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

The endothelium plays a crucial role in the regulation of vascular tone. Recent studies have indicated that endothelial dysfunction develops in the presence of cardiovascular risk factors such as hypertension, diabetes mellitus, hypercholesterolemia and in chronic smokers, as well as in patients with a family history of cardiovascular disease. It has now been established that endothelial dysfunction represents the first indicator of vascular damage. Endothelial function can be assessed in coronary and peripheral conductance and resistance vessels by means of invasive and noninvasive (ultrasound-guided) methods such as intracoronary infusion of acetylcholine, the endothelium-dependent vasodilator. It is interesting that endothelial dysfunction in the presence of cardiovascular risk factors can be almost completely corrected by the acute administration of antioxidants such as vitamin C, pointing to a crucial role of reactive oxygen species in mediating this phenomenon. Superoxide producing enzymes involved in the increased production of reactive oxygen species include NADPH oxidase, nitric oxide synthase in the uncoupled state, mitochondrial superoxide sources, cyclooxygenase and xanthine oxidase. Recent studies indicate that the endothelial dysfunction found in coronary and peripheral conductance and resistance vessels provide prognostic information about future cardiovascular events. The role of endothelial dysfunction in the setting of primary prevention is not yet clear, but is being investigated in the current Gutenberg Heart Study.
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PMID:[Endothelial dysfunction: pathophysiology, diagnosis and prognosis]. 1900 47

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

Here we overview the role of reactive nitrogen species (nitrosative stress) and associated pathways in the pathogenesis of diabetic vascular complications. Increased extracellular glucose concentration, a principal feature of diabetes mellitus, induces a dysregulation of reactive oxygen and nitrogen generating pathways. These processes lead to a loss of the vascular endothelium to produce biologically active nitric oxide (NO), which impairs vascular relaxations. Mitochondria play a crucial role in this process: endothelial cells placed in increase extracellular glucose respond with a marked increase in mitochondrial superoxide formation. Superoxide, when combining with NO generated by the endothelial cells (produced by the endothelial isoform of NO synthase), leads to the formation of peroxynitrite, a cytotoxic oxidant. Reactive oxygen and nitrogen species trigger endothelial cell dysfunction through a multitude of mechanisms including substrate depletion and uncoupling of endothelial isoform of NO synthase. Another pathomechanism involves DNA strand breakage and activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP). PARP-mediated poly(ADP-ribosyl)ation and inhibition of glyceraldehyde-3-phosphate dehydrogenase importantly contributes to the development of diabetic vascular complications: it induces activation of multiple pathways of injury including activation of nuclear factor kappa B, activation of protein kinase C and generation of intracellular advanced glycation end products. Reactive species generation and PARP play key roles in the pathogenesis of 'glucose memory' and in the development of injury in endothelial cells exposed to alternating high/low glucose concentrations.
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PMID:Role of nitrosative stress in the pathogenesis of diabetic vascular dysfunction. 1921 Jul 48

Oxidative stress may play a key role in the pathogenesis of diabetic nephropathy. Propolis and its extract have antioxidant properties. The effect of ethanolic extract of propolis against experimental diabetes mellitus-associated changes was examined. Diabetes was induced experimentally in rats by i.p. injection of streptozotocin (STZ) in a dose of 60 mg/kg bwt for 3 successive days. Blood urea nitrogen (BNU), creatinine, glucose, lipid profile, malondialdehyde (MDA) and urinary albumin were measured. Superoxide dimutase (SOD), glutathione (GSH), catalase (CAT) and MDA were measured in the renal tissue. The results showed decreased body weight and increased kidney weight in diabetic animals. Compared to the control normal rats, diabetic rats had higher blood glucose, BNU, creatinine, total cholesterol, triglycerides, low-density lipoprotein-cholesterol (LDL-C), MDA and urinary albumin and lower high-density lipoprotein-cholesterol (HDL-C) levels. Moreover, renal tissue MDA was markedly increased while SOD, GSH and CAT were significantly decreased. Oral administration of propolis extract in doses of 100,200 & 300 mg/kg bwt improved the body and kidney weights, serum glucose, lipid profile, MDA and renal function tests. Renal GSH, SOD and CAT were significantly increased while MDA was markedly reduced. These results may suggest a strong antioxidant effect of propolis which can ameliorate oxidative stress and delay the occurrence of diabetic nephropathy in diabetes mellitus.
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PMID:Experimental diabetic nephropathy can be prevented by propolis: Effect on metabolic disturbances and renal oxidative parameters. 1933 34

