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

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

Islet amyloid polypeptide (IAPP) has been recently identified as the principal constituent of amyloid deposits in pancreatic islets of patients with type 2 (non-insulin-dependent) diabetes mellitus and causes insulin resistance in some target cells. In addition, glucose-induced insulin secretion is inhibited by IAPP. We studied the effect of IAPP on proinsulin biosynthesis in rat insulinoma (RINr) cells. Glucose at concentrations of 0, 15, 30, 60, 100, and 300 mg/dl stimulated proinsulin biosynthesis in a dose-responsive and and actino-mycin D-inhibitable manner after 6 h of incubation. At a glucose concentration of 300 mg/dl, IAPP decreased the mean responses of proinsulin biosynthesis to 61.2 and 29% at concentrations of 0.1 and 1 microM, respectively, compared with the IAPP-free control. In conclusion, IAPP inhibits glucose-induced proinsulin biosynthesis in RINr cells. IAPP might play an important role in the pathogenesis of type 2 diabetes mellitus.
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PMID:Inhibitory effect of islet amyloid polypeptide of glucose-induced proinsulin biosynthesis in rat insulinoma cells. 164 90

We stably expressed human complement receptor 2 ([CR2] CD21 C3d/Epstein-Barr virus [EBV] receptor) on the rat insulinoma cell line RINm5F with a recombinant retroviral vector. CR2-expressing RINm5F cells secreted 78-33% less insulin than parental cells or cells transduced with an antisense vector and could be infected with high-titer EBV. We tested whether human CR2 expression on RINm5F cells would affect tumorigenesis after transplantation to syngeneic New England Deaconess Hospital rats. Non-CR2-expressing antisense-transduced RINm5F cells rapidly grew tumors and caused hypoglycemia, hyperinsulinemia, and the death of the animals after 15.7 +/- 0.7 days. CR2-expressing RINm5F cells were infiltrated by mononuclear cells at an early stage and eventually caused noninfiltrated tumors and the death of the animals after 33.0 +/- 0.4 days. These tumors were CR2- and are believed to have arisen from a minor CR2- population of tumor cells. The pancreatic islets were histologically normal at all time points. We conclude that expression of a xenoantigen on a rat insulinoma cell line induces an immune response in syngeneic rats but does not result in breakage of tolerance to parental or revertant cells.
Diabetes 1991 Jul
PMID:Expression of functional human Epstein-Barr virus/C3d receptor ([CR2] CD21) on insulinoma cell line. Induction of tumor rejection but not diabetes in syngeneic rats. 164 92

Multiple low doses of streptozotocin are known to induce immune-mediated insulin deficient diabetes and depression of immune reactivity. We show here that immune depression by streptozotocin is not general but that some parts of the immune system are stimulated. Spleen cells from streptozotocin-treated mice showed enhanced cytotoxicity against syngeneic islet cells and various tumour cells including insulinoma cells. Several cell types served as effector cells, including macrophages, asialo GM1+ and Lyt-2+ lymphocytes. The increased cytotoxic activity towards islet cells was mostly due to macrophages and to non-asialo GM1+ and non-Lyt-2+ lymphocytes. A higher activation state of macrophages in low dose streptozotocin-treated mice was demonstrated by measurements of superoxide anion release. We conclude that multiple low doses of streptozotocin stimulate 'natural cytotoxicity', i.e. the non-MHC restricted cytotoxic activity of macrophages, T cells and natural killer lymphocytes.
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PMID:Low dose streptozotocin causes stimulation of the immune system and of anti-islet cytotoxicity in mice. 165 63

Somatostatin, gastrin-releasing peptide (GRP) and gastrin were measured in the stomach of rats with streptozotocin-induced diabetes, insulinoma-bearing rats and their respective controls. Rats injected with streptozotocin exhibited hyperphagia, insulinopenia and severe hyperglycemia. Stomach weights, and the concentrations and total amounts of GRP and gastrin in the stomach, were similar to nondiabetic control rats. The concentration of somatostatin in the stomach of diabetic rats was 25% greater, but the total stomach content of somatostatin was similar to that of control rats. Insulinoma-bearing rats exhibited hyperphagia, hyperinsulinemia and hypoglycemia. Concentrations of GRP and gastrin in the stomach were 72% and 19% lower, respectively, than in control rats. Despite 45% greater stomach weight, the total stomach content of GRP was 61% lower. Stomach concentrations of somatostatin, and total stomach contents of somatostatin and gastrin, were similar in insulinoma-bearing and control rats. The results demonstrate abnormalities in the stomach concentrations of regulatory peptides in rats with diabetes and insulinoma. These abnormalities are not attributable to changes in food intake alone, suggesting specific effects of these metabolic diseases on gastric regulatory peptides and gastric function.
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PMID:Somatostatin, gastrin-releasing peptide and gastrin in the stomach of rats with streptozotocin-induced diabetes and insulinoma. 167 27

IL-2 receptor positive T-cells from leukocyte-infiltrated pancreatic islets of diabetes prone or acutely diabetic NOD mice were propagated in vitro by culture in interleukin-2 containing medium. Of 13 lines obtained after limiting dilution all were positive for the T-cell marker Thy-1 and for CD8. Considerable heterogeneity in T-cell receptor usage was noted. Seven lines expressed T-cell receptors using V beta 8, one line was positive for V beta 5 and two lines expressed a non V beta 5, non V beta 8 receptor. Finally, two further lines lacked T-cell receptors. None of the cell lines were cytotoxic to islet cells although 10 lines showed non MHC restricted lysis of one or more tumour cells including rat insulinoma cells. We conclude that IL-2 receptor positive CD8+ T-lymphocytes from NOD islets are heterogenous with respect to V beta T-cell receptor usage. The majority of these cells are not cytotoxic to islet cells.
Diabetes Res 1991 Feb
PMID:Analysis of IL-2 receptor positive CD8(+)-T-lymphocytes grown from islets of NOD mice. 168 10

