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)

Interleukin-1 (IL-1) may be a mediator of beta-cell damage in insulin-dependent diabetes mellitus (IDDM). The IL-1 mechanism of action on insulin-producing cells probably includes activation of the transcription nuclear factor kappa B (NF-kappa B), increased transcription of the inducible form of nitric oxide synthase (iNOS) and the subsequent production of nitric oxide (NO). Reactive oxygen intermediates, particularly H2O2, have been proposed as second messengers for NF-kappa B activation. In the present study, we tested whether ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one), a glutathione peroxidase mimicking compound, could counteract the effects of IL-1 beta, H2O2 and alloxan in rat pancreatic islets and in the rat insulinoma cell line RINm5F (RIN cells). Some of these experiments were also reproduced in human pancreatic islets. Ebselen (20 microM) prevented the increase in nitrite production by rat islets exposed to IL-1 beta for 6 hr and induced significant protection against the acute inhibitory effects of alloxan or H2O2 exposure, as judged by the preserved glucose oxidation rates. However, ebselen failed to prevent the increase in nitrite production and the decrease in glucose oxidation and insulin release by rat islets exposed to IL-1 beta for 24 hr. Ebselen prevented the increase in nitrite production by human islets exposed for 14 hr to a combination of cytokines (IL-1 beta, tumor necrosis factor-alpha and interferon-gamma). In RIN cells, ebselen counteracted both the expression of iNOS mRNA and the increase in nitrite production induced by 6 hr exposure to IL-beta but failed to block IL-1 beta-induced iNOS expression following 24 hr exposure to the cytokine. Moreover, ebselen did not prevent IL-1 beta-induced NF-kappa B activation. As a whole, these data indicate that ebselen partially counteracts cytokine-induced NOS activation in pancreatic beta-cells, an effect not associated with inhibition of NF-kappa B activation.
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PMID:Ebselen and cytokine-induced nitric oxide synthase expression in insulin-producing cells. 898 32

The gingival crevicular fluid (GCF) and monocytic secretion of prostaglandin E2 (PGE2) and interleukin 1 beta (IL-1 beta) were measured in a group of 39 insulin-dependent diabetes mellitus (IDDM) patients and 64 systemically healthy individuals. Diabetics were divided into Group A (gingivitis or mild periodontal disease) and Group B (moderate or severe periodontal disease). Diabetics had significantly higher GCF levels of both PGE2 and IL-1 beta as compared to non-diabetic controls who were matched with regard to periodontal disease severity (P < 0.00001 and P = 0.0005, respectively). Within the diabetic population, the GCF levels of these inflammatory mediators were almost 2-fold higher in Group B as compared to Group A (P = 0.01, P = 0.006, respectively for GCF-PGE2 and IL-1 beta). Furthermore, diabetics as a group had a significantly higher monocytic PGE2 and IL-1 beta production in response to various concentrations of both Escherichia coli and Prophyromonas gingivalis lipopolysaccharide (LPS) as compared to non-diabetic patients with adult periodontitis (P = 0.0001). LPS dose-response curves demonstrated that monocytes from Group B diabetics produced approximately 3 times more PGE2 than Group A monocytes; however, there was no significant difference in monocytic IL-1 beta secretion within the IDDM patients. The levels of GCF or monocytic mediators did not correlate with age, race, or glycosylated hemoglobin (HbA1C) levels. Our data suggest that the high GCF and monocytic secretion of PGE2 and IL-1 beta in IDDM patients may be a consequence of a systemic response trait and that the presence of Gram-negative infections such as periodontal diseases may interact synergistically to yield high local levels of these mediators and a more severe periodontal condition.
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PMID:Inflammatory mediator response as a potential risk marker for periodontal diseases in insulin-dependent diabetes mellitus patients. 905 29