Superoxide excess plays a central role in tissue damage that results from diabetes, but the mechanisms of superoxide overproduction in diabetic nephropathy (DN) are incompletely understood. In the present study, we investigated the enzyme superoxide dismutase (SOD), a major defender against superoxide, in the kidneys during the development of murine DN. We assessed SOD activity and the expression of SOD isoforms in the kidneys of two diabetic mouse models (C57BL/6-Akita and KK/Ta-Akita) that exhibit comparable levels of hyperglycemia but different susceptibility to DN. We observed down-regulation of cytosolic CuZn-SOD (SOD1) and extracellular CuZn-SOD (SOD3), but not mitochondrial Mn-SOD (SOD2), in the kidney of KK/Ta-Akita mice which exhibit progressive DN. In contrast, we did not detect a change in renal SOD expression in DN-resistant C57BL/6-Akita mice. Consistent with these findings, there was a significant reduction in total SOD activity in the kidney of KK/Ta-Akita mice compared with C57BL/6-Akita mice. Finally, treatment of KK/Ta-Akita mice with a SOD mimetic, tempol, ameliorated the nephropathic changes in KK/Ta-Akita mice without altering the level of hyperglycemia. Collectively, these results indicate that down-regulation of renal SOD1 and SOD3 may play a key role in the pathogenesis of DN.
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PMID:Reduction of renal superoxide dismutase in progressive diabetic nephropathy. 1947 Jun 81

Depression is frequently observed among patients with diabetes and depressive status has been associated to activation of inflammatory processes, suggesting a role of depression in the inflammatory events observed in diabetes. To test that proposal, it was studied the effect of depression induced by forced swimming test (FST) on the evolution of early diabetic nephropathy. Diabetes was induced by streptozotocin injection. Rats were submitted to FST for 15 days. Struggle time was determined during FST and motor activity previously to FST. Nitric oxide, malondialdehyde, reduced glutathione and catalase activity were measured in kidney homogenates by enzymatic and biochemical methods. Superoxide anion, monocyte/macrophage (ED-1 positive cells) and RAGE were determined by histochemical and immunohistochemical methods. Diabetic rats had decreased struggle time and locomotor activity at day 1 of FST. Both control and diabetic rats had those parameters decreased at day 15. Renal oxidative stress, RAGE expression and ED-1 cells were observed increased in diabetic animals. Those parameters were not significantly altered by FST. The depressive status does not alter oxidative and immune parameters during the early renal changes of diabetic nephropathy.
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PMID:Depressive status does not alter renal oxidative and immunological parameters during early diabetic nephropathy in rats. 1953 4

