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)

In cultured mesangial cells (MC), capacitative Ca2+ influx via store-operated channels (SOC) is potentiated by agents that release Ca2+ from intracellular stores, and inhibited by protein kinase C (PKC). Cells grown under high glucose conditions, as a model of the diabetic microenvironment, display reduced Ca2+ signalling in response to vasoconstrictors, probably due to downregulation by elevated PKC activity. Since SOC might be relevant to this phenomenon, we assessed Ca2+ influx by microfluorometry of fura-2-loaded rat MC cultured for 5 days in normal (5.5 mmol/l, NG) or high glucose (30 mmol/l, HG). The addition of 1-10 mmol/l Ca2+ to NG cells equilibrated in Ca(2+)-free media induced an immediate Ca2+ influx with a free cytosolic Ca2+ ([Ca2+]i) plateau of 155 +/- 50 and 318 +/- 114 nmol/l, respectively. Basal influx was reduced to 88 +/- 8 and 145 +/- 17 nmol/l [Ca2+]i (1-10 mmol/l Ca2+, p < 0.01) by 30 mmol/l D-glucose. This effect of HG was confirmed by Mn2+ quenching of fura-2, indicating reduced entry of divalent cations via the capacitative pathway. Equimolar L-glucose had no effect on Ca2+ influx, consistent with a non-osmotic mechanism. Arginine vasopressin (10 mumol/l) elicited weaker release of stored Ca2+ and subsequent influx in HG cells (191 +/- 33 vs 153 +/- 24 nmol/l, 400 +/- 76 vs 260 +/- 33 nmol/l, 1-10 mmol/l Ca2+, NG/HG, p < 0.05). To examine the involvement of PKC in the effect of HG on capacitative Ca2+ influx, the enzyme was activated or downregulated by treatment with 0.1 mumol/l phorbol myristate acetate (PMA) for 3 min or 24 h, respectively. PMA acutely inhibited Ca2+ influx in NG cells, while PKC downregulation restored it in HG cells. Similarly, the PKC inhibitors staurosporin or H-7 normalized SOC activity in HG cells. In summary, impairment of Ca2+ influx via SOC by HG is one mechanism of the reduced MC [Ca2+]i responsiveness to vasoconstrictors. This event is mediated by PKC and may contribute to the glomerular haemodynamic changes in the initial stages of diabetes mellitus.
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PMID:High glucose level inhibits capacitative Ca2+ influx in cultured rat mesangial cells by a protein kinase C-dependent mechanism. 916 19

Metavanadate, orthovanadate, and pervanadate all inhibited [3H]QNB antagonist binding to the human brain muscarinic acetylcholine receptor (mAChR) in the presence of glutathione, with the order of decreasing potency and the concentration required for 50% inhibition (I[50]) being: pervanadate (95 microM) > orthovanadate (132 microM) > metavanadate (452 microM). Omission of glutathione decreased the inhibition of the vanadium compounds 2-6-fold. Preincubating the vanadium compounds with the mAChR in the presence of glutathione at 37 degrees for 1 h markedly decreased the I(50) values as follows: pervanadate (13 microM) > orthovanadate (46 microM) > metavanadate (118 microM). Inhibition by the vanadium compounds was blocked by EDTA, Mn2+, and Trolox, a water-soluble vitamin E analog. Vanadium use in treating diabetes is discussed regarding its inhibition of mAChR function.
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PMID:Inhibition of antagonist binding to human brain muscarinic receptor by vanadium compounds. 944 May

