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)

We investigated the effects of ursodeoxycholic acid (UDCA) on mitochondrial functions and oxidative stress and evaluated their relationships in the livers of rats with alloxan-induced diabetes. Diabetes was induced in male Wistar rats by a single alloxan injection (150 mg kg(-1) b.w., i.p.). UDCA (40 mg kg(-1) b.w., i.g., 30 days) was administered from the 5th day after the alloxan treatment. Mitochondrial functions were evaluated by oxygen consumption with Clark oxygen electrode using succinate, pyruvate+malate or palmitoyl carnitine as substrates and by determination of succinate dehydrogenase and NADH dehydrogenase activities. Liver mitochondria were used to measure chemiluminiscence enhanced by luminol and lucigenin, reduced liver glutathione and the end-products of lipid peroxidation. The activities of both NADH dehydrogenase and succinate dehydrogenase as well as the respiratory control (RC) value with all the substrates and the ADP/O ratio with pyruvate+malate and succinate as substrates were significantly decreased in diabetic rats. UDCA developed the beneficial effect on the mitochondrial respiration and oxidative phosphorylation parameters in alloxan-treated rats, whereas the activities of mitochondrial enzymes were increased insignificantly after the administration of UDCA. The contents of polar carbonyls and MDA as well as the chemiluminescence with luminol were elevated in liver mitochondria of diabetic rats. The treatment with UDCA normalized all the above parameters measured except the MDA content. UDCA administration prevents mitochondrial dysfunction in rats treated with alloxan and this process is closely connected with inhibition of oxidative stress by this compound.
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PMID:Protective effect of ursodeoxycholic acid on liver mitochondrial function in rats with alloxan-induced diabetes: link with oxidative stress. 1751 17

Regular endurance exercise has profound benefits on overall health, including the prevention of obesity, cardiovascular disease, and diabetes. The objective of this study was to determine whether AMP-activated protein kinase (AMPK) mediates commonly observed adaptive responses to exercise training in skeletal muscle. Six weeks of voluntary wheel running induced a significant (P < 0.05) fiber type IIb to IIa/x shift in triceps muscle of wild-type mice. Despite similar wheel running capacities, this training-induced shift was reduced by approximately 40% in transgenic mice expressing a muscle-specific AMPKalpha2 inactive subunit. Sedentary mice carrying an AMPK-activating mutation (gamma1TG) showed a 2.6-fold increase in type IIa/x fibers but no further increase with training. To determine whether AMPK is involved in concomitant metabolic adaptations to training, we measured markers of mitochondria (citrate synthase and succinate dehydrogenase) and glucose uptake capacity (GLUT4 and hexokinase II). Mitochondrial markers increased similarly in wild-type and AMPKalpha2-inactive mice. Sedentary gamma1TG mice showed a approximately 25% increase in citrate synthase activity but no further increase with training. GLUT4 protein expression was not different in either line of transgenic mice compared with wild-type mice and tended to increase with training, although this increase was not statistically significant. Training induced a approximately 65% increase in hexokinase II protein in wild-type mice but not in AMPKalpha2-inactive mice. Hexokinase II was significantly elevated in sedentary gamma1TG mice, without an additional increase with training. AMPK is not necessary for exercise training-induced increases in mitochondrial markers, but it is essential for fiber type IIb to IIa/x transformation and increases in hexokinase II protein.
Diabetes 2007 Aug
PMID:Skeletal muscle adaptation to exercise training: AMP-activated protein kinase mediates muscle fiber type shift. 1751 99

In a previous study, the ciliary neurotrophic factor (CNTF) were demonstrated to lead to weight-loss partly by up-regulating the energy metabolism and the expression of uncoupling protein-1, mitochondrial transcription factor A and nuclear respiratory factor-1 in adipose tissues or muscle. To investigate the up-stream regulators of the expression, recombinant human CNTF (rhCNTF) (0.1, 0.3 and 0.9 mg/kg/day subcutaneously) were administered to KK-Ay mice for 30 days, resulting in reduction of perirenal fat mass, serum free fatty acids and islet triacylglycerol; furthermore, the values of oral glucose tolerance test were found improved. In brown adipose tissues, the gene expressions of peroxisome proliferator-activated receptor alpha (PPARalpha) and peroxisome proliferator-activated receptor coactivator-1 alpha (PGC-1alpha) were found to be up-regulated by rhCNTF. To the best of our knowledge, the changes of gene expression of PPARalpha and PGC-1alpha represent new insights into the mechanisms of anti-diabetes by rhCNTF. In addition, the activity of mitochondrial complexII was found to be increased by rhCNTF. Stimulation of PPARalpha, PGC-1alpha, uncoupling protein-1 and enhanced activity of mitochondrial complex II may be associated with the effects of anti-diabetes. The present study indicates new mechanisms of the activity and mechanisms on anti-diabetes of rhCNTF, which may be a novel anti-diabetes reagent partly acting by enhancing energy metabolism.
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PMID:The novel mechanism of recombinant human ciliary neurotrophic factor on the anti-diabetes activity. 1765 6

