Transient but not chronic hyperglycemia accelerates ocular glymphatic transport

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Glymphatic transport is vital for the physiological homeostasis of the retina and optic nerve. Pathological alterations of ocular glymphatic fluid transport and enlarged perivascular spaces have been described in glaucomatous mice. It remains to be established how diabetic retinopathy, which impairs vision in about 50% of diabetes patients, impacts ocular glymphatic fluid transport. Here, we examined ocular glymphatic transport in chronic hyperglycemic diabetic mice as well as in healthy mice experiencing a daily transient increase in blood glucose. Mice suffering from severe diabetes for two and four months, induced by streptozotocin, exhibited no alterations in ocular glymphatic fluid transport in the optic nerve compared to age-matched, non-diabetic controls. In contrast, transient increases in blood glucose induced by repeated daily glucose injections in healthy, awake, non-diabetic mice accelerated antero- and retrograde ocular glymphatic transport. Structural analysis showed enlarged perivascular spaces in the optic nerves of glucose-treated mice, which were absent in diabetic mice. Thus, transient repeated hyperglycemic events, but not constant hyperglycemia, ultimately enlarge perivascular spaces in the murine optic nerve. These findings indicate that fluid transport in the mouse eye is vulnerable to fluctuating glycemic levels rather than constant hyperglycemia, suggesting that poor glycemic control drives glymphatic malfunction and perivascular enlargement in the optic nerve.
OriginalsprogEngelsk
Artikelnummer26
TidsskriftFluids and Barriers of the CNS
Vol/bind21
Udgave nummer1
Antal sider13
ISSN2045-8118
DOI
StatusUdgivet - 2024

Bibliografisk note

Funding Information:
We thank Helle Hvorup Knudsen (scientific laboratory technician, CTN, University of Copenhagen) for technical assistance with diabetic mice husbandry and cation chromatography. We thank Dan Xue (medical illustrator and graphic designer, CTN, University of Copenhagen) for graphical illustrations and Björn Sigurdsson (PhD, Department of Health Technology, Technical University of Denmark (DTU)) for technical support. For assistance with diabetic mice husbandry and supporting activity tracking we thank Erik Kroesbergen (CTN, University of Copenhagen). We thank Anastasia Tsopanidou (CTN, University of Copenhagen) for assistance with activity analysis. We thank the Core Facility for Integrated Microscopy, Faculty of Health and Medical Sciences, University of Copenhagen for professional electron microscopy support. For comments and critical reading of the manuscript we thank Professor Paul Cumming (Bern University Department of Nuclear Medicine) and Professor Hajime Hirase (CTN, University of Copenhagen). For expert advice on statistical analysis, we thank Antonios Asiminas (PhD, CTN, University of Copenhagen).

Funding Information:
This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 742112), the NNF Laureate grant (NNF13OC0004258), the Lundbeck Foundation (R155-2016–552) and NIH R01AT012312, RF1AG057575, R01AT011439, U19 NS128613 and the U.S. Army under Award No. MURI W911NF1910280.

Publisher Copyright:
© The Author(s) 2024.

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