Jones, Richard Hamilton Vernon; (1993) The aetiology and inhibition of experimental diabetic cataractogenesis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis describes the early aetiology of experimental diabetic cataractogenesis, in particular, perturbations of lenticular metabolism conducive to protein post-translational modification and the resulting subtle modifications evident in each of the lens crystalline types. Reported here is a study of the lenticular antioxidant status, principally the NADPH and glutathione systems, in vitro, under conditions of hyperglycaemia and oxidative stress, and in vivo in the first 21 days of streptozocin diabetes. Detailed studies have also been made of crystallin post-translational modification in the early aetiology of experimental diabetes and the effect of these modifications on the crystallin susceptibility to further metal-catalysed oxidative insult. To clarify the in vivo observations, the effect of in vitro crystallin glycation, by carbohydrates elevated in diabetes, on crystallin modification and crystallin susceptibility to oxidative stress was also studied. Evidence presented here supports the view that cataractogenesis is a multi-farious process, with protein post-translational modification central to many possible routes. Cataract occurs in conjunction with diminished antioxidant status, increased oxidative stress and increased crystallin glycation. Before the occurrence of lenticular opacification, significant post-translational modification of lens crystallins was observed and the susceptibility of the lens crystallins to oxidative stress was increased. In vitro, this increased modification and increased susceptibility to modification was seen to be concomitant with crystallin glycation by both fructose and glucose, supporting the proposal that crystallin glycation and oxidation are inexorably linked in the cataractogenic process. Intervention in the cataractogenic process was attempted using dietary supplementation with an antioxidant, ascorbate, and a glycation inhibiting compound, acetylsalicylic acid. The effect of these agents was shown to be beneficial, preventing not only the post-translational modification of lens crystallin in vivo but also the increase in susceptibility to oxidative stress evident in the non-supplemented diabetic. The possible mechanisms by which these supplements may provide protection are discussed.

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