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 mice, diabetes can be induced by multiple low doses of streptozotocin (MLD-STZ), i.e., 40 mg/kg body wt on each of 5 consecutive days. In this model, diabetes develops only when STZ induces both beta-cell toxicity and T-cell-dependent immune reactions. The target molecule(s) of MLD-STZ-induced beta-cell toxicity are not known, however. In this study, we report that GLUT2 is a target molecule for MLD-STZ toxicity. Ex vivo, a gradual decrement of both GLUT2 protein and mRNA expression was found in pancreatic islets isolated from MLD-STZ-treated C57BL/6 male mice, whereas mRNA expression of beta-actin, glucokinase, and proinsulin remained unaffected. Significant reduction of both GLUT2 protein and mRNA expression was first noted 1 day after the third STZ injection, clearly preceding the onset of hyperglycemia. The extent of reduction increased with the number of STZ injections administered and increased over time, after the last, i.e., fifth, STZ injection. The STZ-induced reduction of GLUT2 protein and mRNA was not due to an essential loss of beta-cells, because ex vivo, not only the total RNA yield and protein content in isolated islets, but also proinsulin mRNA expression, failed to differ significantly in the differently treated groups. Furthermore, islets isolated from MLD-STZ-treated donors responded to the nonglucose secretagogue arginine in a pattern similar to that of solvent-treated donors. Interestingly, the MLD-STZ-induced reduction of both GLUT2 protein and mRNA was prevented by preinjecting mice with 5-thio-D-glucose before each STZ injection. Apparently, GLUT2 is a crucial target molecule of MLD-STZ toxicity, and this toxicity seems to precede the immune reactions against beta-cells.
Diabetes 1998 Jan
PMID:GLUT2 in pancreatic islets: crucial target molecule in diabetes induced with multiple low doses of streptozotocin in mice. 942 74

The cellular and molecular requirements for beta-cell damages in an immune-mediated toxin-induced insulin-dependent diabetes mellitus have been studied in the model of multiple low-dose streptozotocin-induced diabetes in rats and mice. It was found that strain-related susceptibility to diabetes induction correlated with a higher level of IL-2, IFN-gamma, and TNF-alpha production, whereas such differences were not observed when IL-1 and NO production by macrophages were analyzed; elimination of immunoregulatory RT6+T cells that increases IFN-gamma production, enhances susceptibility to MLD-STZ-induced diabetes; mercury-induced Th-2 cells down-regulated the disease; IFN-gamma-mediated macrophage activation to produce proinflammatory cytokines rather than NO is an important event in early diabetogenic effects of invading macrophages; inhibition of IL-1 activity downregulates diabetes induction; and generation of NO in beta cells appears to be important for diabetogenic effects. Taken together, data indicate that MLD-STZ diabetes induced by Th-1 lymphocytes that secrete soluble effector molecules that activate macrophages and promote destruction of beta cells possibly by both nitric oxide and nonnitric oxide-mediated mechanisms.
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PMID:Effector mechanisms in low-dose streptozotocin-induced diabetes. 971 13

In certain animal models of autoimmunity the isoxasol derivative leflunomide has been reported to exert a protective effect against autodestruction. In the present study, the immunomodulatory potential of the main metabolite of leflunomide, A77 1726, in experimentally induced autoimmune diabetes was investigated. The disease was induced in genetically susceptible CBA/H mice by multiple low doses of streptozotocin (MLD-SZ, 40 mg/kg per day, given intraperitoneally for 5 consecutive days). Effects of leflunomide were evaluated by two treatment protocols: mice treated with MLD-SZ were injected intraperitoneally with A77 1726 for 10 consecutive days, either during the first 10 days of the disease (early treatment), or starting from day 10 after disease induction (late treatment). Disease manifestations defined by hyperglycaemia, mononuclear infiltration into pancreas, expression of interferon-gamma (IFN-gamma) and inducible nitric oxide synthase (iNOS) and destruction of the islets of Langerhans were reduced in a dose-dependent fashion after early treatment with A77 1726 (dose range of 5-35 mg/kg per day). Moreover, late treatment with the high dose of the drug (25 mg/kg per day), started when the autoimmune disease was already apparent, arrested progression of ongoing inflammatory response. Analysis of the effects of A77 1726 on the adhesive interactions of spleen-derived or peripheral blood-derived mononuclear cells from MLD-SZ-treated and normal mice demonstrated that the drug inhibits both ex vivo and in vitro spontaneous mononuclear cell aggregation, thus suggesting that an important component of leflunomide's immunomodulatory action is suppression of adhesive interactions. These results demonstrate both preventive and therapeutic effects of leflunomide in a model of MLD-SZ-induced diabetes and suggest that the drug may be considered a potent therapeutic tool for autoimmune inflammatory disorders, including diabetes.
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PMID:Leflunomide protects mice from multiple low dose streptozotocin (MLD-SZ)-induced insulitis and diabetes. 1040 14

