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)

Previous work has shown that interleukin-1beta (IL-1beta) alters protein expression in beta-cells. This alteration is associated with cell death in isolated rat islets but not in isolated rat beta-cells. We examined whether IL-1beta pretreatment of isolated beta-cells influences their sensitivity to toxic agents. After a 24-h culture with IL-1beta (30 U/ml), beta-cells exhibited a lower expression of the beta-cell-specific protein transcription factor pancreatic and duodenal homeobox gene (PDX)-1, glucose transporter GLUT2, and proinsulin convertase PC2, with a marked reduction (60-70%) in glucose-induced insulin production and selective sensitivity to the toxins alloxan (ALX) and streptozotocin (STZ). On the other hand, the cells presented an increased expression of Mn-superoxide dismutase, heat shock protein 70, inducible heme oxygenase, and inducible nitrite oxide synthase. This IL-1beta-induced alteration in beta-cell phenotype resulted in a reduced cellular sensitivity to the beta-cell-specific toxins ALX and STZ; the production of nontoxic conditions of nitric oxide (NO) also rendered the cells less susceptible to radical-induced damage. Exposure to IL-1beta can thus protect beta-cells against conditions that cause necrosis; however, it did not protect against apoptosis induced by the additional presence of interferon-gamma or tumor necrosis factor-alpha. Release of IL-1beta in the endocrine pancreas is thus not necessarily the cause of massive NO-dependent beta-cell destruction. On the contrary, IL-1beta may protect these cells against necrosis, though with a loss of their characteristic phenotype and homeostatic functions.
Diabetes 2000 Mar
PMID:Interleukin-1beta-induced alteration in a beta-cell phenotype can reduce cellular sensitivity to conditions that cause necrosis but not to cytokine-induced apoptosis. 1086 54

In this study, the anti-inflammatory actions of the peroxisome proliferator-activated receptor (PPAR)-gamma agonists 15-deoxy-delta 12,14-prostaglandin J2 (15-d-delta 12,14-PGJ2) and troglitazone have been examined. Treatment of RAW 264.7 cells and CD-1 mouse peritoneal macrophages with lipopolysaccharide (LPS) + interferon-gamma (IFN-gamma) results in inducible nitric oxide synthase (iNOS), inducible cyclooxygenase (COX-2) and interleukin-1 (IL-1) expression, increased production of nitric oxide, and the release of IL-1. In a concentration-dependent manner, 15-d-delta 12,14-PGJ2 inhibits each of these proinflammatory actions of LPS + IFN-gamma, with half-maximal inhibition at approximately 0.5 microg/ml and complete inhibition at 1-5 microg/ml. The inhibitory actions of 15-d-delta 12,14-PGJ2 on LPS + IFN-gamma-induced inflammatory events are not associated with the inhibition of iNOS enzymatic activity or macrophage cell death, but appear to result from an inhibition of iNOS and IL-1 transcription. In addition, the anti-inflammatory actions of 15-d-delta 12,14-PGJ2 are not limited to peritoneal macrophages, as 15-d-delta 12,14-PGJ2 prevents TNF-alpha + LPS-induced resident islet macrophage expression of IL-1beta and beta-cell expression of iNOS stimulated by the local release of IL-1 in rat islets. 15-d-delta 12,14-PGJ2 appears to be approximately 10-fold more effective at inhibiting resident islet macrophage activation (in response to TNF + LPS) than IL-1-induced nitrite production by beta-cells. Two mechanisms appear to be associated with the antiinflammatory actions of both 15-d-delta 12,14-PGJ2 and troglitazone: 1) the direct inhibition of cytokine- and endotoxin-stimulated iNOS and IL-1 transcription; and 2) the inhibition of IL-1 signaling, an event associated with PPAR-gamma agonist-induced activation of the heat shock response (as assayed by heat shock protein 70 expression). These findings indicate that the PPAR-gamma agonists, troglitazone and the J series of prostaglandins, are potent anti-inflammatory agents that prevent cytokine- and endotoxin-stimulated activation of peripheral and resident tissue macrophages and cytokine-induced iNOS expression by beta-cells by the inhibition of transcriptional activation and induction of the heat shock response.
Diabetes 2000 Mar
PMID:Anti-inflammatory actions of 15-deoxy-delta 12,14-prostaglandin J2 and troglitazone: evidence for heat shock-dependent and -independent inhibition of cytokine-induced inducible nitric oxide synthase expression. 1086 55

