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)

In addition to inhibiting matrix metalloproteinase-2 and matrix metalloproteinase-9 activity, recent studies suggest that tissue inhibitor of metalloproteinase (TIMP)-1 may inhibit apoptosis in various cell lines. To address this question in pancreatic islets and beta-cells, we treated rat pancreatic islets and INS-1 cells with a high-dose combination of the cytokines interleukin (IL)-1beta, tumor necrosis factor-alpha, and interferon-gamma with or without the addition of TIMP-1 and TIMP-2 protein. Using flow cytometry, we quantitated DNA fragmentation to assess cellular apoptosis and confirmed these observations with DNA laddering experiments. Next, we transfected the mouse TIMP-1 gene into INS-1 cells and performed Western immunoblotting to demonstrate expression of TIMP-1 protein. We treated TIMP-1-expressing INS-1 cells with high-dose cytokines and again used flow cytometry to assess DNA fragmentation. We also evaluated the effect of TIMP-1 on IL-1beta-induced inhibition of glucose-stimulated insulin secretion (GSIS) in freshly isolated rat pancreatic islets. Finally, we evaluated the effect of TIMP-1 on inducible nitric oxide synthase (iNOS) gene expression and nuclear factor (NF)-kappaB activity in INS-1 cells stimulated with high-dose cytokines. TIMP-1 but not TIMP-2 prevented cytokine-induced apoptosis and cytokine-mediated inhibition of GSIS in rat islets and beta-cells. TIMP-1 mediated these effects by inhibiting cytokine activation of NF-kappaB, but it did not affect nitric oxide production or iNOS gene expression. Therefore, TIMP-1 may be an ideal gene to prevent cytokine-mediated beta-cell destruction and dysfunction in models of type 1 diabetes and islet transplantation rejection.
Diabetes 2001 May
PMID:Tissue inhibitor of metalloproteinase-1 prevents cytokine-mediated dysfunction and cytotoxicity in pancreatic islets and beta-cells. 1133 7

Diabetes mellitus (DM) is a primary risk factor for cardiovascular disease. Although recent studies have demonstrated an important role for extracellular matrix metalloproteinases (MMPs) in atherosclerosis, little is known about the effects of hyperglycemia on MMP regulation in vascular cells. Gelatin zymography and Western blot analysis revealed that the activity and expression of 92-kDa (MMP-9) gelatinase, but not of 72 kDa (MMP-2) gelatinase, were significantly increased in vascular tissue and plasma of two distinct rodent models of DM. Bovine aortic endothelial cells (BAECs) grown in culture did not express MMP-9 constitutively; however, chronic (2-week) incubation with high glucose medium induced MMP-9 promoter activity, mRNA and protein expression, and gelatinase activity in BAECs. On the other hand, high glucose culture did not change MMP-9 activity from vascular smooth muscle cells or macrophages. Electron paramagnetic resonance studies indicate that BAECs chronically grown in high glucose conditions produce 70% more ROS than do control cells. Enhanced MMP-9 activity was significantly reduced by treatment with the antioxidants polyethylene glycol-superoxide dismutase and N-acetyl-L-cysteine but not by inhibitors of protein kinase C. In conclusion, vascular MMP-9 activity is increased in DM, in part because of enhanced elaboration from vascular endothelial cells, and oxidative stress plays an important role. This novel mechanism of redox-sensitive MMP-9 expression by hyperglycemia may provide a rationale for antioxidant therapy to modulate diabetic vascular complications.
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PMID:Diabetes mellitus enhances vascular matrix metalloproteinase activity: role of oxidative stress. 1142 Mar 6

