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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of L-alanine on hepatic glucose production in diabetic rats and the corresponding controls was investigated. Diabetes was obtained with an injection iv of streptozotocin (STZ) or alloxan. Livers from diabetic and control rats after 24 hours of fasting were perfused in situ and glucose production from L-alanine and several gluconeogenic substrates were measured. Hepatic gluconeogenesis from L-alanine was absent in rats with diabetes induced by STZ or alloxan. STZ-diabetic rats also shown this metabolic change when the period of diabetes was prolonged. It was concluded that this effect may be partly at least, the consequence of an increased NADH/NAD+ ratio in the diabetic rat liver, which indicates that the cytosolic redox potential is favorable to pyruvate conversion to L-lactate but not to glucose. However, considering that glucose production from pyruvate, L-lactate, glycerol and sorbitol was not affected by the diabetic condition, the rate of conversion of L-alanine to pyruvate can contribute to the lack of gluconeogenesis when this amino acid was employed as a substrate.
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PMID:Hepatic glucose production from L-alanine is absent in perfused liver of diabetic rats. 909 Jul 51

Four mitochondrial protein kinases have been cloned. These proteins represent a new family of protein kinases, related by sequence to the bacterial protein kinases but by function to the eukaryotic serine protein kinases. Arg288 is required for recognition by BCKDK of the phosphorylation site on the E1alpha subunit of the BCKDH complex. BCKDK inhibits the dehydrogenase activity of the BCKDH complex by introducing a negative charge into the active-site pocket of the E1 component. Protein starvation of rats induces an increase in the amount of BCKDK bound to the BCKDH complex. This causes inactivation of the BCKDH complex and conserves branched-chain amino acids for protein synthesis in the protein-starved state. Expression of the different PDK isoenzymes is tissue specific, and the different PDK isoenzymes are unique with respect to kinetic parameters for ATP and ADP and sensitivity to allosteric effectors (NADH, NAD+, coenzyme A, acetyl-CoA, pyruvate, and dichloroacetate). Preliminary experiments indicate that an increased amount of PDK2 protein partly explains the increase in PDK activity that occurs in rat liver in response to chemically induced diabetes.
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PMID:Mitochondrial alpha-ketoacid dehydrogenase kinases: a new family of protein kinases. 934 45

In our previous study (Diabetes 44:520-526, 1995), endothelial cells cultured in high glucose condition showed impairment of an oxidant-induced activation of the pentose phosphate pathway (PPP) and a reduced supply of NADPH to the glutathione redox cycle. To gain insight into the mechanisms of this impairment, the protective effect of pyruvate was studied in human umbilical vein endothelial cells cultured in either 5.5 mmol/l glucose (normal glucose [NG] condition) or 33 mmol/l glucose (high glucose [HG] condition). Through pretreatment of cells with 0.2 mmol/l pyruvate for 5-7 days in the HG condition, glucose oxidation through the PPP and total cellular NADPH content in the presence of 0.2 mmol/l H2O2 were increased by 54 (P < 0.05) and 34%, respectively, and glutathione-dependent degradation of H2O2 in HG cells was enhanced by 41% (P < 0.01), when compared with those cells to which pyruvate was not added. The addition of pyruvate significantly reduced the fructose 1,6-bisphosphate (FDP) content and free cytoplasmic NADH/NAD ratio, estimated by increased pyruvate/lactate ratio in NG and HG cells exposed to H2O2. Furthermore, the addition of pyruvate also showed a 46% reduction (P < 0.01) of endothelial cell damage induced by H2O2 in HG cells. These results indicate that abnormalities in PPP activation and glutathione redox cycle activity induced by H2O2 in HG cells are compensated, and that the accentuated reductive stress is improved by an addition of pyruvate. These pyruvate effects are associated with protection against an oxidant-induced endothelial cell injury in the high glucose condition.
Diabetes 1997 Dec
PMID:Pyruvate improves deleterious effects of high glucose on activation of pentose phosphate pathway and glutathione redox cycle in endothelial cells. 939 1

