Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.304586
Title: Peripheral nerve and muscle dysfunction in experimental diabetes and the effect of aldose reductase inhibitor treatment
Author: Robertson, Sharon
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 1990
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Abstract:
Peripheral nerve conduction deficits and changes in skeletal muscle contractile and histochemical properties caused by 2-4 months of experimental diabetes were examined in mature rats. The effect of aldose reductase inhibitor treatment was assessed in preventative and reversal studies. The efficacy of 1% dietary myoinositol supplementation was examined in a two month preventative group. Moderate insulin therapy, which reduced but did not normalise blood glucose levels was also employed. Data from diabetic animals was compared with that obtained from rats fed a 40% galactose diet for up to four months, as well as a combined galactose/ARI treated group. The pattern of neuropathy was very similar in diabetic and galactosaemic animals. Fast conducting motor and sensory branches were the most severely affected and at two months conduction velocities were slowed by approximately 25% compared to onset levels. Ponalrestat treatment successfully prevented this effect in both models. In reversal treated diabetic animals there was a differential response to ponalrestat treatment, ranging from complete restoration of conduction in the sensory saphenous to a modest improvement (10%) in the soleus motor branches. Insulin produced a small increase in conduction velocity on its own and conduction was normal when combined with ponalrestat treatment. Myo-inositol treatment had no beneficial effect. There was a marked rise in sciatic nerve polyol levels, in both diabetic and galactosaemic animals, accompanied by a fall in nerve free myoinositol levels. Ponalrestat treatment markedly reduced sciatic nerve polyol accumulation. Nerve myo-inositol content, in both diabetic and galactosaemic animals, was significantly increased by short term ponalrestat treatment. However, in the four month preventative and reversal groups it was notv significantly different from diabetic controls. Diabetes had differential effects on slow and fast twitch muscles. For the soleus, there was a slowing of twitch and tetanic contraction and relaxation times and a reduction of maximum tetanic relaxation rate. Ponalrestat treatment largely prevented the slowing of soleus relaxation, but had little effect on contraction. For the EDL muscle there was little change in twitch contraction times but, maximum tetanic relaxation rate was reduced. In contrast to soleus, which maintained its strength performance, EDL tetanic tension was reduced. This was partly attributed to the profound wasting of the EDL with diabetes, and in particular the marked atrophy of fast glycolytic (FG) fibres. While these effects were partially prevented by ponalrestat treatment, established deficits were harder to restore in the reversal study. A similar pattern of ARI preventable dysfunction was found in both the soleus and EDL muscles of galactose fed animals. Partial insulin therapy prevented the slowing of diabetic soleus twitch contraction time but had no effect on relaxation. For EDL, insulin produced further deleterious effects on tetanic tension and maximum relaxation rate which were antagonised by ponalrestat treatment. A 1% dietary myo-inositol supplementation had no effect on contractile function in slow or fast muscles. Diabetes produced a marked increase in soleus fatiguability. This was associated with a reduction in oxidative enzyme histochemical staining and a decrease in the capillary/fibre ratio. Preventative or reversal ponalrestat treatment produced near normal resistance to fatigue, had beneficial effects on oxidative enzyme staining and capillary/fibre ratio. Galactosaemia produced comparable deficits in soleus fatigue resistance which were prevented by ponalrestat. However, there was little disruption in oxidative enzyme staining. Sorbitol and fructose levels were increased in diabetic muscle. Levels tended to be lower in ARI treated groups. Muscle MI content was also elevated with diabetes and ARI treatment had little effect. There was a large accumulation of galactitol in galactosaemic muscles, which was markedly reduced by ARI treatment. It was concluded that polyol pathway activity is an important factor in the development of peripheral nerve and skeletal muscle dysfunction with diabetes. The data indicate that the underlying mechanisms may not depend on the restoration of myoinositol levels, and suggest that a vascular hypothesis could provide a unified explanation for diabetic effects as well as a basis for aldose reductase inhibitor treatment.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.304586  DOI: Not available
Keywords: Diabetes research Medicine Biochemistry
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