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)

The effect of insulinopenic diabetes on the expression of glucose transporters in the small intestine was investigated. Enterocytes were sequentially isolated from jejunum and ileum of normal fed rats, streptozotocin-diabetic rats, and diabetic rats treated with insulin. Facilitative glucose transporter (GLUT) 2, GLUT5, and sodium-dependent glucose transporter 1 protein content was increased from 1.5- to 6-fold in enterocytes isolated from diabetic animals in both jejunum and ileum. Insulin was able to reverse the increase in transporter protein expression seen after induction of diabetes. There was a four- to eightfold increase in the amount of enterocyte glucose transporter mRNA after diabetes with greater changes in sodium-dependent glucose transporter 1 and GLUT2 than in GLUT5 levels. In situ hybridization showed that after the induction of diabetes there was new hybridization in lower villus and crypt enterocytes that was reversed by insulin treatment. Thus, the increase in total hexose transport caused by diabetes is due to a premature expression of hexose transporters by enterocytes along the crypt-villus axis, causing a cumulative increase in enterocyte transporter protein during maturation. These changes are likely to represent an adaptive response by the organism to increase nutrient absorption in a perceived state of tissue starvation. These adaptive changes may lead to exacerbation of hyperglycemia in uncontrolled diabetes.
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PMID:Small intestine hexose transport in experimental diabetes. Increased transporter mRNA and protein expression in enterocytes. 811 95

The metabolic, ionic, and secretory response to D-glucose was investigated in islets of adult rats either injected with streptozotocin during the neonatal period (STZ rats) or presenting with inherited diabetes (GK rats). At a high concentration of D-glucose (16.7 mM), the ATP/ADP ratio was lower in islets from STZ and GK than control rats. This coincided with an impaired response of perifused islets to a rise in D-glucose concentration in terms of stimulation of insulin release, suppression of effluent radioactivity from islets prelabeled with [2-3H]adenosine, reduction in 86Rb efflux, and induction of a phosphate flush in islets prelabeled with 32P(i). The ratio in either D-[5-3H]glucose utilization or D-[2-14C]glucose oxidation at high/low hexose concentration, as well as the paired ratio between D-[2-14C]glucose oxidation and D-[5-3H]glucose utilization in islets incubated at a high concentration of the hexose, was also lower in STZ and GK rats than in control rats. Such was not the case, however, from the oxidation of [2-14C]pyruvate. Instead, the latter 2-keto acid, when tested at a 5.0 mM concentration, improved more efficiently the overall oxidative response of the islets to a rise in D-glucose concentration in STZ and GK rats than in control animals. It is proposed, therefore, that in both STZ and GK rats, the B-cell secretory defect is primarily attributable to an anomaly in oxidative glycolysis. In islets exposed to a high concentration of D-glucose, this metabolic deficiency results in impaired ATP generation, altered closing of ATP-responsive K+ channels, and, hence, diminished insulin output.
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PMID:Metabolic, ionic, and secretory response to D-glucose in islets from rats with acquired or inherited non-insulin-dependent diabetes. 812 95

Insulin rapidly represses expression of the gene encoding the insulin-responsive glucose transporter (GLUT4) in 3T3-L1 mouse adipocytes. Upon exposure to the hormone the cellular level of GLUT4 mRNA falls (t1/2 approximately 2.5 hr) to 20-30% of its initial level within 10 hr. This is followed by a similar decrease in the level of GLUT4 protein. Down-regulation of GLUT4 mRNA is a result of both rapid repression of transcription of the GLUT4 gene and an increased rate of turnover of the GLUT4 message. As a consequence of prolonged exposure to insulin, 3T3-L1 adipocytes lose their capacity for acute stimulation of hexose uptake by insulin. These findings provide an explanation for the resistance of glucose uptake to insulin in adipose tissue observed in non-insulin-dependent (type 2) diabetes mellitus, particularly that associated with hyperinsulinemia and obesity.
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PMID:Insulin down-regulates expression of the insulin-responsive glucose transporter (GLUT4) gene: effects on transcription and mRNA turnover. 842 83

Abnormal plasma ascorbic acid (AA) and dehydroascorbic acid (DHAA) levels observed in diabetes may be correlated to a deficiency in the recycling of AA. Ascorbic acid and DHAA levels are altered in diabetic liver in the present study. In addition, a coupling of the hexose monophosphate (HMP) shunt by way of NADPH to glutathione reductase and subsequent DHAA reduction is demonstrated. Ascorbic acid production was assayed directly and by way of the HMPS pathway. Results indicate that AA production from DHAA via the HMPS pathway occurs, and is significantly decreased in diabetic liver. Glucose-6-phosphate dehydrogenase (G6PDH) activity is shown to be decreased in diabetic liver. Since G6PDH is essential in providing NADPH for the reduction of glutathione required for subsequent DHAA reduction, its decreased activity is consistent with altered levels of AA and DHAA observed in diabetic tissues.
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PMID:Enzymatic basis for altered ascorbic acid and dehydroascorbic acid levels in diabetes. 846 10

