Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
Diabetes 1992 Dec
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

Hyperactive platelets contribute to angiopathic complications in diabetes mellitus. It is unclear whether the increased platelet function is a primary pathogenetic factor in diabetes or follows vascular injury. Increased platelet size and numbers of glycoprotein receptors on diabetic platelets suggest that thrombopoiesis is altered in diabetes mellitus. For further support of this hypothesis we studied whether megakaryocytes are changed with regard to the DNA-ploidy pattern and the GPIIB/IIIA expression in 10 acute diabetic (AD) and 24 insulin treated diabetic (ITD) BB rats in comparison with 22 diabetes resistant (ND) BB rats. In the AD group megakaryocyte size (P = 0.035) and the modal DNA-ploidy distribution dropped (P = 0.0001) concomitant with increased TNF-alpha activity (P = 0.001). GPIIB/IIIA expression and the peripheral platelet status were unchanged. After 4 weeks of insulin substitution metabolic parameters (glucose, cholesterol, triglycerides) were lowered, but remained still elevated. As compared to the AD group the modal DNA-ploidy pattern reversed, but the relative percentage of 64n megakaryocytes increased 2.3-fold and GPIIB/IIIA expression increased 1.6-fold. Simultaneously, the peripheral platelet count and size increased. From these results we conclude that alterations of the megakaryocyte compartment occur at early onset of diabetes. These changes could reflect a response to increased systemic cytokine production during inflammatory islet cell destruction. The peripheral platelet thrombotic potency increased with insulin treatment. This was associated with an increase of 64n-megakaryocytes with upregulated GPIIB/IIIA expression and could reflect a mitogenic effect of insulin upon the endomitotic cycle of the megakaryocytes.
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PMID:Increased GPIIB/IIIA expression and altered DNA-ploidy pattern in megakaryocytes of diabetic BB-rats. 145 76

Most autoimmune diseases are HLA-associated which supports the notion that they are dependent upon specific immune activation of a limited set of T cell clones. Findings which imply that induction of autoimmune reactivity probably does not differ from normal immune responses are discussed. The possibility of transferring autoimmune disease using T cell clones indicates that target structures for auto-immune attack are also present in healthy individuals. In the present article, it is argued that autoimmune reactions and immunity against nominal conventional antigens in principle are effected and regulated by similar mechanisms. It is assumed that persistent tissue damage occurs if immune attack is directed against tissues that cannot be regenerated, such as in diabetes, or are only slowly reconstituted, such as in rheumatoid arthritis. Normal immune responses are regulated by various inflammatory mediators and cytokines/interleukins. The joint of patients with rheumatoid arthritis is discussed as a model for propagation of immune reactions and tissue destruction in autoimmune disease. Of the different cytokines which are present in the synovial fluid or produced by cells in the synovial tissue, most are presumed to have originated in macrophages/monocytes such as IL-1, IL-6, IL-8, TNF-alpha and TGF-beta. Even so, T cells are believed to have an important role for the continued reactivity associated with autoimmune disease. This discrepancy can be explained in different ways. T cell products might escape detection because they are short-lived, they are immediately consumed or they are produced only during short time intervals.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Specific and non-specific autoreactive immunity. 150 34

In attempt to evaluate biological roles of tumor necrosis factor (TNF), we studied the effects of anti-TNF mAb in non-obese diabetic (NOD) mice. Anti-murine TNF mAb rendered NOD mice hypersensitive to the lethal effects of radiation and prevented the reconstitution of lethally irradiated mice with adoptively transferred lymphocytes. While TNF-alpha reduced the incidence of diabetes development in the adoptive transfer system even when given 6 days post-transfer, mAb to TNF could not reduce or increase the incidence of diabetes compared to control mice. Administration of TNF-alpha for 4 or 8 weeks significantly reduced the incidence of spontaneous insulitis in NOD mice, while anti-TNF mAb given for 8 weeks increased the incidence of insulitis significantly.
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PMID:Monoclonal anti-tumor necrosis factor antibody renders non-obese diabetic mice hypersensitive to irradiation and enhances insulitis development. 151 Jul 87

It was recently proposed that the increased levels of modified lipoproteins in diabetic patients may be responsible for the accelerated development of macrovascular complications associated with the disease. Modified lipoproteins are believed to induce the transformation of macrophages into foam cells and, in some cases, to induce endothelial cell damage. In addition, modified lipoproteins trigger an immune response leading to the formation of antibodies and then to the formation of LDL-containing immune complexes. In this review, we summarize the evidence linking LDL glycation and oxidation with intracellular accumulation of cholesterol esters and foam-cell formation, and we discuss their potential for inducing an autoimmune response and the formation of lipoprotein-containing immune complexes. The formation of LDL-ICs seems particularly significant, because these ICs are avidly taken up by macrophages through their Fc receptors and induce not only massive intracellular accumulation of CE but also a paradoxical increase in LDL-receptor expression. Our experimental data suggest that the uptake of LDL-IC is facilitated by RBC adsorption, in agreement with the role of RBC in the adsorption of circulating IC and their delivery to phagocytic cells. In addition, macrophages are activated when ingesting LDL-IC and release IL-1 beta and TNF-alpha, which can contribute to the initiation and progression of an atheromatous lesion by several mechanisms. Although it is difficult to envisage how LDL-IC could initiate an endothelial lesion, it is easy to speculate about their role as cofactors in the initiation and progression of the atherosclerotic process.
Diabetes 1992 Oct
PMID:Immune mechanisms of atherosclerosis in diabetes mellitus. 152 43

