“Peripheral and Central Biomarkers in Painful Diabetic Peripheral Neuropathy”

Painful diabetic peripheral neuropathy (DPN) is a disabling condition and its pathogenesis is not well understood. This study aimed to improve our understanding of pain mechanisms and also analyse upcoming potential peripheral and central biomarkers of painful DPN. The role of vitamin D has been studied in painful DPN, although many of the previous studies did not assess major confounding factors including seasonal sunlight exposure and daily activity and lacked detailed assessment of peripheral neuropathy. Work undertaken in this thesis addressed these limitations and found a significant reduction of 25(OH) vitamin D levels in a well-characterised group of subjects with painful DPN. A panel of skin nerve and vascular markers were assessed to try and differentiate painful from painless DPN, in patients with type 2 diabetes (T2DM). No differences were found in neural biomarkers including protein gene product 9.5 (PGP9.5), growth associated protein-43 (GAP43) or calcitonin gene-related peptide (CGRP) between painful and painless DPN in our cohort with advanced neuropathy. However, there was increased microvascular staining with Von Willebrand Factor (vWF) in all diabetes groups compared to non-diabetic controls, particularly in painful DPN, which was increased compared with painless DPN (p=0.0001). The ratio of CGRP sub-epidermal nerve fibres to vasculature (CGRP:vWF) showed a significant decrease in painful DPN vs. painless DPN (p=0.014). This increased sub-epidermal microvasculature and its ratio to nociceptors may differentiate painful- from painless DPN. The status of the intracranial inhibitory neurotransmitter Gamma Amino Butyric Acid (GABA) and excitatory neurotransmitter Glutamate (Glx) in the thalamus has been assessed using in-vivo Proton Magnetic Resonance (H-MR) spectroscopy. Lower relative levels of GABA were observed within the thalamus of patients with DPN. A further understanding of the cerebral neuronal excitatory/inhibitory balance inferred from this H-MRS technique may help determine the mechanistic basis of central nervous system involvement in pain perception in DPN. The studies in this thesis were carefully designed and conducted with detailed clinical, neurophysiological and skin biopsy assessment of all participants, in order to carefully phenotype the subjects. The findings provide a better understanding of peripheral and central mechanisms associated with painful DPN and also indicate a few reliable upcoming biomarkers. The studies provide further insight into pain mechanism in painful DPN and pave the way for future studies that might ultimately lead to better treatment strategies.