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)

Accumulating evidence points to a causal role for advanced glycation end products (AGEs) in the development of diabetic vascular complications, including retinopathy. Possible pathogenic mechanisms linking AGEs to diabetic retinopathy include protein kinase C (PKC) activation, oxidative stress, and vascular endothelial growth factor (VEGF) expression. In the present study, we investigated the effect of AGEs on VEGF expression in bovine retinal endothelial cells (BRECs) and determined the role of PKC and oxidative stress in this effect. Incubation of BRECs with AGEs led to enhanced VEGF mRNA and protein expression. This treatment also induced PKC translocation in these cells. The AGE-induced increases in VEGF expression and PKC activation were inhibited by the pan-specific PKC inhibitor, calphostin C, and by the antioxidant drug and compounds, gliclazide, N-acetylcysteine, and vitamin E. In contrast, glyburide which does not exhibit antioxidant properties, did not affect the AGE-induced VEGF expression. Exposure of BRECs to AGEs resulted in a significant increase of nuclear protein binding to the NF-kappa B consensus sequence of the VEGF promoter region. Induction of DNA binding activity for NF-kappa B by AGEs was prevented by gliclazide. Treatment of BRECs with AGEs also increased the proliferation of these cells. This effect was abrogated by incubating the cells with an anti-VEGF antibody and was inhibited in the presence of gliclazide. Overall, these data demonstrate that AGEs increase VEGF expression in retinal endothelial cells through generation of oxidative stress and downstream activation of the PKC pathway. Targeting VEGF expression with specific pharmacological agents, such as antioxidants and PKC inhibitors, may prove efficacious for the treatment of diabetic retinopathy.
J Diabetes Complications
PMID:Advanced glycation end products increase, through a protein kinase C-dependent pathway, vascular endothelial growth factor expression in retinal endothelial cells. Inhibitory effect of gliclazide. 1212 87

Nonalcoholic fatty liver disease (NAFLD) includes a wide spectrum of liver injury ranging from simple steatosis to steatohepatitis, fibrosis, and cirrhosis. Whereas simple steatosis has a benign clinical course, steatohepatitis is a recognized cause of progressive liver fibrosis and can develop into cirrhosis. NAFLD and nonalcoholic steatohepatitis (NASH) are the two most common chronic liver diseases in United States general population with a prevalence of 20% and 3%, respectively. Hepatic steatosis is frequently associated with obesity, type 2 diabetes, and hyperlipidemia with insulin resistance as a key pathogenic factor. A two-hit theory best describes the progression from simple steatosis to NASH, fibrosis, or cirrhosis. These two hits consist of the accumulation of excessive hepatic fat primarily owing to insulin resistance, and oxidative stress owing to reactive oxygen species (ROS). Mitochondria are the major cellular source of ROS in cases of NASH. Currently, treatment is focused on modifying risk factors such as obesity, diabetes mellitus, and hyperlipidemia. Antioxidants such as vitamin E, N-acetylcysteine, betaine, and others may be beneficial in the treatment of NASH.
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PMID:Nonalcoholic fatty liver disease: pathogenesis and the role of antioxidants. 1229 56

Treatment of patients with non-alcoholic steatohepatitis (NASH) has typically been focused on the management of associated conditions such as obesity, diabetes mellitus and hyperlipidaemia. NASH associated with obesity may resolve with weight reduction, although the benefits of weight loss have been inconsistent. Appropriate control of glucose and lipid levels is always recommended, but is not always effective in reversing the liver condition. Results of pilot studies evaluating ursodeoxycholic acid, gemfibrozil, betaine, N-acetylcysteine, alpha-tocopherol, metformin and thiazolidinedione derivatives suggest that these medications may be of potential benefit for patients with NASH. These medications, however, need first to be tested in well-controlled trials with clinically relevant end-points and extended follow-up. A better understanding of the pathogenesis and natural history of NASH will help to identify the subset of patients at risk of progressing to advanced liver disease and, hence, those patients who should derive the most benefit from medical therapy.
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PMID:Treatment of non-alcoholic steatohepatitis. 1240 46

