Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In some tissues containing aldose reductase, increased flux through the polyol pathway has been implicated as being causative in diabetic complications (e.g., cataracts, peripheral neuropathy). We have found CP-45,634 (d-6-fluoro-spiro[chroman-4,4'-imidazolidine]-2',5'-dione) to be a highly potent, structurally novel, uncompetitive inhibitor of calf lens aldose reductase (IC50 approximately 5 X 10(-7)M). In a system in which sorbitol accumulation in isolated rat sciatic nerves was monitored in the presence of high (50 mM) glucose concentrations, CP-45,634 produced inhibition of polyol accumulation at levels as low as 1 X 10(-6)M. To determine if in vitro activity would translate to in vivo models, sorbitol accumulation in rat sciatic nerves was measured 27 hr after induction of diabetes with streptozotocin. Orally administered CP-45,634 was effective at dose levels as low as 0.25 mg/kg, t.i.d., and at 0.75 mg/kg produced an 85% inhibition of sorbitol accumulation. Two weeks after induction of diabetes by streptozotocin, sorbitol levels in rat lens and the sciatic nerve rose to 21,203 nmole/gm and 1,161 nmole/gm, respectively. Subsequent oral administration of CP-45,634 (2.5 mg/kg, b.i.d.) for 1 wk reduced these levels by 92% in nerves and 90% in lenses. In galactosemic rats, CP-45,634 inhibited the rise in lens galactitol and effectively delayed cataract formation at oral doses as low as 5 mg/kg/day. These high levels of in vivo activity suggest that CP-45,634 has potential for assessing the role of the polyol pathway in diabetic complications.
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PMID:CP-45,634: a novel aldose reductase inhibitor that inhibits polyol pathway activity in diabetic and galactosemic rats. 12 97

Studies with the aldose reductase inhibitor alrestatin in animal models have suggested that the sorbitol pathway may be of etiologic significance in the pathogenesis of peripheral neuropathy in diabetes. In normal subjects and in highly selected diabetic patients with severe peripheral neuropathy, alrestatin given either intravenously (50 mg/kg body weight) or orally (1 gm q.i.d.) produced no acute toxicity. The serum half-life of alrestatin was approximately 1 hr, and 99% was recovered in the urine within 24 hr. Two diabetic patients receiving alrestatin intravenously reported subjective improvements in clinical symptoms 2 days following the start of infusions. These improvements lasted approximately 3 wk after infusions were discontinued. However, there were no significant objective changes in peripheral nerve condition velocities, or on neurologic examination. In a 30-day oral trial with alrestatin in 4 diabetics, there were no subjective improvements in clinical symptoms nor were there objective improvements on neurologic examination or in peripheral nerve conduction velocities. In this study, peak serum levels of alrestatin were approximately 3 times lower than those obtained on intravenous administration, and it is possible that a high peak serum level is critical to the attainment of adequate tissue drug concentrations. Furthermore, the patients were suffering from severe clinical peripheral neuropathy, which could represent a stage of permanent irreversible nerve damage. Studies with alrestatin in newly diagnosed diabetics with peripheral nerve conduction velocity deficits but without clinical neuropathy might provide a better test of the sorbitol pathway hypothesis.
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PMID:Aldose reductase inhibition: studies with alrestatin. 12 98

Mixed types of sensory and motor peripheral neuropathy and dementia occurred as neurological complications in patients with established type IV and type V hyperlipoproteinemia. These complications were remedial by control of the hyperlipoproteinemia with diet and/or clofibrate resulting in symptomatic improvement as well as restitution of nerve conduction velocities toward normal. Diabetes mellitus as well as systemic metabolic and toxic disorders which commonly produce neurological complications were excluded. Segmental demyelination with disorganization of myelin lamellae were striking morphological features found on sural nerve biopsy. Fluctuations in memory performance correlated inversely with plasma lipid levels and appear to be a characteristic feature of hyperlipidemic dementia. Hyperlipidemic neuropathy and dementia, although rare, are remediable neurological disorders which should be considered in patients with neuropathy and/or dementia of unknown origin.
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PMID:Hyperlipidemic neuropathy and dementia. 18 Dec 57

Motor nerve conduction velocity was studied in a group of 44 hypertensive patients; velocity was measured at the level of the median and external popliteal sciatic nerves. From the series were excluded those hypertensive subjects with renal insufficiency, diabetes mellitus and peripheral arterial disease. No significant differences were observed in MNCV values compared to controls. Within the hypertense group, no appreciable variations were observed depending on the duration and degree of hypertension, and signs of visceral damage (assessed at myocardial and retinic levels). The results do not confirm previous published data suggesting the existence of MNCV reduction during arterial hypertension, the reduction being considered an subclinical expression of peripheral neuropathy and an index of the gravity of visceral damage during hypertensive disease.
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PMID:[Motor nerve conduction velocity in arterial hypertension]. 18 27

