Glutamate Cysteine Ligase—Modulatory Subunit Knockout Mouse Shows Normal Insulin Sensitivity but Reduced Liver Glycogen Storage
MetadataShow full item record
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.
CitationGlutamate Cysteine Ligase—Modulatory Subunit Knockout Mouse Shows Normal Insulin Sensitivity but Reduced Liver Glycogen Storage 2016, 7 Frontiers in Physiology
SponsorsThe 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.
PublisherFrontiers Media SA
JournalFrontiers in Physiology
- Altered glycogen metabolism in cultured astrocytes from mice with chronic glutathione deficit; relevance for neuroenergetics in schizophrenia.
- Authors: Lavoie S, Allaman I, Petit JM, Do KQ, Magistretti PJ
- Issue date: 2011
- Initial characterization of the glutamate-cysteine ligase modifier subunit Gclm(-/-) knockout mouse. Novel model system for a severely compromised oxidative stress response.
- Authors: Yang Y, Dieter MZ, Chen Y, Shertzer HG, Nebert DW, Dalton TP
- Issue date: 2002 Dec 20
- Lipid metabolism and body composition in Gclm(-/-) mice.
- Authors: Kendig EL, Chen Y, Krishan M, Johansson E, Schneider SN, Genter MB, Nebert DW, Shertzer HG
- Issue date: 2011 Dec 15
- Behavioral phenotyping of glutathione-deficient mice: relevance to schizophrenia and bipolar disorder.
- Authors: Kulak A, Cuenod M, Do KQ
- Issue date: 2012 Jan 15
- Glutathione-deficient mice are susceptible to TCDD-Induced hepatocellular toxicity but resistant to steatosis.
- Authors: Chen Y, Krishan M, Nebert DW, Shertzer HG
- Issue date: 2012 Jan 13