DAN is a serious and frequently underrecognized complication of both type 1 and type 2 diabetes. It can involve the sympathetic and parasympathetic arms of the autonomic nervous system and may affect cardiovascular, gastrointestinal, genitourinary and sudomotor function. Its most extensively studied form, cardiac autonomic neuropathy, impairs cardiovascular control and manifests as resting tachycardia, exercise intolerance, reduced heart rate variability, baroreflex dysfunction and orthostatic hypotension, while raising the risk of arrhythmias and silent myocardial ischemia. The condition is closely tied to disease duration, metabolic control and the presence of other microvascular complications, and it is strongly associated with cardiovascular mortality, impaired quality of life and progressive end-organ dysfunction.

Crucially, the review highlights that parasympathetic dysfunction often appears earlier than sympathetic impairment. Reductions in heart rate variability, or HRV, the beat-to-beat variation in heart rhythm that serves as a noninvasive index of vagal tone, are considered one of the earliest detectable markers of cardiac autonomic neuropathy, often identified in patients with subclinical disease before overt autonomic symptoms become apparent. Because the vagus nerve plays a central role in autonomic regulation, this early parasympathetic withdrawal may have physiological consequences that extend well beyond cardiovascular control, potentially weakening the nervous system’s ability to restrain immune responses throughout the body.

The pathogenesis of DAN is multifactorial. Chronic hyperglycemia activates a cascade of biochemical pathways that injure neurons, including the polyol pathway, the accumulation of advanced glycation end-products, activation of protein kinase C and increased flux through the hexosamine pathway. These metabolic disturbances promote oxidative and nitrosative stress, mitochondrial dysfunction and abnormal intracellular signalling, ultimately causing structural and functional damage to autonomic nerve fibres. In parallel, diabetes sustains a state of chronic low-grade systemic inflammation, characterised by elevated levels of tumour necrosis factor-alpha, interleukin-6 and C-reactive protein, which can further damage neurons through oxidative stress, endothelial dysfunction and direct neurotoxic effects.

The inflammatory reflex, the circuit at the heart of the new hypothesis, is a neuroimmune regulatory loop through which the nervous system detects inflammatory signals and modulates immune activity. It functions much like other homeostatic reflexes: afferent fibres of the vagus nerve sense peripheral inflammatory signals, including cytokines, pathogen-associated molecular patterns and damage-associated molecular patterns, and transmit them to the brainstem, where they are integrated in nuclei such as the nucleus tractus solitarius. The efferent arm then engages the cholinergic anti-inflammatory pathway, or CAP, in which acetylcholine-mediated signalling inhibits the release of pro-inflammatory cytokines from immune cells, providing what researchers describe as a neural brake on inflammation.

A central component of this pathway is the interaction between acetylcholine and nicotinic acetylcholine receptors expressed on immune cells, particularly the alpha-7 nicotinic acetylcholine receptor found on macrophages. Experimental studies have shown that activation of these receptors inhibits nuclear factor-kappa-B signalling and suppresses the production of TNF-alpha, interleukin-6 and interleukin-1 beta. Although the precise anatomical and cellular intermediaries of the pathway remain an area of active investigation, and the afferent arm has been most robustly demonstrated in preclinical animal models, the functional role of cholinergic signalling in restraining immune responses is well supported by experimental and translational research.

The review argues that DAN compromises this circuit at multiple levels. Structural degeneration of vagal fibres, driven by hyperglycemia, oxidative stress and the accumulation of advanced glycation end-products, reduces the anatomical continuity the reflex depends on. Microvascular disease compounds the problem: remodelling of the vasa nervorum, the small vessels supplying the nerves, thickens basement membranes and limits perfusion and oxygenation, producing ischemic injury that accelerates fibre loss. As the functional density of vagal efferents declines, the capacity of efferent signalling to reach immune organs such as the spleen and liver is impaired, effectively disconnecting the central nervous system from its role in managing immune responses.

