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

The Biobreeding Worcester rat provides one of the best models of autoimmune diabetes. Immunopathologic studies of acute diabetes show that the islets are infiltrated by T cells and macrophages. It has been hypothesized that the islets are damaged by the secretion of cytokines such as IL-1 and TNF-alpha and that their function may be altered by IL-6. In this study, we utilized in situ hybridization to determine the expression of the IL-1, TNF, and IL-6 genes within the pancreas of the acute diabetic Biobreeding Worcester rat. These studies showed that cells expressing IL-1, TNF, and IL-6 were present within the islets and in the exocrine pancreas surrounding islets, ducts, and vessels and in an interstitial location. Cells expressing TNF and IL-1 mRNA were present in about 20% of the islets, whereas cells expressing IL-6 were present in about 4% of the islets. Islets containing TNF- or IL-1-positive cells contained about three positive cells per islet whereas only about one IL-6-positive cell was present per islet. In 26% of the islets peri-insular TNF-positive cells were found. Peri-insular IL-1 positive cells were seen in 14% of the islets and 8% showed peri-insular IL-6 positive cells. In nondiabetic 30-day old DP or 90-day-old DR rats intra-islet cytokine gene expression was not seen. Our studies support the view that cytokines are important in beta cell destruction.
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PMID:Cytokine gene expression in the islets of the diabetic Biobreeding/Worcester rat. 201 34

Previous in vitro findings suggest the involvement of interleukin 1 (IL-1) in the pathogenesis of insulin-dependent diabetes mellitus. The aims of the present study were to investigate the effects of single or repeated ip injections of recombinant IL-1 beta on blood glucose and glucose tolerance in vivo. Normal Wistar Kyoto rats were injected ip with a single injection of 4 micrograms/kg of the mature form of recombinant IL-1 beta (amino acids 117-269) or once daily on 5 consecutive days. Control rats were given vehicle and were fed ad libitum or pair-fed together with the rIL-1 beta treated rats. An ip glucose tolerance test (0.2 g D-glucose/100 g) was performed 2 h after injection of rIL-1 beta. A single injection of rIL-1 beta caused a mild depression in blood glucose and an improved glucose tolerance. Multiple injections of rIL-1 beta induced a diminished weight gain, a 24-28% reduction in food intake, a lasting mild depression of blood glucose (7 days) and a transiently impaired glucose tolerance on day 5. We conclude that systemic IL-1 should be considered an important regulator of glucose homeostasis in vivo.
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PMID:Repeated intraperitoneal injections of interleukin 1 beta induce glucose intolerance in normal rats. 203 44

It has been postulated that one of the factors causing immune-mediated pancreatic beta-cell destruction in insulin-dependent diabetes mellitus (IDDM) is interleukin-1 (IL-1). Rat pancreatic islets exposed to human recombinant IL-1 beta (rIL-1 beta) for 48 h in vitro exhibit a markedly reduced glucose-stimulated insulin secretion. Also, a deleterious effect of glucose on beta-cell function, especially under conditions of a reduced beta-cell mass, which may exist in the early phase of IDDM has been suggested. In this study the response of rat pancreatic islets in vitro to a combination of the cytokine and high glucose concentration have therefore been assessed. Thus, islets were cultured for 48 h at either 11.1 or 56 mM glucose with or without 25 U/ml rIL-1 beta. Exposure to the cytokine reduced the islet DNA content at both glucose concentrations by 20-25%. In short-term incubations in the absence of rIL-1 beta after the preceding culture with the cytokine, the glucose-stimulated insulin release was reduced by 70% in islets cultured at 11.1 mM glucose and by only 40% after culture at 56 mM glucose, when compared to the corresponding control islets. The utilization of D-[5-3H]glucose, i.e., the catabolism of glucose in the glycolytic pathway, was the same in all groups of islets. However, the D-[6-14C]glucose oxidation rate, i.e., the metabolism of glucose in the Krebs cycle, was reduced by about 65% in rIL-1 beta exposed islets kept at 11.1 mM glucose and 46% in islets cultured at 56 mM glucose.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Metabolism and beta-cell function of rat pancreatic islets exposed to human interleukin-1 beta in the presence of a high glucose concentration. 208 53