To investigate the target antigen(s) recognized during the autoimmune process in insulin-dependent diabetes mellitus (IDDM), we produced human monoclonal antibodies by Epstein-Barr virus transformation of peripheral blood lymphocytes from a large number (n = 50) of newly diagnosed IDDM patients. Screening by indirect immunofluorescence assay, using the RINm5F rat insulinoma cell line and eight other human or rat tumour cell lines, was performed to identify monoclonal antibodies that reacted with either membrane or cytoplasmic antigens. Eighteen IgM monoclonal antibodies reacting with cytoplasmic antigens of RIN cells were obtained; 14 of them also showed a staining of the cytoplasm of various non-beta-cell lines, while four displayed a binding restricted to beta-cells among the panel tested. However, among three monoclonal antibodies reacting with the membrane of RIN cells, one (HMD-1) produced an IgG antibody with a binding restricted to the membrane of beta-cells (RIN, HIT, and normal rat islet cells). The membrane antigens of HMD-1 were identified in Western blotting as proteins with molecular weights of 64 and 70 kD. This antibody had no apparent cytotoxic effect on RIN cells. These data suggest that, apart from 'natural autoantibodies,' it is feasible to obtain human monoclonal antibodies from IDDM patients that bind specifically to the beta-cell cytoplasm or to the beta-cell membrane.
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PMID:Monoclonal autoantibodies from insulin-dependent diabetic patients: autoantibodies against beta-cell surface or cytoplasmic antigens. 169 82

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)
Diabetes 1990 Oct
PMID:Strong association between diabetes and displacement of mouse anti-rat insulinoma cell monoclonal antibody by human serum in vitro. 169 75

To investigate further the role of cytokines in the pathogenesis of type I insulin-dependent diabetes mellitus, the effects of interleukin-1 beta (IL-1), tumour necrosis factor-alpha (TNF) and gamma-interferon (IFN) were tested on rat insulinoma INS-1 cells. Whereas TNF and IFN had, respectively, a minor or no effect on insulin production, IL-1 caused a time- and dose-dependent decrease in insulin release and lowered the insulin content as well as the preproinsulin mRNA content of INS-1 cells. Both IL-1 and TNF exerted a cytostatic effect, estimated by a decrease in [3H]thymidine incorporation, while only IL-1 decreased cell viability as measured by the colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test. The glutathione content of INS-1 cells was shown to be modulated by the presence of 2-mercaptoethanol in the culture medium, but was not affected by IL-1 or TNF. In conclusion, INS-1 cell culture is considered to be a useful model for studying the effect of cytokines on insulin-producing cells. The differentiated features of these cells will permit several questions to be addressed regarding the mechanism of action of IL-1 and eventually other cytokines, both at the level of gene expression and of intracellular signalling.
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PMID:Effects of cytokines on rat insulinoma INS-1 cells. 173 60

Hypoglycemia unawareness can occur in diabetic as well as nondiabetic individuals. A single causative mechanism for its occurrence is not yet apparent. It is likely to be multifactorial but current evidence favors a major role for some type of CNS adaptation. Certainly in some instances, classic autonomic neuropathy could be a contributory factor in patients with longstanding diabetes. Most, if not all, individuals with this condition have reduced plasma epinephrine and/or norepinephrine responses during mild hypoglycemia. Although it may be difficult to distinguish between mere reductions in the magnitude of a response and a true alteration in the threshold to initiate that response, four studies (44, 59, 65, 86) have provided evidence for an increase in the threshold (greater hypoglycemia required) for activation of counterregulatory hormone secretion associated with reduced awareness of hypoglycemia; in one study (44), diabetic patients had developed abnormalities with improved glycemic control after intensive insulin therapy; in another study (59), diabetic patients had recurrent hypoglycemia but did not differ in glycemic control (as assessed by glycosylated hemoglobin values) from subjects aware of hypoglycemia. In the two other studies, patients with impaired counterregulatory hormone responses and hypoglycemia unawareness had lower glycosylated hemoglobin levels than the other patients (65, 86). Altered tissue sensitivity to catecholamines seems unlikely to provide a primary explanation since not all symptoms are adrenergic and since, as mentioned earlier, most patients with this condition have reduced or delayed catecholamine responses to hypoglycemia, which in themselves could explain reduced awareness of hypoglycemia. Furthermore, patients with diabetic autonomic neuropathy have been reported to have increased sensitivity to catecholamines (143). One frequent observation, dating back to the early descriptions of hypoglycemia unawareness (17-19), is that patients with this condition have had frequent episodes of hypoglycemia. Although it is easy to envision how reduced warning symptoms could result in development of severe hypoglycemia, it is quite possible that frequent episodes of hypoglycemia themselves might initiate the process. For example, as depicted in Fig. 4, episodes of mild hypoglycemia occurring in insulinoma patients, diabetic patients undergoing intensive insulin therapy, or patients with longstanding diabetes complicated by autonomic neuropathy and impaired glucagon secretion could lead to CNS adaptation.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Hypoglycemia unawareness. 176 Sep 93


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