UMLS:C0011849 - FACTA Search

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Query: UMLS:C0011849 (diabetes)
277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Our hypothesis is that impairment of peroxisome proliferator-activated receptor-gamma (PPARgamma) initiates renal dysfunction by increasing renal glomerular matrix metalloproteinase-2 (MMP-2) activity because of increased renal homocysteine (Hcy) and decreased nitric oxide (NO) levels. C57BL/6J mice were made diabetic (D) by being fed a high-fat-calorie diet, and an increase in PPARgamma activity was induced by adding pioglitazone (Pi) to the diet. Mice were grouped as follows: normal calorie diet (N), D, N+Pi, and D+Pi (n = 6/group). The glomerular filtration rate (GFR), renal artery blood flow and pressure, and plasma glucose were measured. Renal glomeruli and preglomerular arterioles were isolated. Plasma and glomerular levels of NO, Hcy, and MMP activity were measured. The contractile response to phenylephrine and the dilatation response to acetylcholine in renal arteriolar rings were measured in a tissue myobath. In N, D, N+Pi, and D+Pi groups, respectively, GFR was 9.4 +/- 1.2, 3.9 +/- 1.1, 9.2 +/- 1.6, and 8.4 +/- 1.4 microl x min(-1) x g body wt(-1). Renovascular resistance was 140 +/- 3, 367 +/- 21, 161 +/- 9, and 153 +/- 10 mmHg x ml x min(-1). Levels of Hcy were increased from 5.8 +/- 1.5 in the N to 18.0 +/- 4.0 micromol/l in the D group. Glomerular levels of MMP-2 were increased in D mice compared with N mice, and there was no change in levels of MMP-9. Treatment with Pi ameliorated glomerular levels of MMP-2 and Hcy in the D group. Renal artery ring contraction and relaxation by phenylephrine and acetylcholine, respectively, were attenuated in the D groups compared with the N groups. Results suggest that a PPARgamma agonist ameliorates preglomerular arteriole remodeling in diabetes by decreasing tissue levels of Hcy and MMP-2 activity and increasing NO.
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PMID:Pioglitazone mitigates renal glomerular vascular changes in high-fat, high-calorie-induced type 2 diabetes mellitus. 1660 49

Impaired angiogenesis could contribute to the increased incidence of coronary and peripheral artery disease in diabetic patients. Angiogenesis is initiated by vascular endothelial growth factor (VEGF), a potent angiogenic cytokine, and suppressed by angiostatin, which is generated by matrix metalloproteinase (MMP)-2 and -9 through proteolytic cleavage of plasminogen. We hypothesized that MMP-2 and -9 were upregulated in the diabetic vasculature, resulting in increased angiostatin production and reduced blood vessel formation. In diabetic internal mammary artery samples (n=32) collected from patients undergoing coronary artery bypass grafting surgery, capillary density was only 30% of that in the nondiabetic vessels (n=32), whereas VEGF expression was reduced by 48%. Diabetes upregulated the expression and the gelatinolytic activity of MMP-2 and -9. Active MMP-2 and -9 were released from diabetic arteries, but not from nondiabetic vessels, during phenylephrine-induced vasoconstriction. Diabetes enhanced transcription and protein expression of tissue inhibitor of MMP (TIMP)-1 but had an opposite effect on TIMP-2. In diabetic vessels angiostatin was increased by 62% and was positively correlated with the activities of MMP-2 and -9 (r2=0.806 and 0.742, respectively). This report indicated a strong correlation between the upregulation of MMP-2 and MMP-9 and the increased angiostatin expression in the human diabetic arterial vasculature. The enhanced angiostatin production with a reduced VEGF formation may explain the pathogenesis of impaired angiogenesis in diabetes mellitus.
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PMID:Reduced expression of vascular endothelial growth factor paralleled with the increased angiostatin expression resulting from the upregulated activities of matrix metalloproteinase-2 and -9 in human type 2 diabetic arterial vasculature. 1677 29

