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)

Recent work from our laboratory revealed a correlation between the degree of protein pigmentation in human cataractous lens and the advanced Maillard reaction as reflected by pentosidine formation. Although the data suggested a role for ascorbate in pentosidine formation in senile cataractous lenses, elevated pentosidine levels in diabetic cataracts suggested that glucosylation may be involved directly in pentosidine biosynthesis. To clarify this issue, we quantified pentosidine in lenses from rats with experimental galactosemia with and without aldose reductase inhibitor treatment. At 12 months, pentosidine-like fluorescence (335/385 nm) was three to six times higher (P < 0.0001) in water soluble and insoluble crystallins of galactosemic compared with nongalactosemic rats. Actual pentosidine levels increased shortly after onset of galactosemia. Contents in water-insoluble crystallins were 6.32 +/- 2.2 and 1.40 +/- 0.66 pmol/mg protein in galactosemic and control lenses, respectively (P < 0.001). Fluorescence and pentosidine were suppressed to almost control levels upon treatment with sorbinil. Incubation experiments showed that pentosidine could form slowly from galactose, but much more rapidly from ascorbate and its oxidation products. Its formation could be inhibited partly by both reduced and oxidized glutathione or epsilon-aminocaproic acid. The requirement of oxygen for pentosidine formation suggests that oxidative stress associated with glutathione depletion and ascorbate oxidation are plausible mechanisms for rapid pentosidine formation upon onset of galactosemia. In contrast, Maillard reaction by glycoxidation products may account for the sustained increase in pentosidine. Both these events may be linked to the newly recognized pseudohypoxic state of cells exposed to high sugar concentrations.
Diabetes 1994 Apr
PMID:Suppression of pentosidine formation in galactosemic rat lens by an inhibitor of aldose reductase. 813 64

Capillary basement membrane thickening has been compared in retina, renal glomerulus, and leg muscle of dogs alloxan-diabetic 5 years and dogs experimentally galactosemic 5 years, and the effects of inhibition of aldose reductase have been examined. Basement membrane in each site became thickened as a result of either galactosemia or diabetes, but showed appreciable variation among the sites. The thickening of basement membrane in retina and muscle of galactosemic animals was similar in quantity and appearance to that seen in the diabetics, notwithstanding large differences between the two animal models with respect to tissue polyol concentrations and nonenzymatic glycation of hemoglobin and plasma protein. Aldose reductase inhibition was without influence on capillary basement membrane thickening in each tissue from dogs diabetic or galactosemic 5 years, despite substantial polyol path inhibition.
J Diabetes Complications
PMID:Capillary basement membrane in retina, kidney, and muscle of diabetic dogs and galactosemic dogs and its response to 5 years aldose reductase inhibition. 821 67

The detection of a cataract in combination with a neurological deficit may provide the physician with important diagnostic help. But a minority of underlying diseases (angiokeratoma corporis diffusum, cerebrotendinous xanthomatosis, diabetes mellitus, galactosemia, hypocalcemia, Refsum's disease, Wilson's disease; Charles Bonnet syndrome; relapsing Perichondritis; adverse effects of medication and intoxications) can be treated causally. Therefore they are summed up and discussed in this paper.
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PMID:[Treatable diseases of the nervous system with cataract formation]. 848 73

To investigate a possible role of excessive polyol production in the pathogenesis of diabetic retinopathy, 16 ALX-induced diabetic dogs and 20 experimentally galactosemic dogs were randomly assigned to 5 yr of treatment with either sorbinil, an aldose reductase inhibitor, or a placebo. The severity of hyperglycemia in sorbinil-treated and placebo groups was monitored throughout the 5-yr study by assay of glycosuria and nonenzymatically glycated plasma protein and HbA1 needed in an effort to avoid confounding possible group differences in hyperglycemia severity with possible drug effects. Inhibition of polyol production by sorbinil was monitored in erythrocytes throughout the study and also in retina and other tissue obtained at autopsy. Trypsin digests of retinal vessels were compared after 60 mo of diabetes and after 42 and 60 mo of galactosemia. In diabetic dogs, development of retinopathy was not significantly influenced by a sorbinil dose (20 mg.kg-1 x day-1) sufficient to prevent elevation of sorbitol levels in retina and other tissue. Likewise, in dogs made experimentally galactosemic for 42-60 mo, administration of sorbinil (60-80 mg.kg-1 x day-1) had no significant effect on the development of retinopathy notwithstanding prevention of 93-96% of the polyol elevation in retina and other tissue. Retinal capillary basement membrane was significantly thicker than normal in diabetic and in galactosemic dogs and was not significantly influenced by administration of sorbinil in either dog model. Thus, no evidence was found that the development of retinopathy is critically dependent on excessive polyol production or accumulation.
Diabetes 1993 Jun
PMID:Aldose reductase inhibition fails to prevent retinopathy in diabetic and galactosemic dogs. 828 59

