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已发表论文
糖尿病多发性神经病变中的脂质转运蛋白 ABCA1：循环代谢物的潜在介导作用
Authors Cao Y , Pan Y, Yan Y, Yao Y, Lu S, Gei L, Jiang W, Zeng W, Chen D
Received 21 April 2025
Accepted for publication 22 September 2025
Published 6 October 2025 Volume 2025:18 Pages 5203—5222
DOI https://doi.org/10.2147/JPR.S535866
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Professor Michael A Ueberall
Yan Cao,1,2,* Yuyan Pan,1,* Yan Yan,3,* Yichen Yao,1 Simin Lu,1 Liba Gei,4 Wenqi Jiang,1 Weian Zeng,1 Dongtai Chen1
1Department of Anesthesiology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China; 2Department of Endocrinology, First Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China; 3Department of Anesthesiology, Huizhou Municipal Central Hospital, Huizhou, 516001, People’s Republic of China; 4Department of Anesthesiology, Peking University Cancer Hospital (Inner Mongolia Campus)/Affiliated Cancer Hospital of Inner Mongolia Medical University/Inner Mongolia Autonomous Region Cancer Hospital, Hohhot, 010010, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Weian Zeng, Department of Anesthesiology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University, Cancer Center, Guangzhou, 510060, People’s Republic of China, Email zengwa@mail.sysu.edu.cn Dongtai Chen, Department of Anesthesiology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University, Cancer Center, Guangzhou, 510060, People’s Republic of China, Email chendt@sysucc.org.cn
Background: Diabetic polyneuropathy (DPN) is a complication of diabetes characterized by peripheral sensory deficits or neuropathic pain. Emerging evidence suggests that DPN is associated with dyslipidemia. Probucol has shown promise in the treatment of diabetes and alleviation of neuropathic pain. However, the influence of probucol on DPN or dyslipidemia incidence is unclear. The study examined the mediating effects of circulating metabolites on the relationship between probucol target gene ATP-binding cassette subfamily A member 1 (ABCA1) and DPN.
Methods: A positive control analysis was done on low density lipoprotein (LDL) to validate genetic instruments. A two-step Mendelian randomization (MR) study was conducted to assess the correlation between the probucol target gene ABCA1 and DPN, focusing on the mediation effects of circulating metabolites connecting them. MR analysis was mainly estimated using Inverse-variance weighted (IVW) and MR-Egger regression conducting SNP heterogeneity and sensitivity analysis.
Results: Predicted based on genetics, the ABCA1 gene is associated with increased risk of LDL and four circulating metabolites. The direct effect of the Probucol target gene ABCA1 on DPN was 0.3006, and the mean diameter for high-density lipoprotein (HDL) particles, total cholesterol in medium LDL, triglycerides in medium very low-density lipoprotein (VLDL), and free cholesterol in very large HDL had partial mediating effects on the association between ABCA1 and DPN incidence.
Conclusion: This study supports an association between genetically predicted Probucol target ABCA1, circulating metabolites, and DPN. Our observations indicate a direct effect of ABCA1 on DPN and a mediating pathway through four blood circulation metabolites. Our findings offer genetic evidence for the mechanisms of Probucol in preventing, alleviating, and treating DPN pain.
Keywords: diabetic polyneuropathy, probucol, ATP-binding cassette subfamily A member 1, circulating metabolites, mendelian randomization
1Department of Anesthesiology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China; 2Department of Endocrinology, First Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China; 3Department of Anesthesiology, Huizhou Municipal Central Hospital, Huizhou, 516001, People’s Republic of China; 4Department of Anesthesiology, Peking University Cancer Hospital (Inner Mongolia Campus)/Affiliated Cancer Hospital of Inner Mongolia Medical University/Inner Mongolia Autonomous Region Cancer Hospital, Hohhot, 010010, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Weian Zeng, Department of Anesthesiology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University, Cancer Center, Guangzhou, 510060, People’s Republic of China, Email zengwa@mail.sysu.edu.cn Dongtai Chen, Department of Anesthesiology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University, Cancer Center, Guangzhou, 510060, People’s Republic of China, Email chendt@sysucc.org.cn
Background: Diabetic polyneuropathy (DPN) is a complication of diabetes characterized by peripheral sensory deficits or neuropathic pain. Emerging evidence suggests that DPN is associated with dyslipidemia. Probucol has shown promise in the treatment of diabetes and alleviation of neuropathic pain. However, the influence of probucol on DPN or dyslipidemia incidence is unclear. The study examined the mediating effects of circulating metabolites on the relationship between probucol target gene ATP-binding cassette subfamily A member 1 (ABCA1) and DPN.
Methods: A positive control analysis was done on low density lipoprotein (LDL) to validate genetic instruments. A two-step Mendelian randomization (MR) study was conducted to assess the correlation between the probucol target gene ABCA1 and DPN, focusing on the mediation effects of circulating metabolites connecting them. MR analysis was mainly estimated using Inverse-variance weighted (IVW) and MR-Egger regression conducting SNP heterogeneity and sensitivity analysis.
Results: Predicted based on genetics, the ABCA1 gene is associated with increased risk of LDL and four circulating metabolites. The direct effect of the Probucol target gene ABCA1 on DPN was 0.3006, and the mean diameter for high-density lipoprotein (HDL) particles, total cholesterol in medium LDL, triglycerides in medium very low-density lipoprotein (VLDL), and free cholesterol in very large HDL had partial mediating effects on the association between ABCA1 and DPN incidence.
Conclusion: This study supports an association between genetically predicted Probucol target ABCA1, circulating metabolites, and DPN. Our observations indicate a direct effect of ABCA1 on DPN and a mediating pathway through four blood circulation metabolites. Our findings offer genetic evidence for the mechanisms of Probucol in preventing, alleviating, and treating DPN pain.
Keywords: diabetic polyneuropathy, probucol, ATP-binding cassette subfamily A member 1, circulating metabolites, mendelian randomization