An update on chronic complications of diabetes mellitus: from molecular mechanisms to therapeutic strategies with a focus on metabolic memory

Abstract

Diabetes mellitus, a chronic metabolic disease, often leads to numerous chronic complications, significantly contributing to global morbidity and mortality rates. High glucose levels trigger epigenetic modifications linked to pathophysiological processes like inflammation, immunity, oxidative stress, mitochondrial dysfunction, senescence and various kinds of cell death. Despite glycemic control, transient hyperglycemia can persistently harm organs, tissues, and cells, a latent effect termed "metabolic memory" that contributes to chronic diabetic complications. Understanding metabolic memory's mechanisms could offer a new approach to mitigating these complications. However, key molecules and networks underlying metabolic memory remain incompletely understood. This review traces the history of metabolic memory research, highlights its key features, discusses recent molecules involved in its mechanisms, and summarizes confirmed and potential therapeutic compounds. Additionally, we outline in vitro and in vivo models of metabolic memory. We hope this work will inform future research on metabolic memory's regulatory mechanisms and facilitate the development of effective therapeutic compounds to prevent diabetic complications.

Keywords: Diabetic complications; Metabolic memory; Models of metabolic memory; Molecular mechanisms; Treatment progress.

Fig. 1

Overview of metabolic memory. A Chronological depiction of key events in the development of metabolic memory. B, C Bibliometric analysis exploring the intersection of metabolic memory and diabetic complications. Search criteria were set as follows: TS = ((“metabolic memory” OR “hyperglycemic memory”) AND (“diabetes” OR “diabetic”)) with a date range of DOP = (2013–08-01/2023–08-01). B Illustration of the annual trend in the number of published articles. C Clustered view of the key terms and concepts emerging from the literature

Fig. 2

Key molecular mechanisms of metabolic memory. Despite the normalization of glucose levels, epigenetic modifications, inflammatory and immune responses, oxidative stress, mitochondrial dysfunction, cellular senescence, and apoptosis persist. These processes constitute the core molecular mechanisms underlying metabolic memory. ncRNAs noncoding RNAs, TXNIP thioredoxin-interacting protein, me-TXNIP thioredoxin-interacting protein, IL-6 interleukin-6, MCP-1 monocyte chemotactic protein 1, H3K9me3 trimethylated histone H3 at lysine 9, ROS reactive oxygen species

Fig. 3

Metabolic memory and chronic complications of diabetes. Hyperglycemia can trigger a range of diabetic complications, including diabetic cardiomyopathy, diabetic arterial vascular disease, diabetic kidney disease, diabetic retinopathy, and diabetic foot. This figure illustrates the intricate relationship between metabolic memory and these chronic conditions