Emerging Viewpoints on Diabetic Neuropathy

Abstract

The prevalence of diabetes continues to rise, particularly in aging populations. Type 2 diabetes (T2D), which accounts for the majority of cases, is a metabolically acquired condition. Diabetic peripheral neuropathy (DPN), the most common microvascular complication of diabetes, involves length-dependent damage to peripheral nerves. While the pathogenesis of DPN is complex, it can fundamentally be seen as a failure in nerve metabolism and bioenergetics, compounded by the unique anatomy of peripheral nerves—long axons supported by glial cells. This anatomical structure, along with the nerve damage caused by T2D, explains the characteristic distal-to-proximal pattern of DPN symptoms. Early research primarily focused on the role of hyperglycemia in nerve injury and bioenergetic dysfunction, but more recent studies also highlight the contributions of obesity and dyslipidemia. This review will explore peripheral nerve structure, bioenergetics, and the interactions between glial cells and axons, providing a foundation for understanding how hyperglycemia and dyslipidemia lead to bioenergetic failure in DPN. The review will also discuss the lack of disease-modifying therapies for DPN, with a focus on emerging mechanism-based approaches.