Accumulating evidence suggests that the pathophysiology of diabetes is analogous to chronic inflammatory states. Circulating levels of inflammatory cytokines such as IL-6 and tumor necrosis factor alpha (TNFalpha) are increased in both type 1 and type 2 diabetes. TNFalpha plays an important role in the pathogenesis of insulin resistance in type 2 diabetes. However, the reason for this increase remains unclear. Levels of the dicarbonyl methylglyoxal (MGO) are elevated in diabetic plasma and MGO-modified bovine serum albumin (MGO-BSA) can trigger cellular uptake of TNF. Therefore we tested the hypothesis that MGO-modified proteins may cause TNFalpha secretion in macrophage-like RAW 264.7 cells. Treatment of cells with MGO-BSA induced TNFalpha release in a dose-dependent manner. MGO-modified ribonuclease A and chicken egg ovalbumin had similar effects. Cotreatment of cells with antioxidant reagent N-acetylcysteine (NAC) inhibited MGO-BSA-induced TNFalpha secretion. MGO-BSA stimulated the simultaneous activation of p44/42 and p38 mitogen-activated protein kinase. PD98059, a selective MEK inhibitor, inhibited MGO-BSA-induced TNFalpha release as well as ERK phosphorylation. Pretreatment of cells with NAC also resulted in inhibition of MGO-BSA-induced ERK phosphorylation. MGO-BSA induced dose-dependent NFkappaB activation as shown by electrophoresis mobility shift assay. The MGO-BSA-induced NFkappaB activation was prevented in the presence of PD98059, NAC, and parthenolide, a selective inhibitor of NFkappaB. Furthermore, the NFkappaB inhibitor parthenolide suppressed MGO-BSA-induced TNFalpha secretion. Confocal microscopy using dichlorofluorescein to demonstrate intracellular reactive oxygen species (ROS) showed that MGO-BSA produced more ROS compared with native BSA. MGO-BSA could also stimulate protein kinase C (PKC) translocation to the cell membrane, considered a key signaling pathway in diabetes. However, there was no evidence that PKC was involved in TNFalpha release based on inhibition by calphostin C and staurosporine. Our findings suggest that the presence of chronically elevated levels of MGO-modified bovine serum albumin may contribute to elevated levels of TNFalpha in diabetes.
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PMID:Methylglyoxal-bovine serum albumin stimulates tumor necrosis factor alpha secretion in RAW 264.7 cells through activation of mitogen-activating protein kinase, nuclear factor kappaB and intracellular reactive oxygen species formation. 1250 94

This study analyzes the effect of chronic treatment with different antioxidants (N-acetyl-cysteine [NAC], taurine, a combination of NAC and taurine, and oxerutin) on long-term experimental diabetes induced by streptozotocin in rats. Glycoxidative damage was evaluated in the skin; glomerular structural changes were studied with morphometry and immunohistochemistry. Oxerutin treatment and the combined NAC plus taurine treatment resulted in reduced accumulation of collagen-linked fluorescence in skin in comparison with untreated diabetic rats. All treatments except taurine reduced glomerular accumulation of N(epsilon)-(carboxymethyl)lysine and protected against the increase in glomerular volume typical of diabetes; furthermore, the apoptosis rate was significantly decreased and the glomerular cell density was better preserved. Glycoxidative markers in the skin turned out to be good indicators of the glomerular condition. The findings that emerged from our study support the hypothesis that glomerular damage in diabetes can be prevented or at least attenuated by supplementation with specific antioxidants. Treatment with oxerutin and combined treatment with NAC plus taurine gave the most encouraging results, whereas the results of taurine-only treatment were either negligible or negative and therefore suggest caution in the use of this molecule in single-drug treatment courses.
Diabetes 2003 Feb
PMID:Comparative trial of N-acetyl-cysteine, taurine, and oxerutin on skin and kidney damage in long-term experimental diabetes. 1254 Jun 27

Radiocontrast administration remains the third leading cause of hospital-acquired acute renal failure. Clinically, radiocontrast-induced nephropathy (RIN) is defined as a sudden decline in renal function after radiocontrast administration. Typically, the serum creatinine level begins to increase at 24 to 72 hours after the administration of contrast, peaks at 3 to 5 days, and requires another 3 to 5 days to return to baseline. RIN increases the incidence of life-threatening complications such as sepsis, bleeding, and respiratory failure and increases the cost of medical care by extending the hospital stay. The increased mortality associated with acute renal failure encountered in this scenario calls for a heightened awareness of the diagnosis and prevention of RIN. Whereas individuals with healthy renal function are not generally considered to be at particular risk for RIN, patients with preexisting renal insufficiency and diabetes mellitus are much more likely to experience acute renal failure after contrast administration. In the past, a variety of therapeutic interventions have been used to prevent or attenuate RIN, including saline hydration, diuretics, mannitol, calcium channel antagonists, theophylline, endothelin receptor antagonists, hemodialysis, and dopamine. More recently, studies demonstrate a positive impact of fenoldopam (dopamine-1 receptor, dopamine-1 agonist) and the antioxidant N-acetylcysteine in ameliorating RIN. This article discusses the pathophysiology, risk factors, and prevention of RIN.
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PMID:Radiocontrast-induced nephropathy. 1262 94