Diabetic nephropathy is characterized by accumulation of mesangial matrix. Glucose-induced inhibition of matrix-degrading enzymes such as collagenases is believed to contribute to matrix accumulation. We have previously demonstrated that 72 kDa type IV collagenase activity is decreased in the rat mesangial cells cultured in high glucose media [Diabetes 1995;44:929-935]. The present studies were designed to investigate if the cytokine transforming growth factor-beta1 (TGF-beta1) mediates this effect of glucose. Type IV collagenases degrade type IV collagen as well as gelatin (denatured collagen) and are thus also called gelatinases. They belong to the family of matrix metalloproteinases (MMPs); MMP activity is controlled by tissue inhibitors of metalloproteinases (TIMPs). The activity of 72 kDa type IV collagenase, also known as matrix metalloproteinase-2 (MMP-2), was assessed using three methods: (1) fluoresceinated gelatin degradation assay to detect free enzyme activity (activity which is present in excess of TIMP-inhibited activity); (2) zymography to measure total (free + TIMP-bound) enzyme activity; (3) ELISA using specific antibodies to measure MMP-2 levels. TGF-beta1 and TIMP-2 levels were also determined by ELISA. Incubation of primary cultures of rat mesangial cells for 5 days in 30 vs. 5 mM glucose resulted in a 3-fold increase in production of total TGF-beta1, a significant decrease in MMP-2 activity and immunoreactive MMP-2 levels, and an increase in TIMP-2 levels. Addition of exogenous TGF-beta1 to mesangial cells incubated in 5 mM glucose replicated the high glucose effect by producing a significant decrease in MMP-2 levels with a concurrent increase in TIMP-2 levels. Furthermore, glucose-induced inhibition of MMP-2 activity was completely blocked by neutralization of TGF-beta1 with anti-TGF-beta1 antibody. We conclude that the decrease in MMP-2 activity induced by glucose loading is mediated via TGF-beta1.
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PMID:High glucose decreases matrix metalloproteinase-2 activity in rat mesangial cells via transforming growth factor-beta1. 1142 24

The activity of matrix metalloproteinase (MMP)-9 was evaluated in placental tissue from healthy subjects (controls) and from patients with gestational and pre-existing diabetes mellitus (GDM and PDM, respectively). Compared with controls, MMP-9 activity was greater in placental tissue from patients with PDM and lower in placental tissue from patients with GDM. The modulatory role of nitric oxide (NO) and reactive oxygen species (ROS) on MMP-9 activity in placental tissue was evaluated. In healthy placenta, NO synthase inhibitors diminished MMP-9 activity, whereas NO donors enhanced it. The addition of xanthine/xanthine oxidase or hydrogen peroxide to placental incubates enhanced MMP-9 activity, while the addition of superoxide dismutase (SOD) diminished it. In placental tissue from patients with PDM, MMP-9 activity was stimulated by NO and by ROS. In placental tissue from patients with PDM, concentrations of nitrates/nitrites and thiobarbituric acid-reactive substances (TBARS) were enhanced, whereas SOD activity was decreased, suggesting that elevated concentrations of NO and ROS may be related to the enhanced MMP-9 concentrations found in these tissues. In placenta from GDM patients, in which a diminished concentration of MMP-9 were detected, nitrate/nitrite concentrations were increased, but placental MMP-9 activity did not change in the presence of either NO donors or inhibitors. The activity of MMP-9 in placental tissue from patients with GDM was stimulated by ROS donor systems and was inhibited by the addition of SOD; however, TBARS and SOD concentrations were unchanged in these tissues compared with controls. These findings demonstrate that placental MMP-9 activity is modulated by NO and ROS and that, in diabetic pathology, NO and ROS may determine changes in MMP-9 activity, which are probably involved in the structural and functional abnormalities of diabetic placental tissue.
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PMID:Membrane-type matrix metalloproteinase-9 activity in placental tissue from patients with pre-existing and gestational diabetes mellitus. 1145 Oct 17

Adipocyte hypertrophy and hyperplasia together with angiogenesis contribute to the growth of the fat mass. Because changes in the extracellular matrix (ECM) components are often associated with such cellular remodeling, we studied the adipocyte expression of the matrix metalloproteinases (MMPs) 2 and 9, two key enzymes involved in the modulation of ECM. The present study provides the first evidence that human adipose tissue produces and secretes MMP-2 and -9 as shown by gelatin zymography analysis performed on media conditioned by human subcutaneous adipose tissue and human preadipocytes in primary cultures and by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis on transcripts from mature human adipocytes. The further characterization performed on the murine 3T3F442A preadipocyte cell line demonstrates that MMP expression, assessed by RT-PCR and Western blot analysis, as well as activity, assessed by gelatin zymography analysis, increased during the adipocyte differentiation, whereas the expression of tissue inhibitor metalloproteinases 1 and 2 were abolished or not affected, respectively. Finally, preadipocyte treatment with MMP inhibitors such as batimastat and captopril, as well as neutralizing antibodies, markedly decreased adipocyte differentiation as demonstrated by the inhibition in the appearance of lipogenic (triglycerides) and lipolytic (glycerol release and hormone-sensitive lipase expression) markers. These data suggest that MMP-2 and -9 could be important key regulators of adipocyte differentiation. Thus, the adipocyte-derived MMPs might represent a new target for the inhibition of adipose tissue growth.
Diabetes 2001 Sep
PMID:Adipocyte produces matrix metalloproteinases 2 and 9: involvement in adipose differentiation. 1152 74

