Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human intoxication with the rodenticide Vacor [N-3-pyridylmethyl-N'-p-nitrophenyl urea or 1-(4-nitrophenyl)-3-(3-pyridylmethyl) urea] induces acute IDDM. We report here that Vacor specifically inhibits the NADH:ubiquinone reductase activity of complex I in mammalian mitochondria. The activity of other respiratory enzymes of mitochondria is unaffected by Vacor at concentrations that completely inhibit the redox and energetic function of complex I. Vacor inhibition of complex I activity quantitatively correlates with the inhibition of insulin release in insulinoma cells and pancreatic islets and is also consistent with the doses reported in cases of human poisoning. These results indicate that the toxic and diabetogenic action of Vacor primarily derives from the inhibition of mitochondrial respiration of NAD-linked substrates in the high-energy demanding cells of the pancreatic islets. This newly identified mechanism of the pathological effects resulting from Vacor intoxication could constitute a paradigm in which to understand environmental or metabolic causes of IDDM.
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PMID:Inhibition of mitochondrial complex I may account for IDDM induced by intoxication with the rodenticide Vacor. 886 57

We have investigated the rates of glucose consumption, lactate production and insulin secretion by mouse insulinoma beta TC3 cells exposed to high glucose and oxygen concentrations in the range of 132 mmHg (normoxia) to 0 mmHg (anoxia). The rates of glucose consumption and lactate production, and the yield of lactate on glucose were 6.4 +/- 0.2 nmol/h - 10(5) cells, 7.7 +/- 0.5 nmol/h - 10(5) cells, and 1.2 +/- 0.1 respectively, at oxygen concentrations between 132-25 mmHg. These values increased gradually as the oxygen concentration was reduced below 25 mmHg, reaching a maximum value of 12.8 +/- 0.4, 23.8 +/- 1.1, 1.9 +/- 0.1 respectively, at complete anoxia. Insulin secretion remained constant at 360 +/- 24 pmol/h - 10(8) cells at oxygen concentrations between 132-7 mmHg, but was inhibited at lower oxygen concentrations, dropping to 96 +/- 24 pmol/h - 10(8) cells at 0 mmHg. The rate of insulin secretion in the presence of high glucose under anoxia was significantly higher than the rate of basal secretion (28.2 +/- 3.0 pmol/h - 10(8) cells) at normoxia. The secretory properties of beta TC3 cells at low oxygen concentrations may have implications in the development of a diffusion-based bioartificial tissue constructs for the long-term treatment of Insulin Dependent Diabetes Mellitus.
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PMID:Effects of oxygen on metabolic and secretory activities of beta TC3 cells. 889 78

Thirty-three IDDM sera that immunoprecipitated full-length IA-2 were tested for reactivity with different fragments of the IA-2 molecule. The fragments were prepared by PCR amplification of IA-2 cDNA and by expression in a rabbit reticulocyte transcription/translation system. Whereas all 33 sera reacted with the intracellular domain (amino acid 604 to 979), none of the sera reacted with the extracellular domain of IA-2 (amino acid 31 to 577). Analysis of the reactivity of IDDM sera with the different regions of the intracellular domain showed that 94% (31 of the 33) reacted with the COOH-terminus (amino acid 771 to 979), 40% reacted with the NH2-terminus (amino acid 604 to 776), and 40% reacted with the middle portion (amino acid 692 to 875). Of the 31 sera that reacted with the COOH-terminus, 14 of these reacted only with the COOH-terminus and with no other region. Of the 13 sera that reacted with the NH2-terminus, only one reacted exclusively with the NH2-terminus. Treatments of the different domains of IA-2 with trypsin showed that only the COOH-terminus was resistant to trypsin, arguing that it is from this region of the IA-2 molecule that the 40-kDa tryptic fragment from insulinoma cells is derived. From these experiments, it is concluded that the major antigenic determinant of IA-2 is located at the COOH-terminus and that minor antigenic determinants are located at the NH2-terminus and middle portion of the intracellular domain.
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PMID:Autoantibodies to IA-2 in IDDM: location of major antigenic determinants. 897 Oct 79

