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

Cataract is the major cause of blindness worldwide and at present the only approved treatment in many countries including the UK and USA is surgical removal of the lens. In other countries various anti-cataract drugs are available without proof of their efficacy. Research is continuing into the possible benefits of several groups of drugs and some vitamins. The first to be studied were sorbitol-lowering agents (aldose reductase inhibitors) based on the sorbitol hypothesis for diabetic cataract. Sorbitol-lowering agents have distinct effects in vitro and many of them delay the development of cataract in galactose-fed rats. A few delay cataract in diabetic rats but none have been proved effective in clinical trials, although these continue. Aspirin, paracetamol (acetaminophen) and ibuprofen delay diabetic cataract in rats, and have been shown to delay other experimental cataracts. Case-control studies from 3 continents indicate that these drugs, or at least aspirin, protect against cataract. Results of studies on all 3 drugs indicate a benefit even at low doses. Population-based studies did not identify any protection against early lens opacities but tiny opacities that do not impair vision are not a problem. Bendazac protects lens proteins in vitro and delays cataractogenesis in x-irradiated rats. In humans, it reached the clinical trial stage but most trials have been small and with subjective criteria of opacification. One objectively monitored trial suffered from a high drop-out rate. Other preparations studied less extensively include vitamins, aminoguanidine to prevent protein cross-linking in diabetes and agents designed to boost glutathione levels. It is probable that some agents which may delay or prevent cataract will be proved effective soon, and in the end there may be different drugs to delay cataract in different high risk groups. This is what might be expected of a multifactorial disease, although compounds that intervene in the final common pathways to cataract could have a broad efficacy.
 ...
PMID:Pharmacological treatment strategies in age-related cataracts. 150 43

1. This study investigated the constrictor responsiveness to endothelin-1 (ET-1, 0.1 nM-0.1 microM) of aortic rings (under 10 g resting tension in Krebs solution) from 2- and 6-week streptozotocin (STZ, 60 mg kg-1, i.v.)-induced diabetic rats and vehicle-treated control rats. 2. In aortae from 2- and 6-week STZ-treated rats, and their corresponding controls, removal of endothelium caused leftward shifts of ET-1 concentration-response curves without affecting maximum responses. 3. Maximum responses to ET-1 were reduced in aortae from both 2- and 6-week STZ-treated rats compared to those from control rats. Such reductions were still evident after removal of the endothelium. 4. Decreased responsiveness to ET-1 of aortae from 2-week STZ-treated rats was still evident after chronic treatment with the aldose reductase inhibitor epalrestat, but not after chronic insulin treatment or in aortae bathed in high glucose (30 mM) Krebs solution. 5. Decreased responsiveness to ET-1 of aortae from 6-week STZ-treated rats (compared with those from controls) was still evident after chronic epalrestat treatment and in high glucose Krebs solution. 6. These data suggest that the decreased responsiveness to ET-1 observed in aortae from 2- and 6-week STZ-induced diabetic rats is not due to abnormal activity of the polyol pathway. The altered responsiveness in aortae from 2-week diabetic rats (compared with those from control rats) may possibly be a manifestation of changes (adaptive or otherwise) which occur as a result of high glucose concentrations in vivo.However, in aortae from rats with diabetes of longer duration, other mechanisms may also play a role in the altered responsiveness, since it was no longer reversible by bathing in high glucose Krebs solution.
 ...
PMID:Effects of glucose, insulin or aldose reductase inhibition on responses to endothelin-1 of aortic rings from streptozotocin-induced diabetic rats. 150 47

