Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Retention of atherogenic apolipoprotein (apo) B- and E- containing lipoproteins by their interaction with arterial wall proteoglycans is important in atherogenesis. Levels of triglyceride (TG)-rich lipoproteins, which contain both apo B and apo E, are increased in type 2 diabetes. Because increased retention of TG-rich lipoproteins in diabetes might explain, in part, the increased atherosclerosis in this disorder, TG-rich lipoproteins were isolated from fasting type 2 diabetic subjects and age-matched controls, and assessed for their ability to bind biglycan, a vascular smooth muscle cell-derived proteoglycan. The binding of TG-rich lipoproteins isolated from diabetic subjects to purified biglycan did not differ from lipoproteins isolated from control subjects. Moreover, contrary to previous reports, no difference in the apo E content of TG-rich lipoproteins was detected between the control and diabetic groups. Additionally, no difference in the binding affinity of TG-rich lipoproteins for the low-density lipoprotein receptor was observed between control and diabetic subjects. Thus, we were unable to confirm previous reports that TG-rich lipoproteins from subjects with diabetes are enriched in apo E compared with age-matched controls, consistent with the lack of difference in binding of these lipoproteins to either biglycan or the low-density lipoprotein receptor. Therefore, increased affinity of TG-rich lipoproteins for biglycan is unlikely to explain the increased atherosclerosis in type 2 diabetes.
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PMID:Triglyceride-rich lipoproteins from subjects with type 2 diabetes do not demonstrate increased binding to biglycan, a vascular proteoglycan. 1178 18

Atherosclerosis is the main cause of morbidity and mortality in diabetes, yet the underlying mechanisms remain unclear. Retention of atherogenic lipoproteins by vascular proteoglycans is thought to play a key role in the development of atherosclerotic lesions. High glucose levels cause a variety of diabetic complications by several mechanisms, including upregulation of the hexosamine pathway. Glucosamine, a component of the hexosamine pathway, is a precursor for the synthesis of glycosaminoglycan components of proteoglycans. This study evaluated whether high glucose or glucosamine supplementation of vascular smooth muscle cells would increase proteoglycan synthesis, leading to increased lipoprotein retention. Aortic smooth muscle cells were exposed to physiologic (5.6 mM) or high (25 mM) glucose levels, such as seen in diabetes, or to glucosamine (12 mM). Extracellular proteoglycans were characterized by sulfate incorporation, molecular sieve chromatography, and SDS-PAGE. LDL interactions were assessed by affinity chromatography and gel mobility shift assay. Proteoglycans synthesized in the presence of high glucose demonstrated no differences in size, sulfate incorporation, or LDL binding affinity compared with proteoglycans synthesized under physiological glucose conditions. However, proteoglycans synthesized in the presence of glucosamine had smaller glycosaminoglycan chains than control proteoglycans with a corresponding decrease in lipoprotein retention.Thus, glucose and glucosamine have different effects on proteoglycan biosynthesis and different effects on lipoprotein retention.
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PMID:Arterial smooth muscle cell proteoglycans synthesized in the presence of glucosamine demonstrate reduced binding to LDL. 1179 34

