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

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    Type
    Article
    Authors
    Lavoie, Suzie
    Steullet, Pascal
    Kulak, Anita
    Preitner, Frederic
    Do, Kim Q.
    Magistretti, Pierre J. cc
    KAUST Department
    Biological and Environmental Sciences and Engineering (BESE) Division
    Bioscience Program
    Date
    2016-04-21
    Permanent link to this record
    http://hdl.handle.net/10754/610552
    
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    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.
    Citation
    Glutamate Cysteine Ligase—Modulatory Subunit Knockout Mouse Shows Normal Insulin Sensitivity but Reduced Liver Glycogen Storage 2016, 7 Frontiers in Physiology
    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.
    Publisher
    Frontiers Media SA
    Journal
    Frontiers in Physiology
    DOI
    10.3389/fphys.2016.00142
    PubMed ID
    27148080
    Additional Links
    http://journal.frontiersin.org/Article/10.3389/fphys.2016.00142/abstract
    ae974a485f413a2113503eed53cd6c53
    10.3389/fphys.2016.00142
    Scopus Count
    Collections
    Articles; Biological and Environmental Science and Engineering (BESE) Division; Bioscience Program

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