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)

Hypercholesterolemia and mesangial cell proliferation have been proposed to play a role in the progression of glomerulosclerosis in diabetic nephropathy and other renal diseases. Although LDL is mitogenic for and cytotoxic to mesangial cells, the effect of HDL on these cells is unknown. HDL stimulates fibroblast mitogenesis and is the principal cholesterol-bearing lipoprotein in the rat, the experimental model for studying the effect of hyperlipidemia on renal disease. Insulin is mitogenic in several cell systems, and its levels are increased in serum in non-insulin-dependent diabetes mellitus. This study investigates whether HDL acts as a growth factor in mesangial cells and whether it functions in parallel with insulin. It was found that HDL at protein concentrations between 10 and 500 microg/ml, both alone and in the presence of 100 nM insulin, increased DNA synthesis in mesangial cells (129 to 165% of control for HDL alone; 140 to 235% for HDL plus insulin), whereas HDL at 1000 microg/ml and greater inhibited mesangial cell proliferation. Insulin alone at 100 nM stimulated [3H]thymidine incorporation in the same cell system (145% of control); the mitogenic effect of insulin was additive to that of HDL. Purified apo A-I had a similar effect, but at significantly lower concentrations. Specific binding of HDL to mesangial cells was demonstrated (B(max) [binding constant] of 5.19 +/- 0.70 x 10(-7) micromol of HDL bound/mg cell protein and K(b) of 2.83 +/- 0.22 nM). Tetranitromethane alters apo A-I, preventing binding to its cognate receptor. Tetranitromethane-modified HDL did not bind to mesangial cells and had no effect on [3H]thymidine incorporation. Addition of HDL to mesangial cells caused an immediate transient increase in free intracellular calcium in several representative mesangial cells, similar to the response seen with platelet-derived growth factor. The mitogenic effect of HDL was not altered after attenuation of cellular protein kinase C activity, but the stimulatory effect of HDL alone and in combination with insulin on DNA synthesis was completely eliminated after inhibition of cellular tyrosine kinases by 24-h pretreatment with 0.25 microM herbimycin A. Thus, HDL binds to a specific apo A-I-dependent receptor, promotes DNA synthesis, and initiates second-messenger events by a tyrosine kinase-dependent and protein kinase C-independent mechanism.
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PMID:HDL causes mesangial cell mitogenesis through a tyrosine kinase-dependent receptor mechanism. 925 51

Renal injury in diabetes mellitus is a major cause of morbidity and mortality. Several manifestations of diabetic nephropathy may be a consequence of altered production and/or response to cytokines or growth factors. Transforming growth factor-beta (TGF-beta) is one such factor because it promotes renal cell hypertrophy and regulates the production of extracellular matrix molecules. In addition, high ambient glucose increases TGF-beta1 mRNA and protein level in cultured proximal tubular cells and glomerular epithelial and mesangial cells. Neutralizing anti-TGF-beta antibodies or antisense TGF-beta1 oligodeoxynucleotides prevents the hypertrophic effects of high glucose and the stimulation of matrix synthesis in renal cells. Several reports have described overexpression of TGF-beta in the glomeruli and tubulointerstitium of experimental and human diabetes mellitus. We recently provided evidence that the kidney in diabetic patients displays net renal production of immunoreactive TGF-beta1, whereas there is net renal extraction in nondiabetic subjects. We also demonstrated that short-term treatment of streptozotocin-diabetic mice with neutralizing monoclonal antibody directed against TGF-beta significantly reduces kidney weight and glomerular hypertrophy, and attenuates the increase in extracellular matrix mRNA levels. The factors that mediate increased renal TGF-beta activity involve hyperglycemia per se and the intermediary action of other potent mediators such as angiotensin II, thromboxane, endothelins, and platelet-derived growth factor.
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PMID:Potential role of TGF-beta in diabetic nephropathy. 952 4