Pheochromocytomas are rare catecholamine-secreting, chromaffin tumors of the autonomic nervous system. Most pheochromocytomas are sporadic, but up to 24% of pheochromocytomas are part of a familial disorder. Here we describe a female patient, who presented to our outpatient clinic 18 years after removal of a pheochromocytoma of the left adrenal gland in China. Now she reported flank pain on the left side and elevated blood pressure. 24-hour urinary catecholamines, metanephrines, and normetanephrines as well as plasma-norepinephrine were elevated. The transabdominal ultrasonography revealed a tumor with reduced echogenicity in the left suprarenal region, which was suspected to be a recurrent pheochromocytoma. This finding was confirmed by MRT and J (123)-MIBG-scan. Parathyroid hormone (PTH) and calcitonin were in the normal range. After surgical excision, histological examination of the adrenal mass proved to be a pheochromocytoma. Molecular genetic analysis with sequencing of the succinate dehydrogenase type B (SDHB) gene revealed a formerly unknown mutation of codon 214 (CAG-->TAG) leading to an amino acid change of glutamine to a stop-Codon (Q214X-mutation) in exon 6. This case report highlights the necessity of re-evaluating patients with nonsyndromic pheochromocytoma who are diagnosed without genetic testing to estimate the risk of a relapse and to initiate testing of first-degree relatives.
Exp Clin Endocrinol Diabetes 2007 Oct
PMID:Relapsing pheochromocytoma in a Chinese women caused by a novel mutation in exon 6 of the SDHB gene: a case report. 1794 98

Exposure to high levels of glucose induces the production of reactive oxygen species (ROS) in cardiomyocytes that may contribute to the development of cardiomyopathy in diabetes. Nuclear factor erythroid 2-related factor 2 (Nrf2) controls the antioxidant response element (ARE)-dependent gene regulation in response to oxidative stress. The role of Nrf2 in defense against high glucose-induced oxidative damage in cardiomyocytes was investigated. Glucose at high concentrations induced ROS production in both primary neonatal and adult cardiomyocytes from the Nrf2 wild type (WT) mouse heart, whereas, in Nrf2 knockout (KO) cells, ROS was significantly higher under basal conditions and high glucose markedly further increased ROS production in concentration and time-dependent manners. Concomitantly, high glucose induced significantly higher levels of apoptosis at lower concentrations and in shorter time in Nrf2 KO cells than in WT cells. Primary adult cardiomyocytes from control and diabetic mice also showed dependence on Nrf2 function for isoproterenol-stimulated contraction. Additionally, cardiomyocytes from Nrf2 KO mice exhibited increased sensitivity to 3-nitropropionic acid, an inhibitor of mitochondrial respiratory complex II, for both ROS production and apoptosis compared with Nrf2 WT cells, further emphasizing the role of Nrf2 in ROS defense in the cells. Mechanistically, Nrf2 was shown to mediate the basal expression and induction of ARE-controlled cytoprotective genes, Nqo1 and Ho1, at both mRNA and protein levels in cardiomyocytes, as both the basal and inducible expressions of the genes were lost in Nrf2 KO cells or largely reduced by Nrf2 SiRNA. The findings, for the first time, established Nrf2 as a critical regulator of defense against ROS in normal and diabetic hearts.
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PMID:Nrf2 is critical in defense against high glucose-induced oxidative damage in cardiomyocytes. 1900 87

