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The pathogenesis of diabetic neuropathy: a proteomic, metabolomic and electrophysiological investigation

Freeman, Oliver

[Thesis]. Manchester, UK: The University of Manchester; 2015.

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Abstract

Diabetes mellitus affects more than 382 million people worldwide and an estimated 30-50% of patients develop some form of neuropathy. Patients typically present with sensory symptoms including hypersensitivity/pain and/or loss of somatosensation. In diabetic neuropathy, the longest nerves of the peripheral nervous system (PNS) show the worst pathology and symptoms are typically felt in the distal extremities. The cause of this apparent length-dependent pathology remains unknown.Through comprehensive integration of untargeted proteomic and metabolomic analyses of the PNS in the streptozotocin rat model of diabetes, we showed that bioenergetic pathways were more dysfunctional in the distal sciatic nerve (SN) than the lumbar 4/5 dorsal root ganglia (DRG) and cranial trigeminal ganglia (TG). Whilst glucose levels increased in all tissues in diabetes, there was extensive upregulation of proteins involved in mitochondrial oxidative phosphorylation in the distal SN compared to healthy age/weight-matched controls which was not evident in the proximal DRG or TG. There were significant changes in lipid metabolites in the SN, a phenomenon which is less apparent in the DRG and not evident in the TG. We investigated the therapeutic potential of copper chelation with triethylenetetramine to reverse such changes and whilst copper chelation prevented nerve conduction velocity deficits, it did not alter aberrant nerve metabolism.To further understand the functional deficits in diabetic neuropathy, we performed in vivo microelectrode recordings from the TG and the thalamic ventral posteromedial (VPM) nucleus in control and diabetic rats in response to precise whisker stimulation. Recordings from the TG showed that the tuning of the primary afferents to graded stimuli is preserved in diabetes. Furthermore, we found that neurons within the VPM showed increased spontaneous activity in diabetes, but maintained tuning to graded whisker stimulation in their evoked firing rate. Thus, the cranial TG appear to be relatively unaffected by diabetes at a biochemical or physiological level, but diabetes may lead to pathophysiological changes within the thalamus which could alter somatosensory processing.Despite a global metabolic insult in diabetes, the molecular consequences are not consistent throughout the nervous system. We show that metabolic dysfunction occurs specifically in regions known to be more affected in neuropathy. Due to such a focal dysfunction, aberrant oxidative phosphorylation in the sciatic nerve may be a key driver to the distal pathogenesis of diabetic neuropathy.

Additional content not available electronically

There are two appendices on a DVD attached within the back cover of this thesis. They comprise the following: Appendix 1 – An Excel document containing all data from our proteomic analyses. The first worksheet contains a guide explaining each of the worksheets and their headings. Appendix 2 – An Excel document containing all data from our metabolomic analyses. The first worksheet contains a guide explaining each of the worksheets and their headings.