Advanced glycation endproducts (AGEs), which result from nonenzymatic reactions of glucose with tissue proteins, have been shown to accumulate on long-lived proteins in advanced aging and diabetes mellitus. Thus, AGEs have been implicated in some of the chronic complications associated with these disorders. In this study, we investigated the effects of the glucose-modified protein on the production of the potent bone resorption factors by cells derived from explants of human bone. AGEs stimulated the release of interleukin-6 (IL-6) in the culture supernatants from the bone-derived cells and increased the levels of IL-6 mRNA in the cells. By contrast, the levels of IL-11 in the culture supernatants were not altered by AGEs, and the other bone resorption factors IL-1 alpha and IL-1 beta were undetectable (< 1.0 pg/ml) either without or with the treatment of AGEs. Electrophoretic mobility-shift assays revealed that the transcription nuclear factor-kappa B, which is critical for the inducible expression of IL-6, was activated in the nuclear extracts from mouse osteoblastic MC3T3-E1 cells treated with AGEs. These results suggest that AGEs are involved in bone remodeling modulation by stimulating IL-6 production in human bone-derived cells.
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PMID:Advanced glycation endproducts stimulate interleukin-6 production by human bone-derived cells. 907 87

The aim of the present study was to examine if the islet donor gender influences the beta-cell sensitivity to possible mediators of beta-cell destruction in insulin-dependent diabetes mellitus (IDDM). We have currently addressed this issue by comparing the action of the cytokine interleukin-1 beta (IL-1 beta) and the alkylating agent streptozotocin (STZ), on isolated pancreatic islets derived from prediabetic female and male nonobese diabetic (NOD) mice. In this mouse strain the females have a much higher incidence of spontaneous IDDM than the males. Pancreatic islets were isolated from female and male mice of the same litter, cultured for 6 days and thereafter either 5-50 U/ml IL-1 beta were added for 48 h or 1.8 mM STZ for 30 min. The cytokine exposure caused a strong increase in the medium insulin accumulation in the cultures of islets obtained from both males and females. The insulin and DNA contents were similar when comparing female and male islets before and after cytokine exposure. The male pancreatic islets exhibited a higher rate of islet glucose oxidation than islets obtained from females after IL-1 beta addition. Non-cytokine treated islets from males showed a higher insulin content compared with corresponding female islets. After IL-1 beta addition male and female islets had a similar inhibition of insulin secretion following stimulation by glucose. On the other hand, islets of both genders were equally sensitive to the inhibitory action of STZ, when studied 6 days after STZ incubation, as assessed by glucose oxidation and insulin release experiments. In conclusion the data of the present study did not demonstrate a clear gender difference in the islet beta-cell sensitivity to immune mediated suppression by IL-1 beta or alkylation damage in IDDM-prone NOD mice. However, it cannot be excluded that in vivo, under the influence of sex hormones, a decisive alteration in beta-cell sensitivity to damage might develop.
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PMID:In vitro response to interleukin-1 beta and streptozotocin in pancreatic islets isolated from male and female nonobese diabetic mice. 913 72

Interleukin-1 (IL-1) is secreted by endothelial cells (ECs) and smooth-muscle cells (SMCs), which are two major component cells of vessels and detected in atherosclerotic lesions. To evaluate the effect of hyperglycemia on the secretion of IL-1 beta in endothelial cells in diabetic patients, we investigated the effects of high glucose and hyperosmolar conditions on the secretion of IL-1 beta from cultured human aortic endothelial cells (HAECs). HAECs were treated with high concentration of glucose or hyperosmolar condition for 3 days. IL-1 beta in the supernatant was measured by high sensitive enzyme-linked immunosorbent assay (ELISA). Under high concentration of glucose (16.6 mmol/L) and hyperosmolar condition (glucose 5.5 mmol/L + mannitol 11.1 mmol/L), the secretion of IL-1 beta was significantly increased (41.0 +/- 2.8 and 26.3 +/- 5.9% increase, respectively, compared with that of 5.5 mmol/L glucose). In conclusion, high glucose and hyperosmolar condition increase the secretion of IL-1 beta in HAECs. The results suggest that diabetic macroangiopathies might be accelerated partly through the increase of IL-1 beta secretion in HAECs.
J Diabetes Complications
PMID:High glucose and hyperosmolarity increase secretion of interleukin-1 beta in cultured human aortic endothelial cells. 917 99