Pharmacological effects of Gosha-jinki-gan-ryo extract (KJE) on experimental diabetes induced by cyproheptadine (CPH), aldose reductase activity, and experimental peripheral neuropathy were studied. The effects of KJE were compared with those of Hachimi-jio-gan-ryo extract (HJE). KJE at 417 mg/kg/day (5 times the daily dose in humans) and HJE at 367 mg/kg/day (5 times the daily dose in humans) significantly inhibited the decrease in glucose tolerance by CPH. KJE and HJE inhibited aldose reductase activity, when DL-glyceraldehyde was used as substrate, with IC50 values of 2.68 x 10(-5) g/ml and 4.45 x 10(-5) g/ml, respectively and when D-glucose was used as substrate, with IC50 values of 1.04 x 10(-4) g/ml and 1.55 x 10(-4) g/ml, respectively. KJE at 209 mg/kg/day (2.5 times the daily dose in humans) and HJE at 367 mg/kg/day significantly reduced peripheral neuropathy induced by crushing the sciatic nerve in rats. The potency of these effects of KJE was stronger than that of HJE, when a comparison was made on the basis of the daily dose.
 ...
PMID:[Pharmacological effects of Gosha-jinki-gan-ryo extract: effects on experimental diabetes]. 150 54

These studies were undertaken to examine effects of elevated glucose levels on glycolysis, sorbitol pathway activity, and the cytosolic redox state of NADH/NAD+ in isolated glomeruli. Blood-free glomeruli were isolated from kidneys of male, Sprague-Dawley rats using standard sieving techniques, then incubated for one hour at 37 degrees C, pH 7.4, pO2 approximately 500 torr, in Krebs bicarbonate/Hepes buffer containing 5 or 30 mM glucose. Elevated glucose levels increased glucose 6-phosphate, fructose 6-phosphate, total triose phosphates, lactate, the lactate/pyruvate ratio, sorbitol, and fructose, but did not affect sn-glycerol 3-phosphate, pyruvate, or myo-inositol levels. The more reduced glomerular cytosolic redox state (manifested by the tissue lactate/pyruvate ratio) induced by 30 mM glucose was completely abrogated by aldose reductase inhibitors added to the diet two to seven days prior to glomerular isolation. These observations, coupled with evidence linking glucose- and diabetes-induced glomerular dysfunction to increased sorbitol pathway metabolism, support the hypothesis that metabolic imbalances associated with a more reduced ratio of cytosolic NADH/NAD+ (resulting from increased glucose metabolism via the sorbitol pathway) play an important role in mediating glucose- and diabetes-induced glomerular dysfunction.
 ...
PMID:Diabetes-induced glomerular dysfunction: links to a more reduced cytosolic ratio of NADH/NAD+. 151

The effects of aldose reductase inhibition on kidney function were studied in rats with streptozotocin-induced diabetes mellitus. Diabetic rats were fed sorbinil (20 and 50 mg/kg) by daily gastric gavage and were compared with untreated diabetic rats and normal rats. The rats were under daily supervision with regard to blood glucose control, insulin administration and body weight. The aim was to promote continuous body growth and to maintain the blood glucose concentration at around 22 mmol/l without large day-to-day fluctuations. The renal functional changes observed in this well-established diabetic model closely resembled those reported in human Type 1 (insulin-dependent) diabetes mellitus. Sorbinil treatment completely prevented renal cortical sorbital accumulation, but did not abolish kidney enlargement or the increase in ultrafiltration pressure and glomerular filtration rate. Albumin excretion was increased to the same extent in the sorbinil-treated and in the untreated diabetic rats. We conclude that increased metabolism of glucose to sorbitol does not cause the hyperfiltration in rats with streptozotocin-induced diabetes.
 ...
PMID:Sorbinil does not prevent hyperfiltration, elevated ultrafiltration pressure and albuminuria in streptozotocin-diabetic rats. 152 21

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.
 ...
PMID:Muscle and nerve dysfunction in rats with experimental galactosaemia. 153 21

