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)

Hypertension is associated with insulin-resistant states such as diabetes and obesity. Nitric oxide (NO) contributes to regulation of blood pressure. To gain insight into potential mechanisms linking hypertension with insulin resistance we directly measured and characterized NO production from human umbilical vein endothelial cells (HUVEC) in response to insulin using an amperometric NO-selective electrode. Insulin stimulation of HUVEC resulted in rapid, dose-dependent production of NO with a maximal response of approximately 100 nM NO (200,000 cells in 2 ml media; ED50 approximately 500 nM insulin). Although HUVEC have many more IGF-1 receptors than insulin receptors (approximately 400,000, and approximately 40,000 per cell respectively), a maximally stimulating dose of IGF-1 generated a smaller response than insulin (40 nM NO; ED50 approximately 100 nM IGF-1). Stimulation of HUVEC with PDGF did not result in measurable NO production. The effects of insulin and IGF-1 were completely blocked by inhibitors of either tyrosine kinase (genestein) or nitric oxide synthase (L-NAME). Wortmannin (an inhibitor of phosphatidylinositol 3-kinase [PI 3-kinase]) inhibited insulin-stimulated production of NO by approximately 50%. Since PI 3-kinase activity is required for insulin-stimulated glucose transport, our data suggest that NO is a novel effector of insulin signaling pathways that are also involved with glucose metabolism.
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PMID:Insulin-stimulated production of nitric oxide is inhibited by wortmannin. Direct measurement in vascular endothelial cells. 877 Aug 59

The small and large vessel disease associated with diabetes mellitus is responsible for its morbidity and mortality. Although much of the pathogenesis remains to be clarified, the role of hyperinsulinemia and hyperglycemia per se in the progression of vascular disease is beginning to emerge. Hyperinsulinemia increases the release of very low density lipoprotein (VLDL) and may also be responsible for the low HDL cholesterol levels in patients with diabetes. Hyperinsulinemia also contributes to increased blood pressure, which independently promotes vascular disease. High glucose concentrations have direct influence on intracellular signal transduction, including effects on sorbitol pathway and associated changes of pyridine nucleotides, the de novo synthesis of diacylglycerol with subsequent stimulation of protein kinase C, and possibly changes in the cellular generation of myoinositol. Hyperglycemia also exerts long-lasting changes in cellular function, which result from non-enzymatic glycosylation of matrix and membrane proteins with subsequent binding of these proteins to specific receptors. These receptors are termed the advanced glycosylation end-products (AGE) receptors. Their activation leads to an increased release of cytokines and growth factors including PDGF, interleukins, TNF-alpha, and TGF-beta, all of which may act concomitantly in the disease process.
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PMID:The role of hyperglycemia and hyperinsulinemia in the pathogenesis of diabetic angiopathy. 890 9

In the diabetic vascular complication, biochemical and mechanical injuries to endothelial cells are involved not only in the process of microangiopathy, but also in diabetic atherosclerosis (or arteriosclerosis) which is so-called macroangiopathy. In the presence of diabetes or persistent hyperglycemia, many cytokines including growth factors such as PDGF, HB-EGF, IL-1 beta and TNF alpha are upregulated in intimal cells of the arterial or aortic wall. These changes alter the cytokine network in the common mechanism of atherosclerosis, "Response-to-injury hypothesis", and further accelerate the formation of atherosclerotic lesion. In addition, diabetes causes abnormal responsibility to HB-EGF, PDGF and TGF-beta in medial smooth muscle cells leading to the elevated activity to their proliferation and migration into the intima. Thus, all cell types consisting arterial or aortic wall are involved in the process of diabetic atherosclerosis.
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PMID:[Mechanism of atherosclerosis in diabetes: altered cytokine network in the vascular wall]. 1019 40

The purpose of this study was to determine the effect of the peroxisome proliferator-activated receptor gamma-(PPAR gamma) ligands troglitazone (TRO), rosiglitazone (RSG), and 15-deoxy-delta prostaglandin J2 (15d-PGJ2) on vascular smooth muscle cell (VSMC) migration directed by multiple chemoattractants. Involvement of mitogen-activated protein kinase (MAPK) in migration also was examined, because TRO was previously shown to inhibit nuclear events stimulated by this pathway during mitogenic signaling in VSMCs. Migration of rat aortic VSMCs was induced 5.4-fold by PDGF, 4.6-fold by thrombin, and 2.3-fold by insulin-like growth factor I (IGF-I; all values of p < 0.05). The PPAR gamma ligands 15d-PGJ2, RSG, or TRO all inhibited VSMC migration with the following order of potency: 15d-PGJ2 > RSG > TRO. Inhibition of MAPK signaling with PD98059 completely blocked PDGF-, thrombin-, and IGF-I-induced migration. All chemoattractants induced MAPK activation. PPAR gamma ligands did not inhibit MAPK activation, suggesting a nuclear effect of these ligands downstream of MAPK. The importance of nuclear events was confirmed because actinomycin D also blocked migration. We conclude that PPAR gamma ligands are potent inhibitors of VSMC migration pathways, dependent on MAPK and nuclear events. PPAR gamma ligands act downstream of the cytoplasmic activation of MAPK and appear to exert their effects in the nucleus. Because VSMC migration plays an important role in the formation of atherosclerotic lesions and restenosis, PPAR gamma ligands like TRO and RSG, which ameliorate insulin resistance in humans, also may protect the vasculature from diabetes-enhanced injury.
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PMID:PPAR gamma-ligands inhibit migration mediated by multiple chemoattractants in vascular smooth muscle cells. 1022 69