We have shown recently that xanthine derivative pentoxifylline (PTX) downregulates an inflammatory autoimmune process triggered in genetically susceptible Dark Agouti rats by multiple low doses of streptozotocin (MLD-SZ, 20 mg/kg/day ip for 5 days). We studied the cellular and molecular consequences of PTX treatment during MLD-SZ-induced diabetes with special emphasis on local vs. systemic production of inflammatory mediators. Administration of PTX (200 mg/kg/day for 10 days) during induction of the disease reduced clinical signs of diabetes and protected rats from development of destructive intrainsulitis. Pentoxifylline did not affect diabetogenic effect of single high dose of SZ (100 mg/kg SZ). Ex vivo analysis of the islets of Langerhans performed in early disease development revealed that PTX downregulates production of proinflammatory cytokines IFN-gamma and TNF, as well as inducible nitric oxide synthase (iNOS) expression and NO production. In addition, PTX treatment suppressed splenocyte autoreactivity, as well as the frequency of cells expressing IL-2R and MHC class II antigens. There was no evidence of any changes in proportion of ICAM-1 and LFA-1 expressing splenocytes in comparison to control MLD-SZ-treated animals. In contrast to suppressed intraislet production, high peripheral expression of both iNOS mRNA and NO was found in MLD-SZ rats treated with PTX. Taken together, the data indicate that the effect on both systemic and intra-islet production of NO, suppression of autoreactive cell activation and of local type 1 cytokine release may contribute to the therapeutic benefit achieved by PTX in the rat.
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PMID:Antidiabetogenic effect of pentoxifylline is associated with systemic and target tissue modulation of cytokines and nitric oxide production. 1122 96

Xanthine derivative, pentoxifylline (PTX), has been recently shown to exert a protective effects in certain animal models of autoimmunity, including diabetes in NOD mice. In the present study, the immunomodulatory potential of PTX was investigated in autoimmune diabetes induced by multiple low doses of streptozotocin (MLD-SZ) in genetically susceptible CBA/H mice (tested with 40 mg SZ/kg b.w. for 5 days) and DA rats (tested with 20 mg/kg b.w. for 5 days). In both species, 2-3 weeks following the MLD-SZ treatment, sustained hyperglycemia developed, as an outcome of inflammatory reaction with endothelial cell activation and accumulation of mononuclear cells. Although there was no evidence of typical insulitis in early disease development (day 10), in both rats and mice, macrophages, CD4+ and CD8+ cells were present in the islets of Langerhans as diffuse mononuclear infiltrates with the expression of IFN-gamma, and inducible NO synthase (iNOS). Administration of PTX (200 mg/kg/day for 10 days) in combination with MLD-SZ reduced insulitis and the production of mediators tested, and prevented the development of hyperglycemia. These results suggest that beneficial effects of PTX involve down-regulation of local proinflammatory cytokine-mediated NO synthase pathway. They also demonstrate that in addition to ameliorating spontaneous autoimmunity in NOD mice, PTX may be effective in downregulating an inflammatory autoimmune process triggered in susceptible host by an external agents, such as streptozotocin.
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PMID:Pentoxifylline prevents autoimmune mediated inflammation in low dose streptozotocin induced diabetes. 1178 71

In the nonobese diabetic (NOD) mouse, the T helper (Th)1-type inflammatory cytokines interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha play a critical role in the development of type 1 diabetes, whereas the Th2-type anti-inflammatory cytokines interleukin (IL)-4 and IL-10 operate counterregulatory. There are no comprehensive analyses on cytokine profiles in the mouse model of diabetes induced with multiple low doses of streptozotocin (MLD-STZ). Therefore, we used islets to study ex vivo effects of MLD-STZ and in vitro effects of STZ on IFN-gamma, TNF-alpha, IL-4, and IL-10 on both levels of protein-producing cells and the mRNA expression, as well as the mRNA expression of the Th3-type cytokine transforming growth factor TGF-beta1. C57BL/6 and BALB/c mice of both genders were injected intraperitoneally with 40 mg/kg body wt STZ on five consecutive days and islets were isolated on day I and 3 after the fifth STZ-injection. Control mice received the solvent of STZ. In islets of C57BL/6 mice of both genders MLD-STZ similarly stimulated production of IFN-gamma and TNF-alpha, but significantly reduced IL-4 and IL-10 levels in male mice only. Opposite results were obtained in islets of BALB/c mice of both genders. Here, MLD-STZ markedly decreased the levels of IFN-gamma and TNF-alpha, but significantly increased the levels of IL-4 and IL-10. The functional results were in line with MLD-STZ effects on the mRNA expression of the cytokines. Moreover, MLD-STZ effects on the TGF-beta1 mRNA expression were reversed to the effects on IFN-gamma and TNF-alpha. The in vitro effects of STZ in islets, in general, were similar to those exerted by MLD-STZ. Apparently, reduction and upregulation of Th2-type cytokines was more associated with susceptibility and resistance, respectively, to MLD-STZ-induced diabetes than upregulation of Th1-type cytokine levels.
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PMID:Differential regulation of Th1-type and Th2-type cytokine profiles in pancreatic islets of C57BL/6 and BALB/c mice by multiple low doses of streptozotocin. 1199 43