Transforming growth factor-beta (TGFbeta) is a key mediator of extracellular matrix (ECM) accumulation in sclerotic kidney diseases such as diabetic nephropathy. One of the main target cells for TGFbeta in the kidney are glomerular mesangial cells, which respond by increasing expression of ECM proteins, such as collagens, laminin and fibronectin, while suppressing the expression of ECM-degrading proteases and increasing the synthesis of ECM protease inhibitors, including plasminogen activator inhibitor-1. Previous studies have shown that exposure of mesangial cells to chronic high-glucose conditions, such as those seen in diabetes, increases ECM deposition in a mechanism involving glucose-mediated up-regulation of TGFbeta expression. Naturally occurring inhibitors of this TGFbeta-dependent fibrotic response include decorin, a small leucine-rich proteoglycan. While the mechanism by which TGFbeta stimulates gene expression via the Smad signal-transduction pathway is becoming clear, the precise mechanism by which decorin may impinge upon TGFbeta activity remains to be established. In this study, for the first time we provide evidence that decorin can disrupt glucose- and TGFbeta/Smad-dependent transcriptional events in human mesangial cells through a mechanism that involves an increase in Ca(2+) signalling, the activation of Ca(2+)/calmodulin-dependent protein kinase II and ensuing phosphorylation of Smad2 at Ser-240. We show that decorin also induces Ser-240 phospho-Smad hetero-oligomerization with Smad4 and the nuclear localization of this complex independently of TGFbeta receptor activation. Thus, in human mesangial cells, the mechanism of decorin-mediated inhibition of TGFbeta signalling may involve activation of Ca(2+) signalling, the subsequent phosphorylation of Smad2 at a key regulatory site, and the sequestration of Smad4 in the nucleus.
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PMID:Decorin suppresses transforming growth factor-beta-induced expression of plasminogen activator inhibitor-1 in human mesangial cells through a mechanism that involves Ca2+-dependent phosphorylation of Smad2 at serine-240. 1187 91

The aim of this study was to determine, if gemfibrozil has anti-atherogenic actions on human vascular smooth muscle cells (SMCs) and whether these actions are affected by high glucose concentrations, which mimic the hyperglycemia of diabetes. Proliferation of SMCs treated with gemfibrozil was estimated by cell counting (Coulter Counter) and [3H]thymidine incorporation, migration in a scrape-wound assay, proteoglycan (PG) biosynthesis and glycosaminoglycan (GAG) synthesis on xyloside by [35S]sulfate labeling and sizing by sodium dodecyl sulphide-polyacrylamide gel electrophoresis (SDS-PAGE). Gemfibrozil (100 micromol/l) did not affect migration in low or high glucose media. Gemfibrozil caused concentration-dependent inhibition of proliferation in low glucose media (24% inhibition at 100 micromol/l, P<0.01) and inhibited the re-initiation of DNA synthesis by 33.3% (100 micromol/l, P<0.05) in low glucose and 31.4% (100 micromol/l, P<0.001) in high glucose conditions. In low and high glucose media, gemfibrozil (100 micromol/l) reduced total PG production in the presence of TGF-beta 1, which was associated with a decrease in the apparent size of PGs. Gemfibrozil and another PPAR-alpha ligand, WY-14643, significantly inhibited basal and TGF-beta1 stimulated GAG synthesis. We conclude that some SMCs properties associated with atherogenesis are favorably affected by gemfibrozil. Hence, direct vascular actions of gemfibrozil observed in this study may contribute to the reduction in cardiovascular disease observed in clinical studies with gemfibrozil.
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PMID:Differential effects of gemfibrozil on migration, proliferation and proteoglycan production in human vascular smooth muscle cells. 1194 5

Glycation is responsible for disruption of lipoprotein functions leading to the development of atherosclerosis in diabetes. The effects of apolipoprotein E (apoE) glycation were investigated with respect to its interaction with receptors. The interaction of apoE with the low density lipoprotein receptor (LDL-R) and scavenger receptor A (SR-A) was measured by competition experiments performed using, respectively, on a human fibroblast cell line 125I-LDL, and on a murine macrophage cell line (J774) 125I-acetylated LDL, and unlabeled apoE/phospholipid complexes. Glycated apoE binding to heparin and heparan sulfates (HS) was assessed by surface plasmon resonance (SPR) technology. Site-directed mutagenesis was then performed on Lys-75, the major glycation site of the protein. The prepared mutant protein proved to be useful as a tool to study the role of Lys-75 in apoE glycation. The findings showed that, although glycation has no effect on apoE binding either to the LDL-R or to SR-A, it impairs its binding to immobilized heparin and HS. The glycation of Lys-75 was found to be proceed rapidly and contributed significantly to total protein glycation. We propose that, in the case of diabetes, glycation may lead to the atherogenicity of apoE-containing lipoproteins disturbing their uptake via the HS proteoglycan pathway.
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PMID:Early-glycation of apolipoprotein E: effect on its binding to LDL receptor, scavenger receptor A and heparan sulfates. 1206 54