In islets from adult rats injected with streptozotocin during the neonatal period, both a nonmetabolized analog of L-leucine and 3-phenylpyruvate augmented 14CO2 output from islets either prelabeled with L-[U-14C]glutamine or exposed to D-[2-14C]glucose and D-[6-14C]glucose, in a manner qualitatively comparable to that found in islets from control rats. The islets of diabetic rats differed, however, from those of control rats by their unresponsiveness to both the L-leucine analog and a high concentration of D-glucose in terms of increasing 3HOH generation from [2-3H]glycerol, an impaired sparing action of the hexose upon 14CO2 output from islets prelabeled with [U-14C]palmitate, and, most importantly, by a decreased rate of D-[2-14C]glucose and D-[6-14C]glucose oxidation when either incubated at a high concentration of the hexose (16.7 mM) or stimulated by nonglucidic nutrient secretagogues at a low concentration of D-glucose (2.8 mM). In islet homogenates, the activity of glyceraldehyde phosphate dehydrogenase, glutamate decarboxylase, and NADP-malate dehydrogenase was lower in diabetic than control islets. Such was not the case for glutamate-alanine transaminase, glutamate-aspartate transaminase, or glutamate dehydrogenase. The neonatal injection of streptozotocin thus affected, in the adult rats, the activity of several islet enzymes. Nevertheless, the metabolic data suggest that an impaired circulation in the glycerol phosphate shuttle, as observed in response to stimulation of the islets by either a high concentration of D-glucose or nonglucidic nutrient secretagogues, represents an essential determinant of the preferential impairment of glucose-induced insulin release in this model of non-insulin-dependent diabetes.
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PMID:Metabolic response to nonglucidic nutrient secretagogues and enzymatic activities in pancreatic islets of adult rats after neonatal streptozotocin administration. 848 60

In perifused pancreatic islets from euglycemic rats, the secretory response to either glibenclamide or glimepiride (1.0 microM each) increases as a function of the concentration of D-glucose (2.8-16.7 mM) present in the perifusion medium. On the contrary, the sulfonylurea-induced increment in 45Ca efflux from prelabeled islets decreases at increasing concentrations of the hexose. Neither glibenclamide nor glimepiride affect D-glucose metabolism in isolated islets, as judged from the production of 3HOH from D-[5-3H]glucose or the generation of 14CO2, as well as 14C-labeled amino acids and acidic metabolites, from D-[3,4-14C]glucose, D-[2-14C]glucose and D-[6-14C]glucose. The insulinotropic action of the hypoglycemic sulfonylureas is not impaired in islets prepared from rats infused for 48 hr with a hypertonic solution of D-glucose. The dimethyl ester of succinic acid is more efficient than D-glucose in supporting the insulin-releasing effect of glibenclamide or glimepiride. Thus, although the insulinotropic action of hypoglycemic sulfonylureas appears unaffected in a model of B-cell glucotoxicity, a potentiation of their secretory effects might be expected, in non-insulin-dependent diabetes, from the combined administration of succinic acid methyl ester.
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PMID:Modulation of the insulinotropic action of glibenclamide and glimepiride by nutrient secretagogues in pancreatic islets from normoglycemic and hyperglycemic rats. 849 43

Isolated ventral and dorsal rat spinal roots incubated in normal (2.5 mM) or high glucose (25 mM) concentrations or in high concentrations of other hexoses were exposed transiently to hypoxia (30 min) in a solution of low buffering power. Compound nerve action potentials, extracellular direct current potentials, and interstitial pH were continuously recorded before, during, and after hypoxia. Ventral roots incubated in 25 mM D-glucose showed resistance to hypoxia. Dorsal roots, on the other hand, revealed electrophysiological damage by hyperglycemic hypoxia as indicated by a lack of posthypoxic recovery. In both types of spinal roots, interstitial acidification was most pronounced during hyperglycemic hypoxia. The changes in the sensitivity to hypoxia induced by high concentrations of D-glucose were imitated by high concentrations of D-mannose. In contrast, D-galactose, L-glucose, D-fructose, and L-fucose did not have such effects. Resistance to hypoxia, hypoxia-generated interstitial acidification, and hypoxia-induced electrophysiological damage were absent after pharmacological inhibition of nerve glycolysis with iodoacetate. These observations indicate 1) that enhanced anaerobic glycolysis produces resistance to hypoxia in hyperglycemic peripheral nerves and 2) that acidification may impair the function of peripheral axons when anaerobic glycolysis proceeds in a tissue with reduced buffering power.
Diabetes 1993 Jul
PMID:The paradox between resistance to hypoxia and liability to hypoxic damage in hyperglycemic peripheral nerves. Evidence for glycolysis involvement. 851 79

