authorPreitner, Fredericen
dc.contributor.authorDo, Kim Q.en
dc.contributor.authorMagistretti, Pierre J.en
dc.date.accessioned2016-05-23T07:58:29Z-
dc.date.available2016-05-23T07:58:29Z-
dc.date.issued2016-04-21-
dc.identifier.citationGlutamate Cysteine Ligase—Modulatory Subunit Knockout Mouse Shows Normal Insulin Sensitivity but Reduced Liver Glycogen Storage 2016, 7 Frontiers in Physiologyen
dc.identifier.issn1664-042X-
dc.identifier.pmid27148080-
dc.identifier.doi10.3389/fphys.2016.00142-
dc.identifier.urihttp://hdl.handle.net/10754/610552-
dc.description.abstractGlutathione (GSH) deficits have been observed in several mental or degenerative illness, and so has the metabolic syndrome. The impact of a decreased glucose metabolism on the GSH system is well-known, but the effect of decreased GSH levels on the energy metabolism is unclear. The aim of the present study was to investigate the sensitivity to insulin in the mouse knockout (KO) for the modulatory subunit of the glutamate cysteine ligase (GCLM), the rate-limiting enzyme of GSH synthesis. Compared to wildtype (WT) mice, GCLM-KO mice presented with reduced basal plasma glucose and insulin levels. During an insulin tolerance test, GCLM-KO mice showed a normal fall in glycemia, indicating normal insulin secretion. However, during the recovery phase, plasma glucose levels remained lower for longer in KO mice despite normal plasma glucagon levels. This is consistent with a normal counterregulatory hormonal response but impaired mobilization of glucose from endogenous stores. Following a resident-intruder stress, during which stress hormones mobilize glucose from hepatic glycogen stores, KO mice showed a lower hyperglycemic level despite higher plasma cortisol levels when compared to WT mice. The lower hepatic glycogen levels observed in GCLM-KO mice could explain the impaired glycogen mobilization following induced hypoglycemia. Altogether, our results indicate that reduced liver glycogen availability, as observed in GCLM-KO mice, could be at the origin of their lower basal and challenged glycemia. Further studies will be necessary to understand how a GSH deficit, typically observed in GCLM-KO mice, leads to a deficit in liver glycogen storage.en
dc.description.sponsorshipThe authors would like to thank Anabela Pimentel from the Mouse Metabolic Evaluation Facility of the University of Lausanne for her implication in the ITTs. We would also like to acknowledge Dr Igor Allaman and Dr Jean-Marie Petit for their critical comments on the manuscript. The authors are also grateful to Adeline Cottier and Joel Gyger for their technical assistance.en
dc.language.isoenen
dc.publisherFrontiers Media SAen
dc.relation.urlhttp://journal.frontiersin.org/Article/10.3389/fphys.2016.00142/abstracten
dc.rightsThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.http://creativecommons.org/licenses/by/4.0/en
dc.subjectglutathioneen
dc.subjectGCLM knockouten
dc.subjectglycogenen
dc.subjectinsulinen
dc.subjectglycemiaen
dc.subjectresident-intruder stressen
dc.subjectcortisolen
dc.titleGlutamate Cysteine Ligase—Modulatory Subunit Knockout Mouse Shows Normal Insulin Sensitivity but Reduced Liver Glycogen Storageen
dc.typeArticleen
dc.contributor.departmentBiological and Environmental Sciences and Engineering (BESE) Divisionen
dc.identifier.journalFrontiers in Physiologyen
dc.eprint.versionPublisher's Version/PDFen
dc.contributor.institutionDepartment of Psychiatry, Centre for Psychiatric Neuroscience, Lausanne University Hospital and University of Lausanne, Lausanne-Prilly, Switzerlanden
dc.contributor.institutionOrygen, The National Centre of Excellence in Youth Mental Health, Centre for Youth Mental Health, The University of Melbourne, Parkville, VIC, Australiaen
dc.contributor.institutionMouse Metabolic Evaluation Facility, Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerlanden
dc.contributor.institutionLaboratory of Neuroenergetics and Cellular Dynamics, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerlanden
dc.contributor.affiliationKing Abdullah University of Science and Technology (KAUST)en
kaust.authorMagistretti, Pierre J.en

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