This morphological study demonstrates a role for endothelial cells in generating reactive oxygen species in early stages of retinopathy in the BBZ/Wor rat, an obese, noninsulin dependent model of diabetes. Hyperglycemia induced pseudohypoxia results in an imbalance in cytosolic NADH/NAD+. In the oxygen-rich environment of the retina, NADH oxidase generates superoxide radical which is dismutated to hydrogen peroxide. Localization of hydrogen peroxide by the cerium NADH oxidase enzyme activity cytochemical localization technique shows a statistically significant increase of peroxide localization in the central retina of diabetic rats as compared to age-matched, nondiabetic controls. Endothelial cell dysfunction, indicated by leakage of endogenous serum albumin, coincided with areas of NADH oxidase activity localization. In diabetic rats there are increased levels of fibronectin in areas of hydrogen peroxide localization. This in vivo, morphological study is the first demonstration of oxidative injury and endothelial cell dysfunction in the retina of a spontaneous, noninsulin dependent model of diabetes.
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PMID:Increased NADH oxidase activity in the retina of the BBZ/Wor diabetic rat. 943 20

The purpose of this work was to study the morphological and quantitative alterations of the myenteric plexus neurons of the duodenum of rats with acute and chronic streptozotocin-induced diabetes and establish a comparison with non-diabetic animals. Samples of duodenum were destined to histological sections stained by Hematoxilin-Eosin and to membrane preparings stained by the Giemsa and NADH-diaphorasis methods. Small, medium and large neurons were found, with a predominance of medium ones on chronic and acute diabetic animals. It was verified that most of the neurons of diabetic and non-diabetic animals have an eccentrical nucleus and thus this characteristic is not an indicative of degenerative process. It was observed that in diabetes there is a decrease in the number of myenteric neurons. It is argued that this initial decrease is due to the toxic effects of the drug and not to the physiopathology of diabetes itself, and also that the expressive smaller proportion of neurons on the chronically diabetic animals is due to the immediate loss related to streptozotocin and the further consequences of aging during nine weeks of diabetes.
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PMID:Morphological and quantitative study of the myenteric plexus of the duodenum of streptozotocin-induced diabetic rats. 945 58

Diabetic retinopathy is thought to result from chronic changes in the metabolic pathways of the retina. Hyperglycemia leads to increased intracellular glucose concentrations, alterations in glucose degradation and an increase in lactate/pyruvate ratio. We measured lactate content in retina and other ocular and non-ocular tissues from normal and diabetic rats in the early stages of streptozotocin-induced diabetes. The intracellular redox state was calculated from the cytoplasmic [lactate]/[pyruvate] ratio. Elevated lactate concentration were found in retina and cerebral cortex from diabetic rats. These concentrations led to a significant and progressive decrease in the NAD+/NADH ratio, suggesting that altered glucose metabolism is an initial step of retinopathy. It is thus possible that tissues such as cerebral cortex have mechanisms that prevent the damaging effect of lactate produced by hyperglycemia and/or alterations of the intracellular redox state.
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PMID:Changes in the redox state in the retina and brain during the onset of diabetes in rats. 958 Mar 89

The purpose of this work was to study the neurons of the myenteric plexus of the cecum of rats with chronic streptozotocin-induced diabetes. We used four experimental groups of animals. In groups D2 and D8 animals were killed two and eight months, respectively, after diabetes induction and groups C2 and C8 were used as controls. We carried out whole-mount preparations stained with Giemsa and NADH-diaphorase. We verified that the diabetes did not alter the shape and disposition of the myenteric ganglia; it provoked decrease on the neuronal density and increase on the incidence of weakly basophilic neurons. The effects of streptozotocin caused dilatation of the cecum still evidenced two months after induction, but no more observed on the eight months after induction. The smaller incidence of neurons in group D8 relative to group C8 was due to the early loss related to the drug toxicity and later to the aging in diabetic condition.
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PMID:Morphological and quantitative analysis of the neurons of the myenteric plexus of the cecum of streptozotocin-induced diabetic rats. 962 27