Like most cytokines, IL-1 transduces its signals for growth, differentiation and diverse cellular functions after binding to specific receptors on the cell surface. Up to now two IL-1 receptors have been reported, type I which induces signal transduction and type II which binds IL-1 but does not transduce signalling. By using the rat insulinoma RIN-5AH cell line that expresses both types of receptor mRNA, and computer-assisted binding analysis, we show that interleukin-1 beta (IL-1 beta) binds to a single class of high affinity receptors with a Kd of 155 pmol/l. The average number of receptors on adherent cell layer is calculated to be 7300 per cell. 125I-IL-1 beta binding can be competed out by unlabelled IL-1 beta. 125I-IL-1 alpha binding can be also obtained and is subject to competition by cold IL-1 alpha. Its saturation curve, however, varies within experiments due to differential receptor up-regulation. These results have also been confirmed by FACS analysis using specific antibodies to type I and II IL-1 receptors, where type I receptor antibody binds strongly to RIN-5AH cells, and type II receptor antibody shows weak staining, also due to inadequate receptor up-regulation. In order to determine whether functional signal transduction occurs via the receptors detected, it is shown that IL-1 beta is able to induce MHC class II antigen expression on the surface of the RIN cells, whereas IL-1 alpha is unable to do so, indicating different signal reception by the cells. IL-1 beta-induced class II upregulation shows moderate signs of p21ras or/and PKC dependency, whereas IL-1 alpha strongly activates both pathways that probably regulate different functions. Finally, both IL-1 alpha and beta induce nitric oxide (NO) production in a time-dependent fashion which appears to be unrelated to the signals and pathways described, but may be involved in the onset of autoimmune type 1 diabetes.
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PMID:IL-1 beta transduces different signals than IL-1 alpha leading to class II antigen expression on beta-insulinoma RIN-5AH cells through specific receptors. 902 92

In order to study cytokine production profile (IFN-gamma, IL-4 and TNF-alpha) and TCRBV-gene usage of peripheral autoreactive T cells from IDDM patients, we have generated antigen-specific T cell lines with either tetanus toxoid, insulinoma membranes or a single beta-cell protein, recombinant ICA69, which has been shown to be a target of both autoantibodies and T cells in IDDM. By semi-quantitative polymerase chain reaction (PCR) analysis, we have determined the composition of the T cell receptor repertoire of these T cell lines and compared this with the general peripheral repertoire. T cell responses against beta-cell antigens and tetanus toxoid (TT) were shown to be associated with IFN-gamma and TNF-alpha production, suggestive of a Th1-like phenotype of the T-cell lines. The production of IFN-gamma was significantly higher in T-cell lines generated with ISG compared to those generated with TT. The cytokine production profiles of the T-cell lines generated with ICA69 did not provide an obvious explanation for the inverse relation between cellular and humoral responses to this protein observed earlier. Upon stimulation with beta-cell antigens, outgrowth of T cells using a restricted set of TCRBV elements was observed in newly diagnosed IDDM patients. However, this skewing in TCRBV-gene expression was patient-specific rather than antigen-associated, since the T-cell repertoire that is used for the recognition of these antigens was, overall, heterogeneous.
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PMID:Th1-like cytokine production profile and individual specific alterations in TCRBV-gene usage of T cells from newly diagnosed type 1 diabetes patients after stimulation with beta-cell antigens. 945 99

