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)

This study was performed to evaluate the composition of the extracellular matrix of the mesangium in both diabetic and nondiabetic rats. Four groups of rats (n = 10 each) were studied. Nondiabetic rats were injected with saline (group 1) or insulin (3.5 U NPH daily) (group 2). Streptozocin-induced diabetic rats were similarly injected with saline (group 3) or insulin (group 4). Six weeks after initiation of study, glomerular diameter (micron) was increased in groups 2 (147 +/- 21), 3 (144 +/- 22), and 4 (150 +/- 7) compared with group 1 (104 +/- 12) (P less than .01). Glomerular hypertrophy was associated with an increase in the relative amount of mesangial matrix as determined by staining for fibronectin. By immunofluorescence microscopy (0-4+ scale), type I collagen antigen was not detected in the mesangium of any of the experimental groups. Staining for type V collagen and thrombospondin was similar between the experimental groups. Type III collagen antigen was not detected in the mesangium of control (group 1) or insulin-deficient diabetic rats (group 3); however, it was detected (2-3+) in the mesangium of both insulin-treated diabetic and nondiabetic rats (Mann-Whitney, P less than .01). Comparable intensity of staining (1+) for type IV collagen antigen was detected in the mesangium of animals from groups 1, 2, and 4; however, the staining intensity was markedly increased (3+) in insulin-deficient diabetic rats (group 3; Mann-Whitney, P less than .01).(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1988 Dec
PMID:Phenotypic expression of collagen types in mesangial matrix of diabetic and nondiabetic rats. 305 64

Although lipids have received most attention in relation to atherosclerosis, vessel injury also has a role in the development of atherosclerotic lesions. Thrombi that form at sites of injury can be incorporated into the wall, causing thickening, and platelets that adhere to damaged vessel walls release a growth factor (PDGF) that stimulates smooth muscle cell proliferation. The early lesions of atherosclerosis are focal and develop around vessel orifices and branches in relation to the patterns of blood flow and areas of increased permeability and endothelial cell damage. Platelets also contribute to the complications of advanced atherosclerosis caused by occlusive thrombi, thromboembolism, and spasm. The causes of vessel wall injury are not established, although there is evidence pointing to disturbed blood flow, hypertension, antigen--antibody complexes, complement, materials originating from platelets and white blood cells, bacteria, endotoxin, viruses, smoking, dietary lipids, homocystinemia, diabetes, other metabolic disorders, and stress. Platelets do not adhere to intact endothelium, but they adhere to the constituents of the subendothelium, release the contents of their granules (including PDGF), and form thromboxanes. If blood flow is disturbed, platelet--fibrin thrombi can form at sites of injury. Platelet adherence to a damaged wall does not require von Willebrand factor except under conditions of high wall shear. Repeated injury of a vessel wall leads to the development of lipid-rich atherosclerotic lesions, even in normocholesterolemic animals, but these lesions do not form if the experimental animals are made thrombocytopenic before injury is induced. Measurable changes in platelets that are associated with the clinical complications of atherosclerosis include shortened survival, release of granule contents (platelet factor 4, beta-thromboglobulin, thrombospondin), formation of thromboxanes, and decreased buoyant density. "Antiplatelet drugs" such as aspirin are proving to be beneficial in selected groups of patients, such as those with unstable angina. Thromboxane synthetase inhibitors and agents that block the thromboxane receptor on platelets are under investigation. Long term administration of "antiplatelet drugs" to affect the rate of development of atherosclerosis seems neither feasible nor desirable. Modification of dietary and smoking habits and control of hypertension are more likely to be beneficial for most individuals.
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PMID:The role of platelets in the development and complications of atherosclerosis. 351 36

