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)

Insulin resistance accounts for glucotoxicity observed in diabetes and atherosclerotic disease. Glucotoxicity depends from the shift of glucose metabolism from the glycolytic pathway to minor forms of glucose metabolism, including sorbitol, hexosamine and AGE pathways. These pathways increase oxidative stress and/or block insulin signalling so leading to a further decline of insulin action. A genetic defect of insulin action (the g972R Insulin Receptor Substrate 1 variant) may sustain endothelial dysfunction, the first defect of vascular homeostasis in the road to atherosclerosis. Furthermore, hyperglycemia even in the absence of insulin resistance, activates the hexosamine pathway in endothelial cells, affects the production of nitric oxide, increases the production and activity of metalloproteinase 2 and 9 and activates endothelium thus provoking endothelial dysfunction. Oxidative stress and inflammation through activtion of IKK-beta could determine insulin resistance impairing IRS-1 ability to activate the metabolic branch of insulin signalling. Furthermore, increased oxidative stress may be speculated to affect glucose metabolism in a proportion of patients with coronary artery disease. In conclusion, type 2 diabetes and atherosclerosis share vascular homeostasis and glucose metabolism and insulin resistance might be the common road where diabetes and atherosclerosis run together.
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PMID:Review article: diabetes and atherosclerosis--running on a common road. 1622 64

We studied the efficacy of four different treatment regimens (sulphonylurea and metformin+/-acarbose versus glimepiride and rosiglitazone versus glimepiride and bedtime NPH insulin versus multiple actrapid and NPH insulin injections) in poorly controlled type 2 diabetes subjects on hs-CRP, VCAM-1 and AGE at 4, 8 and 12 weeks of treatment. Multiple insulin injections rapidly improved HbA(1c) by 0.6+/-0.9% (p<0.005), 1.2+/-1.3% (p<0.0005) and 1.3+/-1.4% (p<0.0005) at week 4, at week 8 and week 12, respectively. Subjects who continued their existing combination treatment of sulphonylurea, metformin+/-acarbose also showed a significant reduction in HbA(1c) (p<0.05). Although effective in reducing glycemic parameters, there was no reduction in CRP levels in either treatment group. The treatment regimen consisting of rosiglitazone and glimepiride significantly lowered hs-CRP by -2.6 (3.9) mg/L (p<0.05) at week 12 in spite of no improvement in blood glucose. AGE improved in all groups irrespective of type of treatment, glycaemic control and CRP levels. Our data indicate rapid glycaemic control alone does not necessarily result in improvement in markers of inflammation in type 2 diabetes patients.
Diabetes Res Clin Pract 2006 Apr
PMID:Improvement in C-reactive protein and advanced glycosylation end-products in poorly controlled diabetics is independent of glucose control. 1625 80

Risk factors for cardiovascular disease, including high cholesterol, high homocysteine, hypertension and inflammation, increase the risk of dementia, including its most common form, Alzheimer's disease (AD). High cholesterol is also associated with elevated beta-amyloid (Abeta), the hallmark of AD. Oxidative damage is a major factor in cardiovascular disease and dementia, diseases whose risk increases with age. Garlic, extracted and aged to form antioxidant-rich aged garlic extract (AGE or Kyolic), may help reduce the risk of these diseases. AGE scavenges oxidants, increases superoxide dismutase, catalase, glutathione peroxidase, and glutathione levels, and inhibits lipid peroxidation and inflammatory prostaglandins. AGE reduces cholesterol synthesis by inhibiting 3-hydroxy-3-methylglutaryl-CoA reductase and is additive with statins in its action. Inhibition of cholesterol, LDL oxidation, and platelet aggregation by AGE, inhibits arterial plaque formation; AGE decreases homocysteine, lowers blood pressure, and increases microcirculation, which is important in diabetes, where microvascular changes increase heart disease and dementia risks. AGE also may help prevent cognitive decline by protecting neurons from Abeta neurotoxicity and apoptosis, thereby preventing ischemia- or reperfusion-related neuronal death and improving learning and memory retention. Although additional observations are warranted in humans, compelling evidence supports the beneficial health effects attributed to AGE in helping prevent cardiovascular and cerebrovascular diseases and lowering the risk of dementia and AD.
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PMID:Garlic reduces dementia and heart-disease risk. 1648 70