The related tyrosine phosphatase-like proteins, islet cell antigen 512 (ICA512) and phosphatase homologue in granules of insulinoma (phogrin), are major targets of autoantibodies in patients with type 1 diabetes. In the current study, we have examined the overlapping specificities and antigenic epitopes of autoantibodies to ICA512 and phogrin and determined whether intramolecular epitope spreading occurs during the development of diabetic autoimmunity. ICA512 autoantibodies and phogrin autoantibodies were detected in 65-70% (n = 110) of patients with new-onset type 1 diabetes and 60-65% (n = 42) of prediabetic relatives of patients with type 1 diabetes. Of the sera, 10% reacted with ICA512 but not phogrin, whereas only 1% of sera reacted with phogrin but not ICA512. The binding of phogrin autoantibodies in 88 dual (ICA512 and phogrin) autoantibody-positive sera could be completely blocked by excess recombinant ICA512, whereas the blocking of ICA512 autoantibodies with recombinant phogrin was only partial (mean inhibition of 58.9 +/- 3.7%, mean +/- SE). Binding and competition analysis using multiple chimeric ICA512/phogrin constructs demonstrated that a major unique epitope for ICA512 autoantibodies is localized to amino acids 762-887. A conformational epitope associated with the carboxy-terminal 31 amino acids of ICA512 was recognized by one-third of sera, and a minor epitope is located on amino acids 601-762 of ICA512. The major epitopes for phogrin-selective autoantibodies were localized to amino acids 640-922 of phogrin. Sequential serum samples were analyzed in 22 relatives who expressed ICA512/phogrin autoantibodies. Intramolecular epitope spreading was found for 5 of 13 relatives who have progressed to type 1 diabetes. Among nine relatives who have remained nondiabetic, three demonstrated a decrease in the number of epitopes recognized. These studies highlight the complexity of autoantibody recognition of ICA512/phogrin and are consistent with the hypothesis that ICA512/phogrin may be recognized as a consequence of beta-cell destruction.
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PMID:Definition of multiple ICA512/phogrin autoantibody epitopes and detection of intramolecular epitope spreading in relatives of patients with type 1 diabetes. 958 44

Islet cell surface antibodies (ICSA) have been demonstrated significantly more often in serum of patients with IDDM and their relatives than in healthy controls, but some investigators have been unable to show binding to human islets. It has therefore been suggested that ICSA is an artefact. We have localised and quantified ICSA binding to different specimens, including human pancreas. ICSA-positive and ICSA-negative patients' serum, determined by a RIA-method, were incubated with ultrathin sections of rat insulinoma (RIN5AH) cells, stained with Goat-anti-human IgG conjugated with 10 nm gold particles. Sections were viewed in transmission electron microscopy (Mag. 30,000 x) and image analyses was used to calculate immunolabelling. To test cell specificity we used (RIN5AH-cells, rat tumour cells producing growth hormone (GH3), normal human pancreas, human insulinoma, and mice liver). Sections showed good morphology. ICSA-positive sera, with or without islet cell antibodies (ICA) gave always higher immunocolloidal labelling then ICSA-negative sera on RIN5AH sections. Thus, the colloidal gold technique could confirm the ICSA results determined with RIA. Immunolabelling was pronounced on normal human pancreas and human insulinoma cells, but none was found on GH3-cells or mice liver cells. ICSA is not an artefact but do exist and bind to human islet cells and therefore maybe can be used as a marker for IDDM immunity.
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PMID:Islet cell surface antibodies (ICSA) do bind to human pancreas: computerised, quantitative determination of ICSA using both pre- and postembedding immunocolloidal techniques. 964 49

