Diabetes, Protein Misfolding, and Heat Stress: Molecular Insights and Translational Perspectives.

Diabetes mellitus (DM), particularly type 1 (T1D) and type 2 (T2D), is a growing global health burden with complex pathophysiology extending beyond glucose dysregulation. Both forms of diabetes involve cellular stress, chronic inflammation, and β-cell dysfunction. Heat shock proteins (HSPs), key mediators of protein homeostasis and immune modulation, are emerging as critical players in the progression and complications of diabetes. In T1D, HSPs act at the crossroads of β-cell stress and autoimmunity, while in T2D, their dysregulation contributes to insulin resistance and mitochondrial dysfunction. Misfolded proteins, particularly amylin aggregates, further drive β-cell apoptosis in T2D and may influence immune activation in T1D. Hyperthermia (HT) and passive heat therapy (hT) activate protective stress responses through HSP induction, mimicking some benefits of exercise and improving glycemic control, insulin sensitivity, and vascular health. Preclinical and early clinical studies suggest that thermal interventions could complement standard care, especially in patients unable to engage in regular physical activity. This review consolidates current evidence on the roles of HSPs, amylin misfolding, and hT in the pathogenesis of diabetes, with a particular emphasis on vascular and thrombotic complications and their therapeutic implications. Targeting these converging molecular pathways may offer new avenues for preserving β-cell function, mitigating metabolic complications, and enhancing diabetes management.