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

Flow cytometry was recently introduced for the detection of antibodies in human serum to a cultured insulin-secreting rat insulinoma cell line (RINm5F) to investigate humoral immune reactivity in newly diagnosed type I (insulin-dependent) diabetic patients. Fifty-three patients were observed for 6-20 mo after clinical onset of diabetes with a reported duration of symptoms of less than 6 wk. Human anti-RINm5F antibodies were detected in 28%, human anti-islet cell antibodies in 62%, and anti-insulin autoantibodies in 36% of patients before initiation of insulin therapy. Occurrence of human anti-RINm5F antibodies at this stage was correlated with human anti-insulin autoantibodies rather than with the formation of anti-islet cell antibodies. Incidence of anti-RINm5F antibodies in individuals with duration of diabetes greater than 6 wk was 38%, whereas human anti-islet cell antibodies and anti-insulin antibodies became detectable in 72 and 61% of the patients, respectively. These findings are in line with previous reports of immunoprecipitation by human diabetic serums of a 64,000-Mr antigenic structure in freshly prepared rat islet cells. The results suggest a reactivity of distinct classes of antibodies in serums of patients with type I diabetes to disparate antigens on human islet cells and cloned rat insulinoma cells and, moreover, reactivity to insulin as the secreted product. Further characterization of the reacting RINm5F antigens and prospective studies in subjects at risk for diabetes are required to validate the application of RIN cells to the investigation of immune mechanisms involved in the pathogenesis of human type I diabetes.
Diabetes 1989 Dec
PMID:Flow-cytometric detection of human anti-rat insulinoma antibodies in relation to anti-human islet cell and anti-insulin antibodies. Recognition of distinct antigens by antibodies in early type I diabetes. 255 42

Recombinant DNA techniques have made it possible to establish the structure of various genes encoding polypeptide hormones. Comparison of nucleotide sequences of the calcitonin (CALC) genes in man has revealed surprising similarities and variations. These findings and the homologies among the sequences in different species offered an opportunity for speculation about relationships between these genes and about their evolutionary origin. The first gene (CALC-I) directing the synthesis of calcitonin (CT) or CT gene-related peptide (CGRP) comprises six exons and gives rise to two mRNAs by an alternative RNA-processing mechanism. The homology between CGRP and CT reflects their common origin. The human genome contains a second gene (CALC-II) that is structurally related to the CALC-I gene. The CALC-II RNA transcripts do not appear to be differentially processed, as only preproCGRP-II mRNA and not preproCT-II is detected. The first and second CT/CGRP genes probably have evolved from a common ancestor gene early in evolution. Meanwhile, a third genomic locus containing nucleotide sequences highly homologous to exons 2 and 3 of both CALC genes was detected and probably generated by duplication of a part of CALC-II. This locus is not likely to encode a CT- or CGRP-related polypeptide hormone. The CALC genes and this last (pseudo) gene are located on the short arm of chromosome 11. Recently, islet- or insulinoma-amyloid polypeptide (IAPP) was isolated as a major constituent of amyloid present in human insulinoma and in pancreatic islet amyloid in noninsulin-dependent diabetes mellitus. IAPP shows 46% amino acid sequence homology with human CGRP-II.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Evolutionary pathways of the calcitonin (CALC) genes. 263 35

Nesidioblastosis, a condition characterized by diffuse islet cell hyperplasia arising from the ductal epithelium, is often associated with hyperinsulinemic hypoglycemia. This is a childhood disease and is rarely found in adults. Only 10 histologically proven cases have been recorded, including 3 new cases described in this article. Most clinical and biochemical features are identical to those of an insulinoma, except the proinsulin-like component of circulating immunoreactive insulin, which is usually within the normal range in nesidioblastosis. Limited observations show that some patients may be managed medically with diazoxide. Patients who remain hypoglycemic despite medical therapy require pancreatectomy, although greater than 90% resection frequently results in insulin dependency and permanent diabetes.
Diabetes Care 1989 Feb
PMID:Pancreatic nesidioblastosis in adults. 269 14