Nitric oxide, induced by pancreatic islet exposure to cytokines, has been implicated in beta-cell destruction in insulin-dependent diabetes mellitus. In this context it could be worthwhile to characterize inhibitors of the nitric oxide generating enzyme. For this purpose rat pancreatic islets were cultured for 48 h in medium supplemented without or with 10, 100 or 500 microM of S-methyl-L-thiocitrulline, in the absence or presence of 25 U/ml of interleukin 1 beta (IL-1 beta). S-methyl-L-thiocitrulline alone did not affect the islet glucose oxidation rate, but all concentrations of S-methyl-L-thiocitrulline prevented IL-1 beta induced suppression of the islet glucose metabolism. Moreover, S-methyl-L-thiocitrulline (100 microM) completely protected against cytokine mediated inhibition of medium insulin accumulation, glucose-stimulated insulin release and (pro)insulin biosynthesis. IL-1 beta caused a more than 10-fold increase in medium nitrite production, an indication of nitric oxide production, which was blocked by S-methyl-L-thiocitrulline. Acutely in the absence of IL-1 beta, islet glucose-stimulated insulin release was enhanced by S-methyl-L-thiocitrulline (100 microM). The efficacy of S-methyl-L-thiocitrulline, NG-monomethyl-L-arginine and aminoguanidine in counteracting IL-1 beta induced nitrite formation was also compared. When estimating the half-maximal inhibitory concentration for this effect, it was approximately 10 microM for S-methyl-L-thiocitrulline and about 1000 microM for NG-monomethyl-L-arginine and aminoguanidine. Next, the efficacy of S-methyl-L-thiocitrulline was tested in an animal model of insulin-dependent diabetes mellitus i.e. multiple low-dose streptozotocin-induced diabetes in male C57BL/Ks mice (40 mg/kg body weight/day for 5 days). It was found that all groups of mice treated with streptozotocin injections gradually developed hyperglycaemia. Administration of S-methyl-L-thiocitrulline (15 mg/kg body weight/day) either for 6-13 days or for 5-11 days after the first STZ injection could not prevent this effect. Moreover, S-methyl-L-thiocitrulline did not appear to influence the evolution of mononuclear cell infiltration and pancreatic insulitis. Thus the present study shows that S-methyl-L-thiocitrulline can potently block cytokine induced activation of nitric oxide synthase in pancreatic islets, but using the presently adopted administration protocol failed to protect against development of insulin-dependent diabetes mellitus in vivo.
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PMID:S-methyl-L-thiocitrulline counteracts interleukin 1 beta induced suppression of pancreatic islet function in vitro, but does not protect against multiple low-dose streptozotocin-induced diabetes in vivo. 919 35

Transplantation of pancreatic islets in alginate polylysine microcapsules is a potential useful method for treating type I diabetes. In this study, the permeability for alginate-polylysine microcapsules to cytokines an immunoglobulines has been investigated by a newly developed method. Magnetic monodisperse polymer particles (Dynabeads) coated with antibodies against selected proteins were encapsulated in 0.7 mm alginate polylysine microcapsules. The capsule membrane permeability to IgG (150 kDa), Transferrin (81 kDa), Tumor necrosis factor (TNF, 51 kDa), Interleukin-1 beta (IL-1 beta, 17.5 kDa), and insulin (5.8 kDa) was estimated by measuring the binding of 125I-labeled proteins to the encapsulated antibody coated Dynabeads. Capsules with an inhomogeneous solid gel core were made of alginates with high guluronic or high mannuronic acid content and poly-L (PLL)- or poly-D-lysine (PDL) of concentrations varied from 0.05-0.2%. The various capsules examined were all impermeable to IgG. The capsules made with a PLL-, but not PDL-membranes were permeable for transferrin. IL-1 beta was found to penetrate all of the different capsule types. The high-G capsules, however, could be made impermeable to TNF and still allowed transferrin to pass. The permeability of these capsules to IL-1 beta, but not to TNF was confirmed in an assay where mouse islets of Langerhans were incubated with TNF and IL-1 beta, and comparing the IL-6 for encapsulated and non-encapsulated islets.
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PMID:Alginate polylysine microcapsules as immune barrier: permeability of cytokines and immunoglobulins over the capsule membrane. 925 12

