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Diabetic autonomic neuropathy (DAN) is a prevalent yet underdiagnosed complication associated with significant morbidity and mortality. Rather than acting solely as an end\u2010stage 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\u2010inflammatory pathway (CAP).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This review synthesises current preclinical and clinical literature examining the physiological architecture of the inflammatory reflex, the molecular mechanisms linking hyperglycemia\u2010induced neurovascular damage to CAP failure (including \u03b17 nicotinic acetylcholine receptor (\u03b17nAChR) signalling), and diagnostic modalities (e.g., heart rate variability) used to evaluate autonomic\u2010immune crosstalk.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Evidence indicates that metabolic stress, oxidative damage, and microvascular ischemia compromise vagal structural integrity and suppress cholinergic anti\u2010inflammatory signalling. This loss of autonomic restraint exacerbates systemic cytokine production (e.g., TNF\u2010\u03b1, IL\u20106), establishing a self\u2010perpetuating, bidirectional pathophysiological loop that accelerates both neural injury and end\u2010organ complications. Emerging therapeutic strategies\u2014such as exercise\u2010induced autonomic reactivation, bioelectronic vagus nerve stimulation (VNS), and targeted \u03b17nAChR agonists\u2014demonstrate promising potential to interrupt this cycle and restore neuroimmune homeostasis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>DAN represents a critical state of autonomic\u2010mediated 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/edm2.70349","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T04:51:42Z","timestamp":1791521502000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Diabetic Autonomic Neuropathy and Impaired Inflammatory Reflex"],"prefix":"10.1002","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6414-4036","authenticated-orcid":false,"given":"Narges","family":"Dastmalchi","sequence":"first","affiliation":[{"name":"Stem Cell Research Center Tabriz University of Medical Sciences  Tabriz 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