In a rosette assay, 63 patients with recent-onset type I (insulin-dependent) diabetes mellitus had a higher (P less than .001) number of lymphocytes adhering to rat insulinoma RINm5F cells (diabetic rosettes) than 153 healthy control (background rosettes) or 20 nondiabetic subjects with other organ-specific autoimmune diseases. Furthermore, lymphocytes from diabetic patients displayed a highly correlated (r = .97, P less than .001) binding on two different xenogeneic beta-cell lines (RIN and hamster insulinoma HIT cells). This phenomenon was not found on a panel of seven non-beta-cell lines (e.g., exocrine pancreatic cells, endocrine cells). By increasing lymphocyte-to-RIN ratios (0.25:1 to 30:1), the supernumerary RIN-adherent lymphocytes from diabetic patients, expressed as the percentage of lymphocytes involved conjugates, were only detectable at lower ratios (0.25:1 to 4:1), and their binding efficiency was two times higher than that of control lymphocytes. This efficiency fell at higher ratios (greater than 4:1) to the level of background rosettes that remained constant through the ratio scale. This specific RIN-rosette formation was abrogated when lymphocytes from diabetic patients were preabsorbed on beta-cells (either HIT or RIN) but not on non-beta-cells, whereas preabsorption of control lymphocytes did not modify the number of background rosettes. In addition, diabetic rosettes, but not background rosettes, were inhibited by competition with RIN membrane extracts but not by non-beta-cell extracts. Moreover, diabetic rosettes were inhibited during blocking experiments with anti-CD3 monoclonal antibody (MoAb) but not with unrelated MoAbs.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1989 May
PMID:In vitro relationship of CD4 cells from type I diabetic patients and xenogeneic beta-cell membranes. 265 34

Clinical and experimental data support the concept that type I diabetes mellitus results from autoimmune destruction of pancreatic beta cells. Although both proteins and glycolipids are targets of anti-islet cell antibodies, the Ag have not been purified or characterized. Previously, we observed that rat insulinoma (RIN) cell lines varied in their reactivity with both human antibodies and murine mAb A2B5, which binds to polysialo gangliosides. To determine the chemical basis of the varied immunoreactivity, we analyzed the glycosphingolipids of 5 RIN lines. Glycolipids bound by two mAb and by antibodies in the sera of type I diabetics were identified. The more immunoreactive RIN lines contained a much higher content of gangliosides and a higher proportion of complex gangliosides. The major gangliosides were GM3, GD3, and GT3. By high performance TLC immunostaining, we demonstrated that A2B5 and R2D6, an anti-beta cell murine mAb, bound most strongly to ganglioside GT3. The binding of human sera to gangliosides was analyzed by an ELISA assay. Although both normal and diabetic sera contained antibodies to various glycolipids, binding to GT3 was significantly elevated in 31 new-onset type I diabetics (p less than 0.001). The presence of the GT3 trisialosyl epitope on human islet cells was shown by immunofluorescent staining by both R2D6 and A2B5. These findings support previous suggestions that gangliosides play an important role in the immunopathology of type I diabetes, and identify for the first time a specific ganglioside Ag that is the target for autoantibodies in a subset of diabetic patients.
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PMID:Antibodies against ganglioside GT3 in the sera of patients with type I diabetes mellitus. 265 94

An enzyme-linked immunosorbent assay (ELISA) was established for the detection of islet cell antibodies in human sera. The antigen was prepared from rat insulinoma (RIN A2) cells. Cells were dissociated in lysis buffer and the lysate was centrifuged at 100,000 x g. The supernatant was used to coat microtiter ELISA plates (10 micrograms protein/ml in PBS pH 7.2). Non-specific binding sites on the plates were blocked with 2% PBS-BSA. Human test sera were preabsorbed on separate plates using 2% PBS-BSA and incubated on precoated plates at an optimal dilution of 1/10 in 60 mM PBS for 60 min at 37 degrees C. Phosphatase-labeled anti-human IgG serum and phosphatase substrate were applied and the reaction was stopped by adding 3 M NaOH. Out of 90 sera from type I diabetic patients, 47 (52.2%) reacted in the new ELISA whereas none of 15 type II diabetics, 50 sera containing non-islet specific antibodies or 100 normal controls were positive. In the same group of patients, ICA were positive in 63.3%. When both, the ELISA and conventional ICA testing were applied, the number of positives was increased to 83%. The ICA-ELISA with the above described antigen preparation provides a well standardized and reproducible test method which is highly specific for type I diabetes. It may therefore be useful for large screening procedures.
Diabetes Res 1989 Feb
PMID:Determination of islet cell antibodies using an ELISA system with a preparation of rat insulinoma (RIN A2) cells. 266 22

Protein kinase C (PKC) has been generally accepted to play a key role in stimulus-response coupling in various secretory cells, including pancreatic islets and pancreatic acini. The enzyme exists as a large family of multiple subspecies with highly related structures (alpha-, beta I-, beta II-, gamma-, delta-, epsilon-, and zeta-PKC). With an immunocytochemical procedure with subspecies-specific antibodies, beta II-PKC-like immunoreactivity was identified to localize in the beta-cells of the rat pancreatic islets. Neither beta I- nor gamma-PKC-like immunoreactivity was found in both islets and acini. Biochemical analysis confirmed that the rat whole pancreatic tissues contain a significant amount of alpha-PKC and a minute amount of beta II-PKC but neither beta I- nor gamma-PKC. On the other hand, beta II-PKC-like immunoreactivity was not detected in rat insulinoma cells, in which insulin secretion was induced in response to 12-O-tetradecanoylphorbol-13-acetate and carbachol but not in response to glucose. These findings suggest that beta II-PKC is the major, if not the sole, subspecies of PKC in beta-cells of rat pancreatic islets and a possible candidate for involvement in glucose-induced insulin secretion.
Diabetes 1989 Aug
PMID:Localization of beta II subspecies of protein kinase C in beta-cells. 266 99

