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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

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Abstract

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 impact brain function indirectly through dysregulation of the hypothalamus–pituitary–adrenal axis. We have recently shown that enhancement of glucocorticoid levels in children with type 1 diabetes is dependent not only on glucocorticoid secretion but also 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 of diabetes showing that excess 11β-HSD1 activity within the hippocampus is associated with hippocampal-dependent memory deficits. Here, to investigate the causal relationships between diabetes, 11β-HSD1 activity and hippocampus-dependent memory deficits, we evaluated the beneficial effect of 11β-HSD1 inhibition on hippocampal-related memory in juvenile diabetic rats. We also examined whether diabetes-associated enhancement of hippocampal 11β-HSD1 activity is due to an increase 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. Inhibition of 11β-HSD1 was obtained by administrating the compound UE2316 twice daily by gavage for 3 weeks, after which hippocampal-dependent object location memory was assessed. Hippocampal 11β-HSD1 activity was estimated by the ratio of corticosterone/dehydrocorticosterone measured by LC/MS. Regulation of 11β-HSD1 activity in response to changes in glucose or insulin levels was determined ex vivo on acute brain hippocampal slices. The insulin regulation of 11β-HSD1 was further 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 glucose conditions (13.9 mmol/l) vs normal glucose conditions (2.8 mmol/l) without insulin. However, 11β-HSD1 activity was not affected by 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 deficits observed in juvenile diabetic rats and that an excess of hippocampal 11β-HSD1 activity stems from high glucose levels rather than insulin deficiency. 11β-HSD1 might be a therapeutic target for treating cognitive impairments associated with diabetes.

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Abbreviations

AAV:

Adeno-associated virus

Cs:

Corticosterone

CTL:

Control group treated by vehicle

CTL+UE:

Control group treated by UE

D:

Diabetic group treated by vehicle

DHC:

Dehydrocorticosterone

D+UE:

Diabetic group treated by UE

fEPSP:

Field excitatory post-synaptic potential

GC:

Glucocorticoids

Hippo-CTL:

Wild-type mice

Hippo-InsRKD:

Mice with specific InsR knockdown in the hippocampus

11β-HSD1:

11β-Hydroxysteroid dehydrogenase type 1

InsR:

Insulin receptor

InsRlox /lox :

Insulin receptorlox/lox

NMDG:

N-Methyl-d-glucamine

OLM:

Object location memory

PFA:

Paraformaldehyde

PPP:

Pentose phosphate pathway

STZ:

Streptozotocin

UE:

UE2316

References

  1. Brands AMA, Biessels GJ, de Haan EHF, Kappelle LJ, Kessels RPC (2005) The effects of type 1 diabetes on cognitive performance. Diabetes Care 28(3):726–735. https://doi.org/10.2337/diacare.28.3.726

    Article  PubMed  Google Scholar 

  2. Shalimova A, Graff B, Gąsecki D et al (2019) Cognitive dysfunction in type 1 diabetes mellitus. J Clin Endocrinol Metab 104(6):2239–2249. https://doi.org/10.1210/jc.2018-01315

    Article  PubMed  Google Scholar 

  3. McCrimmon RJ, Ryan CM, Frier BM (2012) Diabetes and cognitive dysfunction. Lancet 379(9833):2291–2299. https://doi.org/10.1016/S0140-6736(12)60360-2

    Article  PubMed  Google Scholar 

  4. Creo AL, Cortes TM, Jo HJ et al (2021) Brain functions and cognition on transient insulin deprivation in type 1 diabetes. JCI Insight 6(5):e144014. https://doi.org/10.1172/jci.insight.144014

    Article  PubMed  PubMed Central  Google Scholar 

  5. Silver I, Erecinska M (1994) Extracellular glucose concentration in mammalian brain: continuous monitoring of changes during increased neuronal activity and upon limitation in oxygen supply in normo-, hypo-, and hyperglycemic animals. J Neurosci 14(8):5068–5076. https://doi.org/10.1523/JNEUROSCI.14-08-05068.1994

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Gaudieri PA, Chen R, Greer TF, Holmes CS (2008) Cognitive function in children with type 1 diabetes. Diabetes Care 31(9):1892–1897. https://doi.org/10.2337/dc07-2132

    Article  PubMed  PubMed Central  Google Scholar 

  7. Litmanovitch E (2015) Short and long term neuro-behavioral alterations in type 1 diabetes mellitus pediatric population. WJD 6(2):259. https://doi.org/10.4239/wjd.v6.i2.259

