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)

Treatment with vanadium, a representative of a class of antidiabetic compounds, alleviates diabetic hyperglycemia and hyperlipidemia. Oral administration of vanadium compounds in animal models and humans does not cause clinical symptoms of hypoglycemia, a common problem for diabetic patients with insulin treatment. Gene expression, using Affymetrix arrays, was examined in muscle from streptozotocin-induced diabetic and normal rats in the presence or absence of oral vanadyl sulfate treatment. This treatment affected normal rats differently from diabetic rats, as demonstrated by two-way ANOVA of the full array data. Diabetes altered the expression of 133 genes, and the expression of 30% of these genes dysregulated in diabetes was normalized by vanadyl sulfate treatment. For those genes, the ratio of expression in normal animals to the expression in diabetic animals showed a strong negative correlation with the ratio of expression in diabetic animals to the expression in diabetic animals treated with vanadyl sulfate (P = -0.85). The genes identified belong to six major metabolic functional groups: lipid metabolism, oxidative stress, muscle structure, protein breakdown and biosynthesis, the complement system, and signal transduction. The identification of oxidative stress genes, coupled with the known oxidative chemistry of vanadium, implicates reactive oxygen species in the action of this class of compounds. These results imply that early transition metals or compounds formed from their chemical interactions with other metabolites may act as general transcription modulators, a role not usually associated with this class of compounds.
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PMID:Diabetes-altered gene expression in rat skeletal muscle corrected by oral administration of vanadyl sulfate. 1668 4

Low-dose acetylsalicylic acid (ASA) treatment is a standard therapeutic approach in diabetes mellitus for prevention of long-term vascular complications. The aim of the present work was to investigate the effect of long-term ASA administration in experimental diabetes on activities of some liver enzymes: glutathione peroxidase (GSHPx), catalase, glucose-6-phosphate dehydrogenase (G6PDH) and glutathione S-transferase (GST). Blood glucose, glycated hemoglobin, as well as plasma ALT and AST activities increased in rats with streptozotocin-induced experimental diabetes. The long-term hyperglycemia resulted in decreased activities of GSHPx (by 26%), catalase (by 34%), GST (by 38%) and G6PDH (by 27%) in diabetic animals. We did not observe increased accumulation of membrane lipid peroxidation products or altered levels of reduced glutathione in livers. The linear correlation between blood glucose and glycated hemoglobin in diabetic animals was distorted upon ASA treatment, which was likely due to a chemical competition between nonenzymatic protein glycosylation and protein acetylation. The long-term ASA administration partially reversed the decrease in GSHPx activity, but did not influence the activities of catalase and GST in diabetic rats. Otherwise, some decrease in these parameters was noted in ASA-treated nondiabetic animals. Increased ASA-induced G6PDH activity was recorded in both diabetic and nondiabetic rats. While both glycation due to diabetic hyperglycemia and ASA-mediated acetylation had very similar effects on the activities of all studied enzymes but G6PDH, we conclude that non-enzymatic modification by either glucose or ASA may be a common mechanism of the observed convergence.
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PMID:Antioxidative enzyme and glutathione S-transferase activities in diabetic rats exposed to long-term ASA treatment. 1681 74

Previous work from this laboratory has demonstrated that transplantation of allogeneic thymic tissue as part of a composite vascularized graft is far more successful in terms of both engraftment and long-term survival than transplantation of thymic tissue or cells alone. We have subsequently extended this concept to transplantation of allogeneic islets, comparing survival of islet cell suspensions to that of vascularized composite islet-kidneys (IK), prepared by injection of autologous islets underneath the renal capsule 2-3 months prior to allogeneic transplantation of the composite organ. We have utilized partially inbred miniature swine with defined MHC loci as the experimental large animals for this study, permitting reproducible transplantation across specific MHC barriers. Composite IK have been transplanted successfully across minor and full MHC mismatch barriers, using treatment regimens previously demonstrated to induce long-term tolerance of kidney allografts across these barriers. IK allografts containing > or =5000 islet equivalents (IE)/kg recipient body weight were found capable of reversing surgically induced diabetes, while injection of comparable numbers of purified islets via the portal vein or under the renal capsule did not. Studies are also being directed toward preparation of autologous "thymo-isletkidneys" (TIK), for potential use as xenografts, in which the thymic component is intended to induce tolerance and the islets to reverse diabetic hyperglycemia. The use of both types of composite organ transplants may eventually be applicable to the treatment of type I diabetic patients suffering from end-stage diabetic nephropathy.
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PMID:Vascularized composite islet-kidney transplantation in a miniature swine model. 1770 90