Nitric oxide is a potent mediator of the cytokine-induced cytotoxic effect on pancreatic beta cells. It has been shown that the inducible nitric oxide synthase (iNOS) is induced in islets of Langerhans by interleukin-1 beta (IL-1 beta). Interferon regulatory factor-1 (IRF-1), a transcriptional factor known to play an essential role in the induction of the inducible nitric oxide synthase, has also been shown to be induced by IL-1 beta in isolated islets of Langerhans. In the present study we analysed a GT nucleotide repeat polymorphism in the intron 7 of the IRF-1 gene. We typed 123 Danish Caucasian insulin-dependent diabetes mellitus (IDDM) multiplex families (550 individuals including 271 diabetic patients) and 108 control subjects of Danish Caucasian origin. In total, seven alleles were identified. No significant differences in either allele or genotype distribution were found comparing IDDM patients with control subjects (P = 0.7 and P = 0.5, respectively). An extended transmission disequilibrium test (ETDT) did not reveal transmission disequilibrium in an allele-wise manner. A 16-nucleotide deletion was found when sequencing the region containing the polymorphic GT repeat. This new deletion was in linkage disequilibrium with the GT-repeat polymorphism, as it was only seen with alleles of more than 13 GT tandem repeats. No association with IDDM for the deletion was observed. Furthermore, three single base substitutions linked to the 16 nucleotide deletion were identified. Even though we could not associate the GT-repeat polymorphism to IDDM in this study, additional mutation screening is warranted, as we still think the IRF-1 gene is a potential candidate gene for IDDM.
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PMID:No association or linkage to IDDM of an interferon regulatory factor-1 gene polymorphism in a Danish population. The Danish Study Group for Diabetes in Childhood. 944 5

Periodontitis is a chronic inflammatory disease characterized by a progression that is very much dependent on host response. The gingiva can be considered to be in a constant state of wounding (pathologic wounding by bacterial plaque) and a constant state of maintenance/repair. In this context, any metabolic disturbance in the host which compromises tissue repair/wound healing will exacerbate the progression of periodontitis. Diabetes presents an interesting example because two major complications of diabetes are delayed wound healing and periodontitis. Our previous studies indicate that delayed wound healing and periodontitis may be manifestations of a general systemic deficit in diabetes involving alteration of macrophage cytokine gene expression. The present study was designed to determine whether: 1) diabetes-induced metabolic alterations affect gingival cytokine levels; and 2) diabetes-induced metabolic alterations modify the gingival cytokine profile in periodontitis. Sprague-Dawley rats (N=12/group) were injected with streptozotocin (65 mg/kg) into the tail vein to induce diabetes (defined by blood glucose levels > 250 mg/dl) or received the injection vehicle or no treatment as controls. Periodontitis was induced in additional groups of diabetic and control rats by gavage with Porphyromonas gingivalis A7436. After 90 days, serum glucose was analyzed to document diabetes; alveolar bone level was measured to document severity of periodontitis; gingiva was harvested circumferentially from the first and second molars; and cytokines in gingival homogenates were assayed by ELISA using commercial kits. Cytokine levels were expressed as mean+/-SEM pg/microg protein. Diabetes alone did not alter the gingival cytokine profile for platelet-derived growth factor B (PDGF-B), interleukin 1-beta (IL-1beta), transforming growth factor-beta (TGF-beta), and tumor necrosis factor-alpha (TNF-alpha). Periodontitis alone demonstrated a significant increase (P < 0.05) in levels of PDGF-B and IL-1beta. Diabetes superimposed on periodontitis prevented these increases. Thus, diabetes-induced metabolic alterations do not affect gingival cytokine levels per se; however, they do alter the normal host response to periodontitis through blockage of periodontitis-induced increases in PDGF-B and IL-1beta.
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PMID:Diabetes prevents periodontitis-induced increases in gingival platelet derived growth factor-B and interleukin 1-beta in a rat model. 952 9

