Diabetic Sensory Neurons, Dorsal Root Ganglia, and Neuropathy

Sensory neurons are critical targets in diabetes mellitus (DM). Diabetic polyneuropathy (DPN) can be considered a unique form of sensory predominant neurodegeneration that renders loss of distal axon terminals, especially those in the skin, with relative preservation of their cell body (perikarya). Patients experience loss of sensation (numbness), gait instability with falls, unrecognized injury of insensate limbs with skin ulceration, and neuropathic pain. Sensory neurons reside in paraspinal dorsal root (and trigeminal) ganglia (DRGs) possessing unique microvascular and barrier properties that lead to greater vulnerability from DM. The molecular responses of sensory neurons differ from those of axotomized peripheral neurons. In DM the changes emphasize downregulation of key structural proteins, shifts in ion channel expression, and attenuated growth proteins all indicative of chronic neurotoxic stress. Changes in several differentially expressed mRNAs and miRNAs of DRG neurons in DPN, such as CWC22 and mmu-Let-7i, may contribute to sensory dysfunction. Finally, molecular strategies emphasizing regenerative impacts, including topical approaches, have the capacity to reverse features of DPN including loss of skin innervation. These have included local insulin (intrathecal, intranasal, near nerve, intrahindpaw) given in doses that do not alter hyperglycemia, GLP-1 agonists, PTEN (phosphatase and tensin homolog deleted on chromosome 10) inhibition or knockdown, and muscarinic antagonists. Several additional and novel strategies are emerging that may influence axonal degeneration of distal sensory terminals or axon regeneration specifically. Despite a limited clinical trial track record over several decades, new mechanistic insights for translation in DPN offer hope for better trial results.