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
BROSSAUD, Julie
Nutrition et Neurobiologie intégrée [NutriNeuro]
CHU Bordeaux, Nuclear Medicine, 33604, Pessac, France
Nutrition et Neurobiologie intégrée [NutriNeuro]
CHU Bordeaux, Nuclear Medicine, 33604, Pessac, France
MARISSAL-ARVY, Nathalie
Unité de Psychoneuroimmunologie, Nutrition et Génétique [PsyNuGen]
Nutrition et Neurobiologie intégrée [NutriNeuro]
Biologie du fruit et pathologie [BFP]
Leer más >
Unité de Psychoneuroimmunologie, Nutrition et Génétique [PsyNuGen]
Nutrition et Neurobiologie intégrée [NutriNeuro]
Biologie du fruit et pathologie [BFP]
BROSSAUD, Julie
Nutrition et Neurobiologie intégrée [NutriNeuro]
CHU Bordeaux, Nuclear Medicine, 33604, Pessac, France
Nutrition et Neurobiologie intégrée [NutriNeuro]
CHU Bordeaux, Nuclear Medicine, 33604, Pessac, France
MARISSAL-ARVY, Nathalie
Unité de Psychoneuroimmunologie, Nutrition et Génétique [PsyNuGen]
Nutrition et Neurobiologie intégrée [NutriNeuro]
Biologie du fruit et pathologie [BFP]
Unité de Psychoneuroimmunologie, Nutrition et Génétique [PsyNuGen]
Nutrition et Neurobiologie intégrée [NutriNeuro]
Biologie du fruit et pathologie [BFP]
CAMPAS-LEBECQUE, Marie-Neige
Université de Bordeaux [UB]
CHU Bordeaux, Pediatric Endocrinology and DiaBEA unit, Hôpital des Enfants, 33076 Bordeaux, France
Université de Bordeaux [UB]
CHU Bordeaux, Pediatric Endocrinology and DiaBEA unit, Hôpital des Enfants, 33076 Bordeaux, France
HELBLING, Jean-Christophe
Unité de recherche génomique et physiologie de la lactation [GPL]
Unité de Psychoneuroimmunologie, Nutrition et Génétique [PsyNuGen]
Nutrition et Neurobiologie intégrée [NutriNeuro]
Nutrition et Neurobiologie intégrée [NutriNeuro]
Nutrition et Neurobiologie intégrée [NutriNeuro]
Unité de recherche génomique et physiologie de la lactation [GPL]
Unité de Psychoneuroimmunologie, Nutrition et Génétique [PsyNuGen]
Nutrition et Neurobiologie intégrée [NutriNeuro]
Nutrition et Neurobiologie intégrée [NutriNeuro]
Nutrition et Neurobiologie intégrée [NutriNeuro]
BARAT, Pascal
Université de Bordeaux [UB]
CHU Bordeaux, Pediatric Endocrinology and DiaBEA unit, Hôpital des Enfants, 33076 Bordeaux, France
Nutrition et Neurobiologie intégrée [NutriNeuro]
Université de Bordeaux [UB]
CHU Bordeaux, Pediatric Endocrinology and DiaBEA unit, Hôpital des Enfants, 33076 Bordeaux, France
Nutrition et Neurobiologie intégrée [NutriNeuro]
CORCUFF, Jean-Benoît
Nutrition et Neurobiologie intégrée [NutriNeuro]
CHU Bordeaux, Nuclear Medicine, 33604, Pessac, France
< Leer menos
Nutrition et Neurobiologie intégrée [NutriNeuro]
CHU Bordeaux, Nuclear Medicine, 33604, Pessac, France
Idioma
en
Article de revue
Este ítem está publicado en
Diabetologia. 2023-06-10, vol. 66, n° 9, p. 1735-1747
Springer Verlag
Resumen en inglés
Aims/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 ...Leer más >
Aims/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.< Leer menos
Palabras clave en inglés
Glucocorticoids
11β-Hydroxysteroid dehydrogenase
Type 1 diabetes
Orígen
Importado de HalCentros de investigación