Protective Role of Physical Exercise and Exercise‐Induced FNDC5/Irisin in Combating Diabetes‐Related Cognitive Impairment and Autonomic and Peripheral Neuropathies: A Comprehensive Review

The rising prevalence of diabetes has been closely linked to increased mortality and morbidity, particularly as its complications become more widespread. Among the most challenging of these complications are cognitive impairments and diabetic neuropathies, which are neurodegenerative conditions that significantly diminish the quality of life in the diabetic population. Beyond its well-established benefits for improving glycemic control and preventing cardiovascular complications, physical exercise has also been shown to mitigate central and peripheral neurodegenerative complications of diabetes, including cognitive decline, peripheral neuropathies, and autonomic neuropathies. Emerging research suggests that fibronectin type III domain-containing protein 5 (FNDC5), later converted into irisin, an exercise-induced myokine, plays a key role in mediating these protective effects. This narrative review thoroughly examines the protective impact of various forms of physical exercise-including aerobic, resistance, and multimodal training-on diabetic neuropathies and cognitive decline, while also exploring the involvement of FNDC5/irisin in these beneficial outcomes across experimental animal studies, cross-sectional analyses, and controlled trials.