Diabetic Autonomic Neuropathy and Impaired Inflammatory Reflex

This is the authors' abstract. We don't add key points for this paper.

INTRODUCTION: Diabetes mellitus is increasingly recognised as a chronic metabolic-inflammatory disorder. Diabetic autonomic neuropathy (DAN) is a prevalent yet underdiagnosed complication associated with significant morbidity and mortality. Rather than acting solely as an end-stage downstream consequence of hyperglycemia, DAN may serve as an active driver of neuroimmune dysfunction by disrupting the inflammatory reflex and its efferent arm, the cholinergic anti-inflammatory pathway (CAP). METHODS: This review synthesises current preclinical and clinical literature examining the physiological architecture of the inflammatory reflex, the molecular mechanisms linking hyperglycemia-induced neurovascular damage to CAP failure (including α7 nicotinic acetylcholine receptor (α7nAChR) signalling), and diagnostic modalities (e.g., heart rate variability) used to evaluate autonomic-immune crosstalk. RESULTS: Evidence indicates that metabolic stress, oxidative damage, and microvascular ischemia compromise vagal structural integrity and suppress cholinergic anti-inflammatory signalling. This loss of autonomic restraint exacerbates systemic cytokine production (e.g., TNF-α, IL-6), establishing a self-perpetuating, bidirectional pathophysiological loop that accelerates both neural injury and end-organ complications. Emerging therapeutic strategies-such as exercise-induced autonomic reactivation, bioelectronic vagus nerve stimulation (VNS), and targeted α7nAChR agonists-demonstrate promising potential to interrupt this cycle and restore neuroimmune homeostasis. CONCLUSION: DAN represents a critical state of autonomic-mediated immune dysregulation rather than isolated neural damage. While causal mechanisms require further validation through prospective and interventional human trials, reframing DAN as a neuroimmune failure provides novel opportunities for precision phenotyping and targeted therapeutic interventions.