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)

The steady-state levels of mRNA encoding for the alpha 1(IV) collagen chain, laminin B1 and B2 chains, basement membrane HSPG, and alpha 1(I) and alpha 1(III) collagen chains were examined in rat glomeruli at 4, 12, and 24 wk after injection of STZ. The mRNA levels for the alpha 1(IV) collagen chain, laminin B1 and B2 chains, and alpha 1(I) and alpha 1(III) collagen chains increased significantly with age in the STZ-induced diabetic rats before morphological thickening of basement membrane occurred. In contrast, the mRNA levels for HSPG decreased markedly 4 wk after STZ injection and then increased with age compared with those for control rats. The mRNA levels for these ECM components showed a continuous decline with age in controls. Treating the diabetic rats with insulin for 4 wk ameliorated the abnormally regulated ECM gene expression in the glomeruli. These data suggest that the abnormal regulation of ECM gene expression in the glomeruli may contribute to the expansion of mesangial matrix and basement membrane thickening in diabetic rats, and that hyperglycemia may play a role in the abnormal ECM gene expression.
Diabetes 1992 Dec
PMID:ECM gene expression and its modulation by insulin in diabetic rats. 128 Feb 37

To study platelet activation as a phenomenon that may precede development of angiopathy in diabetes mellitus, we compared platelet adhesion and thrombus formation in a flow system with blood from insulin-dependent (type I) diabetic subjects with and without macroangiopathy and age- and sex-matched control subjects. Adhesion and thrombus formation on matrix of cultured human endothelial cells (ECM) and adhesion on matrix of human fibroblasts (FBM) were studied after exposure to flowing blood at shear rates of 300 and 1300 s-1 and exposure times of 1, 3, 5, and 10 min (and 20 min in adhesion experiments). Blood was anticoagulated with trisodium citrate (1:10 vol/vol, 110 mM) or low-molecular-weight heparin ([LMWH] 20 U/ml). Endothelial cell cultures were either unstimulated or stimulated with 4 beta-phorbol 12-myristate 13-acetate (PMA) 16 h before isolating their matrix. Platelet adhesion on ECM and FBM in citrated and LMWH-anticoagulated blood was identical in diabetic patients and control subjects, with comparable increases of adhesion with increasing perfusion times. Platelet aggregate formation on ECM of PMA-stimulated cells with LMWH-anticoagulated blood was similar in diabetic patients, whether macroangiopathy was present, compared with control subjects. Fibrin deposition and fibrinopeptide A generation during perfusion were comparable in diabetic and control subjects. Platelet thromboxane B2 formation after stimulation with arachidonic acid was increased in diabetic patients without macroangiopathy compared with age- and sex-matched control subjects. In the perfusion system, the patterns of platelet adhesion and aggregate formation on extracellular matrix in flowing blood of diabetic patients (with or without macroangiopathy), and healthy age- and sex-matched control subjects followed a similar pattern.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1991 Nov
PMID:Platelet adhesion and aggregate formation in type I diabetes under flow conditions. 193 2

It is well established that the NOD mouse develops T-cell-dependent autoimmune type I diabetes that is abolished by neonatal Tx and enhanced by Tx at weaning. In a previous study, we demonstrated that the NOD thymus displays various abnormalities in the microenvironmental compartment, including abnormal distribution of epithelial cell subsets, precocious decline in thymic hormone production and formation of giant PVS. These latter structures present an internal ECM-containing network filled with T-cells and to a lesser extent B-cells. Herein we have investigated further the giant PVS and particularly the origin of the T-cells that colonize these structures. The thymic origin of intra-PVS T-cells was ascertained by distinct protocols. First, sublethal X-ray irradiation or HC treatment leading to cortical thymocyte depletion showed that intra-PVS lymphocytes were resistant, similar to medullary thymocytes. Second, adoptive transfer experiments that used newborn or adult irradiated Thy-1 congenic recipients demonstrated that intra-PVS accumulation of T-cells did not result from the reentry of peripheral mature T-cells into the thymus. Third, kinetic studies that used BrdUrd pulse chase revealed that labeled intra-PVS cells appear late, simultaneously with medullary thymocytes, and remain only transiently within the PVS. Thus, the kinetics of T-cell reconstitution of PVS was compatible with the progressive differentiation of T-cell precursors originating from the thymic cortex. In this respect, the giant PVS of the NOD mouse thymus may represent a useful model to study the relationships between trafficking thymocytes and ECM proteins.
Diabetes 1993 Jan
PMID:Characterization of the extracellular matrix-containing giant perivascular spaces in the NOD mouse thymus. 809 3