Evidence from case-control studies for the diabetogenicity of introduction of cow's milk-based formulas at early age in infancy is inconclusive. We followed siblings of children with Type 1 diabetes mellitus (Type 1 DM) to investigate a possible relationship between cow's milk consumption during infancy or later in childhood and the emergence of diabetes-associated autoantibodies and progression to clinical Type 1 DM. A cohort of 725 initially unaffected 0 to 25-year-old siblings of 801 index children with Type 1 DM diagnosed in 1986-1989 participated in the study (82% of those invited). The siblings were observed for Type 1 DM associated autoantibodies at intervals of 3-12 months for 4 years, starting from the diagnosis of Type 1 DM in the index child. The follow-up for Type 1 DM started at the same time and ended on 31 October 1995. The combined prevalence of Type 1 DM associated autoantibodies (islet cell antibodies (ICA), insulin autoantibodies (IAA), GAD autoantibodies (GADA), and/or antibodies to the insulinoma associated cDNA2 protein (IA-2A)) was 13.6% (95/697) at the beginning of the study. Of the initially seronegative siblings, 7.5% (45/602) converted to antibody positivity during 4 years, and of all siblings 4.6% (33/725) developed Type 1 DM during the total follow-up time. The age at introduction of supplementary milk feeding was not significantly related to seroconversion to positivity for Type 1 DM associated autoantibodies or to the development of Type 1 DM in the siblings. When adjusted for age, sex, infant feeding patterns, and maternal age and education, high milk consumption in childhood (> or =3 glasses daily) was associated with more frequent emergence of Type 1 DM-associated autoantibodies than low consumption (<3 glasses daily) (adjusted odds ratio 3.97, 95% confidence interval 1.3-11.7, p = 0.01). There was a non-significant association between high milk consumption and progression to clinical Type 1 DM (adjusted hazard ratio 2.75, 95% confidence interval 0.9-8.4, p = 0.07). To conclude, this study suggests that high consumption of cow's milk during childhood may be associated both with seroconversion to positivity for diabetes-associated autoantibodies and progression to clinical Type 1 DM among siblings of children with diabetes.
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PMID:Cow's milk consumption, disease-associated autoantibodies and type 1 diabetes mellitus: a follow-up study in siblings of diabetic children. Childhood Diabetes in Finland Study Group. 973 1

We report the case of a 49-yr-old man affected by coma and hypoglycemia unawareness following repetitive hypoglycemic episodes due to dumping syndrome. The dumping syndrome, which was due to partial gastrectomy and vagotomy performed for recurrent peptic ulcer, was responsible for reactive hyperinsulinemia as demonstrated by an oral glucose tolerance test. While the glucose counterregulatory hormones were all normally sensitive to specific stimulation tests, insulin-induced hypoglycemia failed to induce an adequate counterregulatory response, causing no response in plasma norepinephrine, a slight and short increase in plasma cortisol, ACTH and glucagon and an insufficient increase in plasma epinephrine and GH. This case demonstrates that hypoglycemia unawareness has to be taken into account not only in patients affected by IDDM or insulinoma but also in any case of reactive hypoglycemia.
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PMID:Hypoglycemia unawareness in a patient with dumping syndrome: report of a case. 976 63

Insulin replacement by injection is clearly not a cure for Insulin Dependent Diabetes Mellitus (IDDM). Replacement of the destroyed islets by pancreas or islet allograft transplantation can achieve the good metabolic control required to prevent diabetic complications, but tissue supply is limited. The problem of islet supply to treat the 1 million IDDM patients in the USA could be overcome by using immortalized islet beta-cells as a donor source. However, before either allogeneic or xenogeneic immortalized beta-cells are used, some major problems have to be overcome: control of immortalized cell growth, allograft or xenograft rejection and recurrence of autoimmunity. To tackle these problems we have used a cell impermeable immunoisolation device containing mouse insulinoma cells. Transplantation of devices with insulinomas from NOD mice carrying the Rat-insulin promoter regulated SV40 T-Antigen transgene (RIP-TAg), normalized the blood glucose levels of diabetic NOD mice. Insulinomas from allogeneic CBA/NOD-RIP-TAg mice were also capable of normalizing diabetic NOD mice. Not only were non-fasting blood glucoses normalized but when given an intraperitoneal injection of glucose, the corrected mice had a near normal clearance of glucose from the blood. When the devices were removed from normalized mice they became diabetic again, demonstrating that the immunoisolation device was capable of protecting against both alloimmune and autoimmune destruction. The results with allogeneic mouse beta-cells suggest the possibility that immortalized human beta-cells could be an effective source of tissue to correct diabetes in IDDM patients without the use of immunosuppression.
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PMID:Correction of diabetic nod mice with insulinomas implanted within Baxter immunoisolation devices. 993 Sep 67


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