Abstract
Both type-1 and type-2 DM are related to an increased risk of cognitive impairment, neurovascular complications, and dementia. The primary triggers for complications are hyperglycemia and concomitant insulin resistance in type-2 DM. However, the diverse mechanisms in the pathogenesis of diabetes-related neurovascular complications and extracellular matrix (ECM) remodeling in type-1 and 2 have not been elucidated yet. Here, we investigated the high fat-high sucrose (HFHS) feeding model and streptozotocin-induced type-1 DM model to study the early effects of hyperglycemia with or without insulin resistance to demonstrate the brain microcirculatory changes, perivascular ECM alterations in histological sections and 3D-reconstructed cleared brain tissues. One of the main findings of this study was robust rarefaction in brain microvessels in both models. Interestingly, the HFHS model leads to widespread non-functional angiogenesis, but the type-1 DM model predominantly in the rostral brain. Rarefaction was accompanied by basement membrane thickening and perivascular collagen accumulation in type-1 DM; more severe blood-brain barrier leakage, and disruption of perivascular ECM organization, mainly of elastin and collagen fibers’ structural integrity in the HFHS model. Our results point out that the downstream mechanisms of the long-term vascular complications of hyperglycemia models are structurally distinctive and may have implications for appropriate treatment options.
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The data that support the findings of this study are available on request from the corresponding author.
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The authors gratefully acknowledge the use of the services and facilities of the Koç University Research Center for Translational Medicine (KUTTAM), funded by the Republic of Turkey’s Ministry of Development. The content is solely the authors’ responsibility and does not necessarily represent the official views of the Ministry of Development. E.Ö. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
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This research is funded by Koç University – Seed Fund (SF.00051) of Prof. Yasemin Gürsoy Özdemir.
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EÖ and YCT designed and performed all experiments, analyzed data, and wrote the manuscript. ESK, BY, NS, SS, CÖ, JK, ABK, and MP performed experiments and contributed to manuscript editing. HYE, SK, and MZ contributed to the study design and supervision process. YGÖ initiated and supervised the study, provided financial support, and revised the manuscript. All authors read and approved the final version of the manuscript.
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All experiments and procedures were applied according to the protocols and criterions approved by the Institutional Animal Care and Use Committee (IACUC) of Koç University with approval number 2015.HADYEK.003/009, according to Directive 2010/63/EU of the European Parliament and the Council on the Protection of Animals Used for Scientific Purposes. All experiments were reported in compliance with the Animal Research: Reporting in Vivo Experiments (ARRIVE) guidelines.
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Özkan, E., Çetin-Taş, Y., Şekerdağ, E. et al. Hyperglycemia with or without insulin resistance triggers different structural changes in brain microcirculation and perivascular matrix. Metab Brain Dis 38, 307–321 (2023). https://doi.org/10.1007/s11011-022-01100-7
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DOI: https://doi.org/10.1007/s11011-022-01100-7