Role of CCM3 in lead-induced neurological damage in diabetes

doi:10.4239/wjd.113938

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World Journal of Diabetes

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1948-9358

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

Basic Study

Copyright: ©Author(s) 2026. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution-NonCommercial (CC BY-NC 4.0) license. No commercial re-use. See permissions. Published by Baishideng Publishing Group Inc.

World J Diabetes. Aug 15, 2026; 17(8): 113938
Published online Aug 15, 2026. doi: 10.4239/wjd.113938

Role of CCM3 in lead-induced neurological damage in diabetes

Xu Liang, Liu-Xue Yang, Tao Tao, Wen-Jia Ding, Xin-Yi Tang, Zhi-Bin Shang, Hang Zhou, Yun He, Yi Sun

Xu Liang, Tao Tao, Wen-Jia Ding, Xin-Yi Tang, Zhi-Bin Shang, Hang Zhou, Yi Sun, Department of Toxicology, Guilin Medical University, Guilin 541199, Guangxi Zhuang Autonomous Region, China

Liu-Xue Yang, Department of Endocrinology, The Second Affiliated Hospital of Guilin Medical University, Guilin 541199, Guangxi Zhuang Autonomous Region, China

Yun He, School of Public Health, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China

Co-first authors: Xu Liang and Liu-Xue Yang.

Co-corresponding authors: Yun He and Yi Sun.

Author contributions: Liang X designed the methodology; Yang LX validated the study; Tao T and Ding WJ performed formal analysis; Shang ZB and Tang XY conducted animal experiments; Liang X and Sun Y wrote the original draft; Sun Y reviewed and edited the manuscript; Zhou H administered the project; He Y and Sun Y acquired funding. Liang X and Yang LX contributed equally to this work as co-first authors. Sun Y was a core contributor to manuscript drafting and funding acquisition. She co-authored the original draft with first author Liang X, systematically constructing the research framework, clarifying the correlation between CCM3 expression, lead exposure, diabetic status and neurological damage, and organizing experimental data and discussion content to lay a critical foundation for manuscript revision. Meanwhile, she led research grant applications to secure funding for key experiments. He Y also made indispensable contributions. She collaborated with Sun Y to apply for supplementary funds, resolving financial constraints for advanced detection and international collaboration. More importantly, she provided the specific transgenic mouse models essential for exploring CCM3’s regulatory mechanism in neurological damage under dual stress of diabetes and lead exposure. Without these models, key data and innovative findings could not have been achieved. Additionally, she established and coordinated long-term international partnerships, promoting cutting-edge technology exchange and data cross-validation to enhance the study’s scientific rigor and influence. Throughout the research, He Y and Sun Y maintained close collaboration, jointly participating in project design, critical decision-making, manuscript revision and response to reviewer comments. Their complementary and equally important contributions warrant their designation as co-corresponding authors, which is reasonable, fair and fully compliant with academic authorship standards.

Supported by Natural Science Foundation of Guangdong Province, No. 2023GXNSFAA026122 and No. 2025GXNSFHA069136; National Natural Science Foundation of China, No. 82060586; China Scholarship Council, No. 202208455012; and National Guangxi College Students Innovation and Entrepreneurship Training Program, No. S202410601154, No. S202410601162 and No. X202410601236.

Institutional review board statement: This study was reviewed and approved by the Ethics Committee of Guilin Medical University, No. GYLL2021074.

Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of Guilin Medical University.

Conflict-of-interest statement: The authors of this manuscript have no conflicts of interest to disclose.

ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.

Data sharing statement: No additional data are available.

Corresponding author: Yi Sun, Department of Toxicology, Guilin Medical University, No. 1 Zhiyuan Road, Lingui District, Guilin 541199, Guangxi Zhuang Autonomous Region, China. sunyide163@163.com

Received: September 7, 2025
Revised: November 15, 2025
Accepted: May 28, 2026
Published online: August 15, 2026
Processing time: 332 Days and 1.7 Hours

Abstract

BACKGROUND

China has the largest number of diabetes patients, and nerve injury is an important complication of diabetes. Lead is a residual environmental pollutant with neurotoxicity and endocrine effects.