Chronic hyperglycemia results in a large deficit in nerve blood flow. Both autoxidative- and ischemia-induced lipid peroxidation occurs, with resultant peripheral sensory neuropathy in streptozotocin-induced diabetes in the rat. Free radical defenses, especially involving antioxidant enzymes, have been suggested to be reduced, but scant information is available on chronic hyperglycemia. We evaluated the gene expression of glutathione peroxidase, catalase, and superoxide dismutase (cuprozinc and manganese separately) in L4,5 dorsal root ganglion (DRG) and superior cervical ganglion, as well as enzyme activity of glutathione peroxidase in DRG and sciatic nerve in experimental diabetic neuropathy of 3 months and 12 months durations. We also evaluated nerve electrophysiology of caudal, sciatic-tibial, and digital nerves. A nerve conduction deficit was seen in all nerves in experimental diabetic neuropathy at both 3 and 12 months. Gene expression of glutathione peroxidase, catalase, cuprozinc superoxide dismutase, and manganese superoxide dismutase were not reduced in experimental diabetic neuropathy at either 3 or 12 months. Catalase mRNA was significantly increased in experimental diabetic neuropathy at 12 months. Glutathione peroxidase enzyme activity was normal in sciatic nerve. We conclude that gene expression is not reduced in peripheral nerve tissues in very chronic experimental diabetic neuropathy. Changes in enzyme activity may be related to duration of diabetes or due to post-translational modifications.
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PMID:Gene expression of antioxidant enzymes in experimental diabetic neuropathy. 1078 Jun 78

Apoptosis or programmed cell death, is essential for the normal functioning and survival of most multi-cellular organisms. The morphological and biochemical characteristics of apoptosis, however, are highly conserved during the evolution. It is currently believed that apoptosis can be divided into at least three functionally distinct phases, i.e. induction, effector and execution phase. Recent studies have demonstrated that reactive oxygen species (ROS) and the resulting oxidative stress play a pivotal role in apoptosis. Antioxidants and thiol reductants, such as N-acetylcysteine, and overexpression of manganese superoxide (MnSOD) can block or delay apoptosis. Bcl-2, an endogenously produced protein, has been shown to prevent cells from dying of apoptosis apparently by an antioxidative mechanism. Taken together ROS, and the resulting cellular redox change, can be part of signal transduction pathway during apoptosis. It is now established that mitochondria play a prominent role in apoptosis. During mitochondrial dysfunction, several essential players of apoptosis, including pro-caspases, cytochrome C, apoptosis-inducing factor (AIF), and apoptotic protease-activating factor-1 (APAF-1) are released into the cytosol. The multimeric complex formation of cytochrome C, APAF-1 and caspase 9 activates downstream caspases leading to apoptotic cell death. All the three functional phases of apoptosis are under the influence of regulatory controls. Thus, increasing evidences provide support that oxidative stress and apoptosis are closely linked physiological phenomena and are implicated in pathophysiology of some of the chronic diseases including AIDS, autoimmunity, cancer, diabetes mellitus, Alzheimer's and Parkinson's and ischemia of heart and brain.
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PMID:Oxidative stress and apoptosis. 1099 8

Altered cytosolic Ca2+ is implicated in the aetiology of many diseases including diabetes but there are few studies on the mechanism(s) of the altered Ca2+ regulation. Using human lymphocytes, we studied cytosolic calcium (Cai) and various Ca2+ transport mechanisms in subjects with Type 2 diabetes mellitus and control subjects. Ca2+-specific fluorescent probes (Fura-2 and Fluo-3) were used to monitor the Ca2+ signals. Thapsigargin, a potent and specific inhibitor of the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA), was used to study Ca2+-store dependent Ca2+ fluxes. Significant (P<0.05) elevation of basal Ca, levels was observed in lymphocytes from diabetic subjects. Cai levels were positively correlated with fasting plasma glucose and HbA1c. There was also a significant (P<0.05) reduction in plasma membrane calcium (PMCA) ATPase activity in diabetic subjects compared to controls. Cells from Type 2 diabetics exhibited an increased Ca2+ influx (as measured both by Fluo-3 fluorescence and 45Ca assays) as a consequence of thapsigargin-mediated Ca2+ store depletion. Upon addition of Mn2+ (a surrogate of Ca2+), the fura-2 fluorescence decayed in an exponential fashion and the rate and extent of this decline was steeper and greater in cells from type 2 diabetic patients. There was also a significant (P<0.05) difference in the Na+/Ca2+ exchange activity in Type 2 diabetic patients, both under resting conditions and after challenging the cells with thapsigargin, when the internal store Ca2+ sequestration was circumvented. Pharmacological activation of protein kinase C (PKC) in cells from patients resulted in only partial inhibition of Ca2+ entry. We conclude that cellular Ca2+ accumulation in cells from Type 2 diabetes results from (a) reduction in PMCA ATPase activity, (b) modulation of Na+/Ca2+ exchange and (3) increased Ca2+ influx across the plasma membrane.
Int J Exp Diabetes Res 2001
PMID:Evidence for mechanistic alterations of Ca2+ homeostasis in Type 2 diabetes mellitus. 1146 18