Type 1 diabetes is an autoimmune disease leading to extensive destruction of the pancreatic beta-cells. Our research focusses on the role of beta-cells during the course of the disease, aiming at finding novel strategies to enhance beta-cell resistance against the cytotoxic damage inflicted by the immune system. Special attention has been paid to the possibility that cytokines released by the immune cells infiltrating the pancreatic islets can directly suppress and kill beta-cells. Certain cytokines (interleukin-1beta, tumor necrosis factor-alpha and interferon-gamma) either alone or in combination, are able to activate signal transduction pathways in beta-cells leading to transcription factor activation and de novo gene expression. In this context, it has been found that induction of inducible nitric oxide synthase mediates an elevated production of nitric oxide, which impairs mitochondrial function and causes DNA damage eventually leading to apoptosis and necrosis. However, other induced proteins SUCH AS heat shock protein 70 and superoxide dismutase may reflect a defense reaction elicited in the beta-cells by the cytokines. Our strategy is to further seek for proteins involved in both destruction and protection of beta-cells. Based on this knowledge, we plan to apply gene therapeutic approaches to increase expression of protective genes in beta-cells. If this is feasible we will then evaluate the function and survival of such modified beta-cells in animal models of type 1 diabetes such as the NOD mouse. The long-term goal for this research line is to find novel approaches to influence beta-cell resistance in humans at risk of developing type 1 diabetes.
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PMID:Novel experimental strategies to prevent the development of type 1 diabetes mellitus. 1109 3

Accumulating evidence indicates that oxidative modification of low-density lipoprotein (LDL) plays an important role in vascular dysfunction associated with diabetes mellitus. The aim of the present study was to investigate the effect of gliclazide, a second-generation sulfonylurea with free-radical-scavenging activity, on human aortic smooth muscle cell (HASMC)-mediated LDL oxidation and HASMC dysfunction induced by oxidatively modified LDL. Incubation of HASMCs with native human LDL (100 microg/mL) in the presence of increasing concentrations of gliclazide (1 to 10 microg/mL) resulted in a dose-dependent decrease in HASMC-mediated LDL oxidation. Exposure of HASMCs to gliclazide (1 to 10 microg/mL) and native LDL (100 microg/mL) also led to a dose-dependent decrease in oxidized LDL-induced human monocyte adhesion to HASMCs. In addition, incubation of HASMCs with gliclazide dramatically reduced the ability of oxidized LDL to stimulate the proliferation of these cells. Finally, treatment of HASMCs with gliclazide resulted in a marked decrease in oxidatively modified LDL-induced monocyte chemoattractant protein (MCP)-1 and human heat shock protein 70 (hsp 70) expression, both at the gene and protein levels. These results show that gliclazide, at concentrations in the therapeutic range (5 to 10 microg/mL), is effective in vitro in reducing vascular smooth muscle cell (VSMC) dysfunction induced by oxidatively modified LDL. These observations suggest that administration of gliclazide to type 2 diabetic patients could form part of the strategy for the prevention and management of diabetic cardiovascular diseases.
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PMID:Gliclazide decreases vascular smooth muscle cell dysfunction induced by cell-mediated oxidized low-density lipoprotein. 1139 46

Stress proteins (heat shock proteins, HSP) play essential roles in folding, assembly and translocation of polypeptides and also in maintenance of the integrity of polypeptides as molecular chaperones. Since long-lasting hyperglycemia causes modification of cellular proteins, it is possible that expression of molecular chaperones may be altered during the course of diabetes. Here, we examined the cellular levels of stress proteins such as HSP105, HSP90 and HSC70/HSP70 in various tissues of streptozotocin-induced diabetic rats. In comparison to controls, the levels of HSC70 were markedly decreased in the liver but not in the brain, adrenal gland and pancreas of diabetic rats. The levels of HSP105 and HSP90 were not significantly changed in these tissues of diabetic rats. Furthermore, the induction of HSP70 as well as HSC70 by hyperthermia was significantly reduced in the liver and adrenal gland of diabetic rats. These results suggested that the expression and induction of HSC70/HSP70 may be altered during the course of diabetic disease and may result in impairment of the cytoprotective ability of diabetic rats.
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PMID:Characteristic changes of stress protein expression in streptozotocin-induced diabetic rats. 1171 64