    Article  PubMed  PubMed Central  Google Scholar 

  8. Magariños AM, McEwen BS (2000) Experimental diabetes in rats causes hippocampal dendritic and synaptic reorganization and increased glucocorticoid reactivity to stress. Proc Natl Acad Sci USA 97(20):11056–11061. https://doi.org/10.1073/pnas.97.20.11056

    Article  PubMed  PubMed Central  Google Scholar 

  9. MacLullich AMJ, Seckl JR (2008) Diabetes and cognitive decline: are steroids the missing link? Cell Metab 7(4):286–287. https://doi.org/10.1016/j.cmet.2008.03.012

    Article  CAS  PubMed  Google Scholar 

  10. de Quervain D, Schwabe L, Roozendaal B (2017) Stress, glucocorticoids and memory: implications for treating fear-related disorders. Nat Rev Neurosci 18(1):7–19. https://doi.org/10.1038/nrn.2016.155

    Article  CAS  PubMed  Google Scholar 

  11. Revsin Y, Rekers NV, Louwe MC et al (2009) Glucocorticoid receptor blockade normalizes hippocampal alterations and cognitive impairment in streptozotocin-induced type 1 diabetes mice. Neuropsychopharmacol 34(3):747–758. https://doi.org/10.1038/npp.2008.136

    Article  CAS  Google Scholar 

  12. Stranahan AM, Arumugam TV, Cutler RG, Lee K, Egan JM, Mattson MP (2008) Diabetes impairs hippocampal function through glucocorticoid-mediated effects on new and mature neurons. Nat Neurosci 11(3):309–317. https://doi.org/10.1038/nn2055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zuo Z-F, Wang W, Niu L et al (2011) RU486 (mifepristone) ameliorates cognitive dysfunction and reverses the down-regulation of astrocytic N-myc downstream-regulated gene 2 in streptozotocin-induced type-1 diabetic rats. Neuroscience 190:156–165. https://doi.org/10.1016/j.neuroscience.2011.06.025

    Article  CAS  PubMed  Google Scholar 

  14. Marissal-Arvy N, Moisan M-P (2022) Diabetes and associated cognitive disorders: role of the hypothalamic-pituitary adrenal axis. Metab Open 15:100202. https://doi.org/10.1016/j.metop.2022.100202

    Article  CAS  Google Scholar 

  15. Barat P, Brossaud J, Lacoste A et al (2013) Nocturnal activity of 11β-hydroxy steroid dehydrogenase type 1 is increased in type 1 diabetic children. Diabetes Metab 39(2):163–168. https://doi.org/10.1016/j.diabet.2012.10.001

    Article  CAS  PubMed  Google Scholar 

  16. Brossaud J, Corcuff J-B, Vautier V et al (2021) Altered cortisol metabolism increases nocturnal cortisol bioavailability in prepubertal children with type 1 diabetes mellitus. Front Endocrinol 12:742669. https://doi.org/10.3389/fendo.2021.742669

    Article  Google Scholar 

  17. Marissal-Arvy N, Campas M-N, Semont A et al (2018) Insulin treatment partially prevents cognitive and hippocampal alterations as well as glucocorticoid dysregulation in early-onset insulin-deficient diabetic rats. Psychoneuroendocrinology 93:72–81. https://doi.org/10.1016/j.psyneuen.2018.04.016

    Article  CAS  PubMed  Google Scholar 

  18. Soltesz G, Patterson C, Dahlquist G, EURODIAB Study Group (2007) Worldwide childhood type 1 diabetes incidence – what can we learn from epidemiology? Pediatr Diabetes 8(Suppl 6):6–14. https://doi.org/10.1111/j.1399-5448.2007.00280.x

    Article  PubMed  Google Scholar 

  19. Sarabdjitsingh RA, Zhou M, Yau JLW et al (2014) Inhibiting 11β-hydroxysteroid dehydrogenase type 1 prevents stress effects on hippocampal synaptic plasticity and impairs contextual fear conditioning. Neuropharmacology 81:231–236. https://doi.org/10.1016/j.neuropharm.2014.01.042

    Article  CAS  PubMed  Google Scholar 

  20. Alteba S, Korem N, Akirav I (2016) Cannabinoids reverse the effects of early stress on neurocognitive performance in adulthood. Learn Mem 23(7):349–358. https://doi.org/10.1101/lm.041608.116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ennaceur A, Neave N, Aggleton JP (1997) Spontaneous object recognition and object location memory in rats: the effects of lesions in the cingulate cortices, the medial prefrontal cortex, the cingulum bundle and the fornix. Exp Brain Res 113(3):509–519. https://doi.org/10.1007/PL00005603