It has been suggested that platelet hyperactivity contributes to the early evolution of diabetic vascular disease per se. This study directly evaluates the level of intravascular platelet activation in newly diagnosed IDDM patients before and after tight metabolic control. Platelet activation was determined by the Duesseldorf-III flow cytometry assay in 21 recent-onset hyperglycemic IDDM patients before insulin, after 3 days of treatment with intravenous insulin, and after 14 and 60 days of intensified conventional insulin therapy. The intravasal platelet activation status was quantified by the percentage of platelets exposing the activation-dependent molecules CD62 (P-selectin), thrombospondin (TSP), and CD63 (GP53) as well as the activated fibrinogen receptor (GPIIB/IIIA). Fifty matched normal subjects served as control subjects. Fourteen patients completed the 60-day study design. After initial recompensation, near-normoglycemic control was achieved after 14 days (fasting blood glucose, 117.0 +/- 19.0 mg/dl), and the HbA1 concentration was 7.6 +/- 1.2% after 60 days. CD62+ (4.0 +/- 4.5%), TSP+ (2.0 +/- 1.8%), CD63+ (11.0 +/- 7.0%), and activated-GPIIB/IIIA+ (7.6 +/- 7.7%) platelet levels were initially 5, 3.3, 5.7, and 2.8 times higher than the mean level of normal. There was no correlation with any of the nearly normalized metabolic parameters. Thus, more activated platelets circulate in newly diagnosed IDDM patients, which supports the assumption of a prethrombotic condition even in disease stages without apparent vascular damage.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1995 Aug
PMID:Exposure of adhesion molecules on activated platelets in patients with newly diagnosed IDDM is not normalized by near-normoglycemia. 754 11

Vascular diseases and related complications still represent the main cause of death in diabetic patients. Neuropathy, nephropathy, retinopathy, and disturbed nutritive tissue perfusion may result from reduced capillary microcirculation. These disturbances are diabetes specific. Macroangiopathy does not differ structurally from atherosclerotic lesions of nondiabetic subjects, but leads to accelerated cerebral, coronary, and peripheral artery disease. Occurrence of life-terminating thrombotic events, which are superimposed on those vascular lesions, are increased. Thus, morbidity and mortality of diabetics depend mainly on vascular complications. Normal blood flow is a prerequisite of adequate organ perfusion and results from vasomotion, plasma components, corpuscular blood elements, vascular architecture, and the undisturbed interaction of these components at the endothelial interface. Functional thromboresistance of the endothelial layer is reduced in the diabetic state. Increased intravascular thrombin generation, reduced fibrinolytic potential, and hyperactive platelets lead to a prethrombotic state. This thrombotic diathesis increases the permanent danger of acute flow interruption. Activated platelets operate by three mechanisms: (1) Microembolization of the capillaries; (2) local progression of preexisting vascular lesions by secretion of constrictive, mitogenic, and oxidative substances; (3) trigger of the prognosis-limiting arterial thrombotic event. We were able to show that the increased functional properties of diabetic platelets result from the primary release of larger platelets with enhanced thromboxane formation capacity and increased numbers of functional glycoprotein receptors GPIb and GPIIb/IIIa, which are synthesized in the megakaryocytes. The megakaryocyte-platelet system is turned on in diabetes mellitus. It could be demonstrated with the Duesseldorf III method of flow cytometric activation marker testing (CD62, CD63, thrombospondin) that predominantly large platelets circulate in an activated state in diabetes mellitus.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Platelets in diabetes: the role in the hemostatic regulation in atherosclerosis. 835 57

The physiological meaning of platelets has been best documented for acute coronary syndromes where platelets act as "first responsive elements" triggering the final occlusive thrombus after plaque rupture has occurred. This situation is particularly relevant for patients with NIDDM-type diabetes regularly showing complicated plaque architecture. Predictive power for acute ischemic events e.g. following angioplasty has been proven, and this has dominated the attention exclusively towards the hemostatic function of platelets. Meanwhile, a variety of particularly important platelet features have been identified: a) promotion of liquid phase coagulation; b) regulation of the local vascular tone; c) active modulation of tissue modeling at lesion sites; d) adhesion molecule-mediated communication with a variety of corpuscular blood (and non-blood cells). With emerging recognition of the latter role, the pathophysiological scope of platelets exceeds the well-established role as microemboli, local atherosclerosis amplifiers and triggers of gross thrombosis. In diabetes mellitus of either type, increased populations of circulating platelets have been identified expressing activation dependent adhesion molecules such as activated alpha 2 beta 3 (GPIIbIIIa), lysosomal GP53, thrombospondin or, perhaps most importantly "P-selectin" (CD62 p). This suggests that these adhesion molecules among others can also mediate platelet-leukocyte interactions potentially resulting in inflammatory tissue damaging processes in addition to the immanent tendency towards (micro-)thrombosis. This review works out a more general view on the meaning of platelet activation beyond hemostaseology and updates the actual knowledge of platelet-leukocyte communication checkpoints with particular reference to the diabetic state outlining new pharmacological concepts for intervention.
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PMID:Platelet-leukocyte-cross-talk in diabetes mellitus. 949 1