We combined behavioral testing with brain imaging using (99m)Tc-HMPAO (Amersham Health) to identify CNS structures reflecting alterations in pain perception in the streptozotocin (STZ) model of type I diabetes. We induced diabetic hyperglycemia (blood glucose >300 mg/dl) by injecting male Sprague-Dawley rats with STZ (45 mg/kg i.p.). Four weeks after STZ-diabetic rats exhibited behaviors indicative of neuropathic pain (hypersensitivity thermal stimuli) and this hypersensitivity persisted for up to 6 weeks. Imaging data in STZ-diabetic rats revealed significant increases in the activation of brain regions involved in pain processing after 6 weeks duration of diabetes. These regions included secondary somatosensory cortex, ventrobasal thalamic nuclei and the basolateral amygdala. In contrast, the activation in habenular nuclei and the midbrain periaqueductal gray were markedly decreased in STZ rats. These data suggest that pain in diabetic neuropathy may be due in part to hyperactivity in somatosensory structures coupled with a concurrent deactivation of structures mediating antinociception.
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PMID:Concurrent activation of the somatosensory forebrain and deactivation of periaqueductal gray associated with diabetes-induced neuropathic pain. 1793 73

Glucagon-Like Peptide-1 (GLP-1) is an incretin peptide secreted from intestinal L-cells, whose potent plasma glucose-lowering action has prompted intense efforts to develop GLP-1 receptor-targeting drugs for treatment of diabetic hyperglycemia. More recently, GLP-1 and its analogues have been shown to exert cardiovascular effects in a number of experimental models. Here we tested exendin-4 (Exe-4), a peptide agonist at GLP-1 receptors, and GLP-1(9-36) amide, the primary endogenous metabolite of GLP-1 (both in the concentration range 0.03-3.0 nM), for their protective effects against ischemia-reperfusion injury (IRI) in an isolated rat heart preparation. When administered, the agents were only present for the first 15 min of a 120 min reperfusion period (postconditioning protocol). Exe-4, but not GLP-1(9-36) amide, showed a strong infarct-limiting action (from 33.2% +/-2.7% to 14.5% +/-2.2% of the ischemic area, p<0.05). This infarct size-limiting effect of Exe-4 was abolished by exendin(9-39) (Exe(9-39)), a GLP-1 receptor antagonist. In contrast, both Exe-4 and GLP-1(9-36) amide were able to augment left ventricular performance (left ventricular developed pressure and rate-pressure product) during the last 60 min of reperfusion. These effects were only partially antagonized by Exe(9-39). We suggest that Exe-4, in addition to being currently exploited in treatment of diabetes, may present a suitable candidate for postconditioning trials in clinical settings of IRI. The divergent agonist effects of Exe-4 and GLP-1(9-36), along with correspondingly divergent antagonistic efficacy of Exe(9-39), seem consistent with the presence of more than one type of GLP-1 receptor in this system.
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PMID:Protective effects of GLP-1 analogues exendin-4 and GLP-1(9-36) amide against ischemia-reperfusion injury in rat heart. 1797 35

The polyol pathway is a two-step metabolic pathway in which glucose is reduced to sorbitol, which is then converted to fructose. It is one of the most attractive candidate mechanisms to explain, at least in part, the cellular toxicity of diabetic hyperglycemia because (i) it becomes active when intracellular glucose concentrations are elevated, (ii) the two enzymes are present in human tissues and organs that are sites of diabetic complications, and (iii) the products of the pathway and the altered balance of cofactors generate the types of cellular stress that occur at the sites of diabetic complications. Inhibition (or ablation) of aldose reductase, the first and rate-limiting enzyme in the pathway, reproducibly prevents diabetic retinopathy in diabetic rodent models, but the results of a major clinical trial have been disappointing. Since then, it has become evident that truly informative indicators of polyol pathway activity and/or inhibition are elusive, but are likely to be other than sorbitol levels if meant to predict accurately tissue consequences. The spectrum of abnormalities known to occur in human diabetic retinopathy has enlarged to include glial and neuronal abnormalities, which in experimental animals are mediated by the polyol pathway. The endothelial cells of human retinal vessels have been noted to have aldose reductase. Specific polymorphisms in the promoter region of the aldose reductase gene have been found associated with susceptibility or progression of diabetic retinopathy. This new knowledge has rekindled interest in a possible role of the polyol pathway in diabetic retinopathy and in methodological investigation that may prepare new clinical trials. Only new drugs that inhibit aldose reductase with higher efficacy and safety than older drugs will make possible to learn if the resilience of the polyol pathway means that it has a role in human diabetic retinopathy that should not have gone undiscovered.
Exp Diabetes Res 2007
PMID:The polyol pathway as a mechanism for diabetic retinopathy: attractive, elusive, and resilient. 1822 43