    Article  CAS  PubMed  Google Scholar 

  22. Mumby DG, Gaskin S, Glenn MJ, Schramek TE, Lehmann H (2002) Hippocampal damage and exploratory preferences in rats: memory for objects, places, and contexts. Learn Mem 9(2):49–57. https://doi.org/10.1101/lm.41302

    Article  PubMed  PubMed Central  Google Scholar 

  23. Paxinos G, Franklin KBJ (2019) Paxinos and Franklin’s the mouse brain in stereotaxic coordinates, 5th edn. Academic Press, Cambridge, MA

    Google Scholar 

  24. Titone R, Zhu M, Robertson DM (2018) Insulin mediates de novo nuclear accumulation of the IGF-1/insulin hybrid receptor in corneal epithelial cells. Sci Rep 8(1):4378. https://doi.org/10.1038/s41598-018-21031-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Park J, Li J, Mayer JP et al (2022) Activation of the insulin receptor by an insulin mimetic peptide. Nat Commun 13(1):5594. https://doi.org/10.1038/s41467-022-33274-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Thomazeau A, Bosch-Bouju C, Manzoni O, Layé S (2016) Nutritional n-3 PUFA deficiency abolishes endocannabinoid gating of hippocampal long-term potentiation. Cereb Cortex 27(4):2571–2579. https://doi.org/10.1093/cercor/bhw052

    Article  Google Scholar 

  27. Reusch CE, Liehs MR, Hoyer M, Vochezer R (1993) Fructosamine a new parameter for diagnosis and metabolic control in diabetic dogs and cats. J Vet Int Med 7(3):177–182. https://doi.org/10.1111/j.1939-1676.1993.tb03183.x

    Article  CAS  Google Scholar 

  28. Sooy K, Noble J, McBride A et al (2015) Cognitive and disease-modifying effects of 11β-hydroxysteroid dehydrogenase type 1 inhibition in male Tg2576 mice, a model of Alzheimer’s disease. Endocrinology 156(12):4592–4603. https://doi.org/10.1210/en.2015-1395

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Yau JLW, Seckl JR (2012) Local amplification of glucocorticoids in the aging brain and impaired spatial memory. Front Aging Neurosci 4:24. https://doi.org/10.3389/fnagi.2012.00024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Bhatt S, Hillmer AT, Rusowicz A et al (2021) Imaging brain cortisol regulation in PTSD with a target for 11β-hydroxysteroid dehydrogenase type 1. J Clin Investig 131(20):e150452. https://doi.org/10.1172/JCI150452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Webster SP, McBride A, Binnie M et al (2017) Selection and early clinical evaluation of the brain-penetrant 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor UE2343 (XanamemTM): discovery/clinical evaluation of 11β-HSD1 inhibitor UE2343. Br J Pharmacol 174(5):396–408. https://doi.org/10.1111/bph.13699

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bini J, Bhatt S, Hillmer AT et al (2020) Body mass index and age effects on brain 11β-hydroxysteroid dehydrogenase type 1: a positron emission tomography study. Mol Imaging Biol 22(4):1124–1131. https://doi.org/10.1007/s11307-020-01490-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sandeep TC, Yau JLW, MacLullich AMJ et al (2004) 11β-Hydroxysteroid dehydrogenase inhibition improves cognitive function in healthy elderly men and type 2 diabetics. Proc Natl Acad Sci USA 101(17):6734–6739. https://doi.org/10.1073/pnas.0306996101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Gregory S, Hill D, Grey B et al (2020) 11β-Hydroxysteroid dehydrogenase type 1 inhibitor use in human disease-a systematic review and narrative synthesis. Metabolism 108:154246. https://doi.org/10.1016/j.metabol.2020.154246

    Article  CAS  PubMed  Google Scholar 

  35. Dodd S, Skvarc DR, Dean OM, Anderson A, Kotowicz M, Berk M (2022) Effect of glucocorticoid and 11β-hydroxysteroid-dehydrogenase type 1 (11β-HSD1) in neurological and psychiatric disorders. Int J Neuropsychopharmacol 25(5):387–398. https://doi.org/10.1093/ijnp/pyac014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Liu Y-J, Nakagawa Y, Nasuda K, Saegusa H, Igarashi Y (1996) Effect of growth hormone, insulin and dexamethasone on 11 β -hydroxysteroid dehydrogenase activity on a primary culture of rat hepatocytes. Life Sci 59(3):227–234. https://doi.org/10.1016/0024-3205(96)00288-3

