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Mechanisms Underlying Autonomic Neuropathy in Diabetes
Damage to the nervous system, including autonomic nerves supplying the internal organs and blood vessels, can occur as a complication of diabetes mellitus. Such damage is thought to contribute to symptoms such as postural hypo- tension, disordered gut motility and impotence in diabetic patients. Using an animal model, we have demonstrated changes in autonomic nerves in the cardiovascular, gastro- intestinal and urogenital systems. However, it is clear that not all autonomic nerves are affected in the same way in diabetes. Some nerves undergo degeneration, some have reduced levels of neurotransmitters and some appear to be largely unaffected. In order to find an explanation for this we are investigating possible mechanisms involved in causing nerve damage.
Effect of diabetes on sympathetic neurons in the coeliac ganglion: Note the increase in green immunofluorescence staining tyrosine hydroxylase in the neurons in diabetes. It is also easier to see green fluorescent axons in the diabetic tissue and they appear swollen a characteristic known as neuronal axonal dystrophy. Sympathetic neurons of the superior cervical ganglion do NOT undergo such degenerative changes in diabetes
One factor of particular interest is oxidative stress induced by high levels of glucose in diabetes. Oxidative stress is a condition where there is an increase within cells of certain reactive molecules containing oxygen. These can then react with components of cells, including nerves, and cause damage. Nerves do have defence mechanisms against oxidative stress but they do not necessarily work to the same extent in different populations. Therefore, it is possible that autonomic nerves with a greater level of defence against oxidative stress may be able to resist the effects of diabetes while others with low levels of defence will be particularly susceptible to degenerative changes.
We are investigating the presence of oxidative stress and the status of defence mechanisms in a variety of autonomic nerves supplying the cardiovascular, gastrointestinal and urogenital systems that have been identified according to their neurotransmitter content. We are also looking at the changes that occur in diabetes and investigating the potential of various agents that can act against oxidative stress to prevent or even reverse autonomic nerve damage once it has occurred.
|Adult sympathetic neurons can be dissociated and maintained in culture where they grow neurites. The left hand panel shows a neuron grown under control conditions and stained for a general neuronal marker that reveals the cell body and fine beaded neurites fluorescing red. In the right hand panel TUNEL can be demonstrated in the nucleus of the neuron (yellow fluorescence) indicating that the neuron is undergoing apoptotic cell death. TUNEL staining increases in neurons exposed to high levels of glucose and oxidative stress. This provides an in vitro model with which to investigate the mechanisms underlying autonomic neuropathy in diabetes and to screen potential therapeutic agents|
Collaborative Project with Dr David Becker
Impaired wound healing in diabetes and its treatment
Diminished sensation in the extremities due to neuropathy in diabetes can lead to the development of foot ulcers. Diabetes also impairs wound healing leading to the presence of chronic wounds prone to infection. This condition is the major cause of non-traumatic amputation in humans. Dr. David Becker is researching into the role of connexin proteins in gap junctions in the wound healing process. In collaboration we are investigating how diabetes affects the expression of specific connexins in intact skin and how it affects the dynamic changes in connexin expression that occur during the wound healing process. The aim of the research is also to examine whether manipulation of connexin expression which is known to increase the rate of wound healing under normal conditions can be used to improve wound healing in diabetes.
- Shotton, H.R., Clarke, S. & Lincoln, J. (2003) The effectiveness of treatments of diabetic autonomic neuropathy is not the same in autonomic nerves supplying different organs. Diabetes, 52: 157-164.
- Shotton, H.R., Broadbent, S. & Lincoln, J. (2004) Prevention and partial reversal of diabetes-induced changes in enteric nerves of the rat ileum by combined treatment with alpha-lipoic acid and evening primrose oil. Autonomic Neuroscience: Basic and Clinical, 111: 57-65.
- Semra, Y.K., Smith, N.C.E. & Lincoln, J. (2004) Comparative effects of high glucose on different adult sympathetic neurons in culture. NeuroReport, 15: 2321-2325.
- Shotton, H.R. & Lincoln, J. (2006) Diabetes only affects nitric oxide synthase-containing myenteric neurons that do not contain haem oxygenase-2. Brain Research, 1068: 248-256.
- Shotton, H.R., Adams, A. & Lincoln, J. (2006) Effect of aminoguanidine treatment on diabetes-induced changes in the myenteric plexus of the rat ileum. Autonomic Neuroscience: Basic and Clinical, In Press.
- Semra, Y.K., Wang, M., Peat, N.J., Smith, N.C.E., Shotton, H.R. & Lincoln, J. (2006) Selective susceptibility of different subpopulations of sympathetic neurons to diabetic neuropathy in vivo is reflected by increased vulnerability to oxidative stress in vitro. Neuroscience Letters, In Press.
Page last modified on 25 may 10 13:53