The kidneys of streptozotocin (STZ)-diabetic rats are resistant to certain toxic effects of the antineoplastic drug cisplatin. The mechanism is unknown. This study used the galactosemic rat model to test the hypothesis that the apparent diabetes-induced protection is due to changes in the kidney secondary to chronically elevated hexose concentrations. Galactosemic rats are normoinsulinemic and are free from many of the multiple biochemical abnormalities seen in STZ diabetics. The experiments compared renal cortical platinum (Pt) and blood urea nitrogen (BUN) levels after intraperitoneal injection of 5 mg/kg of cisplatin in galactosemic, STZ-diabetic, and age-matched nondiabetic Sprague-Dawley rats. Nephrotoxicity was defined as a BUN concentration ratio (after to before cisplatin) > 2.5. The results demonstrate that the kidneys of both galactosemic and STZ-diabetic rats became resistant to cisplatin-induced elevation of BUN and, further, that the development of the protection was related to the duration of the diabetic state. Although the protective effect developed more slowly in the galactosemic rats, the attenuation of the rise in BUN was ultimately comparable to that seen in STZ diabetics. Renal cortex [Pt] after cisplatin injection was significantly lower in galactosemics and STZ diabetics compared with age-matched nondiabetics, with the order nondiabetics > galactosemics > STZ diabetics. It was noted, however, that renal Pt accumulation was maximally depressed within 4 weeks of experimental diabetes, whereas the BUN ratio continued to decline with increasing duration of both galactosemia and STZ diabetes. Thus, reduced renal Pt accumulation cannot by itself explain the progressive attenuation of the toxicity. The results support the hypothesis and suggest that the galactosemic rat will be a useful model for mechanistic study of diabetes-induced protection from cisplatin nephrotoxicity.
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PMID:Reduced renal accumulation and toxicity of cisplatin in experimental galactosemia. 851 46

A novel amino acid named aldosine was isolated from acid hydrolysates of bovine aorta elastin. The mass spectral analysis of aldosine indicated a parent compound with a mass of 256 (C12H20N2O4). From the structure identified by spectroscopy of aldosine and its derivatives, it was deduced that aldosine was derived from aldol crosslink and dehydromerodesmosine of elastin and collagen. The aldosine content in aorta of newborn rats was very low, but increased markedly with growth. After maturity was reached, the aldosine content decreased. The aldosine content in bovine aorta decreased gradually from 7 months to 16 years of age. Aldosine was also quantified in the aorta and tail tendon of rats in two models of hyperglycemia: diabetes and galactosemia. Hyperglycemias were significantly affected on aldosine content of organs. In both diabetic and galactosemic animals, aldosine was remarkably lower relative to controls (about one-half and one-sixth, respectively).
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PMID:An amino acid derived from aldol crosslink of elastin and collagen: structure, distribution, aging, and two models of hyperglycemia. 856 94

To reconstruct the mechanisms for the vasoobliteration that transforms diabetic retinopathy into an ischemic retinopathy, we compared the occurrence of cell death in situ in retinal microvessels of diabetic and nondiabetic individuals. Trypsin digests and sections prepared from the retinas of seven patients (age 67 +/- 7 yr) with .9 +/- 4 yr of diabetes and eight age- and sex-matched nondiabetic controls were studied with the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) reaction which detects preferentially apoptotic DNA fragmentation. The count of total TUNEL+ nuclei was significantly greater in the microvessels of diabetic (13 +/- 12 per one-sixth of retina) than control subjects (1.3 +/- 1.4, P = 0.0016), as were the counts of TUNEL+ pericytes and endothelial cells (P < 0.006). The neural retinas from both diabetic and nondiabetic subjects were uniformly TUNEL-. Retinal microvessels of rats with short duration of experimental diabetes or galactosemia and absent or minimal morphological changes of retinopathy, showed TUNEL+ pericytes and endothelial cells, which were absent in control rats. These findings indicate that (a) diabetes and galactosemia lead to accelerated death in situ of both retinal pericytes and endothelial cells; (b) the event is specific for vascular cells; (c) it precedes histological evidence of retinopathy; and (d) it can be induced by isolated hyperhexosemia. A cycle of accelerated death and renewal of endothelial cells may contribute to vascular architectural changes and, upon exhaustion of replicative life span, to capillary obliteration.
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PMID:Accelerated death of retinal microvascular cells in human and experimental diabetic retinopathy. 867 2