Hypertrophy is one mechanism of pancreatic beta-cell growth and is seen as an important compensatory response to insulin resistance. We hypothesized that the induction of protective genes contributes to the survival of enlarged (hypertrophied) beta-cells. Here, we evaluated changes in stress gene expression that accompany beta-cell hypertrophy in islets from hyperglycemic rats 4 weeks after partial pancreatectomy (Px). A variety of protective genes were upregulated, with markedly increased expression of the antioxidant genes heme oxygenase-1 and glutathione peroxidase and the antiapoptotic gene A20. Cu/Zn-superoxide dismutase (SOD) and Mn-SOD were modestly induced, and Bcl-2 was modestly reduced; however, several other stress genes (catalase, heat shock protein 70, and p53) were unaltered. The increases in mRNA levels corresponded to the degree of hyperglycemia and were reversed in Px rats by 2-week treatment with phlorizin (treatment that normalized hyperglycemia), strongly suggesting the specificity of hyperglycemia in eliciting the response. Hyperglycemia in Px rats also led to activation of nuclear factor-kappaB in islets. The profound change in beta-cell phenotype of hyperglycemic Px rats resulted in a reduced sensitivity to the beta-cell toxin streptozotocin. Sensitivity to the toxin was restored, along with the beta-cell phenotype, in islets from phlorizin-treated Px rats. Furthermore, beta-cells of Px rats were not vulnerable to apoptosis when further challenged in vivo with dexamethasone, which increases insulin resistance. In conclusion, beta-cell adaptation to chronic hyperglycemia and, hence, increased insulin demand is accompanied by the induction of protective stress genes that may contribute to the survival of hypertrophied beta-cells.
Diabetes 2002 Feb
PMID:Increased expression of antioxidant and antiapoptotic genes in islets that may contribute to beta-cell survival during chronic hyperglycemia. 1181 49

Insulin-dependent diabetes mellitus (IDDM) is positively associated with HLA-DQ8, DQ2, and DQ6 (B*0604) and negatively with DQ6 (B*0602). The mechanisms by which the DQ molecules control the development of IDDM is not known. DQ6 (B*0602) and DQ6 (B*0604) molecules share the same DQalpha chain but differ in the beta chain by six residues at positions 9, 30, 57, 70, 86, and 87. The aim of the study was to sequence the peptides eluted from both DQ6 molecules and to determine the binding motifs and construct peptides for docking them into the DQ6 peptide binding groove by molecular modeling. EBV transformed B cell line homozygous for DQ6 and hybridoma cell line secreting DQ6 specific antibody were grown in large-scale culture. The DQ6 molecules were precipitated with solid-phase bound antibodies specific for DQ6. The dissociation of peptides from MHC was done with ultrafiltration and separation of peptides by reversed-phase HPLC, using Edman degradation. A special application of Edman degradation is pool sequencing. This approach allowed us to determine common characteristics of all peptides associated with a given MHC molecule. The precipitation of DQ6 molecules and the peptide elution were done successfully. The sequencing of the peptides from DQ6 (B*0602) identified three fractions: (1) IINEPTAAAIAYGLD (Bovine HSP70), (2) IINEPTAAAIAGLDR (Human HSP70), and (3) NPRDAKACVVHGSDLK (Na+/K+ ATPase). Peptide eluted from DQ6 (B*0604) had a sequence ADLFRGTLDPVEK with sequence homology to HSP70 (residues 307-319). We were able to predict the motifs for DQ6 from the ligands eluted. We used molecular modeling as a tool to identify plausible binding motifs for peptides. Our studies show that peptide ADLFRGTLDPVEK and NPRDAKACVVHGSDLK fit well in the respective DQ6 binding grooves. These predicted motifs should then be useful for screening of autoantigens associated with diabetes and identifying the epitopes that are likely to interact with T cells.
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PMID:Molecular modeling of eluted peptides from DQ6 molecules (DQB1*0602 and DQB1*0604) negatively and positively associated with type 1 diabetes. 1202 Nov 32

Protective and/or repair mechanisms are thought to be activated in pancreatic beta cells in response to injury during insulitis. Manifestation of type-1 diabetes may depend on an imbalance between beta cell damage and repair. To prove this hypothesis, the ability of collagenase-isolated islets to respond to heat stress depending on the age of BB rats was investigated. The islets were exposed either to 44 degrees C (HS) or 37 degrees C (control) for 30 min and then kept at 37 degrees C for 5 h. Immediately and 5 h after heat shock, insulin secretion in response to 20 mmol/l glucose and total protein synthesis of heat-exposed islets were significantly diminished as compared with controls. The islet proteins were separated by SDS-PAGE followed by immunoblotting. Islets from BB rats at an age of 6-90 days responded to heat shock with the expression of major heat shock protein 70 (HSP 70). Islets from 3-day old rats, however, did not respond with induction of HSP 70. In contrast we could detect inducible HSP 70 in islets from 3-day old diabetes-resistant LEW rats. In islets from 90-day old BB rats we observed a decreased amount of HSP 70 compared with islets from 9-, 12-, 30- and 60-day old animals. There was also a higher extent of HSP 70 to observe in islets from 90-day old LEW rats as compared with 90-day old BB rats. Differences in HSP 70 expression between islets of 3-day old BB and LEW rats and other age groups of BB rats might represent distinct stages of maturation of islets whereas diminished expression of HSP 70 in islets of 90-day old BB rats at the age of high probability of developing diabetes might result from reduced ability to induce protective mechanisms.
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PMID:Stress response of pancreatic islets from diabetes prone BB rats of different age. 1256 19

