Diabetic neuropathy research advances toward mechanism-based, personalized care

An editorial in Frontiers in Endocrinology surveys recent advances in diabetic sensorimotor polyneuropathy, highlighting evidence that links autonomic dysfunction with peripheral nerve damage, identifies metabolic and biological markers associated with risk, and supports more individualized approaches to diagnosis and treatment. The collection extends the view beyond the peripheral nerves to the spinal cord, brainstem and brain, while emphasizing that no single test or therapy can adequately capture the varied manifestations of diabetic neuropathy. Its central conclusion is that combining clinical assessment, quantitative sensory testing, neurophysiology, biomarkers and structural imaging could help distinguish patients with different underlying mechanisms and disease trajectories.

The editorial draws attention to neuropathy as an early diabetes complication associated with impaired quality of life and elevated mortality. Historical evidence cited by the authors linked neuropathy to subsequent renal impairment, and more recent prospective data have reinforced that relationship. Studies also indicate that cardiac autonomic neuropathy may already be detectable in people with prediabetes or increased prediabetes risk. In a comparison of people with prediabetes, those at increased risk of prediabetes and controls, both prediabetes and increased risk were associated with cardiac autonomic neuropathy independently of age. The authors caution, however, that these findings may point toward broader metabolic influences rather than short-term glycaemic variability alone.

Prospective evidence strengthens the connection between autonomic and somatic nerve involvement. Among people with diabetes who did not have diabetic sensorimotor polyneuropathy at baseline, established cardiac autonomic neuropathy independently predicted its later development under three complementary definitions during an average three-year follow-up. Reduced short-term heart-rate variability also identified people at increased risk and could potentially serve as a practical stratification marker. A separate cross-sectional study of people with type 2 diabetes and diabetic kidney disease found that cardiac autonomic neuropathy was more prevalent in advanced kidney disease and was associated with vitamin D deficiency and impaired heart-rate variability indices. Because that study was cross-sectional, it cannot establish that kidney disease, vitamin D deficiency or autonomic dysfunction caused one another.

Age also emerged as a major influence on the clinical pattern of sensory neuropathy. In a study of 442 patients with type 2 diabetes in a defined metropolitan area, mean age was 65.5 years and mean diabetes duration was 9.6 years. Researchers assessed pressure perception with a 10-g Semmes-Weinstein monofilament, vibration detection with a calibrated 128-Hz tuning fork and symptom reports obtained through three standardized questions about ulcers, persistent pain and lower-limb discomfort. Abnormal results were more frequent with the tuning fork, and the two methods frequently identified different patients. The findings indicate that standard screening tools are not interchangeable and suggest that a simple symptom questionnaire may complement objective testing in routine outpatient care.

Severe neuropathy can also complicate dental diagnosis and treatment, as illustrated by two case reports involving poorly controlled diabetes. A 14-year-old girl with 10 years of poorly controlled type 1 diabetes had marked oral disease, including gingivitis, angular cheilitis, extensive plaque, caries and pericoronaritis, yet showed amplified pain reactions during dental procedures despite adequate local anaesthesia. Quantitative sensory testing documented lower thresholds consistent with generalized sensory hyperexcitability. A 55-year-old man with long-term poor glycaemic control had severe generalized periodontitis, attachment loss, tooth mobility and multiple carious lesions, but reported little or no pain and underestimated the severity of his condition. Testing detected severe, partially maximal hypoesthesia. These cases are not prevalence estimates, but they demonstrate why dental assessment may require individualized strategies and close interdisciplinary cooperation.

Rare causes must also be considered when neuropathy is accompanied by hypoglycaemia. In one case, a 22-year-old woman experienced recurrent hypoglycaemia, numbness, tingling and burning limb pain. Investigations identified multiple radiculopathies and sensorimotor polyneuropathy, followed by a contrast-enhancing tumour near the junction of the body and tail of the pancreas. After laparoscopic distal pancreatectomy, her hypoglycaemia resolved and her neuropathy symptoms improved. The authors identify insulinoma as an uncommon possible cause of neuropathy and argue that early diagnosis is important. The single case does not establish how frequently pancreatic tumours produce this pattern, but it illustrates the value of considering endocrine causes when the clinical presentation is atypical.

