Exploring the differential diagnosis of generalized diabetic peripheral neuropathy

Introduction: Diabetic peripheral neuropathy (DPN) is the most common chronic complication of diabetes mellitus and is frequently assumed to be the sole cause of neuropathic symptoms in patients with diabetes. This diagnostic simplification may lead to misdiagnosis, delayed treatment of alternative etiologies, and preventable neurological disability. Accurate differentiation between DPN and non-diabetic neuropathies remains a major clinical challenge. Areas covered: This narrative review examines the principal differential diagnoses of generalized DPN, integrating clinical presentation, disease tempo, electrophysiological patterns, and targeted laboratory evaluation. A structured literature search of PubMed, Scopus, and Web of Science (2015 2025) was conducted, focusing on inflammatory, nutritional, toxic, hereditary, amyloid, autoimmune, and systemic causes of peripheral neuropathy. Emerging diagnostic tools, including biomarkers and advanced neurophysiological techniques, are also discussed, and a practical diagnostic algorithm is proposed to support real-world clinical decision-making. Expert opinion: DPN should be regarded as a diagnosis of exclusion rather than a default explanation in patients with diabetes. A phenotype-driven and structured diagnostic approach is essential to reduce diagnostic anchoring, prevent iatrogenic harm, and enable early identification of treatable neuropathies, ultimately improving neurological outcomes and precision medicine strategies.