Atherosclerosis is a major vascular complication of diabetes and the primary cause of mortality in persons with this disease. Metabolic abnormalities related to the Insulin Resistance Syndrome or Metabolic Syndrome may importantly contribute to the increased risk of atherosclerosis associated with diabetes. Thiazolidinediones (TZDs) are oral insulin sensitizers in broad clinical use that enhance insulin-stimulated glucose uptake into skeletal muscle. TZDs can also improve cardiovascular risk factors and exert direct effects on vascular cells to potentially retard the atherosclerotic process. Direct vascular effects of TZDs likely result from their activity as ligands for the nuclear receptor, PPARgamma. All of the major cell types in the vasculature express PPARgamma, including intimal macrophages and vascular smooth muscle cells (VSMCs) in human atheroma. TZDs block VSMC growth by inducing cell cycle arrest in G1 through an inhibition of retinoblastoma protein phosphorylation. Migration of monocytes and VSMCs is also inhibited by TZDs, possibly through decreased matrix metalloproteinase production. Activation of PPARgamma by TZDs in macrophages induces ABCA1 transporter expression to promote reverse cholesterol transport. These antiatherogenic activities may also occur in vivo because TZDs have been shown to inhibit lesion formation in several animal models. Thus, TZD activation of PPARgamma may protect against atherosclerosis both by normalizing proatherogenic metabolic abnormalities of the insulin resistance/diabetes milieu and through an inhibition of vascular cell growth and movement.
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PMID:PPARgamma and atherosclerosis: effects on cell growth and movement. 1174 60

The potential role of the matrix metalloproteinase (MMP) system in the pathophysiology of the adipose tissue was investigated in a mouse model of nutritionally induced obesity. mRNA levels of 16 MMPs and 4 tissue inhibitors of MMPs (TIMPs) were measured by semiquantitative RT-PCR in adipose tissue isolated from mice maintained for 15 weeks on a standard or high-fat diet. In mice on standard diet, with the exception of MMP-8, all MMP and TIMP transcripts were detected in both gonadal and subcutaneous depots. In obese mice, the expression of MMP-3, -11, -12, -13, and -14 and TIMP-1 mRNAs was upregulated, whereas that of MMP-7, -9, -16, and -24 and TIMP-4 was downregulated. Most MMP and TIMP mRNAs were expressed at higher levels in stromal-vascular cells than in mature adipocytes. Analysis of adipose tissue by in situ fluorescent zymography revealed MMP-dependent proteolytic activities, demonstrating the presence of active MMPs in the intact tissue. In vitro conversion of adipogenic 3T3-F442A cells into mature adipocytes was associated with substantial modulations of MMP and TIMP expression. Moreover, this in vitro adipogenesis was reduced in the presence of a synthetic MMP inhibitor. Thus, the adipose tissue expresses a large array of MMPs and TIMPs, which modulate adipocyte differentiation.
Diabetes 2002 Apr
PMID:Modulation of adipose tissue expression of murine matrix metalloproteinases and their tissue inhibitors with obesity. 1191 31

