Epigenetic and environmental factors and their impact on β-cell function and insulin action

Abstract

The progression from normoglycemia to prediabetes (PD) and type 2 diabetes (T2D) results from the dynamic interaction between genetic predisposition and environmental factors, with epigenetic modifications representing a key mechanistic link between both. These modifications regulate gene expression without altering the DNA sequence, enabling stimuli such as nutritional excess, physical inactivity, aging, and chronic inflammation to coordinately influence both pancreatic β-cell function and insulin action in peripheral tissues.

During the early stages of insulin resistance (IR), maintenance of normoglycemia depends on an adaptive β-cell response characterized by increased insulin secretion accompanied by transcriptomic and epigenetic remodeling. Emerging evidence indicates that part of this epigenetic remodeling represents a physiological adaptive mechanism aimed at preserving glucose homeostasis in response to increased metabolic demand. However, prolonged exposure to glucotoxicity, lipotoxicity, and chronic inflammation eventually overwhelms these compensatory mechanisms, leading to progressive loss of β-cell identity and function, thereby promoting the transition to PD and T2D.

Concurrently, the metabolic environment induces epigenetic modifications in muscle, liver, and adipose tissue that alter the expression of genes involved in insulin signaling, energy metabolism, and inflammatory pathways, thereby contributing to the persistence of IR. PD should therefore be viewed as the consequence of coordinated epigenetic remodeling that affects both the secretory capacity of pancreatic islets and the responsiveness of peripheral tissues to insulin.

Recent advances in transcriptomics, epigenomics, and single-cell sequencing technologies have revealed remarkable functional heterogeneity among β-cells and demonstrated that islet dysfunction involves dynamic transitions between distinct cellular states rather than simply reflecting irreversible β-cell loss.

Understanding the major epigenetic mechanisms linking environmental factors to β-cell function and insulin action is therefore essential for elucidating the pathophysiology of PD and for highlighting the potential of multi-omics approaches to identify early biomarkers and novel therapeutic targets.