We recently identified a naturally occurring soluble form of RAGE (the receptor for advanced glycation endproducts, receptor for AGE) in cultured human vascular cells, and named it endogenous secretory RAGE (esRAGE). esRAGE is generated by alternative RNA splicing and is able to capture AGE, and exerts protection against AGE-induced endothelial cell injury. In the present study, the presence of esRAGE in human circulation was demonstrated for the first time, and a highly sensitive and specific sandwich ELISA system for esRAGE was developed to see whether esRAGE could be related to an individual resistance to the development of diabetic vascular complications. Sera from 47 type 1 diabetic subjects without clinical nephropathy (urinary albumin excretion <300mg/g creatinine) and 55 healthy controls were analyzed by the ELISA. Circulating esRAGE concentrations in diabetic patients with simple and proliferative retinopathy (0.09+/-0.02ng/mL, n=16 and 0.08+/-0.02ng/mL, n=8, respectively) were significantly lower than in those without retinopathy (0.13+/-0.06ng/mL, n=23). The results indicate that esRAGE can be a useful biomarker to indicate individual variations in susceptibility to diabetic retinopathy.
Diabetes Res Clin Pract 2006 Aug
PMID:Development of an ELISA for esRAGE and its application to type 1 diabetic patients. 1648 5

Exogenous advanced glycation endproducts (AGEs, known atherogenic molecules) abundant in everyday precooked, rich in fat, overheated meals can possibly contribute to the increased risk for diabetes and cardiovascular disease in women with polycystic ovary syndrome (PCOS). The aim of the present study was to investigate the effect of a lipase inhibitor on absorbed food glycotoxins in healthy women and those with PCOS. A 2-day protocol was followed. In the first day, a meal rich in AGE was provided, which on the second day was followed by two 120-mg capsules of lipase inhibitor, orlistat. Serum AGE levels were evaluated at baseline (0 hours), and at 3 and 5 hours postmeal during the study. Thirty-six women were studied, 15 controls (mean age, 28.80 +/- 5.47 years; body mass index, 25.85 +/- 6.73 kg/m(2)) and 21 with PCOS (mean age, 25.29 +/- 5.06 years; body mass index, 30.40 +/- 7.51 kg/m(2)) (University Hospital, Athens, Greece, institutional practice). Serum AGE levels, on day 1, were significantly increased both in the control group and in the PCOS group as compared with basal values (control group, 14.1%; PCOS group, 6.0%; P < .001). The corresponding rise was significantly lower on day 2 when the same meal was combined with orlistat (control group, 4.1%; PCOS group, 2.0%; P < .01). A limitation of the study is that it is a nonplacebo, nonrandomized therapeutic trial where each subject is considered as its own control. In conclusion, this study demonstrated the beneficial effect of orlistat on the absorption of food glycotoxins.
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PMID:Short-term effect of orlistat on dietary glycotoxins in healthy women and women with polycystic ovary syndrome. 1654 80

The formation of "Advanced Glycation End products" (AGEs) is an inevitable consequence of mammalian glucose metabolism. AGE-mediated protein-protein crosslinks lead to detergent-insoluble and protease-resistant protein aggregates, and in Alzheimer's disease (AD) extra cellular senile plaques (SPs) and intracellular neurofibrillary tangles (NFTs) have been shown to contain AGEs. However, to date little is known concerning the most prevalent protein-targets of AGE modification under normal, non-pathological conditions. Here, a combination of 2D-electrophoresis, Western blotting and mass spectrometry has been used to identify preferentially AGE-modified proteins in oligodendrocyte (OLN-93) and neuroblastoma cell lines (SH-SY5Y) in standard culture. Proteomics analysis identified a total of eight targets with structural, metabolic and regulatory function, three of which (beta-actin, beta-tubulin and eukaryotic Elongation Factor 1-alpha) were common to both cell lines. Based on results from prior studies, modification of these proteins may lead to a loss of function. Consequently, the identification of targets for these proteins is of particular interest for a better understanding of the consequences of AGE-modification in aging, neurodegenerative diseases and diabetes.
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PMID:Identification of AGE-modified proteins in SH-SY5Y and OLN-93 cells. 1678 85