The mechanisms of adipogenic diabetes in Zucker diabetic fatty (ZDF) rats, a model of obesity complicated by diabetes, are reviewed. In ZDF rats, a mutation in the leptin receptor, OB-R, is associated with leptin resistance, obesity, and increased fat content of islets. Exaggerated nitric oxide (NO) generation, attributed to high intracellular levels of long-chain fatty acids, impairs beta-cell function and prevents their compensation for obesity-induced diabetes. The resulting diabetic hyperglycemia can be completely prevented by agents that inhibit NO production.
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PMID:How obesity causes diabetes in Zucker diabetic fatty rats. 1840 16

Inappropriate adaptation of beta-cell mass is a primary cause of the development of diabetic hyperglycemia. However, the mechanisms underlying regulation of the beta-cell mass in response to insulin resistance or in the development of type 2 diabetes remain unclear. We determined the insulin signaling in the beta-cells and the adaptation of the beta-cell mass in response to the progression of insulin resistance in OLETF rats. By 25 weeks of age, at the onset of diabetes, compared to control LETO rats, OLETF rats developed obesity (Body weight: LETO vs OLETF = 474.0+/-9.5 vs 581.3+/-21.8 g, P < 0.001, n=6), hyperlipidemia (Cholesterol: LETO vs OLETF = 1.67+/-0.07 vs 2.19+/-0.20 mM, P < 0.05, n=6; triglyceride: LETO vs OLETF = 0.36+/-0.05 vs 1.36+/-0.12 mM, P < 0.001, n=6), and impaired glucose tolerance (AUC: LETO vs OLETF = 10.3+/-3.4 vs 29.6+/-7.8 mM, P < 0.001, n=6). Insulin sensitivities as assessed by the insulin sensitivity index (ISI) and the homeostasis model assessment (HOMA) indicated that OLETF rats developed severe insulin resistance. The measurement of plasma insulin levels by ELISA demonstrated, at the onset of diabetes, that fasting insulin levels were increased by 1.2-fold, and 2 hr postprandial insulin levels were increased by 3-fold (P < 0.05, n=6) in OLETF rats compared to age-matched LETO mates which is suggestive of hyperinsulinemia. Immunostaining detected a significant reduction in the insulin receptor substrate 1 (IRS1) (by 54%, P < 0.001) and IRS2 (by 55%, P < 0.001) in the beta-cells of the OLETF rats. Interestingly, while the beta-cell mass was found to be increased (by 2.2-fold; P < 0.001), the beta-cell insulin content as determined by immunostaining was significantly reduced by 32% (P < 0.001) in the OLETF rats when compared to the controls. Our findings suggest that despite increasing beta-cell mass the impaired beta-cell insulin signaling and reduced beta-cell insulin content may contribute to the onset of overt diabetes in OLETF rats.
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PMID:Increased beta-cell apoptosis and impaired insulin signaling pathway contributes to the onset of diabetes in OLETF rats. 1845 52

The levels of advanced nonenzymatic glycation endproducts (ACE) were investigated by spectrofluorimetry in eye lens proteins obtained from rats with experimental diabetes of 3 and 6 months duration and from normal age-matched control rats. Diabetic animals showed higher AGE levels at both times studied. However the older control animals showed protein ACE levels comparable to those of the experimental 3 months diabetic group. These data suggest that a pathological phenomenon such as enhanced nonenzymatic glycation, associated to diabetic hyperglycemia, can be considered as a process leading to an accelerated aging of proteins. Thus experimental diabetes mellitus may be used as a model to investigate physiological protein senescence.
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PMID:Enhanced nonenzymatic glycation of eye lens proteins in experimental diabetes mellitus: an approach for the study of protein alterations as mediators of normal aging phenomena. 1864 4

Diabetes mellitus is increasingly prevalent worldwide. Diabetic individuals are at markedly increased risk for premature death due to cardiovascular disease. Furthermore, substantial morbidity results from microvascular complications which include retinopathy, nephropathy, and neuropathy. Clinical studies involving diabetic patients have suggested that degree of diabetic hyperglycemia correlates with risk of complications. Recent evidence implicates a central role for oxidative stress and vascular inflammation in all forms of insulin resistance, obesity, diabetes and its complications. Although, glucose promotes glycoxidation reactions in vitro and products of glycoxidation and lipoxidation are elevated in plasma and tissue in diabetics, the exact relationships among hyperglycemia, the diabetic state, and oxidative stress are not well-understood. Using a combination of in vitro and in vivo experiments, we have identified amino acid oxidation markers that serve as molecular fingerprints of specific oxidative pathways. Quantification of these products utilizing highly sensitive and specific gas chromatography/mass spectrometry in animal models of diabetic complications and in humans has provided insights in oxidative pathways that result in diabetic complications. Our studies strongly support the hypothesis that unique oxidants are generated in the microenvironment of tissues vulnerable to diabetic damage. Potential therapies interrupting these reactive pathways in target tissue are likely to be beneficial in preventing diabetic complications.
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PMID:Mass spectrometric quantification of amino acid oxidation products identifies oxidative mechanisms of diabetic end-organ damage. 1875 69


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