High glucose concentrations can decrease degradation of mesangium by reducing the activities of matrix metalloproteinases (MMPs). The aim of this study was to investigate the effects of glycation of mesangium matrix on MMP-2, the principal MMP secreted by mesangial cells to degrade type IV collagen. Also examined were membrane type 1 MMP (MT1-MMP), tissue inhibitors of MMPs (TIMP)-1 and -2, and transforming growth factor-beta (TGF-beta), which together regulate MMP-2 activities in an interacting manner. Human fetal mesangial cells were grown on mesangium matrix glycated by incubation in 500 mmol/l ribose, with or without aminoguanidine. The activities and gene expression of the abovementioned enzymes/inhibitors were measured by degradation of radiolabeled mesangium matrix, RT-PCR, and zymography. Glycation of mesangium matrix resulted in a threefold increase in advance glycation end products and reduced by 45% the matrix-degrading activity of MMPs secreted by mesangial cells. Analogous to the direct effects of high glucose concentrations, glycation of matrix increased the gene expression of MMP-2 and TIMP-1 (control 100 +/- 16.9 vs. glycated 197.3 +/- 30.6% and control 100 +/- 5.3 vs. glycated 152.1 +/- 20.1%, respectively; P < 0.05) and decreased MT1-MMP (control 100 +/- 1.17 vs. glycated 54.1 +/- 15.2%; P < 0.05). However, unlike high glucose concentrations, glycation was not associated with decreased activation of MMP-2. Similarly, glycation but not high glucose increased expression of TIMP-2 (control 100 +/- 5.9 vs. glycated 168.2 +/- 31.4%; P < 0.05), and the effects of glycation on degradation can be abolished by anti-TIMP-2 antibody. Glycation of matrix decreased TGF-beta mRNA by 38.2% and total and active TGF-beta by 35.5 and 21.5%, respectively, opposite the effects of high glucose concentrations. Our results indicate that glycation of matrix affects the balance between MMP-2 and its activator and inhibitors, but this phenomenon is not due to TGF-beta. The process of glycation may impart to the mesangium matrix a memory effect that contributes to the long-term toxicity of hyperglycemia.
Diabetes 2002 Aug
PMID:Effects of mesangium glycation on matrix metalloproteinase activities: possible role in diabetic nephropathy. 1214 78

A number of studies have shown elevated matrix metalloproteinase expression in chronic wound fluid compared to an acute wound; however, little has been done to characterize animal models in a similar manner and thus determine their usefulness. The diabetes mouse is an animal model of type II diabetes that shows impaired dermal wound healing and has been proposed as a model of human impaired wound healing. In this study we have determined the mRNA and protein expression profiles of matrix metalloproteinases 2, 3, and 9 during the first 10 d of dermal healing for the diabetes mouse and its normally healing littermate. Additionally, human wound fluid from diabetic chronic wounds and acute surgical wounds were studied to enable a comparison of the model to the human condition. We show that during the early stages of wound healing the diabetes mouse possesses significantly reduced protein levels of pro-matrix metalloproteinases 2 and 9 within the wound tissue and active matrix metalloproteinase 3 within the fluid. Pro-matrix metalloproteinase 3 levels are also significantly reduced in the diabetes mouse during the later stages of healing. These differences may be contributing to the impaired healing of the diabetes mouse; however, they differ from the human data presented here, which show elevated matrix metalloproteinase 2 and reduced matrix metalloproteinase 9 in human diabetic chronic wound fluid compared to acute wound fluid. Therefore, although clearly showing the importance of appropriate matrix metalloproteinase regulation for normal acute wound healing to occur, the diabetes mouse may not be an ideal model for study of matrix metalloproteinase involvement in human chronic wound healing.
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PMID:Differential expression of matrix metalloproteinases during impaired wound healing of the diabetes mouse. 1216 30

Expression of several matrix metalloproteinases (MMPs) in atherosclerotic plaques has been well documented, and there are findings to indicate that arterial inflammation is reflected in increased serum concentration of matrix metalloproteinase-9 (MMP-9). In coronary atherosclerosis, there is enhanced expression of this MMP, which may be predictive of the severity of the disease. We determined the concentrations of serum MMP-9 in 61 patients (47 males, 14 females) who had >50% obstruction in one or more coronary arteries as assessed by coronary angiography before bypass surgery. In a control group of 19 patients (9 males, 10 females) there were no pathological findings in coronary angiography. ANOVA showed that serum MMP-9 concentrations were highest in patients with 3-vessel coronary artery disease (CAD) (57.3+/-39.1 microg/L, p=0.011). The difference remained statistically significant after adjustment for age, diabetes and sex (p=0.025, ANCOVA). When the groups were compared with each other, serum MMP-9 concentration was higher in the patients with 3-vessel CAD than in those with 1- or 2-vessel CAD (40.4+/-25.1 microg/L, p=0.044) or in the controls (32.2+/- 16.1 microg/L, p=0.007). These results show that serum MMP-9 is elevated in patients with severe coronary stenosis compared with controls. Since MMP-9 has been suggested to reflect inflammation in atherosclerotic plaques, it may be useful in the evaluation of the severity of cardiovascular disease.
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PMID:Serum matrix metalloproteinase-9 concentration in angiographically assessed coronary artery disease. 1238 78


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