Diabetic cardiomyopathy is the leading cause of heart failure among diabetic patients, and mitochondrial dysfunction has been implicated as an underlying cause in the pathogenesis. Cardiac mitochondria consist of two spatially, functionally, and morphologically distinct subpopulations, termed subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM). SSM are situated beneath the plasma membrane, whereas IFM are embedded between myofibrils. The goal of this study was to determine whether spatially distinct cardiac mitochondrial subpopulations respond differently to a diabetic phenotype. Swiss-Webster mice were subjected to intraperitoneal injections of streptozotocin or citrate saline vehicle. Five weeks after injections, diabetic hearts displayed decreased rates of contraction, relaxation, and left ventricular developed pressures (P < 0.05 for all three). Both mitochondrial size (forward scatter, P < 0.01) and complexity (side scatter, P < 0.01) were decreased in diabetic IFM but not diabetic SSM. Electron transport chain complex II respiration was decreased in diabetic SSM (P < 0.05) and diabetic IFM (P < 0.01), with the decrease being greater in IFM. Furthermore, IFM complex I respiration and complex III activity were decreased with diabetes (P < 0.01) but were unchanged in SSM. Superoxide production was increased only in diabetic IFM (P < 0.01). Oxidative damage to proteins and lipids, indexed through nitrotyrosine residues and lipid peroxidation, were higher in diabetic IFM (P < 0.05 and P < 0.01, respectively). The mitochondria-specific phospholipid cardiolipin was decreased in diabetic IFM (P < 0.01) but not SSM. These results indicate that diabetes mellitus imposes a greater stress on the IFM subpopulation, which is associated, in part, with increased superoxide generation and oxidative damage, resulting in morphological and functional abnormalities that may contribute to the pathogenesis of diabetic cardiomyopathy.
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PMID:Diabetic cardiomyopathy-associated dysfunction in spatially distinct mitochondrial subpopulations. 1963 50

Obesity and mild hyperglycemia are characteristic of early or "prediabetes." The associated increase in fatty acid flux is posited to enhance substrate delivery to mitochondria, leading to enhanced superoxide production that results in mitochondrial dysfunction and progressive worsening of the hyperglycemic state. We quantified superoxide production by gastrocnemius muscle, heart, and liver mitochondria in a rodent model that mimics the pathophysiology of prediabetes by administering low-dose streptozotocin to rats fed high fat (HF). Superoxide was rigorously determined indirectly as H(2)O(2) largely released from the matrix and by electron paramagnetic resonance spectroscopy that directly detects superoxide released externally. Both HF and low-dose streptozotocin mildly increased glycemia (P < .05 by 2-way analysis of variance). Matrix and external superoxide production by gastrocnemius mitochondria respiring on the complex II substrate succinate and matrix superoxide production by liver mitochondria respiring on the complex I substrates glutamate plus malate were significantly reduced by HF feeding but not affected by mild hyperglycemia. Superoxide production was not significantly altered by either treatment in heart mitochondria fueled by either complex I or II substrates. The functional status of the mitochondria was assayed as simultaneous respiration and membrane potential that were not affected by HF or mild hyperglycemia. Comparison of substrate and inhibitor effects on superoxide release implied marked differences in the redox mechanisms regulating mitochondrial superoxide production from liver mitochondria compared with muscle and heart. In summary, superoxide production from mitochondria of different insulin-sensitive tissues differs mechanistically. However, in any case, excess superoxide production as an intrinsic property of mitochondria of insulin-sensitive tissues does not result from conditions mimicking the pathophysiology of pre- or early diabetes.
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PMID:Superoxide production by mitochondria of insulin-sensitive tissues: mechanistic differences and effect of early diabetes. 1976 76