The substrate specificities of human aldose reductase and aldehyde reductase toward trioses, triose phosphates, and related three-carbon aldehydes and ketones were evaluated. Both enzymes are able to catalyze the NADPH-dependent reduction of all of the substrates used. Aldose reductase shows more discrimination among substrates than does aldehyde reductase and is generally the more efficient catalyst. The best substrate for aldose reductase is methylglyoxal (kcat = 142 min-1, kcat/Km = 1.8 x 10(7) M-1 min-1), a toxic 2-oxo-aldehyde that is produced nonenzymatically from triose phosphates and enzymatically from acetone/acetol metabolism. D- and L-glyceraldehyde and D- and L-lactaldehyde are also good substrates for aldose reductase. The aldose reductase-catalyzed reduction of methylglyoxal produces 95% acetol, 5% D-lactaldehyde. Further reduction of acetol produces only L-1,2-propanediol. Acetol and propanediol are two products that accumulate in uncontrolled diabetes. Both acetol and methylglyoxal were compared with glucose for their abilities to produce covalent modification of albumin. All three of these carbonyl compounds reacted with albumin to produce modified proteins with new absorption and emission bands that are spectrally similar. Both methylglyoxal and acetol are much more reactive than glucose. A new integrative model of diabetic complications is proposed that combines the aldose reductase/polyol pathway theory and the nonenzymatic glycation theory except that emphasis is placed both on methylglyoxal/acetol metabolism and on glucose metabolism.
 ...
PMID:Reduction of trioses by NADPH-dependent aldo-keto reductases. Aldose reductase, methylglyoxal, and diabetic complications. 153 26

Many patients with diabetes who may benefit from treatment with tolrestat, a new aldose reductase inhibitor, will have nephropathy. Therefore the effect of renal dysfunction on the pharmacokinetics of tolrestat was evaluated in eight subjects maintained on hemodialysis, 11 subjects with partial renal impairment (creatinine clearance values ranging from 14 to 80 ml/min/1.73 m2), and eight normal subjects. Each subject received a single oral dose of 200 mg tolrestat. Blood and urine samples were collected during a 48-hour period, and tolrestat concentrations were measured by HPLC. Renal dysfunction had no apparent effect on the rate of absorption or volume of distribution of tolrestat. However, tolrestat clearance was significantly reduced from 30 +/- 3 (SD) ml/hr/kg in the normal subjects to 15 +/- 5 ml/hr/kg in the subjects receiving dialysis, and tolrestat half-life was prolonged from 11 to 16 hours. Therefore a reduction in tolrestat dose is suggested for patients with severe renal impairment.
 ...
PMID:The effect of renal disease on tolrestat pharmacokinetics. 154 87

Since 1981 a number of aldose reductase inhibitors (ARIs) have been extensively investigated in clinical trials for the treatment or prevention of diabetic complications. In general, the results from these trials have varied from no effect to improvement. In part, the inconclusive results are due to differences in the study designs. Investigation of some ARIs has been discontinued because of lack of efficacy (ponalrestat) or major toxicity (sorbinil). Of the ARIs that have been evaluated, only tolrestat is currently undergoing clinical investigation. Although the most recent studies have shown promising results, the role of ARIs in the treatment or prevention of secondary complications of diabetic neuropathy will be determined in ongoing or future clinical trials.
J Diabetes Complications
PMID:Recent clinical experience with aldose reductase inhibitors. 156 57

Tolrestat is an aldose reductase inhibitor that is undergoing extensive clinical investigation for the treatment of diabetic complications including polyneuropathy. As part of a larger European trial, we report here the results from a single clinical center on the efficacy of tolrestat in patients with confirmed diabetic neuropathy. The trial was conducted in two phases: a 6-month double-blind, placebo-controlled phase, and a 6-month open-label phase in which most patients were treated with tolrestat. Following the double-blind phase, motor and sensory nerve conduction velocity had significantly deteriorated in the placebo group, which did not occur during treatment with tolrestat. Deterioration of vibration threshold also occurred during placebo treatment and did not occur with tolrestat. During the open-label phase, motor nerve condition velocity and vibration threshold improved with tolrestat. Moreover, the deterioration of motor nerve conduction velocity and vibration threshold that had occurred in patients initially treated with placebo, was stopped during open-label treatment with tolrestat.
J Diabetes Complications
PMID:Long-term effects of tolrestat on symptomatic diabetic sensory polyneuropathy. 156 58


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>