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Unlocking pancreatic metabolic memory: Can early interventions reverse obesity and block diabetes before it strikes?
Yu-Jue Wang, Shuai-Yan Wang, Zi-Mu Li, Meng-Ying Zhao, Mo Zhou, Cong-Yi Xie, Jin-Ai Wang, Bin Xu, Guan-Hu Yang, Yun Liu, Tian-Cheng Xu
Yu-Jue Wang, Shuai-Yan Wang, Zi-Mu Li, Mo Zhou, Cong-Yi Xie, Bin Xu, Yun Liu, Tian-Cheng Xu, Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
Meng-Ying Zhao, College of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
Jin-Ai Wang, Nanjing University of Chinese Medicine, School of Acupuncture and Tuina, School of Health and Rehabilitation, Nanjing 210023, Jiangsu Province, China
Guan-Hu Yang, Department of Specialty Medicine, Ohio University, Athens, OH 45701, United States
Guan-Hu Yang, Faculty of Chinese Medicine, Macau University of Science and Technology, Macao 999078, China
Co-first authors: Yu-Jue Wang and Shuai-Yan Wang.
Co-corresponding authors: Yun Liu and Tian-Cheng Xu.
Author contributions: Wang YJ, Wang SY, Li ZM, and Zhao MY wrote the first draft of the manuscript; Wang YJ and Wang SY contributed equally to this article, they are the co-first authors of this manuscript; Zhou M and Xie CY responsible for drafting and organizing the forms; Wang JA responsible for graphical abstract; Xu B, Yang GH, and Xu TC reviewed the manuscript and critically revised it for important intellectual content; Liu Y and Xu TC were responsible for the idea and conceptual framework, they contributed equally to this article, they are the co-corresponding authors of this manuscript; and all authors have reviewed and approved the final version of the manuscript.
Supported by the National Natural Science Foundation of China Youth Science Fund Project, No. 82305376; the Young Talent Support Program of the China Association for Acupuncture-Moxibustion, No. 2024-2026ZGZJXH-QNRC005; the 2024 Jiangsu Provincial Young Scientific and Technological Talent Support Program, No. JSTJ-2024-380; and Talent Cultivation Program for Young Researchers, Key Laboratory of the Ministry of Education Project, No. Zyqt202501 and No. Zyqt202503.
AI contribution statement: AI tools (Doubao) were used solely for linguistic refinement and formatting assistance. It should be clearly stated that no AI-generated writing content was used throughout the entire writing and revision process.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Corresponding author: Tian-Cheng Xu, Associate Professor, Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, No. 138 Xianlin Avenue, Qixia District, Nanjing 210023, Jiangsu Province, China.
xtc@njucm.edu.cn
Received: January 12, 2026
Revised: February 13, 2026
Accepted: March 17, 2026
Published online: May 15, 2026
Processing time: 121 Days and 20.5 Hours
This article synthesizes current evidence to elucidate the role of pancreatic macrophage metabolic memory in linking obesity to type 2 diabetes. Through an integrated analysis of recent studies, we describe how metabolic stress reprograms pancreatic macrophages toward a spectrum of inflammatory phenotypes and establishes persistent memory via epigenetic and exosomal pathways. This memory sustains pro-inflammatory signaling even after metabolic insults cease, leading to impaired β-cell function and dedifferentiation through altered transcriptional regulation and paracrine communication. We conclude that targeting this macrophage memory axis offers a promising therapeutic strategy, with interventions such as exercise, natural products, and epigenetic modulators showing potential to reverse maladaptive polarization. Future research using single-cell omics will be essential to decode macrophage heterogeneity and advance memory-targeted therapies. During the transition from obesity to type 2 diabetes, the islets are often accompanied by persistent inflammation. The metabolic memory formed by pancreatic macrophages may be the core cell-intrinsic mechanism underlying the long-term maintenance of this phenomenon. That is, macrophages, through epigenetic reprogramming, “remember” prior metabolic stress. Even after the external stimuli subside, their pro-inflammatory phenotype continues to be sustained, thereby driving the macroscopically observed state of persistent inflammation. These two phenomena constitute a causal relationship. This concept is distinct from classical “trained immunity”, which refers to the enhanced response of immune cells to a heterologous secondary stimulus, focusing on the boosting of defensive functions. This study primarily utilized the PubMed database for retrieval, employing keywords such as “pancreas”, “metabolic memory” and “macrophage” for subject term searches. It screened for mechanism-based articles and review papers concerning metabolic memory in pancreatic macrophages.
Core Tip: Sustained exposure of pancreatic macrophages to metabolic stress (e.g., obesity, type 2 diabetes) triggers epigenetic reprogramming, leading to the establishment of a persistent “metabolic memory”. This memory maintains chronic local inflammation in the pancreas even after external stimuli subside, resulting in continuous deterioration of β-cell function and thereby driving the progression of type 2 diabetes. Targeting this maladaptive memory through lifestyle interventions or epigenetic modulators represents a highly promising early intervention strategy to halt the disease progression.
