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NG2-Glia Cause Diabetic Blood-Brain Barrier Disruption by Secreting MMP-9
Xiaolong Li, Yan Cai, Zhu Zhong, Maolin Li, Dong Huang, Zhifei Qiao, Hongli Zhou, Zuo Zhang, Jiyin Zhou
Received September 25, 2023  Accepted February 22, 2024  Published online July 23, 2024  
DOI:    [Epub ahead of print]
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AbstractAbstract PDF
Disorders of the blood-brain barrier (BBB) arising from diabetes mellitus are closely related to diabetic encephalopathy. Previous research has suggested that neuron-glia antigen 2 (NG2)-glia plays a key role in maintaining the integrity of the BBB. However, the mechanism by which NG2-glia regulates the diabetic BBB remains unclear.
Type 2 diabetes mellitus (T2DM) db/db mice and db/m mice were used. Evans-Blue BBB permeability tests and transmission electron microscopy techniques were applied. Tight junction proteins were assessed by immunofluorescence and transmission electron microscopy. NG2-glia number and signaling pathways were evaluated by immunofluorescence. Detection of matrix metalloproteinase-9 (MMP-9) in serum was performed using enzyme-linked immunosorbent assay (ELISA).
In T2DM db/db mice, BBB permeability in the hippocampus significantly increased from 16 weeks of age, and the structure of tight junction proteins changed. The number of NG2-glia in the hippocampus of db/db mice increased around microvessels from 12 weeks of age. Concurrently, the expression of MMP-9 increased in the hippocampus with no change in serum. Sixteen- week-old db/db mice showed activation of the Wnt/β-catenin signaling in hippocampal NG2-glia. Treatment with XAV-939 improved structural and functional changes in the hippocampal BBB and reduced MMP-9 secretion by hippocampal NG2-glia in db/db mice. It was also found that the upregulation of β-catenin protein in NG2-glia in the hippocampus of 16-week-old db/db mice was significantly alleviated by treatment with XAV-939.
The results indicate that NG2-glia can lead to structural and functional disruption of the diabetic BBB by activating Wnt/β-catenin signaling, upregulating MMP-9, and degrading tight junction proteins.
Glial and Vascular Cell Regulation of the Blood-Brain Barrier in Diabetes
Xiaolong Li, Yan Cai, Zuo Zhang, Jiyin Zhou
Diabetes Metab J. 2022;46(2):222-238.   Published online March 18, 2022
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  • 326 Download
  • 15 Web of Science
  • 15 Crossref
AbstractAbstract PDFPubReader   ePub   
As a structural barrier, the blood-brain barrier (BBB) is located at the interface between the brain parenchyma and blood, and modulates communication between the brain and blood microenvironment to maintain homeostasis. The BBB is composed of endothelial cells, basement membrane, pericytes, and astrocytic end feet. BBB impairment is a distinguishing and pathogenic factor in diabetic encephalopathy. Diabetes causes leakage of the BBB through downregulation of tight junction proteins, resulting in impaired functioning of endothelial cells, pericytes, astrocytes, microglia, nerve/glial antigen 2-glia, and oligodendrocytes. However, the temporal regulation, mechanisms of molecular and signaling pathways, and consequences of BBB impairment in diabetes are not well understood. Consequently, the efficacy of therapies diabetes targeting BBB leakage still lags behind the requirements. This review summarizes the recent research on the effects of diabetes on BBB composition and the potential roles of glial and vascular cells as therapeutic targets for BBB disruption in diabetic encephalopathy.


