Voukali, E; (2013) A study of selective vulnerability to diabetes of nerves supplying the ileum using in vitro models. Doctoral thesis , UCL (University College London).

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Abstract

Autonomic neuropathy is a complication of diabetes and, where the innervation of the gut is involved, results in disordered gut motility. In vivo, sympathetic nerves and subpopulations of enteric neurons supplying the ileum are differentially affected by diabetes. The overall of aim of this study was to establish whether such differential susceptibility could be reproduced in vitro using wholemount preparations of myenteric plexus and sympathetic ganglion explants from the adult rat and to use such models to examine potential mechanisms underlying the development of neuropathy and its prevention. Preparations were exposed to a range of stimuli that mimic the diabetic environment including high glucose, advanced glycation endproducts (AGEs), carbonyl stress and oxidative stress. Evidence is presented that exposure of myenteric neurons to oxidative stress in vitro mimicked the effects of diabetes as reflected by increased expression of vasoactive intestinal polypeptide (VIP), decreased expression of neuronal nitric oxide synthase (nNOS) and unaltered calbindin expression. However, the mechanism underlying oxidative stress was not uniform, increased VIP expression only occurred on exposure to high glucose and carbonyl stress whereas decreased nNOS expression was only induced by AGEs. Neurons containing calbindin were resistant to all stimuli. Potential therapeutic agents produced differing effects depending on whether they primarily acted against oxidative or carbonyl stress. Using two photon microscopy and fluorescence lifetime imaging (FLIM), the effect of high glucose on reduced nicotinamide adenine (phosphate) (NAD(P)H) metabolism was investigated over time. Comparisons were made between sympathetic neurons from superior cervical ganglia (SCG), which are unaffected in diabetes, and from superior mesenteric/coeliac ganglia (CG/SMG) which develop axonal dystrophy. High glucose temporarily increased NAD(P)H levels selectively in the CG/SMG which coincided with a significant difference between the two ganglia in the fluorescence lifetime of free NAD(P)H. These results may explain the complex pattern of change that occurs in enteric nerves in diabetes.

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