Deciphering the Neuroprotective Role of Glucagon-like Peptide-1 Agonists in Diabetic Neuropathy: Current Perspective and Future Directions

Diabetic neuropathy is referred to as a subsequential and debilitating complication belonging to type 1 and type 2 diabetes mellitus. It is a heterogeneous group of disorders with a particularly complex pathophysiology and also includes multiple forms, ranging from normal discomfort to death. The evaluation of diabetic neuropathy is associated with hyperglycemic responses, resulting in an alteration in various metabolic pathways, including protein kinase C pathway, polyol pathway and hexosamine pathway in Schwann and glial cells of neurons. The essential source of neuronal destruction is analogous to these respective metabolic pathways, thus identified as potential therapeutic targets. These pathways regulating therapeutic medications may be used for diabetic neuropathy, however, only target specific drugs could have partial therapeutic activity. Various antidiabetic medications have been approved and marketed, which possess the therapeutic ability to control hyperglycemia and ameliorate the prevalence of diabetic neuropathy. Among all antidiabetic medications, incretin therapy, including Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors, are the most favorable medications for the management of diabetes mellitus and associated peripheral neuropathic complications. Besides enhancing glucose-evoked insulin release from pancreatic β-cells, these therapeutic agents also play a vital role to facilitate neurite outgrowth and nerve conduction velocity in dorsal root ganglion. Furthermore, incretin therapy also activates cAMP and ERK signalling pathways, resulting in nerve regeneration and repairing. These effects are evidently supported by a series of preclinical data and investigations associated with these medications. However, the literature lacks adequate clinical trial outcomes related to these novel antidiabetic medications. The manuscript emphasizes the pathogenesis, current pharmacological approaches and vivid description of preclinical and clinical data for the effective management of diabetic neuropathy.