Periodontitis is a chronic inflammatory disease characterized by a progression that is very much dependent on host response. The gingiva can be considered to be in a constant state of wounding (pathologic wounding by bacterial plaque) and a constant state of maintenance/repair. In this context, any metabolic disturbance in the host which compromises tissue repair/wound healing will exacerbate the progression of periodontitis. Diabetes presents an interesting example because two major complications of diabetes are delayed wound healing and periodontitis. Our previous studies indicate that delayed wound healing and periodontitis may be manifestations of a general systemic deficit in diabetes involving alteration of macrophage cytokine gene expression. The present study was designed to determine whether: 1) diabetes-induced metabolic alterations affect gingival cytokine levels; and 2) diabetes-induced metabolic alterations modify the gingival cytokine profile in periodontitis. Sprague-Dawley rats (N=12/group) were injected with streptozotocin (65 mg/kg) into the tail vein to induce diabetes (defined by blood glucose levels > 250 mg/dl) or received the injection vehicle or no treatment as controls. Periodontitis was induced in additional groups of diabetic and control rats by gavage with Porphyromonas gingivalis A7436. After 90 days, serum glucose was analyzed to document diabetes; alveolar bone level was measured to document severity of periodontitis; gingiva was harvested circumferentially from the first and second molars; and cytokines in gingival homogenates were assayed by ELISA using commercial kits. Cytokine levels were expressed as mean+/-SEM pg/microg protein. Diabetes alone did not alter the gingival cytokine profile for platelet-derived growth factor B (PDGF-B), interleukin 1-beta (IL-1beta), transforming growth factor-beta (TGF-beta), and tumor necrosis factor-alpha (TNF-alpha). Periodontitis alone demonstrated a significant increase (P < 0.05) in levels of PDGF-B and IL-1beta. Diabetes superimposed on periodontitis prevented these increases. Thus, diabetes-induced metabolic alterations do not affect gingival cytokine levels per se; however, they do alter the normal host response to periodontitis through blockage of periodontitis-induced increases in PDGF-B and IL-1beta.
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PMID:Diabetes prevents periodontitis-induced increases in gingival platelet derived growth factor-B and interleukin 1-beta in a rat model. 952 9

Advanced glycation endproducts have been implicated in a number of diabetic and aging changes. Some of these effects occur in part through induction of cytokines such as platelet-derived growth factor (PDGF), which is expressed by the retinal pigment epithelium (RPE). In this study, cultures of RPE were evaluated for PDGF expression after treatment with pentosidine, a well characterized advanced glycation endproduct. Northern analysis provided evidence for the increased expression of a 3.7 kb PDGF-B transcript over unstimulated controls in the established ARPE-19 cell line. Western analysis demonstrated increased PDGF-BB protein in conditioned medium compared to controls of ARPE-19 cells. In addition, two different early passage cultures of RPE showed increased PDGF-BB protein after pentosidine treatment compared to unstimulated controls. The enhanced production of PDGF-BB could play a role in the maintenance of the RPE-Bruch's membrane complex and influence changes associated with diabetes and aging.
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PMID:The advanced glycation endproduct pentosidine induces the expression of PDGF-B in human retinal pigment epithelial cells. 959 35

Vanadate has been considered in the treatment of diabetes because of its insulin-like effects. However, it has severe toxic effects in both animal and man. In cultured cells, vanadate can either cause death or be growth stimulatory, depending on the cell type and growth conditions. Here, we report that in baboon aortic smooth muscle cells (SMCs), vanadate induced p42/p44 mitogen-activated protein kinase (MAPK) activity. This effect was abolished in the presence of the specific MAPK kinase (MAPKK) inhibitor PD098059. Although activation of p42/p44MAPK/MAPKK is generally thought to be necessary for proliferation, in SMCs, vanadate did not promote DNA synthesis and inhibited thymidine incorporation stimulated by platelet-derived growth factor (PDGF)-BB in a dose dependent fashion (IC50: 30 microM). Prolonged exposure to vanadate exerted cytotoxic effects. Cells retracted, rounded up and detached from the substratum. These vanadate-induced morphological changes were blocked in the presence of PD098059. The addition of PDGF-BB further activated p42/p44MAPK/MAPKK in the presence of vanadate and substantially increased vanadate toxicity. We conclude from these observations that activation of the p42/p44MAPK/MAPKK signalling module contributes to the cytotoxic effects induced by vanadate.
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PMID:The mitogen-activated protein kinase pathway contributes to vanadate toxicity in vascular smooth muscle cells. 965 83