Esophageal function was determined in 50 unselected patients with diabetes mellitus (DM). Fourteen age-matched healthy subjects served as controls. The presence of peripheral neuropathy (PN) was determined by a neurological examination and by nerve conduction studies. An intraluminal transducer assembly placed in the distal esophagus measured pressure in the lower esophageal sphincter and body of the esophagus. Esophageal function was studied both before and after edrophonium chloride, 80 microgram per kg intravenously. There was no significant difference in peristaltic amplitude between the controls and diabetics. There was also no difference in amplitude when DM was divided into presence or absence of PN. However, there was a significant decrease in velocity of peristalsis in DM with PN when compared to DM without PN and to controls. Resting lower esophageal sphincter pressure in DM was similar to controls, with no difference with or without PN. Twenty-eight patients (56%) with DM had abnormal motility, characterized by frequent spontaneous contractions, and decreased prevalence of peristalsis. Abnormal motility in DM was associated with PN and was characterized by a dysfunction of esophageal innervation with intact smooth muscle function.
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PMID:Esophageal function in diabetes mellitus and its relation to peripheral neuropathy. 19 34

The pain of diabetic peripheral neuropathy responds poorly to current modes of treatment. We treated eight patients with this disorder whose pain was refractory to standard regimens but who experienced remarkable pain relief within two to five days after treatment with fluphenazine hydrochloride, amitriptyline hydrochloride, or a combination of the two. In four patients whose regimens were discontinued, pain recurred within two days and again remitted on reinstitution of the drug regimens. These findings suggest that fluphenazine alone or in combination with amitriptyline may be of benefit in treating the painful peripheral neuropathy associated with diabetes.
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PMID:Peripheral diabetic neuropathy treated with amitriptyline and fluphenazine. 19 54

Ketotic, insulin-requiring diabetes mellitus and a severe peripheral neuropathy developed in a previously healthy 25-year-old man several days after he attempted suicide with rat poison containing N-3-pyridylmethyl N'-p-nitrophenyl urea. Study of islet-cell function ten months after ingestion showed a reduced disappearance rate of intravenous glucose and depressed C-peptide response to intravenous glucose when compared with a normal control but no impairment of glucagon release after intravenous arginine stimulation. Nerve conduction studies demonstrated severe sensory and mild motor neuropathy. Quadriceps capillary basement membrane thickness was in the diabetic range. Because at least 15 similar occurrences have been reported to the manufacturer, this agent appears to be diabetogenic in man, probably causing beta-cell destruction. Niacinamide, which can prevent glucose intolerance in both streptozocin- and alloxan-treated animals and prevents death in rats given this rodenticide, may be a useful antidote.
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PMID:Diabetes mellitus following rodenticide ingestion in man. 20 29

Autonomic and pudendal neuropathies are frequent and neglected diseases affecting the genitourinary system. In the initial stages they frequently are asymptomatic. Autonomic neuropathy is seen in association with peripheral neuropathy in a wide range of metabolic diseases, including diabetes mellitus. Diagnosis can only be made directly by electrophysiologic methods. Treatment is based upon an adequate laboratory study of genitourinary function.
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PMID:Autonomic neuropathy and the genitourinary system. 20 85

The incidence of TIA, stroke, and neuropathy was studied in a community-based maturity-onset diabetic population. The frequencies of TIA and stroke were increased in maturity-onset diabetic patients as compared to the population of Rochester, Minnesota. The median age of occurrence of TIA and stroke in diabetics was 74 years, not significantly different from that in non-diabetics. Diabetic patients with hypertension at the time of diagnosis of diabetes mellitus had an increased frequency of TIA and stroke. Control of hypertension and/or diabetes mellitus was associated with a decreased frequency of TIA or stroke. Obesity, clinical coronary heart disease, and an abnormal electrocardiogram at the time of diagnosis of diabetes mellitus were not associated with a significantly increased frequency of TIA or stroke. The most common type of peripheral neuropathy in diabetes mellitus was distal polyneuropathy. Mononeuropathy and autonomic neuropathy were much less frequent. The frequency of distal polyneuropathy increased with the duration of diabetes mellitus. The frequency of neuropathy was increased in patients with poor control, reemphasizing the importance of diabetic control in the prevention of diabetic complications.
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PMID:Neurologic complications of diabetes mellitus: transient ischemic attack, stroke, and peripheral neuropathy. 21 54

A case of acromegaly with peripheral neuropathy characterized by acroparaesthesiae in the median nerve field of both sides is presented. Electrophysiological examination shows bilateral slowing of the motor conduction velocity of the median nerve through the carpal tunnel. The possible pathogenetic mechanisms of the peripheral neuropathy in acromegalic are discussed in the light of the most recent theories about the GH action. Suggestions are made that some associated hormonal disorders diabetes, hyperaldosteronism, hyperthyroidism) can play some part in the neuropathy pathogenesis.
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PMID:[A case of peripheral neuropathy in an acromegalic subject. Pathogenetic considerations]. 23 43


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