Painful Diabetic Neuropathy: Sex-Specific Mechanisms and Differences from Animal Models to Clinical Outcomes

Diabetes is a chronic and progressive disease associated with high blood glucose levels. Several co-morbidities arise from diabetes, the most common and severe one is diabetic neuropathy whose symptoms also include pain hypersensitivity. Currently, there are no effective therapies to counteract painful diabetic neuropathy or slow down the progression of the disease, and the underlying mechanisms are yet to be fully understood. Emerging data in recent decades have provided compelling evidence that the molecular and cellular mechanisms underlying chronic pain are different across the sexes. Interestingly, relevant differences have also been observed in the course and clinical presentation of painful diabetic neuropathy in humans. Here, we reviewed the current state of the art on sex differences in diabetic neuropathy, from animal models to clinical data. Comparing the output of both preclinical and clinical studies is necessary for properly orienting future choices in pain research, refining animal models, and interpreting clinical data. The identification of sex-specific mechanisms may help to develop more targeted therapies to counteract pain symptoms in diabetes.