Diabetes (type I and type II) affects approximately 13 million people in the United States. Delayed and incomplete healing of wounds can be a major problem for diabetic patients. Macrophages are an important cell in the complex process of wound repair representing the major source of cytokines throughout the wound healing process. Cytokines mediate many of the cellular responses critical to timely wound repair. It has been suggested that diabetes impairs wound healing through disruption of local cytokine production. We previously demonstrated that platelet-derived growth factor B chain (PDGF-B) levels are deficient at the wound site of diabetic rats. In the present study, we measured the levels of several marker cytokines released from cultured peritoneal macrophages of diabetic, nondiabetic hyperlipidemic, and normal rats. The diabetic condition was associated with a generalized reduction of macrophage cytokine release. Nondiabetic hyperlipidemic animals demonstrated similar cytokine reduction supporting the hypothesis that elevated serum lipids are the primary determinants of diabetes-induced reductions in macrophage cytokine release. Thus, manipulation of serum lipids may be a therapeutically useful modality for controlling macrophage cytokine release in the inflammatory and/or wound environment.
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PMID:Diabetes-induced impairment of macrophage cytokine release in a rat model: potential role of serum lipids. 976 8

Fibronectin seems to play an important role in promoting the characteristic changes of vascular smooth muscle cells in diabetes mellitus including overexpression of the platelet-derived growth factor beta-receptor. To determine the regulatory mechanism of the beta-receptor by fibronectin, we have analyzed the effect of fibronectin on the expression of the beta-receptor in cultured rat aortic smooth muscle cells using the beta-receptor promoter/luciferase expression vector system. Fibronectin was found to stimulate the expression of the beta-receptor at the transcriptional level. Both a MEK1 inhibitor PD98059 and a tyrosine kinase inhibitor herbimycin A significantly inhibited the fibronectin-stimulated receptor transcription. Herbimycin A also completely inhibited the fibronectin-stimulated increase in tyrosine phosphorylation of focal adhesion kinase. These data suggest the involvement of the integrin-mediated mitogen-activated protein kinase pathway downstream of fibronectin stimulation in the activation process of the beta-receptor promoter.
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PMID:Fibronectin stimulates transcription of the platelet-derived growth factor beta-receptor in cultured rat aortic smooth muscle cells. 979 Sep 68

The transcriptional nuclear factor (NF)-kappaB can be activated by diverse stimuli such as cytokines, mitogens, oxidative stress, and lipids, leading to the transactivation of several genes that play important roles in the development of atherosclerosis. Because oxidative stress may play a key role in the pathogenesis of diabetic vascular disease, we have examined whether culture of porcine vascular smooth muscle cells (PVSMCs) under high glucose (HG) conditions (25 mmol/l) to simulate the diabetic state can lead to the activation of NF-kappaB, and also whether cytokine- or growth factor-induced NF-kappaB activation is altered by HG culture. We observed that PVSMCs cultured in HG showed significantly greater activation of NF-kappaB in the basal state compared with cells cultured in normal glucose (NG) (5.5 mmol/l). Treatment of the cells with cytokines, such as tumor necrosis factor (TNF)-alpha and interleukin-1beta, or with growth factors, such as platelet-derived growth factor, insulin-like growth factor-I, and epidermal growth factor, all led to NF-kappaB activation in cells cultured in both NG and HG. However, their effects were markedly greater in HG. The augmented TNF-alpha-induced NF-kappaB activation in HG was associated with increased TNF-alpha-mediated transcriptional activation of the vascular cell adhesion molecule-1 promoter. Immunoblotting with an antibody to the p65 subunit of NF-kappaB indicated that the levels of this protein were higher in the nuclear extracts from cells cultured in HG compared with NG. Cells cultured in HG also produced significantly greater amounts of the reactive oxygen species superoxide. HG-induced NF-kappaB activation was inhibited by a protein kinase C inhibitor, calphostin C. These results suggest that hyperglycemia-induced activation of NF-kappaB in VSMCs may be a key mechanism for the accelerated vascular disease observed in diabetes.
Diabetes 1999 Apr
PMID:Hyperglycemia-induced activation of nuclear transcription factor kappaB in vascular smooth muscle cells. 1010 4