1. To further explore the effect of antioxidants in preventing diabetes-induced vascular and neural dysfunction we treated streptozotocin-induced diabetic rats daily with subcutaneous injections of 10 mg kg(-1) of M40403 (n=11) and compared the results obtained from 17 control rats and 14 untreated diabetic rats. M40403 is a manganese(II) complex with a bis(cyclo-hexylpyridine)-substituted macrocyclic ligand that was designed to be a selective functional mimetic of superoxide dismutase. Thus, M40403 provides a useful tool to evaluate the roles of superoxide in disease states. 2. Treatment with M40403 significantly improved diabetes-induced decrease in endoneurial blood flow, acetylcholine-mediated vascular relaxation in arterioles that provide circulation to the region of the sciatic nerve, and motor nerve conduction velocity (P<0.05). M40403 treatment also reduced the appearance of superoxide in the aorta and epineurial vessels and peroxynitrite in epineurial vessels. Treating diabetic rats with M40403 reduced the diabetes-induced increase in thiobarbituric acid reactive substances in serum but did not prevent the decrease in lens glutathione level. Treating diabetic rats with M40403 did not improve sciatic nerve Na(+)/K(+) ATPase activity or the sorbitol, fructose or myo-inositol content of the sciatic nerve. 3. These studies provide additional evidence that diabetes-induced oxidative stress and the generation of superoxide and perhaps peroxynitrite may be partially responsible for the development of diabetic vascular and neural complications.
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PMID:Effect of M40403 treatment of diabetic rats on endoneurial blood flow, motor nerve conduction velocity and vascular function of epineurial arterioles of the sciatic nerve. 1152 93

Maternal undernutrition during critical periods of organ development is known to impair fetal growth and predispose to the development of adulthood diseases, such as hypertension, coronary heart disease and type II diabetes that are linked to low birth weight and are characterized by endothelial dysfunction. Increased oxidative stress, in rats submitted to intrauterine undernutrition, provides a potential explanation for the endothelial dysfunction development. The aim of this study was to determine the oxidative stress and its consequence on mesenteric arteriolar responses to vasoactive agents in offspring from diet-restricted dams. For this, female pregnant Wistar rats were fed either normal or 50% of normal intake diets, during the whole gestational period. In male offspring, arterial blood pressure was determined by the tail cuff method in anesthetized rats, mesenteric arteriolar reactivity and superoxide anion generation were studied using intravital microscopy and superoxide dismutase activity was determined in mesentery by spectrophotometric assay. Intrauterine undernutrition induced hypertension, decreased vasodilation to acetylcholine and bradykinin but did not alter the responses to sodium nitroprusside. Topical application of superoxide dismutase and superoxide dismutase mimetic manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin significantly improved the altered arteriolar responses to acetylcholine and bradykinin. A decreased superoxide dismutase activity and an increased superoxide anion concentration were observed in the offspring of diet-restricted dams. This study shows for the first time that intrauterine undernutrition enhances oxidative stress in vivo and relates this to the impaired endothelium-dependent vasodilation.
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PMID:Enhanced oxidative stress as a potential mechanism underlying the programming of hypertension in utero. 1235 11

The 9 kinds of Chinese traditional medicines which are used to cure diabetes including Xiaokewan, Yuquanwan, Kelening, Jiangtangshu, Jiangtang I-V are digested with HNO3-HClO4 (4:1) mixed acid. The 12 trace elements of copper, zinc, nickel, cobalt, manganese, chromium, molybdenum, iron, calcium, magnesium, cadmium and lead in the solution are determined by atomic absorption spectrometry. Its recovery ratio by standard addition is 97%-105%, and RSD is lower than 5%. This method has good accurate. The results obtained show that except Cd and Pb all other ten trace elements contents in the drug are high. The results of this paper provide useful data for studying the relation between the contents of these trace elements and the medical effect.
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PMID:[Determination of trace elements in Chinese traditional medicines by atomic absorption spectrometry]. 1293 50