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

Diabetic lens glucose metabolism in vivo can be altered by a number of exogenous substrates. We have chosen two, one a glucose epimer (mannose) and the other a glycolytic intermediate (pyruvate), to demonstrate the possibility of this approach. D(+)-Mannose is a D(+)-glucose epimer but in lenses incubated in 35.5 mM mannose, no mannitol (the sorbitol equivalent) was detected, while both lactate production and 31P profile appeared normal. Mannose therefore is a good glucose substitute causing no polyol formation. Mannose metabolism in the rat lens in vivo was then examined. Diabetic rats fed mannose-enriched diet over a period of 14 days showed retardation of changes in 31P metabolites, specifically the levels of phosphorylcholine and glycerophosphorylcholine, suggesting a protective effect. Rat lenses incubated in 35.5 mM glucose in the presence of 5 mM pyruvate (pyr) showed 50% lower sorbitol than without pyr. With 5 mM pyr in the drinking water, i.e. pretreatment in vivo during a 3-day diabetes induction period, the diabetic rat lens accumulated acetate and alanine when incubated in the presence of pyr. The decrease in sorbitol was most likely due to a lower glucose flux rather than an increased polyol dehydrogenase activity. Increasing glucose concentration from 5.5 to 35.5 mM or provision of exogenous pyr both caused an intermediate increase in O2 consumption in the normal lens; a maximal activity was reached with both 35.5 mM glucose and 5 mM pyruvate in the incubating medium. In the diabetic lens, O2 consumption could reach the intermediate but not the maximal level. Dietary pyr pre-treatment also prevented normal and diabetic lenses from maximal pyr-stimulated O2 consumption. The NMR and O2 consumption data together indicated activation of alanine dehydrogenase and saturation of Krebs cycle. It appears that dietary supplement of mannose can preserve 31P membrane metabolites in the diabetic lens. Mannose can be used in conjunction with hypoglycemic therapy for the management of diabetic cataract. In addition, pyruvate may be effective in enhancing lens energy metabolism and lower sorbitol production.
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PMID:Manipulating rat lens glucose metabolism with exogenous substrates. 854 89

This study was undertaken to determine whether there are age-related changes in the specific activities of several glycosidases in fresh retinal pigment epithelial cells (RPE) isolated from the posterior pole of human donor eyes. One hundred and twenty-one pairs of eyes from human donors, between the ages of 43 and 95 years, were obtained from the National Disease Research Interchange (NDRI, Philadelphia, PA) and the Cleveland Ohio Eye Bank within 18 to 24 h of death. None had histories of diabetes, hepatitis, HIV infection, intraocular surgery, or documented age-related macular degeneration, although several older donors with evidence of drusen were included in the study. RPE cells were isolated from the posterior third of the retina using the conventional rush method and homogenized with a glass, Broeck tissue grinder. All post-nuclear supernatants were analyzed for glycosidase activity; a smaller number of nuclear pellets were assayed to verify that the majority of the enzyme activity was associated with the post-nuclear sypernatants. Glycosidase activity was quantitated fluorometrically by measuring the enzymatic release of umbelliferone from synthetic substrate preparations, specific for each enzyme. Total protein was determined by a micro BCA protein assay. Regression analysis revealed statistically significant age-related decreases for the specific activities of alpha-mannosidase (p = 0.0001), beta-galactosidase (p = 0.0001), N-acetyl-beta-glucosaminidase (p = 0.0001), and N-acetyl beta galactosaminidase (p = 0.0001) in fresh human donor RPE cells taken from the region of the posterior third of the retina that included the macula. Mannose and N-acetyl-glucosamine are major carbohydrate monomers of the oligosaccaride chains of human rhodopsin, and a relatively high percentage of the oligosaccharide chains are galactosylated. Defects in their degradation may lead to the accumulation of undigested residual material in the RPE.
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PMID:Age-related changes of glycosidases in human retinal pigment epithelium. 867 Jul 43


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