Interleukin-1 (IL-1) may be one of the effector molecules involved in the destruction of the pancreatic islet B cells resulting in insulin-dependent diabetes mellitus. Isolated islets exposed to IL-1 show an acutely increased substrate metabolism and insulin release, which is followed by a metabolic and functional suppression. Since an increased cellular uptake of calcium in the islets may be associated with both nutrient-induced insulin release and cell damage, the effects of recombinant IL-1 beta (rIL-beta) on net cellular calcium uptake by isolated rat pancreatic islets were investigated. In short-term experiments the islets were exposed to 25 U/ml rIL-1 beta for 120 min in the presence of 1.7 mM or 16.7 mM glucose, or 16.7 mM glucose plus 5 mM verapamil. In these experiments rIL-1 beta induced an increase both in net cellular uptake of calcium and in insulin release only in the presence of 16.7 mM glucose. The stimulatory effect of rIL-1 beta at 16.7 mM glucose was blocked by verapamil. By long-term experiments, under tissue culture conditions in the presence of 11.1 mM glucose, islet net calcium uptake, insulin release and glucose oxidation were measured at different time points over a 24-h period. During the first 2 h of incubation 25 U/ml rIL-1 beta effected a significant increase of net calcium uptake, insulin release and glucose oxidation. However, after 4-5 h of incubation with the cytokine no such stimulatory effects were seen. After longer incubations with rIL-1 beta all the islet functions studied were suppressed.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Short-term exposure of rat pancreatic islets to human interleukin-1 beta increases cellular uptake of calcium. 208 54

Previous studies have demonstrated a stimulatory effect of interleukin-1 beta (IL-1 beta) on insulin and glucagon release from the perfused rat pancreas, accompanied by selective lysis of 20% of beta-cells as assessed by electronmicroscopy. However, we have not observed an inhibitory action of IL-1 beta on insulin release from the perfused pancreas as shown for isolated islets. To test whether periodical exposure of the endocrine pancreas to circulating IL-1 beta in vivo affects insulin release from the intact perfused pancreas, rats were treated with daily intraperitoneal injections of 4 micrograms IL-1 beta/kg or saline for 5 days. On day 5 the pancreata were isolated 2 h after the last injection and perfused from 0 to 72 min with 11 mmol/l D-glucose and from 72 to 84 min with 20 mmol/l D-glucose. Saline or IL-1 beta was added from 12 to 72 min. In pancreata from animals pre-treated with IL-1 beta glucose-stimulated as well as IL-1 beta potentiated glucose-stimulated insulin release was almost completely abolished. Furthermore, a decline in insulin release was observed at 11 mmol/l D-glucose, in contrast to an increase in insulin release in controls. The total extractable insulin content in pancreata from IL-1 beta pre-treated rats was higher than in pancreata from saline-treated controls. In contrast to the inhibitory effect of in vivo administration of IL-1 beta on beta-cell function glucagon secretion was stimulated. These observations suggest that circulating IL-1 beta is an important modulator of alpha- and beta-cell secretory function in vivo and that IL-1 beta should be considered a contributory pathogenetic factor in the development of insulin-dependent (type 1) diabetes mellitus.
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PMID:Intra-peritoneal administration of interleukin-1 beta induces impaired insulin release from the perfused rat pancreas. 210 5

The effect of the cytokine interleukin-1 beta on the insulin secretory responsiveness of single beta-cells (HIT-T15) was investigated. In the short-term, IL-1 beta induced a dosage-dependent stimulation of insulin release. In contrast, in the long-term, IL-1 beta, inhibited both basal and secretagogue-stimulated insulin secretion. We also demonstrate the simultaneous presence of specific high and low affinity binding sites for IL-1 beta on beta-cells. IL-1 beta, which has been implicated in the pathogenesis of insulin-dependent diabetes, may therefore mediate its opposing effects on beta-cells through a specific plasma membrane receptor.
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PMID:Insulin-secreting beta-cells possess specific receptors for interleukin-1 beta. 213 89

Interleukin-1 beta (IL-1 beta) has been implicated in the pathogenesis of insulin-dependent diabetes mellitus. In the present study we have investigated the effects of IL-1 beta on glucose metabolism in clonal HIT-T15 beta cells. In the short-term (1 h), 25 U/ml IL-1 beta significantly increased the rates of insulin release and glucose utilisation, but not glucose oxidation. In contrast, after 48 h, IL-1 beta inhibited insulin release and glucose utilisation and oxidation. By assaying enzymes (hexokinase, glucokinase, pyruvate dehydrogenase, glucose 6-phosphatase) and nucleotides (ATP, ADP) associated with the regulation of glycolysis and glucose oxidation, we conclude that the inhibitory effects of IL-1 beta may be due to impaired glucokinase activity.
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PMID:Interleukin-1 beta inhibits glucokinase activity in clonal HIT-T15 beta-cells. 219 15