Several glucose transporters have recently been identified in glomeruli, and in cultured glomerular cells. These include the facilitative glucose transporter isoforms GLUTs 1, 3 and 4, and sodium-glucose cotransport activity with characteristics of SGLT1. GLUTs 1, 3 and 4 are all high affinity, low capacity, facilitative glucose transporters which typically would be saturated at or near physiologic glucose concentrations. The SGLT transporter of mesangial cells is also a high affinity transporter which similarly could be saturated under normal glucose conditions. This suggests that in order for mesangial cells to take up excessive quantities of glucose in diabetes, changes in glucose transporter expression, translocation or activity may be required. Accordingly, recent investigations discovered positive-feedback regulation of the mesangial cell GLUT1 transporter by glucose, and a regulatory role for GLUT1 in glucose metabolism and extracellular matrix synthesis. Future investigations of glucose transporters in the pathogenesis of diabetic renal disease will now likely proceed in multiple directions, including but not limited to: (1) examination of their regulation by growth factors implicated in diabetic nephropathy, and the resultant effects on ECM synthesis; (2) determination of the mechanisms by which GLUT1 regulates the expression of aldose reductase, PKC, GLUT1, and other genes in the mesangial cell; and (3) Suppression of glucose transporters in attempts to prevent high glucose-induced diabetic glomerulosclerosis.
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PMID:Glucose transporters of the glomerulus and the implications for diabetic nephropathy. 928 9

Due to their elasticity, glomeruli will undergo excessive expansion and repetitive cycles of distension contraction under conditions of impaired glomerular pressure autoregulation and systemic arterial hypertension. These alterations in glomerular volume are associated with mesangial cell stretch which in turn stimulates the synthesis and deposition of ECM with eventual mesangial expansion and glomerulosclerosis. Hyperactivity of growth factors with prosclerotic activity is an important component in the translation of cellular mechanical strain into the abnormal metabolism of ECM components. Although mesangial cell mechanical strain is expected to occur in both remnant glomeruli and in glomeruli of diabetic kidneys, quantitatively different factors will determine the resultant metabolic consequences. In remnant glomeruli, the mechanical stretch is intense, being accounted for largely by the marked glomerular hypertrophy and increased glomerular compliance. In diabetic glomeruli, however, the mechanical stretch is less prominent but its effect on ECM synthesis is markedly aggravated by the presence of hyperglycaemia. There are presently no methods clinically available to diminish the prosclerotic action of growth factors at the glomerular level. In addition, there are no effective means to specifically improve glomerular pressure autoregulation. Therefore, current therapies must be aimed at decreasing systemic arterial pressure, blocking angiotensin II action and reducing glomerular hypertrophy. While there are effective drugs for the treatment of hypertension and for angiotensin II inhibition, protein restriction is the only measure available to diminish glomerular hypertrophy. Finally, in diabetes correction of systemic and glomerular hypertension should be coupled with strict glycaemic control to correct both glomerular autoregulation and increased ECM deposition.
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PMID:Mechanical strain of glomerular mesangial cells in the pathogenesis of glomerulosclerosis: clinical implications. 1038 90

Diabetic nephropathy is characterized by the rapid onset of hypertrophy and ECM expansion. Previously, we showed that calcineurin phosphatase is required for hypertrophy and ECM synthesis in cultured mesangial cells. Therefore, we examined the effect of calcineurin inhibition on renal hypertrophy and ECM accumulation in streptozotocin-induced diabetic rats. After 2 wk of diabetes, calcineurin protein was increased in whole cortex and glomeruli in conjunction with increased phosphatase activity. Daily administration of cyclosporin A blocked accumulation of both calcineurin protein and calcineurin activity. Also associated with calcineurin upregulation was nuclear localization of the calcineurin substrate NFATc1. Inhibition of calcineurin reduced whole kidney hypertrophy and abolished glomerular hypertrophy in diabetic rats. Furthermore, calcineurin inhibition substantially reduced ECM accumulation in diabetic glomeruli but not in cortical tissue, suggesting a differential effect of calcineurin inhibition in glomerular vs. extraglomerular tissue. Corresponding increases in fibronectin mRNA and transforming growth factor-beta mRNA were observed in tubulointerstitium but not in glomeruli. In summary, calcineurin plays an important role in glomerular hypertrophy and ECM accumulation in diabetic nephropathy.
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PMID:Calcineurin is activated in diabetes and is required for glomerular hypertrophy and ECM accumulation. 1238 27