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    Tissue Barriers.2024;[Epub]     CrossRef
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  • Dynamic changes in key factors of the blood-brain barrier in early diabetic mice
    Zhi-yong Xu, Shu-xian Fu, Hui-chao Zhao, Yin-min Wang, Yan Liu, Jin-you Ma, Yan Yu, Jia-Le Zhang, Zhan-peng Han, Ming-xue Zheng
    Journal of Neuropathology & Experimental Neurology.2024;[Epub]     CrossRef
  • The NG2-glia is a potential target to maintain the integrity of neurovascular unit after acute ischemic stroke
    Xiaoyan Hu, Panpan Geng, Xiaoyun Zhao, Qian Wang, Changqing Liu, Chun Guo, Wen Dong, Xinchun Jin
    Neurobiology of Disease.2023; 180: 106076.     CrossRef
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    Ma Ludivina Robles-Osorio, Ernesto Sabath
    World Journal of Diabetes.2023; 14(7): 1013.     CrossRef
  • Function and therapeutic value of astrocytes in diabetic cognitive impairment
    Fanyu Meng, Jiafeng Fu, Lin Zhang, Mengqing Guo, Pengwei Zhuang, Qingsheng Yin, Yanjun Zhang
    Neurochemistry International.2023; 169: 105591.     CrossRef
  • Exploring the Molecular Targets for Type 2 Diabetes-Induced Alzheimer’s Disease Through Bioinformatics Analysis
    Lin Gao, Chengyu Huang, Hui Li, Shidi Wu, Xiaoyan Zhou, Changjiang Ying
    Epigenomics.2023; 15(11): 619.     CrossRef
  • In vivo retinal imaging is associated with cognitive decline, blood-brain barrier disruption and neuroinflammation in type 2 diabetic mice
    May Majimbi, Samuel McLenachan, Michael Nesbit, Fred K. Chen, Virginie Lam, John Mamo, Ryu Takechi
    Frontiers in Endocrinology.2023;[Epub]     CrossRef
  • Diabetic microvascular disease in non-classical beds: the hidden impact beyond the retina, the kidney, and the peripheral nerves
    Dídac Mauricio, Mònica Gratacòs, Josep Franch-Nadal
    Cardiovascular Diabetology.2023;[Epub]     CrossRef
  • Transcranial photobiomodulation improves insulin therapy in diabetic microglial reactivity and the brain drainage system
    Shaojun Liu, Dongyu Li, Tingting Yu, Jingtan Zhu, Oxana Semyachkina-Glushkovskaya, Dan Zhu
    Communications Biology.2023;[Epub]     CrossRef
  • NG2‐glia crosstalk with microglia in health and disease
    Zuo Zhang, Xiaolong Li, Hongli Zhou, Jiyin Zhou
    CNS Neuroscience & Therapeutics.2022; 28(11): 1663.     CrossRef
  • Accelerated amyloid angiopathy and related vascular alterations in a mixed murine model of Alzheimer´s disease and type two diabetes
    Maria Vargas-Soria, Juan Jose Ramos-Rodriguez, Angel del Marco, Carmen Hierro-Bujalance, Maria Jose Carranza-Naval, Maria Calvo-Rodriguez, Susanne J. van Veluw, Alan W. Stitt, Rafael Simó, Brian J. Bacskai, Carmen Infante-Garcia, Monica Garcia-Alloza
    Fluids and Barriers of the CNS.2022;[Epub]     CrossRef
Original Articles
Association between Type 2 Diabetes Mellitus and Brain Atrophy: A Meta-Analysis
Tianqi Zhang, Marnie Shaw, Nicolas Cherbuin
Diabetes Metab J. 2022;46(5):781-802.   Published online March 8, 2022
  • 7,253 View
  • 305 Download
  • 15 Web of Science
  • 22 Crossref
AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Type 2 diabetes mellitus (T2DM) is known to be associated with cognitive decline and brain structural changes. This study systematically reviews and estimates human brain volumetric differences and atrophy associated with T2DM.
PubMed, PsycInfo and Cochrane Library were searched for brain imaging studies reporting on brain volume differences between individuals with T2DM and healthy controls. Data were examined using meta-analysis, and association between age, sex, diabetes characteristics and brain volumes were tested using meta-regression.
A total of 14,605 entries were identified; after title, abstract and full-text screening applying inclusion and exclusion criteria, 64 studies were included and 42 studies with compatible data contributed to the meta-analysis (n=31,630; mean age 71.0 years; 44.4% male; 26,942 control; 4,688 diabetes). Individuals with T2DM had significantly smaller total brain volume, total grey matter volume, total white matter volume and hippocampal volume (approximately 1% to 4%); meta-analyses of smaller samples focusing on other brain regions and brain atrophy rate in longitudinal investigations also indicated smaller brain volumes and greater brain atrophy associated with T2DM. Meta-regression suggests that diabetes-related brain volume differences start occurring in early adulthood, decreases with age and increases with diabetes duration.
T2DM is associated with smaller total and regional brain volume and greater atrophy over time. These effects are substantial and highlight an urgent need to develop interventions to reduce the risk of T2DM for brain health.