In this review paper, the classical and more recently described mechanisms responsible for the structural and functional characteristics of large artery rigidity are described. Mostly important, these characteristics appear to be non-specific to the primary disease process involved in arterial hypertension, diabetes mellitus, dyslipidemia, congestive heart failure, chronic uremia, and perhaps senescence, including vascular dementia. Nonspecific in terms of aetiology, the vasculopathy encountered in these diseases exhibits common structural and functional abnormalities. The identification of such abnormalities could well become the target of potent nonpharmacological and (or) pharmacological interventions capable of preventing or retarding morbidity and mortality. The structural characteristics responsible for large artery rigidity include smooth muscle cell hypertrophy, matrix collagen deposition, and recently described, dysfunction in proteoglycan metabolism. Functional abnormalities, such as bradykinin-dependent hyper-reactivity of smooth muscle cells and vasa vasorum microcirculation network disturbances, also appear to alter aortic wall rigidity. The physiopathology of target organ damage is then revisited, based on endothelial dysfunction, documented in large and resistance arteries, as well as in microcirculation networks, where altered permeability to macromolecules leads to interstitial matrix disorganization and cell damage. The clinical evaluation of large artery rigidity is described, and one of the noninvasive methods, evaluation of pulse-wave velocity, is validated in normal conditions and in disease processes. Finally, non-pharmacological and pharmacological therapeutic measures are presented, and includes physical exercise to reduce insulin resistance, and renin-angiotensin-II-aldosterone modulators.
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PMID:Mechanisms and consequences of large artery rigidity. 1273 19

The study of protein and carbohydrate components of extracellular matrix in patients with alcoholic and non alcoholic steatohepatitis developed on the background of type 2 diabetes mellitus has shown a significant increase in collagen and glycosaminoglycan synthesis along with the enhancement of proteolytic and compensatory collagenous activity of blood plasma in patients with alcoholic steatohepatitis and inhibition of collagenolytic and proteolytic activity of blood plasma in patients with non alcoholic steatohepatitis against the background of diabetes mellitus, decrease in glycoprotein synthesis. Glutargin enhances metabolism of connective tissue by impeding collagen and glycosaminoglycan synthesis, activating proteoglycan production, augmenting blood plasma activity in patients with non alcoholic steatohepatitis, hindering proteolysis in patients with alcoholic steatohepatitis as well as increasing the excretion of connective tissue metabolites through urinary tracts.
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PMID:[Changes in indices of connective tissue in patients with alcoholic and non-alcoholic steatohepatitis and their correction with glutargin]. 1572 6

The exchangeable apolipoproteins present in small, dense LDL (sdLDL) and large, buoyant LDL subclasses were evaluated with a quantitative proteomic approach in patients with the metabolic syndrome and with type 2 diabetes, both with subclinical atherosclerosis and the B LDL phenotype. The analyses included surface-enhanced laser adsorption/ionization, time-of-flight mass spectrometry, and subsequent identification by mass spectrometry or immunoblotting and were carried out in LDL subclasses isolated by ultracentrifugation in deuterium oxide gradients with near physiological salt concentrations. The sdLDLs of both types of patients were enriched in apolipoprotein C-III (apoC-III) and were depleted of apoC-I, apoA-I, and apoE compared with matched healthy controls with the A phenotype. The LDL complexes formed in serum from patients with diabetes with the arterial proteoglycan (PG) versican were also enriched in apoC-III. In addition, there was a significant correlation between the apoC-III content in sdLDL in patients and the apparent affinity of their LDLs for arterial versican. The unique distribution of exchangeable apolipoproteins in the sdLDLs of the patients studied, especially high apoC-III, coupled with the augmented affinity with arterial PGs, may contribute to the strong association of the dyslipidemia of insulin resistance with increased risk for cardiovascular disease.
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PMID:A proteomic study of the apolipoproteins in LDL subclasses in patients with the metabolic syndrome and type 2 diabetes. 1599 72