The disruption may also occur at the level of the immune cells themselves. In the chronic pro-inflammatory environment of diabetes, macrophages and monocytes become primed toward a pro-inflammatory phenotype, a bias that reduced vagal tone can no longer adequately counterbalance. Moreover, experimental data indicate that hyperglycemia and oxidative stress can modify the expression or functional sensitivity of macrophage nicotinic acetylcholine receptors, including the alpha-7 receptor, potentially reducing cholinergic suppression of cytokine release. In other words, even the anti-inflammatory signals that do get transmitted may be received by unresponsive cells, a phenomenon the authors characterise as a form of cholinergic resistance, though human evidence on receptor sensitivity in diabetes remains scarce. The result is a proposed bidirectional vicious cycle in which inflammation damages autonomic nerves, while autonomic failure removes the neural restraint on inflammation.

Translating this framework into the clinic, the authors suggest that assessment should move beyond isolated organ dysfunction toward evaluation of the neuroimmune axis as a whole. Standard cardiovascular autonomic reflex tests, including heart rate responses to deep breathing, the Valsalva manoeuvre and orthostatic challenge, remain the diagnostic reference for cardiac autonomic neuropathy, while HRV analysis offers a noninvasive index of vagal tone. These measures could be paired with circulating inflammatory markers such as TNF-alpha, interleukin-6 and interleukin-1 beta, so that the combination of reduced HRV and elevated cytokines serves as an initial indicator of neuroimmune dissociation. Direct evaluation of reflex integrity, including cholinergic signalling capacity and receptor function, remains confined to research settings for now.

Therapeutically, the review points toward a shift from symptomatic relief to the restoration of neuroimmune homeostasis. Strict glycemic control remains the cornerstone for preventing further nerve degeneration, but agents with pleiotropic effects are attracting growing interest. Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors have been shown to attenuate systemic inflammation, reduce oxidative stress and improve HRV, while metformin’s activation of AMPK offers anti-inflammatory and microvascular benefits. Lifestyle interventions such as regular physical activity can enhance HRV and endogenous anti-inflammatory capacity, and investigational approaches including vagus nerve stimulation and alpha-7 receptor agonists may eventually allow direct manipulation of the inflammatory reflex, though their application to diabetic autonomic neuropathy remains largely experimental.

The authors are careful to emphasise that the human evidence linking autonomic dysfunction with systemic inflammation is largely observational and correlational. It remains difficult to determine whether impaired autonomic regulation contributes to sustained inflammation or whether both phenomena arise in parallel as independent manifestations of metabolic injury. Future research priorities include longitudinal studies with dynamic modelling to establish temporal relationships, better biomarkers that capture the specific efferent capacity of the cholinergic pathway, stratified analyses accounting for differences between type 1 and type 2 diabetes and comorbidities such as hypertension and chronic kidney disease, and characterisation of alpha-7 receptor expression and signalling on immune cells from diabetic patients. Ultimately, randomised controlled trials testing whether restoring autonomic function reduces inflammatory burden and mitigates microvascular complications will determine whether the inflammatory reflex is a genuinely modifiable therapeutic target.

If validated, the implications would be considerable. Reframing diabetic autonomic neuropathy as a state of autonomic-mediated immune dysregulation suggests that current strategies prioritising glycemic regulation, while necessary, may be insufficient, and that optimal management must eventually address the restoration of the cholinergic anti-inflammatory pathway. By converging diabetology, neurology and immunology, this framework opens a potential path toward precision-medicine approaches that move beyond managing symptomatic decline toward the proactive preservation of autonomic and inflammatory balance in people living with diabetes.

