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

## TL;DR

This review explores how heat stress and protein misfolding contribute to diabetes, highlighting potential new therapeutic strategies involving heat therapy and heat shock proteins.

## Contribution

The paper integrates insights on heat shock proteins, amylin misfolding, and heat therapy as novel therapeutic targets in diabetes.

## Key findings

- Heat shock proteins play a key role in both type 1 and type 2 diabetes by linking β-cell stress and immune responses.
- Amylin misfolding contributes to β-cell death in type 2 diabetes and may influence autoimmunity in type 1 diabetes.
- Thermal interventions can improve glycemic control and insulin sensitivity, offering benefits similar to exercise.

## Abstract

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.