Decoctions and infusions of Artocarpus communis (Forst.) (family: Moraceae) root-bark are commonly used traditionally among the Yoruba-speaking people of Western Nigeria as folk remedies for the management, control and/or treatment of an array of human diseases, including type 2, adult-onset diabetes mellitus. Although numerous bioactive flavonoids have been isolated from the roots, stem-bark and leaves of A. communis, to the best of our knowledge, the effects of the plant's root-bark extract on animal model of diabetes mellitus and on liver tissues have hitherto, not been reported in the biomedical literature. In view of this, the present study was undertaken to investigate the glycaemic effect of, and hepatic tissue ultrastructural, morphological and metabolic changes induced by A. communis root-bark aqueous extract (ACE) in Wistar rats. The ultrastructural, morphological and metabolic effects of ACE have been compared with those induced by streptozotocin (STZ) in rat experimental paradigms. Four groups (A, B, C and D) of Wistar rats, each group containing 10 rats, were used. Diabetes mellitus was induced in the diabetic groups B and C animals by intraperitoneal injections of STZ (75 mg/kg body weight), while group A rats received A. communis root-bark aqueous extract (ACE, 100 mg/kg body weight, i.p.) alone. Control group D rats received distilled water in quantities equivalent to the volume of ACE administered intraperitoneally. The rats in group C were additionally treated with ACE (100 mg/kg body weight i. p.) daily from day 3 to day 10 after STZ treatment. Hepatic glucokinase, hexokinase, glutamate dehydrogenase, succinate dehydrogenase, beta-hydroxybutyrate dehydrogenase, serum insulin and blood glucose levels of the animals were measured and recorded before and after ACE, STZ and STZ+ACE treatments. Hepatic tissues were also processed for transmission electron microscopy. Electron microscopic examinations showed toxic, deleterious alterations in the ultrastructures of groups A, B and C hepatic cells, the most prominent deleterious effects being on the hepatocytes. Ultrastructural changes observed within the hepatocytes of groups A, B and C rats include disrupted mitochondria with increase in lipid droplets, extensive hepatocellular vacuolation, scanty rough endoplasmic reticulum (RER) and ribosomes. Large glycogen clusters were also noticed displacing the mitochondria and RER in group A rats. Group A rats also developed significant hyperglycemia (p<0.05) immediately after ACE administration, while groups B and C rats developed hyperglycemia 24 hours after STZ treatment. When compared with the control group D rats, the activities of all the three subsystems were disrupted, leading to overall inhibition of oxidative phosphorylation of the liver mitochondria in groups A, B and C rats, but remain normal in the untreated group D control rats. The findings of the present study indicate that A. communis root-bark aqueous extract induces hyperglycaemia in the experimental animal model used, and that the plant's extract disrupts the ultrastructural characteristics and architecture of hepatocytes as well as oxidative energy metabolism.
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PMID:Artocarpus communis Forst. root-bark aqueous extract- and streptozotocin-induced ultrastructural and metabolic changes in hepatic tissues of Wistar rats. 2016 8

This was a study of the microscopic, ultrastructural, immunohistochemical, and enzyme cytochemical features of giant eosinophilic granules encountered in pancreatic acinar cells of alloxan-induced diabetic rats. Seven male F344 rats with diabetes induced by a single i.v. dose of alloxan were sacrificed after twenty-five weeks of treatment. Histologically, the pancreatic acini were diffusely atrophied, and the islets showed marked atrophy or had disappeared, and giant eosinophilic granules and small vacuoles were observed in almost all acinar cells. The eosinophilic granules showed negative reactions for periodic acid-Schiff (PAS) and acid phosphatase, as well as fat stains such as Nile blue, Oil red O, and Sudan III. Ultrastructurally, the giant eosinophilic granules were huge structures surrounded by a double membrane containing many irregular cristae. A large amount of small lipid droplets was also apparent in the basal area of the acinar cells. Immunohistochemical analysis of prohibitin, a kind of protein located in the mitochondrial inner membrane, was partially positive in the marginal area of some giant eosinophilic granules, but negative for the central area. The enzyme activity for succinic dehydrogenase (SDH), one of the mitochondrial enzymes, showed a localizing pattern similar to that of prohibitin. These findings confirmed that the giant eosinophilic granules in the exocrine pancreas of alloxan-induced diabetic rats were giant mitochondria.
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PMID:Giant mitochondria in pancreatic acinar cells of alloxan-induced diabetic rats. 2044 86

Diabetic encephalopathy, characterized by cognitive deficits involves hyperglycemia-induced oxidative stress. Impaired mitochondrial functions might play an important role in accelerated oxidative damage observed in diabetic brain. The aim of the present study was to examine the role of mitochondrial oxidative stress and dysfunctions in the development of diabetic encephalopathy along with the neuroprotective potential of N-acetylcysteine (NAC). Chronic hyperglycemia accentuated mitochondrial oxidative stress in terms of increased ROS production and lipid peroxidation. Significant decrease in Mn-SOD activity along with protein and non-protein thiols was observed in the mitochondria from diabetic brain. The activities of mitochondrial enzymes; NADH dehydrogenase, succinate dehydrogenase and cytochrome oxidase were decreased in the diabetic brain. Increased mitochondrial oxidative stress and dysfunctions were associated with increased cytochrome c and active caspase-3 levels in cytosol. Electron microscopy revealed mitochondrial swelling and chromatin condensation in neurons of diabetic animals. NAC administration, on the other hand was found to significantly improve diabetes-induced biochemical and morphological changes, bringing them closer to the controls. The results from the study provide evidence for the role of mitochondrial oxidative stress and dysfunctions in the development of diabetic encephalopathy and point towards the clinical potential of NAC as an adjuvant therapy to conventional anti-hyperglycemic regimens for the prevention and/or delaying the progression of CNS complications.
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PMID:Protective effect of N-acetylcysteine supplementation on mitochondrial oxidative stress and mitochondrial enzymes in cerebral cortex of streptozotocin-treated diabetic rats. 2105 8


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