AIM

To investigate the effects of lead exposure, diabetes, and CCM3 deficiency on neurovascular damage using CCM3^+/- diabetic mice exposed to lead and samples from diabetic patients. The study aims to elucidate the mechanisms by which lead exposure, diabetes, and CCM dysfunction contribute to neurovascular injury and to provide a theoretical foundation for the prevention and treatment of neurological disorders associated with diabetes, lead exposure, and CCM3 gene defects.

METHODS

Using a CCM3^+/- diabetic mouse model exposed to lead, the Morris water maze test was performed to evaluate the effects of lead exposure, blood glucose, and CCM3 deficiency on learning and memory. Neurovascular injury was assessed by immunofluorescence co-localization staining of neural and vascular markers. Differentially expressed proteins and associated signaling pathways were identified through proteomic analysis, and key findings were validated by Western blotting. Glutathione (GSH) levels were measured to assess alterations in these factors and related proteins and metabolite levels in the hippocampus. Lastly, urinary lead and neurotransmitter metabolites were measured using inductively coupled plasma mass spectrometry (ICP-MS) and high-performance liquid chromatography (HPLC), respectively. Single-nucleotide polymorphisms (SNPs) in the CCM3 gene were analyzed using kompetitive allele-specific PCR (KASP) genotyping.

RESULTS

Compared with the control group, CCM3^+/- mice exposed to lead showed the highest blood glucose and blood lead levels. Additionally, diabetic mice exposed to lead exhibited significantly increased escape latency (P = 0.003). The fluorescence intensity of glial fibrillary acidic protein staining was significantly lower in the lead-exposed group compared with that in the control group (P = 0.005). Proteomic analysis identified significant changes in AKT, and Western blotting results showed that PI3K and AKT expression significantly decreased in the lead-exposed group (P = 0.009; P = 0.007). GPX4 expression decreased in both the lead-exposed and diabetic groups (P < 0.001). GSH levels in the hippocampus of the lead-exposed group was lower than the control group (P < 0.001). Finally, in diabetic patients, urine lead levels were weakly but positively correlated with vanillylmandelic acid (VMA) (r_s = 0.426, P < 0.001) and homovanillic acid (HVA) (r_s = 0.410, P < 0.001) in both the low and high urine lead groups. Additionally, there was an interaction between urine lead, blood glucose, and the rs6784267 locus on VMA (F = 9.838, P < 0.001) and HVA (F = 4.788, P = 0.003).

CONCLUSION

In our study, lead exposure, diabetes and the CCM3 gene may jointly increase blood glucose and lead levels, thereby affecting both vascular and neural function, with neural damage occurring earlier than vascular damage. In this process, inhibition of the PI3K-AKT pathway appears to play a crucial regulatory role in ferroptosis. Furthermore, the interaction among urine lead levels, blood glucose, and the rs6784267 locus of the CCM3 SNP was confirmed in diabetic patients.

Keywords: CCM3; Lead; Diabetes; PI3K-AKT; Ferroptosis

Core Tip: Using a diabetic, CCM3-deficient mouse model with lead exposure, this study demonstrates that lead exposure, diabetes, and CCM3 deficiency synergistically increase blood glucose and lead levels, resulting in neural injury that precedes vascular damage. Lead triggers early neural impairment by inhibiting the PI3K-AKT signaling pathway and promoting ferroptosis, a mechanism distinct from glucose-related effects. Epidemiological analyses further confirm that interactions among urinary lead levels, blood glucose, and the CCM3 single-nucleotide polymorphism rs6784267 significantly influence the neurotransmitter metabolites vanillylmandelic acid and homovanillic acid, consistent with animal findings. Collectively, these results provide a scientific basis for the prevention of early neural damage involving environmental, metabolic, and genetic factors.