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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ion channels in beta cells regulate electrical and secretory activity in response to metabolic, pharmacologic, or neural signals by controlling the permeability to K+ and Ca2+. The ATP-sensitive K+ channels act as a switch that responds to fuel secretagogues or sulfonylureas to initiate depolarization. This depolarization opens voltage-dependent calcium channels (VDCC) to increase the amplitude of free cytosolic Ca2+ levels ([Ca2+]i), which triggers exocytosis. Acetyl choline and vasopressin (VP) both potentiate the acute effects of glucose on insulin secretion by generating inositol 1,4,5-trisphosphate to release intracellular Ca2+; VP also potentiates sustained insulin secretion by effects on depolarization. In contrast, inhibitors of insulin secretion decrease [Ca2+]i by either hyperpolarizing the beta cell or by receptor-mediated, G-protein-coupled effects to decrease VDCC activity. Repolarization is initiated by voltage- and Ca(2+)-activated K+ channels. A human insulinoma voltage-dependent K+ channel cDNA was recently cloned and two types of alpha 1 subunits of the VDCC have been identified in insulin-secreting cell lines. Determining how ion channels regulate insulin secretion in normal and diabetic beta cells should provide pathophysiologic insight into the beta cell signal transduction defect characteristic of non-insulin dependent diabetes (NIDDM).
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PMID:The role of ion channels in insulin secretion. 138 42

Since their demonstration in 1975, ICSAs have been proposed as serological markers and pathogenic elements in IDDM. ICSAs are detected in the sera of most newly diagnosed IDDM patients by indirect IFL that uses viable preparations of rat islet or insulinoma cells as substrate, but they also can be detected by using human insulinoma or fetal islet cells. We have tried to demonstrate ICSAs in the sera of 31 newly diagnosed diabetic patients, including 6 positive samples on human fetal islet cells, which used their natural target for the first time: normal human islet cells. In spite of using different types of preparations of these cells (i.e., freshly dispersed cell suspensions, monolayer cultures, or dispersed islets after culture), ICSAs could not be detected by IFL under the UV microscope, nor by flow cytometry. In contrast, 9 of 29 of the sera gave a positive staining on the RIN rat insulinoma cells. In an attempt to establish whether the putative ICSA autoantigen is present in the surface of human islet cells in the diabetic pancreas, the insulitis microenvironment was emulated by exposing the islets to three types of stress: 1) cytokines (IFN-gamma and TNF-alpha); 2) heat shock; and 3) hyperglycemia. However, diabetic sera failed again to recognize membrane antigens on the islet cells after either of these treatments. Neither were islet cells from a newly diagnosed diabetic patient stained by its autologous serum (ICA titer > 80 JDF U). These results suggest that ICSA autoantigen is not expressed in the membrane of human islet cells and therefore raises doubts about their proposed pathogenic role.
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PMID:Reevaluation of autoantibodies to islet cell membrane in IDDM. Failure to detect islet cell surface antibodies using human islet cells as substrate. 144 4

Viral infection has been suggested to play a triggering role in the pancreatic beta cell destruction which occurs in insulin-dependent diabetes (IDDM). However, the underlying mechanism of this phenomenon is unknown. In this study a human insulinoma cell line has been infected with measles, mumps and rubella viruses since a temporal association is reported between the clinical onset of IDDM and diseases caused by these viruses. The infection with measles and mumps viruses induced the release of interleukin-1 (IL-1) and interleukin-6 (IL-6) by the cell line as assessed by a bioassay and up-regulated the expression of human leucocyte antigen (HLA) class I and class II antigens as evaluated by cytofluorimetric analysis. Stimulation with rubella virus induced the release of IL-6 only and had no effect on HLA antigen expression. These data show for the first time that IL-1 and IL-6 secretion by an insulinoma cell line may occur after viral infection and suggest that cytokine release and increased expression of HLA molecules by beta cells may act to induce the immune response towards beta cells in IDDM.
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PMID:Viral infection induces cytokine release by beta islet cells. 159 39

