Date of Award
Doctor of Philosophy (PhD)
Thomas E. Adrian
Juma Al Kaabi
The majority of diabetics develop neuropathy, which can be debilitating, but the underlying pathophysiological mechanisms are poorly understood. Diabetic neuropathy progresses in a distal to proximal manner. Previous studies have shown that glutamate, the most common excitatory neurotransmitter, plays a role in the pathogenesis of neuropathy. The reason why the role of glutamate in nociception becomes a problem in diabetes and the mechanisms that are involved are unknown. Based on the preliminary data, the hypothesis was that glutamate pathways are likely to be involved in diabetic neuropathy particularly neuropathic pain. Pathways were investigated to look for changes that might reflect neuropathic pain and fit with previously established pharmacological evidence. The aim of this project was to identify changes in expression of genes and their protein products that are involved in glutamate signalling in diabetes. This will help to further the understanding of the mechanisms of diabetic neuropathy. In diabetic rats, there were consistent changes in expression, particularly in the lumbar and sacral dorsal root ganglia of the spinal cord and in the sympathetic ganglia. The changes were consistent between the different groups of animals as well as between adjacent groups of ganglia. The most prominent changes in both the GK groups included marked upregulation of Gria4 (ionotropic AMPA receptor), downregulation of Grik3 and Grik4 (both ionotropic, kainite receptors) and Grin1 and Grin2A (both ionotropic, NMDA receptors), activation of all of which has been shown to induce hyperalgesia; downregulation of Slc1a6 (excitatory amino acid transporter 4) and upregulation of Slc1a1 (excitatory amino acid transporter 3), both of which mediate neural reuptake of glutamate from the synaptic cleft; and upregulation of Gclc (glutathione synthase), which reflects a response to protect against oxidative damage. Despite many theories existing about the pathogenesis of diabetic neuropathy, there is no unifying hypothesis. It is possible that changes in glutamate signalling can contribute to these other mechanisms and possibly unify these different theories. A better understanding of the role that glutamate plays in development of diabetic neuropathy may pave the way for future therapeutic intervention.
Hussain, Nadia, "THE ROLE OF GLUTAMATE SIGNALLING IN DIABETIC NEUROPATHY" (2014). Dissertations. 18.