Amines such as agmatine, putrescine, spermidine and spermine have been reported to be involved in a variety of physiological and biochemical phenomena. However, it is not known whether they are also involved in the homeostasis of intracellular fibronectin content via upregulation of protein kinase C (PKC), extracellular signal-regulated kinase (ERK), and transforming growth factor-beta1 (TGF-beta1). To determine this, we have studied the effect of multiple amines on fibronectin, TGF-beta1, ERK, and PKC levels in mesangial cells under high glucose conditions. All the amines tested (at 0.1-1 mM) affected neither the viability of mesangial cells for 42 h nor LDH release into the medium. Agmatine reduced TGF-beta1 and ERK levels but not PKC at concentrations of 0.1-1 mM. However, levels of fibronectin, TGF-beta1, ERK, and PKC were unaffected by either putrescine or spermidine. A decrease in fibronectin secretion was accompanied by decreases in TGF-beta1 and ERK. Such cumulative results lead us to hypothesize that agmatine reduces high glucose-induced fibronectin secretion via several pathways including ERK-TGF-beta1-fibronectin and spermine, via a decrease in TGF-beta1. Possible roles of enzymes involved in agmatine and polyamine biosynthesis are discussed in relation to secretion of ECM proteins.
Diabetes Res Clin Pract 2004 Nov
PMID:Regulation of fibronectin levels by agmatine and spermine in mesangial cells under high-glucose conditions. 1553 78

Expansion of pancreatic islet cell populations, especially the beta cells, using a currently available ex vivo gene transfer technology is important to develop cell therapies to treat Type I diabetes. In this study, we evaluated adenovirus mediated gene transfer efficiency in primarily isolated mouse islet cells in two types of culture conditions: freshly isolated suspended islets and cultured islets with monolayer formation. A recombinant replication deficient adenovirus vector encoding a green fluorescence protein (GFP) cDNA, Ad/ CMV-GFP, was used in the present transduction experiments. Rat 804G derived extracellular matrix (804G-ECM) and 3-isobutyl-1-methylxanthine (IBMX) were used to facilitate monolayer formation of the isolated mouse pancreatic islets. Suspended islets were transfected with Ad/CMV-GFP at more than 95% efficiency. However, analysis of immunohistochemical stains for insulin and glucagon in thin sliced sections of the islets revealed that GFP expression was localized just in the outer cells of the islets, almost all of which were glucagon positive alpha-cells. The beta-cells existing at the inner area of the suspended islets were GFP negative. In contrast, under the condition of the islets in monolayer formation cultures, all of the islet cells including the beta-cells were efficiently infected with Ad/CMV-GFP. To achieve an efficient adenoviral gene transfer to the pancreatic beta-cells, monolayer formation of the islets is critical. Such culture conditions were facilitated by combining 804G-ECM with IBMX.
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PMID:Adenovirus mediated gene transduction of primarily isolated mouse islets. 1567 93

Changes in glucose transporter expression in glomerular cells occur early in diabetes. These changes, especially the GLUT1 increase in mesangial cells, appear to play a pathogenic role in the development of ECM expansion and perhaps other features of diabetic nephropathy. In addition, it appears that at least some diabetic patients may be predisposed to nephropathy because of polymorphisms in their GLUT1 genes. GLUT1 overexpression leads to increased glucose metabolic flux which in turn triggers the polyol pathway and activation of PKC alpha and B1. Activation of these PKC isoforms can lead directly to AP-1 induced increases in fibronectin expression and ECM accumulation. Other, more novel effects of GLUT1 on cellular hypertrophy and injury could also promote changes of diabetic nephropathy. Strategies to prevent GLUT1 overexpression could ameliorate or prevent the progression of diabetic nephropathy.
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PMID:Glucose transporters in diabetic nephropathy. 1571 66

PPAR-gamma ligands, including thiazolidinediones, have recently become clinically available for treating insulin-resistant diabetes mellitus. Accumulating evidence suggests that these drugs not only significantly improve insulin sensitivity but also may have antiproteinuric effects in genetically obese diabetic rodents and patients with type II diabetes and diabetic nephropathy. Moreover, troglitazone reduced expression of ECM proteins and transforming growth factor-beta in glomeruli from streptozotocin-induced diabetic rats. Many other properties including antiproteinuric, hemodynamic, and antihypertensive effects in insulin-dependent diabetes mellitus suggest that PPAR-gamma ligands might have a direct, beneficial renal effect, independent of their capacity to improve glucose tolerance. Besides their antidiabetic effects, thiazolidinediones have been shown to lower blood pressure in diabetic patients with hypertension and patients with diabetic nephropathy through multiple mechanisms. Several studies showed the efficacy of PPAR-gamma agonists to ameliorate the progression of glomerulosclerosis. The effect is independent of insulin effects and could only be partially due to lipid effects. These renal protective effects of PPAR-gamma agonists suggest that they may provide a novel intervention strategy to prevent vascular and glomerular sclerosis.
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PMID:PPAR-gamma-agonists' renal effects. 1624 47


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