Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of up to 4 months dietary supplementation with 40% galactose on muscle and nerve function were examined in rats. Galactitol, a polyol pathway metabolite, accumulated to high levels in both tissues. This led to changes similar to those found in experimental diabetes, which were largely prevented by treatment with an inhibitor of the first enzyme in the pathway, aldose reductase. For fast twitch extensor digitorum longus muscle there was weight loss, fibre damage, slowing of twitch time to peak, increased twitch tension, and reduced tetanic tension. There were no relaxation deficits. For slow twitch soleus there were no changes in tension production. However, contraction and relaxation for both twitch and tetanus were prolonged. Fatigue resistance was reduced after 1 week. Damage in soleus led to a reduction in mean fibre area after 2 months, which largely recovered by 4 months. There was a selective loss of fast oxidative glycolytic fibres. Histochemical staining for succinic dehydrogenase was normal in galactosaemic soleus, in contrast to the marked reduction seen in diabetes. Sciatic nerve conduction velocity was reduced after 2 months, particularly in normally fast conducting motor and sensory fibres. Resistance to hypoxic conduction block was increased in galactosaemic nerves to diabetic levels. It was concluded that polyol pathway hyperactivity is likely to contribute to the aetiology of diabetic myopathy and neuropathy, and that experimental galactosaemia provides a good model in which to study pathway effects without the complicated hormonal changes found in diabetes.
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PMID:Muscle and nerve dysfunction in rats with experimental galactosaemia. 153 21

This study examined the effect of inhibition of aldose reductase, the first enzyme in the polyol pathway, on fast and slow twitch skeletal muscle morphology and function in streptozotocin-induced diabetes in rats. There was a preventative investigation with diabetes duration of 4 months, and a reversal investigation where treatment was given for 2 months following an untreated period of 2 months. For slow twitch soleus muscle, contractions were prolonged by diabetes, and this was partially prevented but not reversed by treatment. Relaxation was profoundly slowed, and both prevention and reversal ameliorated the changes. Diabetes had minimal effects on tension production for soleus. However, for fast twitch extensor digitorum longus, although there was little effect on speed-related contractile parameters, tetanic tension production was progressively reduced with diabetes duration. This effect was antagonized by treatment. Soleus fatigue resistance was markedly reduced by diabetes, but restored to normal by treatment. There was a reduction in oxidative enzyme staining (succinic dehydrogenase), and capillary-fibre ratio, both of which were ameliorated by aldose reductase inhibition. Mean soleus fibre area was reduced after 4 months of diabetes, and this was prevented but not reversed by treatment. Fibre area was also reduced in extensor digitorum longus, particularly for fast glycolytic fibres. There was a small amelioration with treatment. It is concluded that enhanced polyol pathway activity makes a contribution to diabetic myopathy, and that aldose reductase inhibitors can prevent this by actions on muscle fibres and their vascular supply.
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PMID:Polyol pathway-related skeletal muscle contractile and morphological abnormalities in diabetic rats. 847 Dec 37

Increased glucose flux through the polyol pathway and the resultant oxidative stress is thought to be a major mechanistic contributor to microvascular diabetic complications. Inhibition of flux through this pathway can be blocked through inhibition of either of 2 enzymes, aldose reductase (AR) or sorbitol dehydrogenase (SDH). This report describes the pharmacokinetics, biomarker pharmacodynamics, and safety of CP-642,931, a potent and specific sorbitol dehydrogenase inhibitor (SDI). CP-642,931 was administered for 7 days to 57 healthy volunteers in doses ranging from 1 to 35 mg daily. After the 35-mg dose, CP-642,931 showed a t((1/2)) of 20.1 hours and t(max) at 0.5 to 1.25 hours. After a 35-mg dose, maximum inhibition of SDH was 91% (on days 1 and 7), and maximum serum sorbitol increase was 152-fold on day 7 compared to control. Five participants discontinued the study due to adverse events, including myalgia, muscle spasm, and muscle fatigue. All symptoms resolved in all but 1 participant, who continued to report intermittent muscle fasciculations upon follow-up. In conclusion, CP-642,931 is a potent and specific SDI that is rapidly absorbed through the oral route and effectively inhibits SDH. However, the drug is not well tolerated due to adverse neuromuscular effects.
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PMID:Pharmacokinetics, pharmacodynamics, tolerability, and safety of a novel sorbitol dehydrogenase inhibitor in healthy participants. 2022 44

Cardiac autonomic neuropathy (CAN) is a frequent chronic complication of diabetes mellitus with potentially life-threatening outcomes. CAN is caused by the impairment of the autonomic nerve fibers regulating heart rate, cardiac output, myocardial contractility, cardiac electrophysiology and blood vessel constriction and dilatation. It causes a wide range of cardiac disorders, including resting tachycardia, arrhythmias, intraoperative cardiovascular instability, asymptomatic myocardial ischemia and infarction and increased rate of mortality after myocardial infarction. Etiological factors associated with autonomic neuropathy include insufficient glycemic control, a longer period since the onset of diabetes, increased age, female sex and greater body mass index. The most commonly used methods for the diagnosis of CAN are based upon the assessment of heart rate variability (the physiological variation in the time interval between heartbeats), as it is one of the first findings in both clinically asymptomatic and symptomatic patients. Clinical symptoms associated with CAN generally occur late in the disease process and include early fatigue and exhaustion during exercise, orthostatic hypotension, dizziness, presyncope and syncope. Treatment is based on early diagnosis, life style changes, optimization of glycemic control and management of cardiovascular risk factors. Medical therapies, including aldose reductase inhibitors, angiotensin-converting enzyme inhibitors, prostoglandin analogs and alpha-lipoic acid, have been found to be effective in randomized controlled trials. The following article includes the epidemiology, clinical findings and cardiovascular consequences, diagnosis, and approaches to prevention and treatment of CAN.
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PMID:Diabetes and cardiac autonomic neuropathy: Clinical manifestations, cardiovascular consequences, diagnosis and treatment. 2568 80