Coronary angioplasty is used to treat coronary atherosclerotic disease in many patients. One problem with coronary angioplasty is the phenomenon of restenosis. Restenosis appears to be a universal response to arterial wall injury. The biological events that underlie restenosis are characterized by: platelet adhesion and aggregation at sites of damaged endothelium, and within dissections into the medial layers, release of platelet derived growth-promoting substances, inflammation of the injured medial zone, transformation, migration, and proliferation of smooth muscle cells of the media following their activation by growth-promoting substances, secretion of copious amounts of extracellular matrix material, and finally, termination of the growth process following regrowth of endothelium over the damaged area. More than a decade of research work has helped identify clinical correlates of restenosis after coronary angioplasty. Patient-related correlates include male gender, unstable angina, diabetes, and continued smoking after angioplasty. Lesion-related correlates include multilesion and multivessel procedures, higher post-angioplasty residual stenosis, proximal vessel location, location in the left anterior descending coronary artery, location in a vein graft, long lesions, and total occlusions. However, for the purposes of individual patient care, clinical correlates are not particularly helpful. No group of variables has predicted complete freedom from restenosis, and conversely no group of variables has reliably indicated its presence. All patients undergoing angioplasty will require some form of follow-up evaluation. Symptom status by itself has not been found to be useful for predicting restenosis. However, when symptom status is combined with exercise thallium-201 scintigraphy, performed 4-6 months after angioplasty, it is less than ideal, but has a negative predictive value of over 90%. This means that over 90% of patients who are asymptomatic and have no evidence of ischemia by thallium-201 scintigraphy, will not have angiographic restenosis. Numerous clinical trials have been performed in order to reduce or prevent restenosis. Almost all have been disappointing, while a few have been encouraging. Studies of antiplatelet agents such as aspirin, dipyridamole (Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA), and Ticlopidine (Syntex, Humgcao, Puerto Rico) have not shown efficacy, yet studies of an inhibitor of platelet-derived growth factor have been provocatively encouraging. No reduction in restenosis rates was found with the anticoagulants Coumadin (Du Pont Pharmaceuticals, Wilmington, DE, USA) and Heparin (Wyeth-Ayerst, Philadelphia, PA, USA). Fish oils (omega fatty acids) have been found in several clinical trials to provide modest, but encouraging, reductions in restenosis, but await further confirmation.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Restenosis after coronary angioplasty. 1015 Oct 16

Insulin resistance is central to the pathophysiology of type 2 diabetes. It has been known for some time that down-regulation and reduced kinase activity of the insulin receptor play a role in insulin resistance; however, it has recently emerged that defects in the intracellular responses to insulin are also very important. We studied the molecular basis of insulin resistance in mice in which injection with gold thioglucose led to the development of hyperphagia, obesity and insulin resistance over a 4-month period. We found that the insulin-stimulated activation of MAP kinase was defective in obese, insulin-resistant mice. Similarly, we investigated insulin-stimulated PI3-kinase activation in the isolated soleus muscle of lean and obese mice, and found a marked reduction in the PI3-kinase activation of obese animals. The magnitude of the effect was greater than the reduction in insulin receptor activation, suggesting that impairment of PI3-kinase activation is a very important element in the development of insulin resistance in obese mice. In keeping with this, we found that the defect in PI3-kinase activation developed in young obese mice before the emergence of overt insulin resistance. We investigated different mechanisms by which defects in the components of the insulin signalling cascade could emerge, including down-regulation and abnormal phosphorylation of signal molecules. In adipocytes from young obese mice in which insulin resistance had not yet developed, we found that there were already marked defects in IRS-1 tyrosine phosphorylation. Increased IRS-1 phosphorylation on serine and threonine residues affects tyrosine phosphorylation. Such a process could contribute to the defective IRS-1 tyrosine phosphorylation in insulin-resistant animals. We found that brief exposure of 3T3-L1 adipocytes to platelet-derived growth factor led to IRS-1 serine/threonine phosphorylation through a PI3-kinase-dependent pathway, and that this prevented phosphorylation of the tyrosine residues of IRS-1. Such a mechanism, induced by growth factors, TNF-alpha or some other agent, may play an important role in the development of insulin resistance in obese mice.
Exp Clin Endocrinol Diabetes 1999
PMID:Molecular mechanisms of insulin action in normal and insulin-resistant states. 1032 50


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