Reports have shown differences in gene expression in the skin of diabetic and normal mice both at baseline and after injury. Cluster analysis identified distinct expression patterns within intermediate filaments and extracellular proteins. This report addresses the effect of diabetes and injury on the expression of keratin-associated proteins, keratin complexes, procollagen, and collagenase (matrix metalloproteinase; MMP) genes. At baseline keratin-associated proteins and keratin complexes gene expression was increased in diabetic mice. After surgery, the level of expression for keratin-associated proteins and keratin complexes genes decreased in diabetic mice, but did not change in normal mice. If the expression of a procollagen gene differed between diabetic and normal mice, the expression was lower in diabetic mice. Procollagen gene expression was elevated after skin excision compared with noninjured skin. At baseline, the level of MMP and tissue inhibitor of metalloproteinase gene expression was comparable between mouse strains. With injury, the expression of several MMP genes was increased in both mouse strains, but to higher levels in diabetic mice. At day 7, the level of MMP-9 activity in granulation tissue was elevated. This alteration may contribute to delayed healing in diabetic mice. Therefore, differences in gene expression exist between mouse strains and can assist in understanding of physiological manifestations, including delayed healing, in diabetic mice.
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PMID:Expression of intracellular filament, collagen, and collagenase genes in diabetic and normal skin after injury. 1680 8

Although inflammation has long been known as a localized protective reaction of tissue to irritation, injury, or infection, characterized by pain, redness, swelling, and sometimes loss of function, there has been a new realization about its role in a wide variety of diseases, including cancer. While acute inflammation is a part of the defense response, chronic inflammation can lead to cancer, diabetes, cardiovascular, pulmonary, and neurological diseases. Several pro-inflammatory gene products have been identified that mediate a critical role in suppression of apoptosis, proliferation, angiogenesis, invasion, and metastasis. Among these gene products are TNF and members of its superfamily, IL-1alpha, IL-1beta, IL-6, IL-8, IL-18, chemokines, MMP-9, VEGF, COX-2, and 5-LOX. The expression of all these genes are mainly regulated by the transcription factor NF-kappaB, which is constitutively active in most tumors and is induced by carcinogens (such as cigarette smoke), tumor promoters, carcinogenic viral proteins (HIV-tat, HIV-nef, HIV-vpr, KHSV, EBV-LMP1, HTLV1-tax, HPV, HCV, and HBV), chemotherapeutic agents, and gamma-irradiation. These observations imply that anti-inflammatory agents that suppress NF-kappaB or NF-kappaB-regulated products should have a potential in both the prevention and treatment of cancer. The current review describes in detail the critical link between inflammation and cancer.
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PMID:Inflammation and cancer: how hot is the link? 1688 56

We previously reported that supplementation with 17beta-estradiol (E2) attenuates albuminuria, glomerulosclerosis, and tubulointerstitial fibrosis in diabetic nephropathy. The present study examined the mechanisms by which E2 regulates extracellular matrix (ECM) metabolism, a process that contributes to the development of glomerulosclerosis and tubulointerstitial fibrosis. The study was performed in female nondiabetic (ND), streptozotocin-induced diabetic (D), and diabetic with E2 supplementation (D+E2) Sprague-Dawley rats for 12 wk. Diabetes was associated with an increase in the renal expression of collagen alpha type IV [ND, 0.22 +/- 0.02; D, 0.99 +/- 0.09 relative optical density (ROD); P < 0.05] and fibronectin protein (ND, 0.36 +/- 0.08; D, 1.47 +/- 0.08 ROD; P < 0.05), as measured by Western blot analysis. E2 supplementation partially attenuated this increase in collagen alpha type IV (D+E2, 0.47 +/- 0.10 ROD) and fibronectin (D+E2, 0.71 +/- 0.16 ROD) protein expression associated with D. Diabetes was also associated with a decrease in the expression of matrix metalloproteinase (MMP) isoform MMP-2 (ND, 0.79 +/- 0.01; D, 0.62 +/- 0.06 ROD; P < 0.05) and MMP-9 protein (ND, 0.49 +/- 0.02; D, 0.33 +/- 0.03 ROD; P < 0.05). E2 supplementation restored MMP-2 and MMP-9 protein to levels similar or even greater than in the ND kidneys (MMP-2, 0.75 +/- 0.06; MMP-9, 0.73 +/- 0.01 ROD). The activities of MMP-2 (ND, 7.88 +/- 0.44; D, 5.60 +/- 0.54 ROD; P < 0.05) and MMP-9 (ND, 29.9 +/- 1.8; D, 12.9 +/- 2.3 ROD; P < 0.05), as measured by zymography, were also decreased with D. E2 supplementation restored MMP-2 and MMP-9 activity to levels similar to that in ND kidneys (MMP-2, 7.66 +/- 0.35; MMP-9, 21.4 +/- 2.9 ROD). We conclude that E2 supplementation is renoprotective by attenuating glomerulosclerosis and tubulointerstitial fibrosis by reducing ECM synthesis and increasing ECM degradation.
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PMID:17beta-Estradiol supplementation reduces tubulointerstitial fibrosis by increasing MMP activity in the diabetic kidney. 1693 52