We studied T-cell proliferative responses (stimulation index: SI) and autoantibodies to human HSP60, HSP70 and HSP90 proteins in 25 children (mean age 10.1+/-3.8 years) newly diagnosed with Type 1 diabetes. The control group for T cells included 25 adults and three pediatric donors without Type 1 diabetes. Controls for antibodies included 10 pediatric subjects. The T-cell responses to HSP70 of the test group (mean SI=4.5+/-3.1) were significantly greater than those of the control group (meanSI=1.4+/-0.6; p<0.0001); the incidence of HSP70 responders was (85%) compared to 14% in the control group. All but three of the Type 1 children who responded to HSP70 also responded to HSP60 (85%). The T-cell responses of the Type 1 group to HSP90 (mean SI=1.7+/-1.1) were similar to those of the control group (mean SI=1.5+/-0.7). We mapped HSP70 epitopes recognized by T cells in seven subjects using overlapping peptides of the molecule. Among the Type 1 subjects, IgG seropositivity was 45% to HSP60, 30% to HSP70, and 15% to HSP90. Thus, we conclude that children with newly diagnosed Type 1 diabetes manifest heightened T-cell autoimmunity to HSP70 and HSP60, but not to HSP90.
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PMID:T cells and autoantibodies to human HSP70 in type 1 diabetes in children. 1279 17

Gastric mucosa of diabetic rats is highly vulnerable to acute injury, but little is known about the influence of diabetic conditions on the healing of gastric ulcers. In this study, streptozotocin (70 mg/kg injected intraperitoneally) was used to induce diabetes mellitus in rats. Four weeks after streptozotocin injection, gastric ulcers were induced using the acetic acid method, and 10 days later, the healing rate and the gastric blood flow (GBF) were measured by planimetry and hydrogen (H(2))-gas clearance method, respectively. Six major groups of rats with gastric ulcers were used: (1) vehicle (saline); (2) streptozotocin alone; (3) insulin (4 IU/day intraperitoneally); (4) streptozotocin plus insulin; (5) pentoxifylline, an inhibitor of synthesis and release of tumor necrosis factor-alpha (TNF alpha); and (6) aspirin, a non-selective inhibitor of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), and rofecoxib, the highly selective COX-2. In the diabetic rats, a significant delay in ulcer healing ( approximately by 300%), accompanied by a decrease in the gastric mucosal blood flow was observed. The prolongation of the healing in diabetic animals was associated with an increase in gastric mucosal expression and release of TNFalpha, interleukin-1 beta (IL-1 beta), suppression of the vascular endothelial growth factor (VEGF), platelet endothelial cell adhesion molecule-1 (PECAM-1) and the mucosal overexpression of heat shock protein 70 (HSP 70). Administration of insulin reversed the delay in ulcer healing and significantly decreased the expression of IL-1 beta and TNF-alpha, while producing the rise in the expression of VEGF and PECAM. Pentoxifylline, an inhibitor of TNF-alpha, which by itself accelerated ulcer healing in non-diabetic rats, counteracted the increase in the area of gastric ulcer induced by streptozotocin, raised significantly gastric blood flow and suppressed the plasma TNF-alpha levels. Aspirin and rofecoxib, that significantly suppressed the mucosal prostaglandin E(2) generation in ulcer area, delayed significantly the rate of ulcer healing and decreased the GBF at ulcer margin in non-diabetic rats, and these changes were significantly augmented in diabetic animals. We conclude that: (1) Experimental diabetes dramatically impairs ulcer healing, depending upon the increased release of proinflammatory cytokines and the attenuation of angiogenesis that can limit the ulcer healing effects of locally produced HSP 70 and TNF-alpha. (2) Insulin reversed this impairment of ulcer healing in diabetic rats, mainly due to the enhancement of angiogenesis and reduction in expression of cytokines in the ulcer area. (3) Classic non-steroidal anti-inflammatory drugs such as aspirin prolonged ulcer healing under diabetic conditions due to suppression of endogenous prostaglandins and the fall in the microcirculation at the ulcer margin and these effects were mimicked by selective, so called "safe" COX-2 inhibitor, rofecoxib, suggesting that both COX isoforms are important sources of prostaglandins that are essential in the ulcer healing in diabetes.
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PMID:Impaired gastric ulcer healing in diabetic rats: role of heat shock protein, growth factors, prostaglandins and proinflammatory cytokines. 1464 93


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