3,7-dimethyl-1-(5-oxohexyl) xanthine, pentoxifylline (PTX) is shown to affect cytokine-induced apoptosis in several experimental models and clinical conditions. It had been also shown to prevent insulitis and hyperglycemia in non-obese diabetic (NOD) mice, and mice and rats susceptible to diabetes induction with multiple low-doses of streptozotocin (MLD-STZ). We therefore analysed the development of diabetes and apoptosis of pancreatic beta islet cells in CBA/mice after diabetes induction with MLD-STZ. We have evaluated the effect of PTX on the level of apoptosis in the islet at different time intervals after diabetes induction. Complementary histological and immunohistochemical studies and analyses of the expression of cytokines and nitric oxide have also been done. It was concluded that PTX significantly attenuated apoptosis of the beta-cells in the islet and suppressed the induction of diabetes. Our data are compatible with the notion that interferon-gamma (IFN-gamma)/tumor necrosis factor (TNF)/nitric oxide (NO)-induced apoptosis of beta-cells in experimental diabetes is attenuated by PTX.
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PMID:Downregulation of apoptosis in the target tissue prevents low-dose streptozotocin-induced autoimmune diabetes. 1200 72

We have investigated the immunomodulatory potential of mycophenolate mofetil (MMF) on the development of autoimmune diabetes induced by multiple low doses of streptozotocin (MLD-SZ) in genetically susceptible DA rats. Administration of 25 mg/kg MMF continuously during the 7 weeks of MLD-SZ treatment, or as a 10-day treatment starting together with MLD-SZ (early treatment), or 5 days after the last dose of SZ (late treatment) significantly suppressed the development of hyperglycemia. Ex vivo analyses performed on day 10 after diabetes induction showed that MMF treatment down-regulates adhesive interactions and proliferation of autoreactive spleen cells. Similar effects were observed in vitro when MLD-SZ-derived splenocytes were cultured with an active metabolite of MMF, mycophenolic acid (MPA). These results suggest that the antidiabetogenic effect of MMF involves inhibition of the expansion and migration of autoreactive cells.
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PMID:Antidiabetogenic effect of mycophenolate mofetil is associated with down-regulation of adhesive interactions and autoreactive cell activation. 1202 Oct 95

The purpose of our study was to determine the clinical, angiographic, and procedural variables that predict the risk for 2-year target lesion revascularization (TLR) and other clinical events in a large cohort of patients treated with coronary stenting. Between March 1996 and March 1999, 1,340 patients were prospectively enrolled. They underwent at least one stenting procedure with one of the four coronary stent types used during this time period in our institution: Wiktor-I, Nir, Bard XT, or Tenax. Clinical follow-up was obtained for 99.1% of eligible patients (mean, 19.38 +/- 4.97 months). The overall TLR rate was 10.7% at 24 months. Two variables were independently associated with the long-term outcome: MLD post stenting and stent type. Implantation of silicon carbide-coated stents was associated with a twofold decrease in 24-month TLR (P < 0.01). The major adverse cardiac event rate at 2 years was 20.8%. Multivariate analysis showed that three parameters were predictive: diabetes (P < 0.002), recent onset of symptoms (P < 0.03), and high diffusion of coronary atherosclerosis as assessed by Gensini score (P < 0.0069). In conclusion, stent type, and particularly passive silicon carbide coating, appears to affect the 24-month TLR rate but not other major cardiac events.
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PMID:Does stent design affect the long-term outcome after coronary stenting? 1211 81

Cytokines produced by immune cells infiltrating pancreatic islets have been incriminated as important mediators of beta-cell destruction in insulin-dependent diabetes mellitus. In non insulin-dependent diabetes, cytokines are also associated with impaired beta-cell function in high glucose condition. By the screening of various natural products blocking beta-cell destruction, we have recently found that epigallocatechin gallate (EGCG) can prevent the in vitro destruction of RINm5F cell, an insulinoma cell line, that is induced by cytokines. In that study we suggested that EGCG could prevent cytokine-induced beta-cell destruction by down-regulation of nitric oxide synthase (NOS) through inhibition of NF-kappaB activation. Here, to verify the in vivo antidiabetogenic effect of EGCG, we examined the possibility that EGCG could also prevent the experimental autoimmune diabetes induced by the treatment of multiple low doses of streptozotocin (MLD-STZ), which is recognized as an inducer of type I autoimmune diabetes. Administration of EGCG (100 mg/day/kg for 10 days) during the MLD-STZ induction of diabetes reduced the increase of blood glucose levels caused by MLD-STZ. Ex vivo analysis of beta-islets showed that EGCG downregulates the MLD-STZ-induced expression of inducible NOS (iNOS). In addition, morphological examination showed that EGCG treatment ameliorated the decrease of islet mass induced by MLD-STZ. In combination these results suggest that EGCG could prevent the onset of MLD-STZ-induced diabetes by protecting pancreatic islets. Our results therefore revealed the possible therapeutic value of EGCG for the prevention of diabetes mellitus progression.
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PMID:Epigallocatechin gallate prevents autoimmune diabetes induced by multiple low doses of streptozotocin in mice. 1293 49


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