Gene expression profiling of islets from pre-diabetic male Zucker diabetic fatty (ZDF) rats showed increased expression of hypoxia-related genes, prompting investigation of the vascular integrity of the islets. The islet microvasculature was increased approximately twofold in young male ZDF rats by both morphometric analysis and quantifying mRNA levels of endothelial markers. ZDF rats at 12 weeks of age showed a significant reduction in the number of endothelial cells, which was prevented by pretreatment with pioglitazone. Light and electron microscopy of normoglycemic 7-week-old ZDF rats showed thickened endothelial cells with loss of endothelial fenestrations. By 12 weeks of age, there was disruption of the endothelium and intra-islet hemorrhage. Islets from 7- and 12-week-old ZDF rats showed an approximate three- and twofold increase in vascular endothelial growth factor (VEGF)-A mRNA and VEGF protein secretion, respectively, compared with lean controls. Thrombospondin-1 mRNA increased in 7- and 12-week-old rats by 2- and 10-fold, respectively, and was reduced by 50% in 12-week-old rats pretreated with pioglitazone. Islets from young male control rats induced migration of endothelial cells in a collagen matrix only after pretreatment with matrix metalloproteinase (MMP)-9. Islets from 7-week-old ZDF rats showed a fivefold increase in migration score compared with wild-type controls, even without MMP-9 treatment. Islets from 15-week-old ZDF rats did not induce migration; rather, they caused a significant rounding up of the duct-derived cells, suggesting a toxic effect. These data suggest that in the ZDF rat model of type 2 diabetes, an inability of the islet to maintain vascular integrity may contribute to beta-cell failure.
Diabetes 2006 Nov
PMID:Islet microvasculature in islet hyperplasia and failure in a model of type 2 diabetes. 1706 32

Diabetes mellitus (DM) is a major risk factor for atherosclerosis and causes multiple cardiovascular complications. Although high glucose can induce matrix metalloproteinases (MMPs), its inhibitors and cell apoptosis, little is known about the roles of MMPs in regulating cell apoptosis in response to high glucose. To address this issue, we elucidated the relationship between MMPs, its inhibitors and cell apoptosis in human umbilical vein endothelial cells (HUVECs). HUVECs were treated with medium containing 5.5 mM or 33 mM of glucose in the presence or the absence of ascorbic acid and MMP inhibitors (GM6001 and endogenous tissue inhibitors of MMPs, TIMP-1, and TIMP-2). For detection of cell apoptosis, the cell death detection ELISA assay was used. The results revealed that high glucose-induced apoptosis could be suppressed by ascorbic acid, GM6001 and TIMP-2, but not by TIMP-1. The activities of MMP-2, MMP-9 and its inhibitors, TIMP-1, TIMP-2 after high glucose treatment, were also detected by ELISA method. We found that the activated form of MMP-2, but not MMP-9, was increased, while the level of TIMP-2, but not TIMP-1, was decreased. In Western blot and RT-PCR analysis, the expression of TIMP-2, but not TIMP-1, after high glucose treatment was downregulated, whereas the levels of MMP-2 and -9 proteins and mRNA were not changed. The present study indicated that oxidative stress induced by high glucose might be involved in the opposite effects on MMP-2 activation and TIMP-2 downregulation. This reactive oxygen species (ROS)-dependent MMP-2 activation in turn mediates high glucose-induced cell apoptosis in HUVECs.
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PMID:Opposite effects of high glucose on MMP-2 and TIMP-2 in human endothelial cells. 1720 68

The authors hypothesized that matrix metalloproteinase (MMP)-2, -9, and tissue inhibitor metalloproteinase (TIMP)-1, -2 would be abnormal in acute coronary syndromes (ACSs). MMP-2, -9, and TIMP-1, -2 plasma levels were measured in diabetic patients with ACSs compared to nondiabetic patients with ACSs. A total of 46 diabetic and 78 nondiabetic patients with ACSs were enrolled. The following parameters were measured: body mass index (BMI), glycosylated hemoglobin (HbA1c), fasting plasma glucose (FPG), fasting plasma insulin (FPI), homeostasis model assessment index (HOMA index), systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (Tg), lipoprotein(a) [Lp(a)], plasminogen activator inhibitor-1 (PAI-1), homocysteine (Hct), fibrinogen (Fg), high-sensitivity C-reactive protein (hs-CRP), and plasma levels of MMP-2, MMP-9, TIMP-1, and TIMP-2. Significant HbA1c, FPG, FPI, HOMA index, DBP, Tg, Hct, and Fg increases were present in the diabetic group with ACSs, whereas hs-CRP was lower in these patients compared to nondiabetic patients with ACSs. MMP-9, TIMP-1, and TIMP-2 plasma levels were higher in diabetic patients with ACSs compared to nondiabetic patients with ACSs. MMP-9, TIMP-1, and TIMP-2 plasma levels were increased in diabetic patients with ACSs, which may reflect abnormal extracellular matrix metabolism in diabetes during acute event.
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PMID:Metalloproteinase-2 and -9 in diabetic and nondiabetic subjects during acute coronary syndromes. 1736 96

