Diabetes-Associated Enteric Neuropathy: An Overlooked Driver of Gastrointestinal Dysfunction

Diabetes mellitus is frequently accompanied by gastrointestinal symptoms, but these symptoms are not fully explained by extrinsic autonomic neuropathy and should not be equated with a single enteric lesion. Human biopsy and motility studies, complemented by experimental models, indicate that the enteric nervous system (ENS) and its neuromuscular niche can be injured in segment- and cell-specific ways. Human evidence supports gastric changes in interstitial cells of Cajal (ICC) and macrophages, and colonic enteric neuronal loss associated with oxidative stress; plexus-resolved and repair mechanisms are derived mainly from animal or in vitro studies. Recurrently implicated pathways include redox imbalance, immune remodeling, impaired glial cell line-derived neurotrophic factor (GDNF)-phosphoinositide 3-kinase (PI3K)/Akt signaling, enteric glial stress, and microbiota-metabolite signaling. Myenteric injury is most directly linked to dysmotility, whereas submucosal injury may alter secretion, barrier function, and local neuroimmune control. Current care remains symptom-directed. Heme oxygenase-1, interleukin-10, neurotrophic rescue, nicotinamide riboside, 5-hydroxytryptamine 4 receptor agonism, microbiota-derived butyrate, and extracellular vesicles are investigational rather than established disease-modifying therapies. Segment-specific biomarkers and human translational models are needed to connect cellular injury with symptoms and treatment response.