Decorin, a small leucine-rich proteoglycan, affects the synthesis of the elastic fiber component fibrillin-1 in the kidney via hitherto unknown mechanisms. Here, we show that decorin binds to and induces phosphorylation of insulin-like growth factor-I (IGF-I) receptor in renal fibroblasts. Inhibition of the IGF-I receptor tyrosine kinase and its downstream target phosphoinositide-3 kinase prevented decorin-mediated synthesis of fibrillin-1. Furthermore, decorin induced phosphorylation of phosphoinositide-dependent kinase 1, protein kinase B/Akt, mammalian target of rapamycin (mTOR), and p70 S6 kinase. Accordingly, the enhanced synthesis of fibrillin-1 was blocked by rapamycin, an inhibitor of mTOR. Notably, IGF-I, which signals through the same pathway, also stimulated fibrillin-1 synthesis. Systemic administration of rapamycin to mice subjected to unilateral ureteral obstruction, a model of renal fibrosis and increased fibrillin-1 synthesis, markedly reduced the number of interstitial fibroblasts and fibrillin-1 deposition. In streptozotocin-induced diabetes, IGF-I receptor was up-regulated in the kidneys from decorin-null mice. However, this could not compensate for the decorin deficiency, resulting ultimately in decreased fibrillin-1 content. This study provides evidence for the involvement of decorin and the IGF-I receptor/mTOR/p70 S6 kinase signaling pathway in the translational regulation of fibrillin-1.
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PMID:Decorin-mediated regulation of fibrillin-1 in the kidney involves the insulin-like growth factor-I receptor and Mammalian target of rapamycin. 1720 Feb 3

The protein kinase C (PKC)-beta isoform has been implicated to play a pivotal role in the development of diabetic kidney disease. We tested this hypothesis by inducing diabetic nephropathy in PKC-beta-deficient (PKC-beta(-/-)) mice. We studied nondiabetic and streptozotocin-induced diabetic PKC-beta(-/-) mice compared with appropriate 129/SV wild-type mice. After 8 weeks of diabetes, the high-glucose-induced renal and glomerular hypertrophy, as well as the increased expression of extracellular matrix proteins such as collagen and fibronectin, was reduced in PKC-beta(-/-) mice. Furthermore, the high-glucose-induced expression of the profibrotic cytokine transforming growth factor (TGF)-beta1 and connective tissue growth factor were significantly diminished in the diabetic PKC-beta(-/-) mice compared with diabetic wild-type mice, suggesting a role of the PKC-beta isoform in the regulation of renal hypertrophy. Notably, increased urinary albumin-to-creatinine ratio persisted in the diabetic PKC-beta(-/-) mice. The loss of the basement membrane proteoglycan perlecan and the podocyte protein nephrin in the diabetic state was not prevented in the PKC-beta(-/-) mice as previously demonstrated in the nonalbuminuric diabetic PKC-alpha(-/-) mice. In summary, the differential effects of PKC-beta deficiency on diabetes-induced renal hypertrophy and albuminuria suggest that PKC-beta contributes to high-glucose-induced TGF-beta1 expression and renal fibrosis, whereas perlecan, as well as nephrin, expression and albuminuria is regulated by other signaling pathways.
Diabetes 2007 Feb
PMID:Deletion of protein kinase C-beta isoform in vivo reduces renal hypertrophy but not albuminuria in the streptozotocin-induced diabetic mouse model. 1725 78


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