玛扎鲁肽，一种靶向胰高血糖素样肽-1受体（GLP-1R）和胰高血糖素受体（GCGR）的双重激动剂，可减轻糖尿病相关的认知功能障碍：多组学分析的机制见解

Mazdutide, a dual agonist targeting GLP-1R and GCGR, mitigates diabetes-associated cognitive dysfunction: mechanistic insights from multi-omics analysis.

作者信息

Dong Wanqing, Bai Jie, Yuan Qibin, Zhang Yingyu, Zhang Yongjiang, Zhang Ziyue, Yang Maoxing, Li Hanxiao, Zhao Ziyue, Jiang Hongwei

机构信息

The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, China; Luoyang Key Laboratory of Clinical Multiomics and Translational Medicine, Luoyang, 471003, China; Key Laboratory of Hereditary Rare Diseases of Health Commission of Henan Province, Luoyang, 471003, China; Henan Key Laboratory of Rare Diseases, Luoyang, 471003, China; Endocrinology and Metabolism Center, Luoyang, 471003, China.

State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, 300000, China; Frontiers Science Center for Cell Responses, Nankai University, Tianjin, 300000, China; College of Pharmacy, Nankai University, Tianjin, 300000, China.

出版信息

EBioMedicine. 2025 Jun 5;117:105791. doi: 10.1016/j.ebiom.2025.105791.

DOI:10.1016/j.ebiom.2025.105791

PMID:40479843

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12205698/

Abstract

BACKGROUND

Cognitive impairment and dementia are highly associated with obesity and type 2 diabetes mellitus (T2DM). Recent studies have demonstrated that GLP-1 receptor agonists can improve cognitive function through brain activation in patients with T2DM, compared to other oral glucose-lowering drugs. Mazdutide, a dual agonist of the glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR), has been shown to simultaneously reduce body weight, blood glucose levels, and other comorbidities associated with obesity in patients with T2DM. While its insulinotropic and glucose-lowering effects through the GLP-1 pathway are well-established, mazdutide may also enhance energy expenditure via activation of the GCGR pathway. However, its potential impact on cognitive function remains to be elucidated.

METHODS

This study aimed to investigate the effects of mazdutide on cognitive behaviour and cerebral pathology in male db/db mice, a model of T2DM, in comparison to dulaglutide, a GLP-1 receptor agonist. All animal findings are applicable to male mice only. Behavioural tests were conducted to evaluate cognitive function, and pathological analyses were performed to assess neurodegenerative markers in the brain. Furthermore, transcriptomic, proteomic, and metabolomics analyses were employed to explore the underlying molecular mechanisms of mazdutide's effects.

FINDINGS

Compared to dulaglutide, mazdutide significantly improved cognitive performance in db/db mice, as evidenced by comprehensive behavioural tests. Pathological assessments revealed improvements in neuronal structure and brain tissue integrity in the mazdutide-treated group. Multi-omics analyses further identified distinct molecular pathways involved in neuroprotection, energy metabolism, and synaptic plasticity, suggesting that dual GLP-1/GCGR activation contributes to enhanced cognitive resilience.

INTERPRETATION

Our findings indicate that mazdutide, via its dual GLP-1/GCGR activation effects, exerts multifactorial improvements in cognitive function in the context of obesity and T2DM. These results suggest that mazdutide is a promising therapeutic option for mitigating cognitive deficits associated with metabolic disorders.

FUNDING

Medical Science and Technology Research and Development Plan Major Project Jointly Constructed by the Henan Province and Ministerial Departments in China (No. SBGJ202301010).

摘要

背景

认知障碍和痴呆与肥胖及2型糖尿病（T2DM）高度相关。最近的研究表明，与其他口服降糖药相比，胰高血糖素样肽-1受体激动剂（GLP-1受体激动剂）可通过激活大脑改善T2DM患者的认知功能。司马鲁肽是一种胰高血糖素样肽-1受体（GLP-1R）和胰高血糖素受体（GCGR）的双重激动剂，已被证明可同时降低T2DM患者的体重、血糖水平以及与肥胖相关的其他合并症。虽然其通过GLP-1途径的促胰岛素分泌和降糖作用已得到充分证实，但司马鲁肽也可能通过激活GCGR途径增加能量消耗。然而，其对认知功能的潜在影响仍有待阐明。