In an attempt to identify novel pancreatic beta-cell surface antigens, mouse monoclonal antibodies (MoAbs) were raised against rat insulinoma (RIN5F) cells with standard techniques. Several clones were identified whose antibodies bound specifically to RIN5F cells but not to other rat, mouse, and human target cells. Each of these MoAbs was radiolabeled, and the specificity of binding of each MoAb was determined by the ability of excess cold homologous MoAb to displace the labeled MoAb. Six RIN5F cell-specific MoAbs of different epitopic specificities were identified. The relevance of these beta-cell epitopes to human insulin-dependent diabetes (IDDM) was demonstrated by the differential ability of human serums from control and diabetic children to displace the radiolabeled MoAbs from the RIN5F cells. Serums from 333 children without diabetes or a family history of diabetes and from 156 newly diagnosed IDDM patients were tested. Only one IgM MoAb was specifically displaced by the IDDM serums, i.e., 146 of 156, compared to serums from control children, i.e., 10 of 333. With immunofluorescence, the serum component responsible for the displacement of the mouse MoAb was identified as IgG. Most of the positive control serums were from children with active autoimmune thyroiditis. Serums from children with other forms of glucose intolerance did not displace MoAb 1A2. There was no correlation between age and the degree of displacement of 1A2. Thus, the displacement of 1A2 is a specific and sensitive marker of diabetes susceptibility easily applicable to mass screening.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Strong association between diabetes and displacement of mouse anti-rat insulinoma cell monoclonal antibody by human serum in vitro. 169 75

Counterregulatory hormone responses were evaluated in a 37-yr-old woman before and after removal of a benign insulin-producing islet cell tumor. Counterregulatory hormone concentrations were measured during a glucose clamp with graded reductions of plasma glucose from 5.2 to 2.6 mmol/L. In the study before surgery, the increase in plasma epinephrine concentration was markedly blunted (by greater than 90%) compared to that in the study after surgery. The peak plasma norepinephrine concentration was similarly reduced by 71%, and plasma cortisol by 63%. In addition, the glycemic thresholds for secretion of the counterregulatory hormones were lower before removal of the tumor. Peak plasma GH responses were equivalent before and after surgery, but the threshold for GH secretion was 21% lower in the first hypoglycemia study. We conclude 1) that there is evidence for abnormal glucose counterregulatory hormone secretion in this patient, which may contribute to the pathogenesis of hypoglycemia seen in patients with insulinoma; 2) the reversal of reduced counterregulatory hormone secretion after tumor resection suggests that these defective hormonal responses may be related to recurrent hypoglycemia, persistent hyperinsulinemia, or both; and 3) that abnormal glucose counterregulation may exist in the absence of type 1 diabetes.
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PMID:Deficient counterregulatory hormone responses during hypoglycemia in a patient with insulinoma. 200 2

A simple and rapid enzyme-linked immunosorbent assay (ELISA) for the detection of islet cell membrane antibodies (ICMA) in the sera of IDDM has been recently established. This new method has been made possible by using affinity purified islet cell membrane antigens from a monoclonal insulin secreting cell line obtained from a transplantable rat insulinoma (RINm5F). One hundred and thirty-three sera of newly diagnosed diabetic patients (duration of symptoms of less than 3 months) were tested, and ICMA positivity was found in 21% of patients. In the same group we found 64% ICA positive subjects, but no correlation has been found between ICA and ICMA. Therefore these two auto-antibodies should be considered as expression of different steps of the autoimmune beta-cell damage. In this light ICMA could represent a very early marker of autoimmune process and it could be useful to recognize, among risk subjects, those who are developing IDDM.
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PMID:Serum reactivity against RINm5F purified membrane antigens (ICMA) in newly diagnosed diabetic subjects. 213 3

The present study was undertaken to compare the changes in islet cell antibodies (ICA), islet cell surface antibodies using rat insulinoma cells (RINr-ICSA), and anti-bovine serum albumin antibodies (BSA-Ab) in the clinical course of type 1 (insulin-dependent) diabetes. Sera were obtained from 57 patients with type 1 diabetes and 47 normal controls. ICA, RINr-ICSA and BSA-Ab were detected by an enzymatic immunohistochemical method, an indirect immunofluorescence method and an enzyme-linked immunosorbent assay, respectively. The incidence of ICA significantly decreased with the duration of diabetes: less than 1 year: 5/6 (83%); 1-2 years: 3/6 (50%); 2-3 years; 2/6 (33%); greater than 3 years 6/39 (15%). There was a significant positive correlation between RINr-ICSA and BSA-Ab (P less than 0.05). These findings suggest that RINr-ICSA or BSA-Ab may be produced by some similar immune mechanism which is, however, different from ICA, and that they have no direct relation to the clinical course of diabetes.
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PMID:Comparison of islet cell antibodies, islet cell surface antibodies and anti-bovine serum albumin antibodies in type 1 diabetes. 222 20