Subject of Research: Diabetic autonomic neuropathy and impairment of the cholinergic anti-inflammatory reflex

Article Title: Diabetic Autonomic Neuropathy and Impaired Inflammatory Reflex

Article References: Dastmalchi, N., Doustvandi, M. A., Rahbarghazi, R., & Hajiasgharzadeh, K. (2026). Diabetic Autonomic Neuropathy and Impaired Inflammatory Reflex. Endocrinology, Diabetes & Metabolism, 9(6), Article e70349. https://doi.org/10.1002/edm2.70349

Image Credits: AI Generated

DOI: 10.1002/edm2.70349

Keywords: diabetic autonomic neuropathy, inflammatory reflex, cholinergic anti-inflammatory pathway, vagus nerve, heart rate variability, alpha-7 nicotinic acetylcholine receptor, chronic inflammation, hyperglycemia, oxidative stress, microvascular injury, cytokines, neuroimmune dysregulation

The commentary, authored by Lotte Habermann-Horstmeier of the Villingen Institute of Public Health in Germany, does not present new experimental data. Instead, it offers something arguably more valuable at this stage of the field: a structured, testable framework. Drawing on a targeted synthesis of literature from PubMed and Web of Science, the author sorts evidence into three categories—direct SLE findings, findings from ME/CFS research, and cross-condition mechanistic inference—and insists that these be kept rigorously separate. The result is a hypothesis-generating proposal for an SLE–ME/CFS research phenotype, a defined subgroup of lupus patients whose symptoms persist for at least six months, worsen after exertion, and include unrefreshing sleep, cognitive symptoms, or orthostatic intolerance, once alternative explanations and comorbidities have been systematically excluded.

The clinical rationale for such a phenotype rests on a well-documented gap between conventional disease measures and patient experience. In lupus, indices of inflammatory activity often normalize under treatment, yet patient-reported outcomes tell a different story. Fatigue ranks among the most prevalent and disabling complaints across the disease course, and studies of patients in remission have repeatedly documented impaired physical function, reduced exercise capacity, sleep disturbance, and neurocognitive symptoms that conventional lupus metrics fail to capture. This discordance has practical consequences: patients whose laboratory values look reassuring may nonetheless be functionally limited, and clinicians lack a framework for understanding—or investigating—why.

What makes the proposed phenotype more than a descriptive label is the mechanistic scaffolding beneath it. The commentary assembles direct evidence from lupus research pointing to several interacting biological systems. Residual immune activation persists in many patients despite apparent disease control, with ongoing immune cell activation and inflammatory signaling detectable below the threshold captured by clinical indices. Oxidative stress, an imbalance between reactive oxygen species and antioxidant defenses, has been documented in SLE and can damage cellular components ranging from lipids to DNA. Mitochondrial alterations—the dysfunction of the organelles that generate cellular energy—have likewise been reported, offering a plausible route from biochemical injury to the fatigue and exercise intolerance patients describe.

Vascular and autonomic mechanisms form a second pillar of the framework. Endothelial dysfunction, a impairment of the blood vessels’ inner lining that precedes atherosclerosis, is well established in lupus and contributes to the disease’s elevated cardiovascular risk, but it may also compromise tissue perfusion during exertion and in the brain. Dysautonomia—disordered regulation by the autonomic nervous system—has been described in SLE patients and can produce orthostatic intolerance, the lightheadedness, palpitations, and cognitive dulling that occur when standing disrupts cerebral blood flow. These findings matter because they map directly onto symptoms that dominate the lived experience of the proposed subgroup: exercise that triggers a disproportionate crash, sleep that does not restore, and thinking that falters when upright.

It is here that the commentary’s most provocative move occurs: importing carefully flagged mechanistic insights from ME/CFS research. That field, long marginalized but increasingly rigorous, has accumulated human evidence of impaired cellular energetics, with studies suggesting that energy metabolism in patient cells behaves abnormally under stress; of autonomic dysfunction measurable in the clinic; of altered cerebral perfusion on neuroimaging; and of neuroimmune dysregulation involving inflammatory signaling that reaches the central nervous system. Post-exertional symptom exacerbation—the hallmark worsening of symptoms hours to days after physical or cognitive effort—serves as the condition’s defining feature and a key anchor for the proposed lupus phenotype. The author is explicit that these ME/CFS findings are hypotheses for lupus, not established facts: they converge plausibly with direct SLE evidence, but they require direct validation in lupus cohorts before any conclusion can be drawn.

