Abstract
**Diabetes mellitus** is a non-communicable metabolic disease with an increasing prevalence worldwide; it is estimated that by 2030 there will be 578 million people with diabetes, and by 2045 approximately 700 million. It causes numerous complications, including distal symmetric peripheral neuropathy, which affects over 50% of patients and increases progressively with disease duration, being more common in type 2 diabetes than in type 1. Hyperglycemia causes microvascular damage leading to ischemia along with metabolic dysregulation (via the polyol pathway, hexosamine pathway, protein kinase C pathway, and advanced glycation end products), resulting in structural and functional alterations of peripheral nerves. Building on this underlying mechanism, in individuals with one or more risk factors—such as genetic phenotype (voltage-gated Na⁺ channels), duration of diabetes, obesity, female sex, elevated methylglyoxal levels, vitamin D deficiency, and reduced blood flow—pain arising from diabetic peripheral neuropathy may develop. Pain in diabetic peripheral neuropathy occurs in approximately 20–50% of cases and is highly heterogeneous (spontaneous pain, dysesthesia, hyperalgesia, paresthesia, etc.), and is often accompanied by sleep disturbances (41.6–43.8%), depression (50.6–65.6%), and anxiety (60.4–73.7%). Patterns of sensory disturbance can be quantified using the NerveCheck device, and pain due to peripheral neuropathy can be predicted by measuring advanced glycation end products using a skin autofluorescence device. In addition to good glycemic control, pain management should be individualized when accompanying symptoms such as insomnia, anxiety, or depression are present, and attention should also be paid to potential adverse effects on the cardiovascular, gastrointestinal, and urinary systems, among others. Preferred agents with multimodal mechanisms of action include pregabalin and duloxetine, alongside concurrent remyelination support with B-complex vitamins, vitamin E, and vitamin D.