Previous experiments have shown that AGE-products added to human skin fibroblast cultures increased the number of dead cells floating on top of the culture fluid and took up vital dye [1]. In these experiments, we tested several rhamnose-rich polysaccharides for protection against the cytotoxic effect of AGE-s. Added at relatively low concentrations (between 10 and 100 microg/ml) to the culture medium, several of the tested rhamnose-rich oligo- and polysaccharides (RROP-s) gave a significant protection against AGE-induced cytotoxicity. Their effect on cell proliferation was also tested. The number of cells at saturation density was also shown to be influenced by AGE-products added to the cultures. This effect was also, at least partially, corrected by the rhamnose-rich oligo- and polysaccharides. These substances might therefore be considered as of potential therapeutical interest against hyperglycemia induced cytotoxic effects as in type II-diabetes.
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PMID:Protection by rhamnose-rich polysaccharides against the cytotoxicity of Maillard reaction products. 1688 28

With the rapid increase of life expectancy in western societies, appeared also a new phenomenon, obesity, which took during the recent decades pandemic dimensions. One of the consequences was the appearance of type II diabetes in much younger persons than before. The result of intensive research in this field over the last decades led, among other achievements to the identification of biological and molecular symptoms which together were reclassified as the "metabolic syndrome". Questionable as far as its originality is concerned, it did however good service to practitioners by formulating criteria for diagnostic and therapeutical purposes. Among the underlying biochemical mechanisms the Maillard reaction, the non enzymatic glycosylation of proteins and nucleotide bases followed by the formation of advanced glycation and products (AGE-s) plays an important role. Several recent experimental results confirm this statement, some of them are published in this issue. The reviews and original contributions form together an up to date report on this important pathology and support again the importance of posttranslational and environmental factors influencing gene expression and cellular functions.
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PMID:The metabolic syndrome and the Maillard reaction. An introduction. 1697 98

This review summarizes evidence on the effect of excess circulating glucose concentration and AGE-albumin on the aortic endothelial cells (ECs) phenotype, transport function, and expression of signalling molecules. The recent reports on the ECs dysfunction in diabetes are briefly reviewed, to provide a broader view on the link between ECs structural changes, functional alterations, and the underlying biochemical mechanisms. The original results emerging from streptozotocin-injected mice and human aortic endothelial cells grown in high (25 mM) glucose concentration are presented. Compared to physiological condition, in diabetes aortic ECs switch to a biosynthetic phenotype, present an increased number of caveolae, and enhance (by approximately 20%) transcytosis of AGE-albumin (AGE-Alb). In cultured ECs, 25 mM glucose induces approximately 2.6 fold increase in pSTAT-3 and pERK1 and approximately 1.8 fold increase in pERK2; further exposure to 5 microM AGE-Alb causes approximately 4.3 fold increase in pERK1/2 (vs. 5 mM glucose). Together, these data may explain the phenotypic change, enhanced permeability, and proliferation of aortic ECs in diabetic conditions.
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PMID:Cellular mechanisms and signalling pathways activated by high glucose and AGE-albumin in the aortic endothelium. 1717 1

In this review, the impacts of mitochondrial reactive oxygen species (ROS) on diabetes and its complications are described. In endothelial cells, high-glucose treatment increases mitochondrial ROS and normalization of the ROS production by inhibitors of mitochondrial metabolism, or by overexpression of UCP-1 or MnSOD, prevents glucose-induced activation of PKC, formation of AGE, and accumulation of sorbitol, all of which are believed to be the main molecular mechanisms of diabetic complications. Glomerular hyperfiltration, one of the characteristics of early diabetic nephropathy, may be caused by mitochondrial ROS through activation of COX-2 gene transcription, followed by PGE2 overproduction. In pancreatic beta cells, hyperglycemia also increases mitochondrial ROS, which suppresses the first phase of glucose-induced insulin secretion, at least in part, through the suppression of GAPDH activity. In liver cells, similar to that in hyperglycemia, TNF-alpha increases mitochondrial ROS, which in turn activates apoptosis signal-regulating kinase 1 (ASK1) and c-jun NH2-terminal kinases (JNK), increases serine phosphorylation of IRS-1, and decreases insulin-stimulated tyrosine phosphorylation of IRS-1, leading to insulin resistance. These results suggest the importance of mitochondrial ROS in the pathogenesis of diabetes mellitus and its complications through modification of various cellular events in many tissues, including vessels, kidney, pancreatic beta cells, and liver.
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PMID:Impact of mitochondrial ROS production in the pathogenesis of diabetes mellitus and its complications. 1718 77


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