Nephropathy in patients with type I and II diabetes mellitus is a rapidly increasing problem worldwide. Studies using both glomerular and tubular cells have delineated some of the consequences induced by acute hyperglycemia. In vitro studies have clearly demonstrated that exposure of cultured renal cells, such as glomerular mesangial cells and proximal tubular epithelial cells, to elevated glucose concentrations, may alter cell proliferation and/or extracellular matrix turnover. The latter is effected both directly and indirectly by the alteration of cytokine generation. Furthermore, these in vitro studies have allowed detailed examination of the mechanisms by which exposure of these cells to high ambient glucose concentrations may alter cell function. Extension of these studies to the experimental in vivo situation has confirmed most of the in vitro findings. Important insights gained from models of type I diabetes (i.e. streptocotocin-induced diabetes) as well as type II diabetes (i.e. Goto-Kakizaki (GK) rats and obese Zucker rats) include: (1) The demonstration that increased glomerular cell proliferation and renal matrix accumulation, driven by TGF-beta and/or PDGF, occur in streptocotocin-induced diabetes, yet that nephropathy in these rats does not progress to renal failure. (2) The demonstration that prolonged mild type II diabetes does induce morphological changes characteristic of pre-clinical diabetic nephropathy in GK-rats but does not result in albuminuria or progressive renal disease. (3) The demonstration that the association of type II diabetes with hyperlipidemia in obese Zucker rats results in early podocyte damage and subsequent progression to glomerulosclerosis, tubulointerstitial damage, and renal insufficiency. Identification of the mediators involved in the above processes and in particular of the conditions that will determine progression of subclinical morphological changes to overt nephropathy and renal failure will likely result in future novel therapeutic approaches to diabetic nephropathy.
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PMID:Progression of diabetic nephropathy. Insights from cell culture studies and animal models. 1035 11

Accumulation of substantial numbers of monocyte/macrophages, as well as activated T lymphocytes, in focal areas of arterial intima appears to be a hallmark of atherogenesis. Our report demonstrated that lysophosphatidylcholine (lyso-PC), a polar phospholipid component that is increased in atherogenic lipoproteins, such as oxidized LDL and remnants lipoproteins in diabetic and type III hyperlipidemic patients, can upregulate adhesion molecules for monocytes and T lymphocytes, and growth factors, such as heparin-binding epidermal growth factor-like growth factor and PDGF-A and B chains. Recently we identified the novel receptor for oxidized LDL, named Lox-1. Therefore in this paper we summarize the importance of the interaction between oxidized LDL and its receptor, LOX-1 in terms of early stage of atherogenesis.
Diabetes Res Clin Pract 1999 Sep
PMID:Oxidized LDL and expression of monocyte adhesion molecules. 1058 64

Rat glomerular mesangial cells (GMC) express P2Y(2) purinoceptors and respond to nucleotide stimuli with a transient increase in the cytosolic Ca(2+) concentration and the receptors desensitize upon repeated stimulation with nucleotide. We demonstrate that there is a cross-talk from the signaling of tyrosine kinase to P2Y(2) receptors. For most cells repeated applications of ATP completely abolished the response, as did activation of PKC with 500 nM PMA. In contrast, preincubation with the PKC inhibitor chelerythrine (100 nM) prevented desensitization. Desensitization after application of ATP was reversed by subsequent incubation with PDGF-BB (50 ng/ml) or insulin (660 mU/ml). We conclude that the desensitization is caused by phosphorylation due to PKC and is under the control of growth factors. The findings support the hypothesis that growth hormones potentiate nucleotides as proinflammatory mediators and we hypothesize that they have bearing on the hyperfiltration seen in diabetes.
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PMID:Growth hormones reverse desensitization of P2Y(2) receptors in rat mesangial cells. 1075 69