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  • Cognitive deficits among people with schizophrenia and prediabetes or diabetes
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    Frontiers in Neuroinformatics.2024;[Epub]     CrossRef
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    European Journal of Epidemiology.2024; 39(4): 409.     CrossRef
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  • Association between Type 2 Diabetes Mellitus and Brain Atrophy: A Meta-Analysis (Diabetes Metab J 2022;46:781-802)
    Tianqi Zhang, Marnie Shaw, Nicolas Cherbuin
    Diabetes & Metabolism Journal.2022; 46(5): 815.     CrossRef
  • Association between Type 2 Diabetes Mellitus and Brain Atrophy: A Meta-Analysis (Diabetes Metab J 2022;46:781-802)
    Se Hee Min
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Glucagon-Like Peptide-1 Receptor Agonist Differentially Affects Brain Activation in Response to Visual Food Cues in Lean and Obese Individuals with Type 2 Diabetes Mellitus
Jae Hyun Bae, Hyung Jin Choi, Kang Ik Kevin Cho, Lee Kyung Kim, Jun Soo Kwon, Young Min Cho
Diabetes Metab J. 2020;44(2):248-259.   Published online November 4, 2019
  • 8,054 View
  • 238 Download
  • 7 Web of Science
  • 8 Crossref
AbstractAbstract PDFSupplementary MaterialPubReader   

To investigate the effects of a glucagon-like peptide-1 receptor agonist on functional brain activation in lean and obese individuals with type 2 diabetes mellitus (T2DM) in response to visual food cues.


In a randomized, single-blinded, crossover study, 15 lean and 14 obese individuals with T2DM were administered lixisenatide or normal saline subcutaneously with a 1-week washout period. We evaluated brain activation in response to pictures of high-calorie food, low-calorie food, and nonfood using functional magnetic resonance imaging and measured appetite and caloric intake in participants who were given access to an ad libitum buffet.


Obese individuals with T2DM showed significantly greater activation of the hypothalamus, pineal gland, parietal cortex (high-calorie food vs. low-calorie food, P<0.05), orbitofrontal cortex (high-calorie food vs. nonfood, P<0.05), and visual cortex (food vs. nonfood, P<0.05) than lean individuals with T2DM. Lixisenatide injection significantly reduced the functional activation of the fusiform gyrus and lateral ventricle in obese individuals with T2DM compared with that in lean individuals with T2DM (nonfood vs. high-calorie food, P<0.05). In addition, in individuals who decreased their caloric intake after lixisenatide injection, there were significant interaction effects between group and treatment in the posterior cingulate, medial frontal cortex (high-calorie food vs. low-calorie food, P<0.05), hypothalamus, orbitofrontal cortex, and temporal lobe (food vs. nonfood, P<0.05).


Brain responses to visual food cues were different in lean and obese individuals with T2DM. In addition, acute administration of lixisenatide differentially affected functional brain activation in these individuals, especially in those who decreased their caloric intake after lixisenatide injection.


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