Blood cells are in continuous contact with the vascular endothelium. Endothelial cell culture, intravital videomicroscopy allowed the investigation of blood cell-endothelium interactions in dynamic conditions. In the various diseases, diabetes mellitus, sickle cell anemia and malaria, erythrocytes have an increased adhesion to endothelial cells. The presence of advanced glycation end products (AGE) on erythrocytes of diabetics is responsible for their binding to the receptor RAGE present on the endothelium. The AGE-RAGE binding provokes an oxidant stress and induces the expression of the adhesion molecule. Furthermore, erythrocyte AGE induce an increase in vascular permeability. In sickle cell anemia, the increased adhesiveness and the sickling of red blood cells are responsible for thrombosis. Plasmodium falciparum infestation of erythrocytes induces knob formation at the cell surface and the P. falciparum protein binding to CD36, ICAM-1 and thrombospondin present on the endothelium, and facilitates the parasite dissemination.
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PMID:[Erythrocyte adhesion to the vascular endothelium]. 1066 97

We have previously demonstrated that thrombospondin-1 (TSP-1) promotes activation of latent TGF-beta1 in cultured human mesangial cells (MCs) [Nephron 79 (1998) 38.]. This study was performed to clarify the relationship between protein kinase C (PKC) activity and activation of TGF-beta1 and TSP-1 production in cultured human MCs exposed to high glucose levels. MCs grown in 33 mmol/l glucose demonstrated a significant (P< .01) increase in activation of TGF-beta1 compared with those in 5 mmol/l glucose, which were evaluated by both an ELISA and a bioassay. High glucose-induced increase in active TGF-beta1 was completely inhibited by coincubation with 5 micromol/l GFX, a PKC inhibitor, and was mimicked by the addition of 0.1 micromol/l phorbol 12,13-dibutyrate (PDBu). On the other hand, increased TSP-1 production from MCs stimulated by 0.1 nmol/l recombinant TGF-beta1 and 0.1 micromol/l PDBu were significantly (P< .01) reduced by the addition of 10 nmol/l latency-associated peptide (LAP), a specific inhibitor of TGF-beta1 activity. The amount of TSP-1 secreted from MCs increased by a high ambient glucose. The glucose-induced increase in TSP-1 production was markedly attenuated by the treatment with GFX and LAP, while those agents did not affect TSP-1 production in low-glucose concentrations. Taken together, our results suggest that glucose-induced activation of TGF-beta1 is dependent on PKC activity, leading to a sequential increase in TSP-1 synthesis in cultured human MCs. Thus, we propose that high glucose conditions induce an increase in PKC-TGF-beta1 activity-TSP-1 pathway, and that glucose-induced increase in TSP-1 may synergistically facilitate TGF-beta1 activation in an autocrine manner in MCs.
J Diabetes Complications
PMID:High glucose levels enhance TGF-beta1-thrombospondin-1 pathway in cultured human mesangial cells via mechanisms dependent on glucose-induced PKC activation. 1145 71

Transforming growth factor-beta (TGF-beta) may be critical in the development of diabetic nephropathy (DN), and genetic predisposition is an important determinant of DN risk. We evaluated mRNA expression levels of TGF-beta system components in cultured skin fibroblasts (SFs) from type 1 diabetic patients with fast versus slow development of DN. A total of 125 long-standing type 1 diabetic patients were ranked by renal mesangial expansion score (MES) based on renal biopsy findings and diabetes duration. Patients in the highest quintile of MES who were also microalbuminuric or proteinuric (n = 16) were classified as "fast-track" for DN, while those in the lowest quintile who were also normoalbuminuric (n = 23) were classsified as "slow-track" for DN. Twenty-five normal subjects served as control subjects. SFs were cultured in medium with 25 mmol/l glucose for 36 h. SF mRNA expression levels for TGF-beta1, TGF-beta type II receptor (TGF-beta RII), thrombospondin-1, and latent TGF-beta binding protein-1 (LTBP-1) were measured by real-time RT-PCR. LTBP-1 mRNA expression was reduced in slow-track (0.99 +/- 0.38) versus fast-track patients (1.65 +/- 0.52, P = 0.001) and control subjects (1.41 +/- 0.7, P = 0.025). mRNA levels for TGF-beta1, TGF-beta RII, and thrombospondin-1 were similar in the three groups. Reduced LTBP-1 mRNA expression in SFs from slow-track patients may reflect genetically determined DN protection and suggests that LTBP-1 may be involved in the pathogenesis of DN through the regulation of TGF-beta activity.
Diabetes 2002 Dec
PMID:Cellular basis of diabetic nephropathy: II. The transforming growth factor-beta system and diabetic nephropathy lesions in type 1 diabetes. 1245 17