Islet-specific autoimmune reactivity (humoral and cell-mediated) is the basis for the insulitis process of type I diabetes mellitus. In this report a delayed-type hypersensitivity (DTH) skin test was used to monitor the presence of an islet-specific cell-mediated autoimmune component in BB/O rats. The BB/O rat is a strain characterized by the spontaneous development of type I diabetes. Intact RINm5F cells as well as a RINm5F cell membrane preparation were used as DTH skin test antigens. Rats of different ages and disease stages were tested in the ear with the insulinoma cell line and its cell membrane preparation. As control antigens, the fibroblast cell line 3Y1 and a cell membrane preparation made thereof were used. The DTH reaction system showed a positive cell-mediated reactivity in BB/O rats for membrane-bound RINm5F cell antigens, and not for the control fibroblast 3Y1 cell membrane determinants. The true DTH character of the skin test was established by the time-course of the reaction (maximum at 24 h), the histopathology (infiltration by dendritic cells, lymphocytes and macrophages), and the possibility to transfer the reaction with spleen cells and lymph node cells. The DTH test towards RINm5F cells showed the highest prevalence of positivity (100%) in BB/O rats around the onset of diabetes (3 weeks before to 3 weeks after the onset of glucosuria). The prevalence of DTH positivity was 56% in the period of more than 3 weeks before the onset of glucosuria. In BB/O rats with a duration of glucosuria of more than 3 weeks, the prevalence of positivity was around 60-70%.
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PMID:A delayed-type hypersensitivity skin-test system using the insulinoma cell line RINm5F to monitor beta cell-specific cellular autoimmune reactivity in the spontaneously diabetic BB/O rat. 226 92

IFN-gamma and TNF-alpha injure the pancreatic beta-cell and may be involved in the pathogenesis of autoimmune type 1 diabetes. Because the induction of IL-6 appears to be an important host cell response to injury, we have examined whether IL-6 is produced by murine pancreatic islets or rat insulinoma (RIN-m5F) cells after their exposure to IFN-gamma and TNF-alpha. Islet culture supernatants contained detectable IL-6 activity which was increased 6-fold when islets were exposed to IFN-gamma and 40- and 115-fold when islets were exposed to TNF-alpha and TNF-alpha + IFN-gamma, respectively. A mAb against murine IL-6 abolished (control and IFN-gamma) or significantly reduced (TNF-alpha and TNF-alpha + IFN-gamma) the IL-6 activity in islet supernatants. The magnitude for the effects of IFN-gamma and TNF-alpha on the production of IL-6 from mouse islets was found to be both time and dose dependent. Northern blot hybridization analysis of islet total cytoplasmic RNA with a cDNA probe to murine IL-6 revealed a band at 1.3 kb, the intensity of which increased in islets exposed to IFN-gamma + TNF-alpha. IL-6 activity was also detected in culture supernatants from RIN-m5F cells exposed to TNF-alpha + IFN-gamma. Islets cultured with rIL-6 secreted higher levels of insulin compared with control islets. Pancreatic islet cells, in all probability beta-cells, produce IL-6, the expression of which is up-regulated by IFN-gamma and/or TNF-alpha. In addition to a possible role in regulating pancreatic beta-cell function we propose that IL-6 produced by the pancreatic beta-cell may act as a costimulator for autoreactive B and T lymphocytes in autoimmune diabetes.
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PMID:Evidence for IL-6 production by and effects on the pancreatic beta-cell. 250 90

Insulin-dependent (type 1) diabetes mellitus (IDDM) is due to the selective autoimmune-mediated destruction of pancreatic beta cells possibly initiated by viruses. To elucidate the possible role of viruses and cytokines in the pathogenesis of IDDM, we have examined the effect of reovirus infection on beta cell major histocompatibility complex (MHC) expression and the effect of interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha) on beta cell function in vitro. Infection of RIN-m5F (rat insulinoma) cells with reovirus-1 or reovirus-3 was associated with a tenfold increase in class 1 MHC protein and mRNA expression. Reovirus infection did not induced the expression of class 11 MHC by RIN-m5F cells. Exposure of reovirus to ultraviolet light almost completely abolished its ability to induce class 1 MHC protein expression on infected cells. Murine islets cultured for 3 days with IFN-gamma and/or TNF-alpha had a significantly reduced insulin response to glucose, which was more marked with a combination of the cytokines. During 6 days of culture in IFN-gamma plus TNF-alpha islets underwent noticeable degeneration associated with an 80% reduction in insulin content. These findings together with previous data suggest viruses and cytokines may have multiple roles in beta cell destruction, indirectly through enhanced MHC protein expression and directly through functional impairment and loss of viability.
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PMID:Viruses and cytokines: evidence for multiple roles in pancreatic beta cell destruction in type 1 insulin-dependent diabetes mellitus. 254 35


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