Immune Memory in Diabetes: Recent discoveries and clinical implications

Abstract

Abstract

Diabetes mellitus (DM) is a complex immunometabolic disorder characterized not only by chronic hyperglycemia but also by persistent immune dysregulation that contributes to chronic inflammation, impaired host defense, and the development of microvascular and macrovascular complications. Increasing evidence indicates that long-term immune alterations persist despite adequate glycemic control, highlighting the importance of immune memory in disease progression. Recent advances have demonstrated that immune memory extends beyond adaptive immunity to include trained immunity, whereby innate immune cells undergo durable metabolic and epigenetic reprogramming, resulting in enhanced inflammatory responses upon subsequent stimulation. This review summarizes current knowledge regarding the mechanisms of innate and adaptive immune memory in diabetes, emphasizing the interplay between trained immunity, metabolic memory, epigenetic regulation, and immunometabolism. It also discusses how chronic hyperglycemia reshapes immune-cell function through alterations in glycolysis, mitochondrial metabolism, histone modifications, chromatin remodeling, and inflammatory signaling pathways. Furthermore, recent discoveries obtained through single-cell transcriptomics, epigenomics, metabolomics, and other multi-omics technologies are highlighted, together with their potential applications in biomarker discovery, disease monitoring, and precision medicine. The review also examines the role of the gut microbiota in modulating immune memory and discusses emerging therapeutic approaches, including antigen-specific immunotherapy, cytokine-targeted therapies, metabolic and epigenetic interventions, microbiota-based strategies, and nanoparticle-mediated drug delivery systems. Finally, current challenges, knowledge gaps, and future research priorities are addressed. A better understanding of immune memory is expected to facilitate the development of personalized immunotherapeutic strategies that restore immune homeostasis, reduce chronic inflammation, prevent diabetic complications, and improve long-term clinical outcomes in individuals with diabetes.