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

Type 1 diabetes provokes a protein kinase C (PKC)-dependent accumulation of superoxide anion in the renal medullary thick ascending limb (mTAL). We hypothesized that this phenomenon involves PKC-dependent NAD(P)H oxidase activation. The validity of this hypothesis was explored using mTAL suspensions prepared from rats with streptozotocin-induced diabetes and from sham (vehicle-treated) rats. Superoxide production was 5-fold higher in mTAL suspensions from diabetic rats compared with suspensions from sham rats. The NAD(P)H oxidase inhibitor apocynin caused an 80% decrease in superoxide production by mTAL from diabetic rats (P<0.05 vs untreated) without altering superoxide production by sham mTAL. NAD(P)H oxidase activity was >2-fold higher in mTAL from diabetic rats than in sham mTAL (P<0.05). Pretreatment with calphostin C (broad-spectrum PKC inhibitor) or rottlerin (PKCdelta inhibitor) reduced NAD(P)H oxidase activity by approximately 80% in both groups; however, PKCalpha/beta or PKCbeta inhibition did not alter NAD(P)H oxidase activity in either group. Protein levels of Nox2, Nox4, and p47phox were significantly higher in diabetic mTAL than in mTAL from sham rats. In summary, elevated superoxide production by mTAL from diabetic rats was normalized by NAD(P)H oxidase inhibition. PKC-dependent, PKCdelta-dependent, and total NAD(P)H oxidase activity was greater in mTAL from diabetic rats compared with sham. Protein levels of Nox2, Nox4, and p47phox were increased in mTAL from diabetic rats. We conclude that increased superoxide production by the mTAL during diabetes involves a PKCdelta-dependent increase in NAD(P)H oxidase activity in concert with increased protein levels of catalytic and regulatory subunits of the enzyme.
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PMID:Protein kinase C-dependent NAD(P)H oxidase activation induced by type 1 diabetes in renal medullary thick ascending limb. 2003 46

Treatment with autologous bone marrow transplantation (ABMT) can change the natural history of diabetes in patients with new-onset Type 1 diabetes (T1D). Effects of syngeneic bone marrow transplantation (syn-BMT) on diabetic nephropathy were studied in streptozotocin-induced diabetic mice. Diabetic mice received sibling's bone marrow on days 3, 10, 20, or 40 after T1D onset, respectively. Renal pathology, levels of oxidative stress, and the expressions of angiotensinogen (AGT), monocyte chemoattractant protein-1 (MCP-1) and transforming growth factor beta 1 (Tgf-beta1) mRNA were investigated. Treatment with syn-BMT when disease was early-onset reduced mesangial area expansion and kidney enlargement; besides, if it is given on day 10, syn-BMT attenuated glomerular hypertrophy. Oxidative stress factors such as catalase (CAT) and superoxide radical anion O(2-) (O(2-)) were markedly maintained by syn-BMT compared to mice without treatment. In diabetic mice without treatment, renal AGT and MCP-1 mRNA were increased, while they were effectively suppressed by syn-BMT. But it showed no changes or even increment in Tgf-beta1 mRNA after syn-BMT. Syn-BMT, if applied when disease was early-onset, ameliorated diabetic renal injury. These preventive effects could be partly via maintaining oxidative stress and expression of AGT and MCP-1 in kidney in streptozotocin-diabetic mice.
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PMID:Preventive effects of syngeneic bone marrow transplantation on diabetic nephropathy in mice. 2004 60

Vascular disease in hypertension and diabetes is associated with increased oxidants. The oxidants arise from NADPH oxidase, xanthine oxidase, and mitochondria. Superoxide anion and hydrogen peroxide are produced by both leukocytes and vascular cells. Nitric oxide is produced in excess by inducible nitric oxide synthase, and the potent oxidant, peroxynitrite, is formed from superoxide and nitric oxide. The damage to proteins caused by oxidants is selective, affecting specific oxidant-sensitive amino acid residues. With some important vascular proteins, for example, endothelial nitric oxide synthase, prostacycline synthase, and superoxide dismutase, oxidation of a single susceptible amino acid inactivates the enzyme. The beneficial effects of antioxidants, at least in animal models of hypertension and diabetes, can in part be ascribed to protection of these and other proteins. Mutant proteins lacking their reactive constituent can recapitulate some disease phenotypes suggesting a pathogenic role of the oxidation. Thus, many of the shared functional abnormalities of hypertensive and diabetic blood vessels may be caused by oxidants. Although studies using antioxidants have failed in patients, the successful treatment of vascular disease with HMG-CoA reductase inhibitors, thromboxane A2 antagonists, and polyphenols may depend on their anti-inflammatory effects and ability to decrease production of damaging oxidants.
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PMID:Vascular oxidative stress: the common link in hypertensive and diabetic vascular disease. 2042 35


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