We examined the correlation between the activation of nuclear factor kappaB (NFkappaB), stimulated by environmental factors involving cytokines and growth factors in ligament cells, and the onset of ossification of the spinal ligaments (OSL) or diffuse idiopathic skeletal hyperostosis (DISH). Aseptic samples were taken carefully from non-ossified sites during surgery (75 patients). We carried out preliminary hematoxylin and eosin and toluidine blue staining, using five portions of each specimen, and excluded samples containing chondrocytic, osteoblastic, or inflammatory cells (n = 25). We used specimens from the remaining 50 patients (35 men and 15 women, ranging in age from 45-81 years); average age, 59.5 years (18 nuchal ligament specimens, and 32 yellow ligament specimens). OSL or DISH had occurred in 25 patients, 20 patients were in the non-OSL group (8 with cervical spondylotic myelopathy, and 12 with lumbar canal stenosis), and the remaining 5 samples were collected from patients with injury. For culture study, we used portions of the 14 largest samples from the above 50 patients. We extracted nuclear proteins and cytoplasmic proteins from non-ossified spinal ligaments in 50 patients and detected p65RelA/NFkappaB by Western blotting. Tumor necrosis factor-alpha (TNF alpha), interleukin 1beta (IL-1beta), platelet-derived growth factor BB (PDGF-BB) and transforming growth factor-beta1 (TGF-beta1) in cytoplasm were quantified by enzyme-linked immunosorbent assays (ELISA). Cultured cells from the 14 samples were then stimulated with 10, 100, 250, or 500 ng/ml of recombinant human (rh)PDGF-B or TGFbeta1. A control experiment was performed without rhPDGF-BB or TGFbeta1 stimulation. Alkaline phosphatase (ALP) activity was standardized by the DNA content of the cells. The number of NFkappaB-positive samples was significantly higher in patients with OSL or DISH than in non-OSL patients. This tendency was obvious in the case of OSL or DISH with non-insulin-dependent diabetes mellitus (NIDDM). In OSL and in DISH patients, significantly greater amounts of PDGF-BB and TGFbeta1 were seen in ligament cells than in non-OSL patients (P < 0.05). There was a positive correlation between the detection of p65RelA/NFkappaB band and the content of PDGF-BB and TGFbeta1 in ligament cells (P < 0.05). ALP activity tended to be higher in cells in the OSL group not receiving any other treatment. Our results indicate the possibility that NFkappaB, stimulated by environmental factors involving PDGF-BB and TGFbeta1 in ligament cells, influences the osteoblastic differentiation of undifferentiated mesenchymal cells.
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PMID:Activation of nuclear factor kappaB at the onset of ossification of the spinal ligaments. 1118 Sep 21

The association of atherosclerosis with the most common risk factors including elevation of low density lipoprotein (LDL) levels, diabetes, hypertension and cigarette smoking, led to the hypothesis of "response to injury" to explain how the lesions develop. According to this hypothesis, one of the earliest events in atherogenesis is the accumulation of LDL in the arterial wall where they undergo oxidation. These LDL impair endothelial function, and thus, all the antiatherogenic properties of the endothelium. In addition, macrophages and smooth muscle cells take up these LDL, through different receptors, and become foam cells. The accumulation of foam cells in the arterial wall contributes to lesion development. Therefore, lesion development involves the activation of endothelial cells, as well as smooth muscle cells and monocytes/macrophages. In this activation different growth factors (PDGF, EGF, etc.), cytokines (IL-1b, TNFa, etc.) and the modified LDL themselves, play an important role. Through several signal transduction pathways these molecules activate transcription factors, such as the nuclear factor kappa B (NF-kB) or protooncogenes such as c-fos, c-myc, that regulate the expression of genes involved in the inflammatory/proliferative response of the lesions.
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PMID:[Cellular and molecular biology of atherosclerotic lesions]. 1118 11

Angiogenesis is an essential biological process not only in embryogenesis but also in the progression of a variety of major diseases such as cancer, diabetes and inflammation. Vascular endothelial growth factor (VEGF) family and its receptor system has been shown to be the fundamental regulator in the cell signaling of angiogenesis. Other systems, Angiopoietin-Tie and EphrinB2-Eph4B etc. are also involved in and cooperate with VEGF system to establish the dynamic blood vessel structures. VEGF receptor belongs to PDGF receptor super-gene family, and carries seven Ig-domains in the extracellular region and a tyrosine kinase domain in the intracellular region. Three members of VEGF receptor family, Flt-1, KDR/Flk-1 and Flt-4, have unique characteristics in terms of the signal transduction, and regulate angiogenesis, lymphangiongenesis and vascular permeability. Further studies on VEGF-VEGF receptor system may significantly facilitate our understanding on the physiological as well as pathological vascular systems in the body and the development of new strategies to control and suppress the major diseases in humans.
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PMID:Structure and function of VEGF/VEGF-receptor system involved in angiogenesis. 1134 1


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