Brain-Body Crosstalk in T2DM: An Integrative Framework from Central Sensing to Peripheral Feedback.

Brain-body crosstalk describes the dynamic and bidirectional interactions between the central nervous system and peripheral organs, whereby the brain regulates systemic physiology while peripheral signals reciprocally influence central function. The pathophysiology of type 2 diabetes mellitus (T2DM) has expanded beyond peripheral insulin resistance to encompass dysregulated bidirectional communication between the central nervous system and peripheral organs. Despite growing recognition of brain-body crosstalk in T2DM, existing studies have largely examined individual pathways in isolation, limiting an integrated understanding of neuro-metabolic regulation. Here, we conceptualize brain-body crosstalk as a hierarchical yet reciprocal network comprising central sensing and integration, peripheral execution, and feedback regulation, and further frame its disruption in T2DM as a self-reinforcing cascade of dysregulation. We systematically examine how central neural circuits modulate peripheral organs via autonomic and neuroendocrine outputs, and how peripheral metabolic, immune, and microbial signals feedback to reshape central function. Building on this integrative framework, we critically assess emerging neuromodulation strategies and highlight key unresolved questions. This framework positions T2DM as a disorder of progressively destabilized brain-body homeostasis and identifies critical points at which this pathological feedback loop may be therapeutically interrupted.