Remodeling of extracellular matrix (ECM) is an important physiological feature of normal growth and development. Recent studies have emphasized the role of matrix metalloproteinases (MMP-2 and MMP-9) in normal mouse nephrogenesis. We have demonstrated previously in the rat that in utero exposure to maternal diabetes impairs renal development leading to a 30% reduction in the nephron number. Transforming growth factor-beta1 (TGF-beta1) and connective tissue growth factor (CTGF) are known to mediate high glucose effects on matrix degradation. The aim of the present study was to address the expression of type IV collagenase and TGF-beta1/CTGF systems in rat kidney during normal development and after in utero exposure to maternal diabetes. Both MMP-2 and MMP-9 mRNA metanephric expressions and activities were dramatically downregulated in kidneys issued from diabetic fetuses and in metanephros cultured in the presence of high glucose concentration. TGF-beta1 and CTGF expressions were significantly enhanced in diabetic fetal kidneys and in high glucose cultured metanephroi. Conditioned media obtained from metanephroi grown with high glucose concentration upregulated functional TGF-beta activity in transfected ATDC5 cells. In conclusion, in impaired nephrogenesis resulting from in utero exposure to maternal diabetes, alteration of both type IV collagenase and TGF-beta1/CTGF systems may lead to abnormal remodeling of ECM, which may, in turn, induce defects in ureteral bud branching leading to the observed reduction in the nephron number with consequences later in life: progression of chronic renal disease and hypertension.
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PMID:Expression of matrix metalloproteinases MMP-2 and MMP-9 is altered during nephrogenesis in fetuses from diabetic rats. 1749 4

Matrix metalloproteinases (MMPs) have been implicated in the atherosclerotic process and risk factors for the disease such as hypertension, hyperlipidemia, or diabetes mellitus in adults. So far, circulating levels of MMPs and their tissue inhibitors (TIMPs) have not been assessed in children and adolescents with obesity, a known risk factor for cardiovascular disease. Plasma levels of MMP-9 and TIMP-1 were measured immunoenzymatically in 45 obese children and adolescents, aged 15 +/- 1.8 years. The control group consisted of 28 healthy children, aged 14.5 +/- 2.5 years. MMP-9 and TIMP-1 concentrations were higher in obese children than in the control group (MMP-9: 553.5 +/- 311 vs 400.4 +/- 204 ng/mL, respectively; P = .02; TIMP-1: 161.2 +/- 32 vs 143.1 +/- 20.1 ng/mL, respectively; P = .03). We found significantly higher levels of MMP-9 in obese children with coexisting hypertension than in obese normotensive patients (635 +/- 308 vs 450 +/- 289 ng/mL, respectively; P = .04). MMP-9 correlated with body mass index (BMI) (r = 0.33, P = .005) and fasting insulin (r = 0.3, P = .013); TIMP-1 correlated with BMI (r = 0.35, P = .006). In the group of obese hypertensive children (n = 25), MMP-9 correlated with BMI (r = 0.41, P = .001), systolic blood pressure (r = 0.41, P = .002), fasting insulin (r = 0.37, P = .006), and homeostasis model assessment index of insulin resistance (r = 0.27, P = .03). TIMP-1 correlated with BMI (r = 0.33, P = .025) and systolic (r = 0.38, P = .008) and diastolic (r = 0.47, P = .001) blood pressure. In the regression models, MMP-9 was found to be dependent on fasting insulin (R(2) = 0.16, P = .04), and TIMP-1 on BMI (R(2) = 0.14, P = .04). In the obese hypertensive group, TIMP-1 was dependent on diastolic blood pressure (R(2) = 0.18, P = .04). Obese children and adolescents have elevated plasma concentrations of MMP-9 and TIMP-1. Coexistence of hypertension may exacerbate alterations of extracellular matrix turnover in these patients. It might be hypothesized that elevated MMP and TIMP concentrations may be related to increased cardiovascular risk in obese and particularly in obese hypertensive children and adolescents.
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PMID:Elevated matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 in obese children and adolescents. 1751 13

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