Oxidative stress and modulation of anti-oxidant enzymes may contribute to the deleterious consequences of diabetes mellitus and to the effects of chronic (i.e. 21 day) stress in the CNS. We therefore compared the effects of short- and long-term exposure to diabetes-induced hyperglycemia, restraint stress and the combined effects of restraint stress and diabetes upon parameters of oxidative stress in the rat hippocampus. Whereas 7 days of restraint stress or hyperglycemia, or the combination, produced similar increases in oxidative stress markers 4-hydroxy-2-nonenal (HNE) and malondialdehyde (MDA) throughout the hippocampus, 21 days of stress or hyperglycemia did not increase these markers in the dentate gyrus. In contrast, Ammon's horn still showed elevated levels of these lipid peroxidation products, especially in diabetic rats subjected to 21 days of restraint stress. The expression of two anti-oxidant enzymes, copper/zinc superoxide dismutase (Cu/Zn-SOD) and manganese SOD, was also differentially regulated by stress and hyperglycemia in a time- and region-specific manner in the rat hippocampus. Although long-term stress decreased both SOD isoforms, diabetes increased Cu/Zn-SOD expression in DG with or without 21 days of repeated stress. These increases may account for the finding that protein-conjugated HNE and MDA levels returned to control levels between 7 days and 21 days of hyperglycemia or the combination of diabetes and stress. These results suggest that while other anti-oxidant pathways may account for decreases in oxidative stress in the long-term stress paradigm, increases in Cu/Zn-SOD expression may contribute to the region-specific attenuation of oxidative stress in the diabetic rat hippocampus.
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PMID:Region specific increases in oxidative stress and superoxide dismutase in the hippocampus of diabetic rats subjected to stress. 1294 6

The aim of the present study was to investigate whether altered serum total sialic acid (TSA), lipid-associated sialic acid (LSA), copper (Cu), manganese (Mn), zinc (Zn), chromium (Cr), iron (Fe), and magnesium (Mg) levels had an interactive connection with diabetes and also whether they were correlated with each other in diabetic patients. Two study groups (control and type 2 diabetic subjects) were included. Two hundred patients (108 female and 92 male), diagnosed and treated for type 2 diabetes in the Yuzuncu Yil University Hospital (Van, Turkey), were selected consecutively to represent type 2 diabetic patients. Fifty healthy individuals (29 female and 21 male) served as the control group matched for age, sex, body mass index, and smoking status were selected from hospital staff and other outpatient clinics. All participants had not taken vitamin or mineral supplements for at least 2 wk before sampling. Blood samples were drawn after an overnight fasting in both groups for the determination of serum glucose, TSA, LSA, Cu, Zn, Mn, Cr, Fe, and Mg. It was found that diabetics had higher TSA, LSA, Fe, Mn, Fe/Zn, and Cu/Zn levels, and lower Zn and Mg levels than those of controls. Although, Cu levels were higher, and Cr levels were lower in total and male diabetic patients, they were not different in female diabetic patients than in controls. The Cu/Fe ratio was lower in total and female diabetic patients, but not different in male diabetic patients than controls. The Zn/Cr ratio, on the other hand, was not different in diabetics than in controls. There was only a positive correlation between Fe-Mn levels in male diabetic patients. There was a negative correlation in LSA-Mn, Fe-Cu, Cu-Fe/Zn, and Mn-Cu/Zn levels in total diabetic patients. There was a positive correlation in TSA-Cr, TSA-Mg, LSA-Cu/Fe, LSA-Zn/Cr levels, and a negative correlation in TSA-Cu/Zn, LSA-Mn, Fe-Cu, Mn-Cu, Cu-Fe/Zn, Fe-cholesterol, and Cr-cholesterol in female diabetic patients. Our results showed that TSA, LSA, and selected minerals have interactive connections with diabetes mellitus (DM). There are also many sex-related positive or negative correlations between the altered parameters in diabetic patients. These parameters might be used as diagnostic index in patients with DM.
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PMID:Serum sialic acid levels and selected mineral status in patients with type 2 diabetes mellitus. 1297 87


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