Effects of antioxidants on hyperglycemia-induced alterations of retinal metabolism were evaluated in rats diabetic or experimentally galactosemic for 2 months. Oxidative stress was estimated by measuring lipid peroxides (measured as thiobarbituric acid reactive substances [TBARS]) in retina and plasma. Erythrocyte osmotic fragility, another measure of oxidative stress, also was determined in the same groups of rats. In diabetic rats, TBARS were elevated by 74% in retina and 87% in plasma. In galactose-fed rats, TBARS were significantly elevated in retina (P < 0.05), but were normal in plasma. The administration of supplemental dietary ascorbic acid and alpha-tocopherol acetate for 2 months prevented the elevation of retinal TBARS and the decrease of Na(+)-K(+)-ATPase and calcium ATPase activities in retinas of diabetic animals without having any beneficial effect on plasma TBARS. In galactosemic rats, these antioxidants had a partial beneficial effect on the activity of retinal Na(+)-K(+)-ATPase, but failed to have any effect on calcium ATPase. The beneficial effects of antioxidants in diabetes and experimental galactosemia were not caused by the amelioration of hyperglycemia or retinal polyol accumulation. Erythrocyte osmotic fragility was increased by more than twofold in diabetes, but was normal in experimental galactosemia, and antioxidants prevented diabetes-induced increases in erythrocyte osmotic fragility-Diabetes-induced increased oxidative stress and subnormal ATPase activities in the retina can be inhibited by dietary supplementation with antioxidants.
Diabetes 1996 Sep
PMID:Abnormalities of retinal metabolism in diabetes or experimental galactosemia. III. Effects of antioxidants. 877 28

Activities of enzymes that protect the retina from reactive oxygen species were investigated in experimentally diabetic rats and experimentally galactosemic rats, two animal models known to develop vascular lesions consistent with diabetic retinopathy. Diabetes or experimental galactosemia of 2 months duration significantly decreased the activities of glutathione reductase and glutathione peroxidase in the retina while having no effect on the glutathione synthesizing enzymes glutathione synthetase and gamma-glutamyl cysteine synthetase. Activities of two other important antioxidant defense enzymes-superoxide dismutase (SOD) and catalase-also were decreased (by more than 25%) in retinas of diabetic rats and galactosemic rats. Administration of supplemental antioxidants, vitamins C and E, for the 2 months prevented the diabetes-induced impairment of antioxidant defense system in the retina. In experimentally galactosemic rats, the supplemental antioxidants were not as effective: SOD activity was normalized, but the enzymes of the glutathione redox cycle were only partly restored, and the subnormal catalase activity was unaffected. Diabetes or experimental galactosemia results in significant impairment of the antioxidant defense system in the retina, and exogenous antioxidant supplementation can help alleviate the subnormal activities of antioxidant defense enzymes.
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PMID:Abnormalities of retinal metabolism in diabetes or experimental galactosemia. IV. Antioxidant defense system. 901 21

In the retinas of diabetic animals, protein kinase C (PKC) activity is elevated, and Na+-K+-ATPase and calcium ATPase activities are subnormal. These abnormalities are also present in another model of diabetic retinopathy, experimental galactosemia. We have investigated the relationship between hyperglycemia-induced abnormalities of PKC and ATPases using a selective inhibitor of beta isoform of PKC (LY333531). Diabetes or experimental galactosemia of 2 months' duration resulted in > 50% elevation of PKC activity in the retina, and administration of LY333531 prevented the elevation. In retinas of the same rats, the LY333531 prevented hyperglycemia-induced decreases of both Na+-K+-ATPase and calcium ATPase activities. Retinal microvessels, the main site of lesions in diabetic retinopathy, likewise showed elevated activity of PKC and inhibition of ATPases in diabetes and in experimental galactosemia, and administration of LY333531 to diabetic animals prevented these abnormalities. PKC activity in sciatic nerves, in contrast, became subnormal in diabetes and experimental galactosemia, and LY333531 had no effect on PKC activity in the sciatic nerve. PKC activity in the cerebral cortex was not affected by diabetes or experimental galactosemia. The results suggest that diabetes-induced reductions in Na+-K+-ATPase and calcium ATPase in the retina are mediated in large part by PKC-beta. The availability of an agent that can normalize the hyperglycemia-induced increase in PKC activity in the retina should facilitate investigation of the role of PKC in the development of diabetic retinopathy.
Diabetes 1998 Mar
PMID:Abnormalities of retinal metabolism in diabetes or experimental galactosemia: V. Relationship between protein kinase C and ATPases. 951 55


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