Long term effects of in vivo treatment with human rIL-1 beta on diabetogenesis and thyroid disease were determined in the Biobreeding rat. Administration of high dose (10 micrograms/kg) IL-1 beta accelerated the onset of insulin-dependent diabetes mellitus compared to saline-injected controls. High dose treatment resulted in goiter development, pronounced LT, reduced serum T4 levels, and overall growth reduction. In contrast, low dose IL-1 beta (0.5 microgram/kg) administration significantly reduced the frequency of insulin-dependent diabetes mellitus (48%) compared to placebo (86%) and high dose IL-1 beta (93%) treatment groups. Rats protected by low dose IL-1 beta had unaffected growth rates and minimal to no pancreatic and thyroid pathology. Our results demonstrate that exogenous administration of IL-1 beta modulates Biobreeding rat idiopathic autoimmune diabetes and thyroid disease in a dose-dependent manner.
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PMID:IL-1 beta modulation of spontaneous autoimmune diabetes and thyroiditis in the BB rat. 233 31

Recently it has been postulated that interleukin-1 (IL-1) locally released by infiltrating mononuclear cells may destroy the pancreatic B cells during the development of insulin-dependent diabetes mellitus. Since IL-1 is a potent inducer of interleukin-6 (IL-6) in various cells, it is conceivable that IL-6 is a second mediator of the IL-1 action. In the present study the effects of IL-6 alone or in combination with IL-1 were studied on pancreatic islet function in vitro after tissue culture and compared with the effects observed after exposure to IL-1 only. Rat pancreatic islets were cultured in medium RPMI 1640 + 10% calf serum with or without the addition of human recombinant IL-6 (500-5000 pg/ml) for 48 h. The medium insulin accumulation was increased by 40-50% after culture with 500-2000 pg/ml IL-6, but was similar to the controls at 5000 pg/ml. When islets were cultured for 18 h only, also 5000 pg/ml IL-6 stimulated the medium insulin accumulation. IL-6 did not affect the islet insulin content and the rates of islet (pro)insulin and total protein biosynthesis. It inconsistently decreased the islet DNA content. In short-term experiments after 48-h culture with IL-6, there was a dose-dependent inhibition of the glucose-stimulated insulin release. On the other hand, islets cultured with IL-6 (5000 pg/ml) exhibited an elevated glucose oxidation and oxygen uptake, but a lower ATP content at 16.7 mM glucose and an unaffected glucose utilization and glutamine oxidation compared to the controls. This raises the possibility that IL-6 had induced a condition with an increased energy expenditure, resulting in an enhanced mitochondrial metabolism of glucose. Islets cultured with human recombinant IL-1 beta (25 units/ml) showed a strong inhibition of the insulin accumulation in the culture medium and of glucose-stimulated insulin release and a marked decrease in the islet DNA and insulin content. A combination of IL-1 (25 U/ml) + IL-6 (1000 pg/ml) did not alter the inhibitory action of IL-1 alone. The present findings thus show that IL-6 induces a dissociation between insulin secretion and glucose oxidation in islets in vitro. This has not been observed in islets exposed to IL-1, which suggests that IL-6 does not solely mediate the inhibitory effects of IL-1 on islet function.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interleukin-6 affects insulin secretion and glucose metabolism of rat pancreatic islets in vitro. 240 46

This study was designed to investigate whether the genetic predisposition to insulin-dependent diabetes mellitus (IDDM) might be caused by an inherited increased sensitivity of the pancreatic B-cells to immune effector molecules e.g. the monokine interleukin 1 (IL-1), which is selectively cytotoxic to B-cells in vitro. Islets of Langerhans isolated from newborn diabetes prone and diabetes resistant Bio-Breeding rats, as well as from the inbred non-diabetic rat strains Wistar Furth, Brown-Norway and Lewis-Scripps were exposed to 0-1000 ng/l [corrected] of recombinant human IL-1 beta for 7 days. Strain-related differences in the sensitivity to IL-1 were studied by comparing the dose-responses of insulin release at 11 mmol/l glucose and islet light microscopic morphology to varying concentrations of IL-1. Statistical analyses showed a significant impact of strain on B-cell sensitivity to IL-1, Brown-Norway islets being relatively resistant to the action of IL-1. However, the the diabetes prone islets were not more sensitive to the cytotoxic effect of IL-1 than the non-diabetic control strain islets. We conclude that genetic differences in the response to IL-1 exist in vitro, but that this phenomenon is unrelated to the propensity to develop IDDM.
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PMID:Genetically determined differences in newborn rat islet sensitivity to interleukin-1 in vitro: no association with the diabetes prone phenotype in the BB-rat. 264 51


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