Insulin resistance is characterized by impaired glucose utilization in the peripheral tissues, accelerated muscle protein degradation, impaired antioxidant defences and extensive cell death. Apparently, both insulin and IGF-1 at physiological concentrations support cell survival by phosphatidylinositol 3 kinase-dependent and independent mechanisms. Postprandial hyperglycemia and hyperinsulinemia are found in insulin resistance, which accompanies the so-called noninsulin dependent diabetes mellitus (diabetes type 2). Evidence also indicates that increased susceptibility of muscle cells and cardiomycoytes to oxidative stress is among the harmful complications of insulin resistance and diabetes. Limited knowledge showing benefits of preconditioning with anti- oxidants (vitamin C, E, a-lipoic acid, N-acetylcysteine) in order to protect insulin action under oxidative stress prompted the author to discuss the theoretical background to this approach. It should be stressed that antioxidant preconditioning is relevant to prevention of both diabetes- and insulin resistance-associated side-effects such as low viability and cell deletion. Furthermore, antioxidant conditioning promises to provide higher efficacy for clinical applications in myoblast transfer therapy and cardiomyoplasty.
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PMID:Justification for antioxidant preconditioning (or how to protect insulin-mediated actions under oxidative stress). 1268 23

The aim of the present study was to investigate whether diabetic embryopathy may be associated with the inhibition of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) resulting from an excess of reactive oxygen species (ROS) in the embryo. Recent demonstrations of enhanced ROS production in mitochondria of bovine aortic endothelial cells exposed to high glucose have supported the idea that the pathogenesis of diabetic complications may involve ROS-induced GAPDH inhibition. We investigated whether a teratogenic diabetic environment also inhibits embryonic GAPDH activity and alters GAPDH gene expression and whether antioxidants diminish such GAPDH inhibition. In addition, we determined whether the inhibition of GAPDH with iodoacetate induces dysmorphogenesis, analogous to that caused by high glucose concentration, and whether antioxidants modulated the putative teratogenic effect of such direct GAPDH inhibition. We found that embryos from diabetic rats and embryos cultured in high glucose concentrations showed decreased activity of GAPDH (by 40-60%) and severe dysmorphogenesis on gestational days 10.5 and 11.5. GAPDH mRNA was decreased in embryos of diabetic rats compared to control embryos. Supplementing the high-glucose culture with the antioxidant N-acetylcysteine (NAC) increased GAPDH activity and diminished embryonic dysmorphogenesis. Embryos cultured with iodoacetate showed both decreased GAPDH activity and dysmorphogenesis; supplementing the culture with NAC increased both parameters toward normal values. In conclusion, dysmorphogenesis caused by maternal diabetes is correlated with ROS-induced inhibition of GAPDH in embryos, which could indicate that inhibition of GAPDH plays a causal role in diabetic embryopathy.
Diabetes 2003 May
PMID:Maternal diabetes in vivo and high glucose in vitro diminish GAPDH activity in rat embryos. 1271 56

Contrast-induced nephropathy is one of the adverse events of diagnostic and therapeutic intravascular application of contrast agent. In general, the condition was defined as an increase in the serum creatinine concentration of more than 44 mmol/l or of more than 25% within 48 hours after the contrast agent administration. Other cause of creatinine increase should be excluded. Contrast-induced nephropathy has been reported to be the third leading cause of acute nephropathy in hospitalized patients, occurring at a rate of 1-6% in unselected population and of 30-50% in high-risk patients. One year mortality can be as high as 45% in high-risk patient population. The most important risk factors are chronic renal insufficiency, diabetes mellitus and high volume of contrast agent. Clinical presentation is mostly asymptomatic, but in some patients acute renal failure with necessity of hemodialysis can occur. Prevention is underlying tool in reducing of contrast-induced nephropathy incidence. It is based on the identification of risk patients, stop of medication which can increase risk of contrast-induced nephropathy and proper hydratation of patients before, during and after the contrast agent administration. In high-risk patients, non-ionic and low-osmolarity contrast agent should be used. Several clinical studies testing different drugs to prevent contrast-induced nephropathy were performed, but no convincing result has been found. Promising substancies are N-acetylcysteine and fenoldopam.
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PMID:[Contrast nephropathy and its prevention]. 1272 80

Treatment of patients with non-alcoholic fatty liver disease (NAFLD) has typically been focused on the management of associated conditions such as obesity, diabetes mellitus and hyperlipidaemia. NAFLD associated with obesity may be resolved by weight reduction, although the benefits of weight loss have been inconsistent. Improving insulin sensitivity with lifestyle modifications or medications usually improves glucose and lipid levels in patients with diabetes and hyperlipidaemia. Improving insulin sensitivity is expected to improve the liver disease but in many diabetic/hyperlipidaemic patients with NAFLD, the appropriate control of glucose and lipid levels is not always accompanied by improvement of the liver condition. Results of pilot studies evaluating ursodeoxycholic acid, gemfibrozil, betaine, N-acetylcysteine, alphatocopherol, metformin and thiazolidinedione derivatives suggest that these medications may be of potential benefit. This article reviews the treatment modalities currently available for patients with NAFLD, including emerging data from clinical trials evaluating promising medications as well as possibilities for the future.
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PMID:Current best treatment for non-alcoholic fatty liver disease. 1273 88


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