Mechanistic research offers potential targets but does not yet amount to proven disease-modifying therapy. One review places oxidative stress at the center of diabetic nerve injury, connecting hyperglycaemia-activated pathways with mitochondrial dysfunction, endoplasmic reticulum stress and chronic inflammatory signaling. Other reviews examine emerging agents for painful diabetic neuropathy, including pilavapadin, an orally administered selective inhibitor of adapter protein-2-associated kinase 1, and vixotrigine, a broad-spectrum voltage-gated sodium-channel inhibitor. Experimental studies suggest possible effects of GLP-1 receptor agonists and SGLT2 inhibitors on neural damage, but the available clinical evidence comes mainly from small, short phase II randomized trials with inconsistent results for clinical and neurophysiological outcomes. Translation review similarly describes distal axon degeneration, impaired regeneration and the continuing absence of an established disease-modifying treatment.

Several studies in the collection examine early detection and risk prediction rather than therapeutic benefit. Current perception threshold testing showed moderate diagnostic accuracy for early C-fiber dysfunction in type 1 diabetes. A random-forest model identified age, diabetes duration, HbA1c, glycated serum protein and 25-hydroxyvitamin D as major predictors of diabetic polyneuropathy. In a propensity score-matched cohort, glycaemic variability was associated with the presence and severity of polyneuropathy independently of HbA1c, with systemic inflammation partly mediating the association. Mendelian randomization produced hypothesis-generating associations between selected phosphatidylcholine species and neuropathy risk. Additional reviews address Schwann-cell injury and potential roles for apoptosis, autophagy, pyroptosis, ferroptosis and necroptosis, as well as the integrated use of metabolic, renal, hepatic, inflammatory, thyroid and vitamin-related laboratory markers.

Interventions beyond medication remain under study. A meta-analysis of seven trials reported improved nerve conduction and glycaemic outcomes with dapagliflozin plus methylcobalamin, although the limited evidence base requires larger, more rigorous and more broadly generalizable trials. In a randomized study, high-intensity interval training and moderate-intensity continuous training both improved metabolic, inflammatory and neurological outcomes, with larger effects reported for high-intensity interval training. A network meta-analysis of antimicrobial dressings for diabetic foot ulcers ranked antibiotic-impregnated bone cement and silver dressings most favorably, while also identifying the need for direct comparative and cost-effectiveness studies. These findings cover different outcomes and interventions, so they should not be read as evidence that one approach universally outperforms the others.

The editorial ultimately argues for precision medicine in diabetic neuropathy because the condition varies in the nerve fibers affected, sensory manifestations, pain burden, mechanisms and individual course. Longitudinal sensory profiling has identified distinct trajectories of dysfunction, while magnetic resonance neurography has associated distinct sciatic-nerve structural patterns with different peripheral sensory phenotypes in type 2 diabetes. Quantitative sensory testing combined with C-fiber-oriented electrical stimulation also revealed that people with markedly impaired heat-pain perception could retain substantial electrically evoked pain responses, showing that loss of a sensory function does not necessarily mean loss of the corresponding excitable axons. The next step is to link mechanistic phenotypes to treatment response through robust prospective studies, targeted therapies and interventions that actually modify the disease rather than only its symptoms.

Subject of Research: Advances in diagnosing, stratifying and treating diabetic sensorimotor polyneuropathy

Article Title: Editorial: Frontiers in diagnostic and therapeutic approaches in diabetic sensorimotor neuropathy, volume II

Article References: Kender, Z., & Kempler, P. (2026). Editorial: Frontiers in diagnostic and therapeutic approaches in diabetic sensorimotor neuropathy, volume II. Frontiers in Endocrinology, 17, Article 2009636. https://doi.org/10.3389/fendo.2026.2009636

Image Credits: AI Generated

DOI: 10.3389/fendo.2026.2009636

Keywords: diabetic neuropathy, sensorimotor polyneuropathy, cardiac autonomic neuropathy, sensory phenotyping, quantitative sensory testing, neuroimaging, neuropathic pain, precision medicine, diabetes complications, Editorial, Frontiers, diagnostic