    Article  CAS  PubMed  Google Scholar 

  37. Fan Z, Du H, Zhang M, Meng Z, Chen L, Liu Y (2011) Direct regulation of glucose and not insulin on hepatic hexose-6-phosphate dehydrogenase and 11β-hydroxysteroid dehydrogenase type 1. Mol Cell Endocrinol 333(1):62–69. https://doi.org/10.1016/j.mce.2010.12.010

    Article  CAS  PubMed  Google Scholar 

  38. Yao F, Chen L, Fan Z et al (2017) Interplay between H6PDH and 11β-HSD1 implicated in the pathogenesis of type 2 diabetes mellitus. Bioorg Med Chem Lett 27(17):4107–4113. https://doi.org/10.1016/j.bmcl.2017.07.043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Dzyakanchuk AA, Balázs Z, Nashev LG, Amrein KE, Odermatt A (2009) 11β-Hydroxysteroid dehydrogenase 1 reductase activity is dependent on a high ratio of NADPH/NADP+ and is stimulated by extracellular glucose. Mol Cell Endocrinol 301(1–2):137–141. https://doi.org/10.1016/j.mce.2008.08.009

    Article  CAS  PubMed  Google Scholar 

  40. Qi W, Zhong L, Li X et al (2012) Hyperglycemia induces the variations of 11 β -hydroxysteroid dehydrogenase type 1 and peroxisome proliferator-activated receptor-γ expression in hippocampus and hypothalamus of diabetic rats. Exp Diabetes Res 2012:107130. https://doi.org/10.1155/2012/107130

  41. Rebelos E, Rinne JO, Nuutila P, Ekblad LL (2021) Brain glucose metabolism in health, obesity, and cognitive decline—does insulin have anything to do with it? A narrative review. J Clin Med 10(7):1532. https://doi.org/10.3390/jcm10071532. (1-16)

  42. Lavery GG, Walker EA, Draper N et al (2006) Hexose-6-phosphate dehydrogenase knock-out mice lack 11β-hydroxysteroid dehydrogenase type 1-mediated glucocorticoid generation. J Biol Chem 281(10):6546–6551. https://doi.org/10.1074/jbc.M512635200

    Article  CAS  PubMed  Google Scholar 

  43. Takahashi S, Izawa Y, Suzuki N (2012) Astroglial pentose phosphate pathway rates in response to high-glucose environments. ASN Neuro 4(2):e00078. https://doi.org/10.1042/AN20120002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. University of Bordeaux, INRAE, Bordeaux INP, NutriNeurO, UMR 1286, Bordeaux, France

    Julie Brossaud, Clémentine Bosch-Bouju, Nathalie Marissal-Arvy, Marie-Neige Campas-Lebecque, Jean-Christophe Helbling, Xavier Fioramonti, Guillaume Ferreira, Pascal Barat, Jean-Benoît Corcuff & Marie-Pierre Moisan

  2. CHU Bordeaux, Nuclear Medicine, Pessac, France

    Julie Brossaud & Jean-Benoît Corcuff

  3. British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK

    Scott P. Webster & Brian R. Walker

  4. Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK

    Brian R. Walker

  5. CHU Bordeaux, Pediatric Endocrinology and DiaBEA Unit, Hôpital des Enfants, Bordeaux, France

    Pascal Barat

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  1. Julie Brossaud
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Corresponding author

Correspondence to Julie Brossaud.

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Acknowledgements

The development of UE2316 was funded by the Wellcome Trust.

Data availability

The data are available on request from the authors.

Funding

This work was supported by a grant from SFEDP (Société Française d’Endocrinologie et Diabétologie Pédiatrique).

Authors’ relationships and activities

BRW and SPW are inventors on relevant patents owned by the University of Edinburgh and licensed to Actinogen Medical Ltd. The authors declare that there are no other relationships or activities that might bias, or be perceived to bias, their work.

Contribution statement

JB, CB-B, XF, PB, J-BC and M-PM contributed to the conception and design of the study. JB, J-CH, NM-A, M-NC-L, CB-B and M-PM acquired the data. JB, CB-B, SPW, BRW, XF, GF and M-PM analysed and interpreted the data. JB, CB-B, J-CH, XF and M-PM drafted the manuscript and JB, CB-B, NM-A, M-NC-L, SPW, BRW, GF, PB, J-BC and M-PM revised it. All authors approved the manuscript. JB and M-PM are the guarantors of this work.

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Brossaud, J., Bosch-Bouju, C., Marissal-Arvy, N. et al. 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. Diabetologia 66, 1735–1747 (2023). https://doi.org/10.1007/s00125-023-05942-3

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