Statins exert pleiotropic effects on several other cellular functions besides lipid-lowering. Previously, it was found that cerivastatin is a very potent inhibitor of human arterial smooth muscle cell (haSMC) growth. However, because increased extracellular matrix (ECM) synthesis also accounts mainly for intimal plaque formation, the effects of cerivastatin on ECM expression was examined in this study. Furthermore, the influence of varying glucose and low-density lipoprotein (LDL) levels on cerivastatin-treated haSMCs was analyzed to mimic the conditions in patients with diabetes or hypercholesterolemia. The haSMCs were treated with 0.001-5.0 microM cerivastatin in the presence of 5.5-18.9 m glucose and 10-1000 microg/ml LDL. After 3 days, the messenger RNA (mRNA) expression of eight ECM proteins was analyzed and, after 7 days, mitotic and mitochondrial activities and thrombospondin (TSP)-1 protein expression were analyzed. TSP-1 and TSP-2 mRNA expression was inhibited highly significantly at cerivastatin doses >or=0.01 microM with maximums of 72% and 35%, respectively, at high glucose levels. The mRNA signals of the third glycoprotein fibronectin were not influenced. Furthermore, collagen-1 mRNA was inhibited highly significantly up to 71% and biglycan mRNA was similarly inhibited up to 45%. The mRNA expression of the matrix-stimulating transforming growth factor (TGF)-beta1 and matrix metalloproteinase (MMP)-2 was not altered significantly, whereas mRNA expression of the tissue inhibitor of metalloproteinase (TIMP)-2 was stimulated clearly up to 150%. Mevalonate, but not LDL replacement, reversed the effects. Immunofluorescence staining showed an unaltered TSP-1 pattern with cerivastatin doses up to 0.1 microM whereas higher doses impaired TSP-1 excretion. The effects of cerivastatin on haSMC growth and mRNA expression of the eight ECM components were not diminished by the increase in LDL and glucose levels. Since accelerated SMC growth and ECM formation contribute mainly to intimal thickening, cerivastatin may be protective against the development of atherosclerotic and restenotic lesions by its direct cellular effects. Increased LDL and glucose levels, as in diabetes, do not mitigate the beneficial effects of cerivastatin on cell growth and ECM formation in vitro.
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PMID:Effects of cerivastatin on human arterial smooth muscle cell growth and extracellular matrix expression at varying glucose and low-density lipoprotein levels. 1260 21

High-protein diets exacerbate glomerular hyperfiltration and the progression of diabetic nephropathy. The purpose of this study was to determine whether amino acids also produce nonhemodynamic injury in the glomerulus. When rat mesangial cells were cultured with an amino acid mixture designed to replicate the composition in plasma after protein feeding, production of mRNA (Northern blot analysis) and/or protein (ELISA or Western blot analysis) for transforming growth factor-beta1 (TGF-beta1), fibronectin, thrombospondin-1 (TSP-1), and collagen IV were enhanced in a manner comparable to a culture with high glucose (30.5 mM). The bioactive portion of total TGF-beta (NRK assay) increased in response to amino acids. The TSP-1 antagonist LSKL peptide reduced bioactive TGF-beta and fibronectin, indicating the dependence of TGF-beta1 activation on TSP-1. DNA synthesis ([3H]thymidine incorporation), an index of cellular proliferation, increased in response to amino acids and was further enhanced by culture with increased levels of both amino acids and glucose. TGF-beta1 and matrix proteins increased when mesangial cells were cultured with excess l-arginine (2.08 mM) alone. Although l-arginine is the precursor of nitric oxide (NO), such responses to amino acids do not appear to be mediated through increased NO production. NO metabolites decreased in the media, and these responses to mixed amino acids or l-arginine were not prevented by NO synthase inhibition. In conclusion, amino acids induce indicators of response to injury in mesangial cells, even when hemodynamic stress is absent. In conditions associated with increased circulating amino acids, such as diabetes and/or a high-protein diet, direct cellular effects could contribute to glomerular injury.
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PMID:Amino acids induce indicators of response to injury in glomerular mesangial cells. 1264 43


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