Alterations in glucose metabolism have been implicated in the cardiovascular complications of diabetes. Previous work in this laboratory demonstrated that hearts from diabetic animals have an elevated cytosolic redox ratio (NADH/NAD+) and that this redox imbalance is probably due to elevated polyol pathway flux. We therefore hypothesized that 1) the elevated cytosolic redox ratio of diabetic hearts could result in inhibition of glycolytic enzymes sensitive to the redox state, 2) polyol pathway inhibition could restore the abnormal glucose metabolism of diabetic hearts, and 3) the relative incorporation of mixed substrates into hearts from diabetic animals would demonstrate less glycolytic and more fatty acid oxidation. Hearts from diabetic (BB/W) and nondiabetic control rats were perfused with buffers containing 13C-labeled substrates, and the metabolism of these hearts was analyzed using 13C NMR spectroscopy. Tissue samples were analyzed for metabolite levels using biochemical assay. Compared with controls, diabetic hearts had glyceraldeyde 3-phosphate levels that were four times greater than nondiabetic hearts and exhibited 91% less 13C labeling of lactate and 92% less 13C labeling of glutamate (P < 0.03). Aldose reductase inhibition with zopolrestat restored the metabolite labeling of diabetic hearts. Diabetic hearts perfused with a mixture of substrates used 53% more acetate than nondiabetic control hearts (P < 0.05), and aldose reductase inhibition lowered the acetate utilization of diabetic hearts by 9% (P < 0.05). These data suggest that glycolytic flux in diabetic hearts is inhibited at glyceraldehyde-3-phosphate dehydrogenase and that inhibition of the polyol pathway with zopolrestat increases glycolytic flux in these hearts. Furthermore, hearts from diabetic animals showed a marked dependence on fatty acids for substrate utilization compared with nondiabetic controls, consistent with inhibition of the pyruvate dehydrogenase complex in diabetic hearts.
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PMID:Aldose reductase inhibition improves altered glucose metabolism of isolated diabetic rat hearts. 968 98

Mutations in the hepatocyte nuclear factor-1alpha (HNF-1alpha) gene cause maturity onset diabetes of the young type 3, a form of type 2 diabetes mellitus. In mice lacking the HNF-1alpha gene, insulin secretion and intracellular calcium ([Ca2+]i) responses were impaired following stimulation with nutrient secretagogues such as glucose and glyceraldehyde but normal with non-nutrient stimuli such as potassium chloride. Patch clamp recordings revealed ATP-sensitive K+ currents (KATP) in beta-cells that were insensitive to suppression by glucose but normally sensitive to ATP. Exposure to mitochondrial substrates suppressed KATP, elevated [Ca2+]i, and corrected the insulin secretion defect. NAD(P)H responses to glucose were substantially reduced, and inhibitors of glycolytic NADH generation reproduced the mutant phenotype in normal islets. Flux of glucose through glycolysis in islets from mutant mice was reduced, as a result of which ATP generation in response to glucose was impaired. We conclude that hepatocyte nuclear factor-1alpha diabetes results from defective beta-cell glycolytic signaling, which is potentially correctable using substrates that bypass the defect.
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PMID:Defective pancreatic beta-cell glycolytic signaling in hepatocyte nuclear factor-1alpha-deficient mice. 973 37

Alloxan is known to induce diabetes in experimental animals through destruction of insulin-producing 3-cells of pancreas. The mechanism of DNA damage induced by alloxan was investigated using 32P-labeled human DNA fragments. Cu(II)-dependent DNA damage increased with the concentration of alloxan and NADH. Alloxan induced DNA cleavage frequently at thymine and cytosine residues in the presence of NADH and Cu(II). Catalase and bathocuproine, a Cu(I)-specific chelator, almost completely inhibited DNA damage, suggesting the involvement of H2O2 and Cu(I). Alloxan induced Cu(II)-dependent production of 8-oxodG in calf thymus DNA in the presence of NADH. UV-visible and electron spin resonance (ESR) spectroscopic studies showed that superoxide anion radical and alloxan radical were generated by the reduction of alloxan by NADH, and also by the autoxidation of dialuric acid, the reduced form of alloxan. These results suggest that the copper-oxygen complex derived from the reaction of H2O2 with Cu(I) participates in Cu(II)-dependent DNA damage by alloxan plus NADH and dialuric acid. The mechanism of DNA damage is discussed in relation to diabetogenic action of alloxan.
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PMID:Metal-mediated DNA damage induced by diabetogenic alloxan in the presence of NADH. 974 96


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