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Memory deficits in a juvenile rat model of type 1 diabetes are due to excess 11β-HSD1 activity, which is upregulated by high glucose concentrations rather than insulin deficiency

hal.structure.identifierNutrition et Neurobiologie intégrée [NutriNeuro]
hal.structure.identifierCHU Bordeaux, Nuclear Medicine, 33604, Pessac, France
dc.contributor.authorBROSSAUD, Julie
hal.structure.identifierNutrition et Neurobiologie intégrée [NutriNeuro]
dc.contributor.authorBOSCH-BOUJU, Clémentine
hal.structure.identifierUnité de Psychoneuroimmunologie, Nutrition et Génétique [PsyNuGen]
hal.structure.identifierNutrition et Neurobiologie intégrée [NutriNeuro]
hal.structure.identifierBiologie du fruit et pathologie [BFP]
dc.contributor.authorMARISSAL-ARVY, Nathalie
hal.structure.identifierUniversité de Bordeaux [UB]
hal.structure.identifierCHU Bordeaux, Pediatric Endocrinology and DiaBEA unit, Hôpital des Enfants, 33076 Bordeaux, France
dc.contributor.authorCAMPAS-LEBECQUE, Marie-Neige
hal.structure.identifierUnité de recherche génomique et physiologie de la lactation [GPL]
hal.structure.identifierUnité de Psychoneuroimmunologie, Nutrition et Génétique [PsyNuGen]
hal.structure.identifierNutrition et Neurobiologie intégrée [NutriNeuro]
hal.structure.identifierNutrition et Neurobiologie intégrée [NutriNeuro]
hal.structure.identifierNutrition et Neurobiologie intégrée [NutriNeuro]
dc.contributor.authorHELBLING, Jean-Christophe
hal.structure.identifierUniversity of Edinburgh [Edin.]
dc.contributor.authorWEBSTER, Scott
hal.structure.identifierUniversity of Edinburgh [Edin.]
dc.contributor.authorWALKER, Brian
hal.structure.identifierNutrition et Neurobiologie intégrée [NutriNeuro]
dc.contributor.authorFIORAMONTI, Xavier
hal.structure.identifierNutrition et Neurobiologie intégrée [NutriNeuro]
dc.contributor.authorFERREIRA, Guillaume
hal.structure.identifierUniversité de Bordeaux [UB]
hal.structure.identifierCHU Bordeaux, Pediatric Endocrinology and DiaBEA unit, Hôpital des Enfants, 33076 Bordeaux, France
hal.structure.identifierNutrition et Neurobiologie intégrée [NutriNeuro]
dc.contributor.authorBARAT, Pascal
hal.structure.identifierNutrition et Neurobiologie intégrée [NutriNeuro]
hal.structure.identifierCHU Bordeaux, Nuclear Medicine, 33604, Pessac, France
dc.contributor.authorCORCUFF, Jean-Benoît
hal.structure.identifierNutrition et Neurobiologie intégrée [NutriNeuro]
dc.contributor.authorMOISAN, Marie-Pierre
dc.contributor.editorSpringer
dc.date.accessioned2024-06-07T02:04:30Z
dc.date.available2024-06-07T02:04:30Z
dc.date.issued2023-06-10
dc.identifier.issn0012-186X
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/200329
dc.description.abstractEnAims/hypothesis Children with diabetes may display cognitive alterations although vascular disorders have not yet appeared.Variations in glucose levels together with relative insulin deficiency in treated type 1 diabetes have been reported to impactbrain function indirectly through dysregulation of the hypothalamus–pituitary–adrenal axis. We have recently shown thatenhancement of glucocorticoid levels in children with type 1 diabetes is dependent not only on glucocorticoid secretion butalso on glucocorticoid tissue concentrations, which is linked to 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity.Hypothalamus–pituitary–adrenal axis dysfunction and memory alteration were further dissected in a juvenile rat model ofdiabetes showing that excess 11β-HSD1 activity within the hippocampus is associated with hippocampal-dependent memorydeficits. Here, to investigate the causal relationships between diabetes, 11β-HSD1 activity and hippocampus-dependentmemory deficits, we evaluated the beneficial effect of 11β-HSD1 inhibition on hippocampal-related memory in juvenilediabetic rats. We also examined whether diabetes-associated enhancement of hippocampal 11β-HSD1 activity is due to anincrease in brain glucose concentrations and/or a decrease in insulin signalling.Methods Diabetes was induced in juvenile rats by daily i.p. injection of streptozotocin for 2 consecutive days. Inhibitionof 11β-HSD1 was obtained by administrating the compound UE2316 twice daily by gavage for 3 weeks, after whichhippocampal-dependent object location memory was assessed. Hippocampal 11β-HSD1 activity was estimated by the ratioof corticosterone/dehydrocorticosterone measured by LC/MS. Regulation of 11β-HSD1 activity in response to changes inglucose or insulin levels was determined ex vivo on acute brain hippocampal slices. The insulin regulation of 11β-HSD1 wasfurther examined in vivo using virally mediated knockdown of insulin receptor expression specifically in the hippocampus.Results Our data show that inhibiting 11β-HSD1 activity prevents hippocampal-related memory deficits in diabetic juvenile rats.A significant increase (53.0±9.9%) in hippocampal 11β-HSD1 activity was found in hippocampal slices incubated in high glucoseconditions (13.9 mmol/l) vs normal glucose conditions (2.8 mmol/l) without insulin. However, 11β-HSD1 activity was not affectedby variations in insulin concentration either in the hippocampal slices or after a decrease in hippocampal insulin receptor expression.Conclusions/interpretation Together, these data demonstrate that an increase in 11β-HSD1 activity contributes to memory deficitsobserved in juvenile diabetic rats and that an excess of hippocampal 11β-HSD1 activity stems from high glucose levels ratherthan insulin deficiency. 11β-HSD1 might be a therapeutic target for treating cognitive impairments associated with diabetes.
dc.language.isoen
dc.publisherSpringer Verlag
dc.rights.urihttp://hal.archives-ouvertes.fr/licences/copyright/
dc.subject.enGlucocorticoids
dc.subject.en11β-Hydroxysteroid dehydrogenase
dc.subject.enType 1 diabetes
dc.title.enMemory deficits in a juvenile rat model of type 1 diabetes are due to excess 11β-HSD1 activity, which is upregulated by high glucose concentrations rather than insulin deficiency
dc.typeArticle de revue
dc.identifier.doi10.1007/s00125-023-05942-3
dc.subject.halSciences du Vivant [q-bio]
bordeaux.journalDiabetologia
bordeaux.page1735-1747
bordeaux.volume66
bordeaux.hal.laboratoriesBiologie du Fruit & Pathologie (BFP) - UMR 1332*
bordeaux.issue9
bordeaux.institutionUniversité de Bordeaux
bordeaux.institutionINRAE
bordeaux.peerReviewedoui
hal.identifierhal-04602078
hal.version1
hal.popularnon
hal.audienceInternationale
hal.origin.linkhttps://hal.archives-ouvertes.fr//hal-04602078v1
bordeaux.COinSctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Diabetologia&rft.date=2023-06-10&rft.volume=66&rft.issue=9&rft.spage=1735-1747&rft.epage=1735-1747&rft.eissn=0012-186X&rft.issn=0012-186X&rft.au=BROSSAUD,%20Julie&BOSCH-BOUJU,%20Cl%C3%A9mentine&MARISSAL-ARVY,%20Nathalie&CAMPAS-LEBECQUE,%20Marie-Neige&HELBLING,%20Jean-Christophe&rft.genre=article


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