Impaired islet function is a feature of non-insulin-dependent diabetes mellitus (NIDDM), which is manifested in part by disproportionate proinsulin release. A disproportionate increase in proinsulin also occurs in insulinomas, suggesting that enhanced proinsulin release results from an increase in synthesis and premature release of proinsulin-rich immature granules in both conditions. However, recent human and animal studies suggest that normal beta-cells respond to an increase in synthetic demand by enhancing their ability to process proinsulin. Thus, impaired processing of proinsulin is likely in NIDDM. A new point of similarity with insulinoma has been the demonstration of a novel pancreatic peptide isolated from insulinomas and the pancreas of patients with NIDDM. This peptide, named islet amyloid polypeptide or amylin, is also present in normal islets. Because of its association with two apparently dissimilar disease states, we propose a hypothesis that encompasses the observations related to proinsulin and islet amyloid polypeptide and suggest they are manifestations of the same abnormality. In this hypothesis, we suggest that this new pancreatic peptide is a normal participant in the process of proinsulin processing and storage. We also suggest that in the presence of defective proinsulin processing and insulin release, as occurs in NIDDM, hyperglycemia stimulates amylin biosynthesis so that this peptide is deposited in increased quantities in the islet as amyloid. This then further exacerbates the diabetic process, resulting in progressive hyperglycemia and deterioration in islet function.
Diabetes 1989 Nov
PMID:Hyperproinsulinemia and amyloid in NIDDM. Clues to etiology of islet beta-cell dysfunction? 269 69

Monoclonal antibody (Mab) 1.93B7 was obtained by fusion of spleen cells from a diabetic NOD mouse with P3X63Ag8.653 myeloma cells and screening for complement mediated lysis of rat insulinoma (RIN) cells. Immunofluorescence studies revealed that this Mab binds to RIN cells but not to the rat pituitary tumour line GH3. The binding of Mab 1.93B7 to RIN cells was abolished by trypsin but not by neuraminidase treatment of the cells, suggesting that the antigen recognized is a protein. Mab 1.93B7 bound to approximately 30% of mouse (BALB/c) and rat islet cells which had been subjected to trypsin digestion and incubated as a single cell suspension for 12h to allow reexpression of trypsin sensitive antigens. Since Mab 1.93B7 is potentially pathogenic, as suggested by its reactivity to primary islet cells and its complement fixing capacity, we injected it into BALB/c and NOD mice. Cytotoxic activity against RIN cells was detected in the serum of the animals injected with Mab 1.93B7, but the Mab did not exert a diabetogenic action and failed to reverse diabetes when administered at onset in NOD mice. No modification of the course of spleen cell mediated transfer of diabetes in NOD mice was observed when the Mab was administered from the time of spleen cell inoculation to the appearance of glycosuria. The implications of the lack of an effect in vivo of Mab 1.93B7 under the conditions employed are discussed.
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PMID:A cytotoxic monoclonal islet cell surface antibody from the NOD mouse. 269 57

Titre of islet cell surface antibodies (ICSA) in 114 sera from healthy control probands and 177 sera from first-degree relatives of Type 1 diabetic patients was determined by indirect immunofluorescence using rat insulinoma (RIN) cells as target. All sera were tested at four dilutions (1/40-1/320). 10(5) RIN cells were incubated with 100 microliters diluted serum overnight at 4 degrees C followed by a 45 min-incubation with a FITC-labelled goat anti-human globulin. Titre curves were calculated by double logarithmic regression. ICSA titre was defined as the serum dilution producing cell surface fluorescence on 40% of RIN cells. Based on these data a serum is defined as ICSA positive when the ICSA titre calculated is higher than 1:142, quantil Q (0.97). Twenty-five out of 177 (14%) sera of first-degree relatives of Type 1 diabetes were ICSA positive with a mean titre of 1/393, range 1/145-1/1,740, while 2/114 (1.7%) control sera were weakly positive for ICSA. These data demonstrate the significantly increased ICSA prevalence in first-degree relatives of Type 1 diabetic patients. The present study suggests that RIN cells may represent a useful tool for standardization of ICSA assay.
Diabetes Res 1989 Sep
PMID:Determination of islet cell surface antibodies in first-degree relatives of type 1 diabetic patients using rat insulinoma cells. 269 2


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