The framework’s deliberate non-linearity is one of its distinguishing technical features. Rather than proposing a single causal chain—molecule X causes symptom Y—the author describes interacting immune, metabolic, vascular, autonomic, and neurocognitive mechanisms that may reinforce one another dynamically over time. Mitochondrial dysfunction, for instance, could amplify oxidative stress, which in turn could worsen endothelial function and autonomic regulation, while neuroimmune signaling could sensitize the brain’s fatigue and cognitive circuits. Such feedback structures resist the one-biomarker-one-diagnosis model and instead call for multidimensional phenotyping: simultaneous measurement of immune markers, redox balance, vascular function, autonomic testing, exercise physiology, and neurocognitive performance in the same patients, tracked longitudinally.

Methodological caution runs throughout the proposal. The commentary is explicitly a theoretical, non-systematic synthesis, prioritizing human studies, systematic reviews, meta-analyses, and translational work, and it stops short of defining a new diagnostic entity or a fixed disease trajectory. The proposed phenotype is framed as a research construct—a way to stratify patients for prospective longitudinal studies—rather than a clinical diagnosis. This distinction is important for lupus care, where symptoms such as fatigue and cognitive difficulty can also arise from hypothyroidism, anemia, sleep apnea, depression, medication side effects, or active disease that standard measures miss. The framework therefore requires structured exclusion or assessment of alternative explanations before a patient is classified within the subgroup, mirroring the case-definition discipline developed in ME/CFS research.

If the hypothesis survives prospective testing, the implications could be substantial. A validated SLE–ME/CFS research phenotype would give investigators a stratification tool for clinical trials, separating patients whose persistent symptoms arise from ongoing inflammatory activity from those whose illness follows a different biological path. It could sharpen biomarker discovery by directing attention toward autonomic, endothelial, mitochondrial, and neuroimmune measures rather than conventional serology alone. And it could reshape supportive care, since interventions developed for ME/CFS—pacing strategies to avoid post-exertional crashes, graded approaches to rehabilitation, orthostatic management—might be adapted and formally tested in the lupus subgroup, rather than applied indiscriminately to all patients.

The proposal also carries a message about how medicine handles diseases that fall between specialties. Lupus is the rheumatologist’s territory; ME/CFS remains contested and under-resourced; and patients whose illness straddles the two risk falling into the gap. By articulating a phenotype that borrows mechanistic rigor from one condition to explain unresolved symptoms in the other, the commentary offers a template for hypothesis-driven bridge-building across diagnostic boundaries. The author is careful to frame the work as hypothesis-generating, and the next step—longitudinal, multidimensional studies of lupus patients with persistent symptoms—will determine whether the SLE–ME/CFS research phenotype describes a real biological subgroup or merely a useful way of organizing uncertainty. Either outcome would advance a conversation that many patients, whose suffering persists long after their inflammation has quieted, have been waiting for the field to have.

Subject of Research: Persistent fatigue and related symptoms in long-standing systemic lupus erythematosus and their proposed mechanistic overlap with ME/CFS

Article Title: Persistent symptom burden in long-standing systemic lupus erythematosus: a subgroup-focused hypothesis for an SLE–ME/CFS research phenotype

Article References: Habermann-Horstmeier, L. (2026). Persistent symptom burden in long-standing systemic lupus erythematosus: a subgroup-focused hypothesis for an SLE–ME/CFS research phenotype. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-08867-8

Image Credits: AI Generated

DOI: 10.1186/s12967-026-08867-8

Keywords: systemic lupus erythematosus, ME/CFS, chronic fatigue, post-exertional malaise, dysautonomia, endothelial dysfunction, mitochondrial dysfunction, oxidative stress, neuroimmune dysregulation, orthostatic intolerance, disease phenotype, Journal of Translational Medicine