When aiming at preventing IDDM in man, knowledge of the molecular mechanisms leading to beta cell destruction may facilitate identification of new possible intervention modalities. A model of IDDM pathogenesis in man suggests that cytokines, and IL-1 in particular, are of major importance in the initial events (Nerup et al 1994) (Fig. 1). In vitro rat experiments demonstrated that rhIL-1 beta inhibits beta cell function and induces beta cell death both in isolated islets of Langerhans and in the isolated perfused pancreatic gland. With the long term goal of identifying new modalities capable of preventing IDDM in man, the aim af this review was to investigate the effects of rhIL-1 beta on beta-cell function and viability in normal rats. This review discussed 1) the pharmacokinetics of IL-1 beta in rats as the basis for choice of route of administration and dose of rhIL-1 beta, 2) the effects and molecular mechanisms of IL-1 beta on temperature and food intake used as control parameters for successful injection of rhIL-1 beta in rats, 3) the effects of one or more injection of IL-1 beta on rat beta cell function, 4) the molecular mechanisms leading to IL-1 beta induced beta cell inhibition in vivo, and some possible intervention modalities based on the molecular mechanisms, 5) the effects of IL-1 beta on spontaneous diabetes mellitus in DP BB rats, and 6) the effects and molecular mechanisms of IL-1 beta induced inhibition of thyroid epithelial cell function and aggravated thyroiditis in DP BB rats, compared to the effects of IL-1 beta on rat beta cell function. Finally, this review discussed the effects of IL-1 beta on human beta cells in vitro, and the clinical relevance of these experiments, with special reference to a clinical trial with the aim of preventing IDDM in man. The pharmacokinetic studies suggested that IL-1 beta is distributed according to a two-compartment model with a first-order elimination. Interleukin-1 beta reached all the investigated organs in the rats, was accumulated in kidneys and was excreted in the urine. The data suggested that IL-1 beta also accumulated in the islets of Langerhans. After injection of 4.0 micrograms/kg pathophysiologically relevant concentrations of rhIL-1 beta were reached and intact rhIL-1 beta persisted for up to 5 hrs in plasma. Peripheral injections of IL-1 beta dose-dependently induced fever and anorexia in rats, probably via induction of PGE2 in the brain or in peripheral tissues thereafter passing the blood-brain barrier. Nitric oxide produced by cNOS seems to be a molecular mediator of IL-1 beta induced fever but not of anorexia. Fever and anorexia are well described effects of IL-1 beta in rats, and are as such usefull control parameters of the absorption and biological activity of IL-1 beta after peripheral injection. Injections of rhIL-1 beta to normal, non-diabetes prone rats induced initial beta cell stimulation followed by inhibition, in accordance with in vitro data. Furthermore, induction of peripheral insulin resistance coincided with beta cell inhibition after one daily injection for 5 days, leading to a transient diabetes mellitus-like state, characterized by hyperglycemia and hypoinsulinemia. At this time point, electron-microscopy did not demonstrate beta cell destruction. However, IL-1 beta induced intercellularly edema and microvillous processes on the beta cells, which might be early evidence of apoptosis. The diabetes mellitus-like state was not aggravated if the daily injections were continued beyond 5 days. Daily injections of rhIL-1 beta for 2 to 4 weeks induced formation of blocking IL-1 beta-antibodies in normal rats. Hence, injections exceeding 2 weeks should only be performed using species homologous IL-1 beta. The molecular mechanism of IL-1 beta induced beta cell inhibition in rats in vivo as in vitro, are likely to involve binding of IL-1 beta to the IL-1RtI, since the IL-1RtII is considered to be a decoy receptor. (ABSTRACT TRUNCATED)
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PMID:Interleukin-1 beta induced transient diabetes mellitus in rats. A model of the initial events in the pathogenesis of insulin-dependent diabetes mellitus? 958 1


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