The effects of dietary supplementation with omega-3-polyunsaturated fatty acids (omega-3-PUFA) on the proliferative response of PBMC and on the secretion of monokines and arachidonic acid metabolites from PBMC and monocytes (Mo) from healthy subjects and patients with recent-onset insulin-dependent diabetes mellitus (IDDM) were examined. Three groups of eight to nine healthy individuals were randomized to either 2.0 g/day or 4.0 g/day of omega-3-PUFA devoid of vitamins A and D, or an isocaloric amount of placebo. Furthermore, eight patients with recent-onset IDDM received 4.0 g/day of omega-3-PUFA. IL-1 beta production and TNF-alpha secretion was determined before and after 7 weeks of treatment, and 10 weeks after withdrawal of treatment. Significant increases in platelet and PBMC membrane eicosapentaenoic acid was found in omega-3-PUFA-treated individuals. omega-3-PUFA treatment significantly reduced the content of IL-1 beta in lysates of PBMC, but did not affect PBMC or Mo secretion of IL-1 beta, TNF-alpha or prostaglandin E2 (PGE2) or PBMC leukotriene B4 (LTB4) secretion in healthy subjects or in IDDM patients. A significant inhibition of the PHA-stimulated, but not the spontaneous or PPD-stimulated, proliferative response of PBMC was observed in healthy and diabetic subjects treated with omega-3-PUFA. No correlation was found between PHA-stimulated PBMC proliferation and PBMC secretion of TNF-alpha and IL-1 beta. There were no significant differences in the spontaneous or the PPD- or PHA-stimulated proliferative responses of PBMC between diabetic and healthy individuals at entry. We conclude that although dietary supplementation with 4.0 g/day of omega-3-PUFA inhibits the proliferation of PBMC and reduces IL-1 beta immunoreactivity in PBMC and Mo, it does not alter monokine, PGE2 or LTB4, secretion in healthy or IDDM subjects.
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PMID:Dietary supplementation with omega-3-polyunsaturated fatty acids decreases mononuclear cell proliferation and interleukin-1 beta content but not monokine secretion in healthy and insulin-dependent diabetic individuals. 165 17

At present, only islet cell lines of animal origin have been successfully generated (e.g. RIN, HIT). A fully differentiated human beta cell line would be advantageous for diabetes research. We now report the generation of a human endocrine pancreatic cell line obtained by transfection using a plasmid containing the early region of SV40 viral DNA. Viral integration and transcription was assessed by Southern and Northern blotting. This cell line has been growing continuously for more than 2 years and maintains several of the characteristics of the parental cells from which they were generated. The presence of Neuron Specific Enolase, Protein Gene Product 9.5, cytokeratin, microvilli, cytoplasmic electrodense granules and the secretion of insulin, glucagon and somatostatin supports the neuroendocrine origin of this cell line. However, hormone production progressively decreased and finally stopped at passage 8. Flow cytometric analysis showed that HLA expression in this cell line is readily induced by IFN-gamma and modulated by TNF-alpha. The establishment of this human endocrine cell line indicates the feasibility of immortalizing human islets by transfection with viral oncogenes. To obtain a fully differentiated cell line it may be necessary to use other DNA constructs which immortalize the cells without fully transforming their phenotype.
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PMID:Transfection with SV40 gene of human pancreatic endocrine cells. 168 Mar 32

Cytokines are known to play an important role in autoimmunity and have been suggested to be involved in the pathogenesis of insulin-dependent diabetes (IDDM). In the present study we have measured IL-1, IL-2, IL-4, IL-6, interferon-gamma (IFN-gamma) and tumour necrosis factor (TNF) (using both immunoassays and bioassays) in sera from 50 patients affected by IDDM at the time of clinical diagnosis and 51 age and sex matched controls. Detectable levels of IL-1, IL-2, IL-6 and IFN-gamma were found in the serum of a small percentage of subjects and were not significantly different between patients and controls. IL-4 was detectable in a higher number of both patients and controls and circulating TNF-alpha (greater than 1 U/ml) was found in a percentage of patients (24%) significantly higher than controls (P less than 0.01). Raised levels of TNF-alpha were detectable using an immunoenzymatic assay whereas TNF bioactivity in these samples was negligible. We conclude that the presence of immunoreactive TNF-alpha in the patient's sera may reflect an increased localized production of this cytokine at pancreatic level. However, the measurement in serum of other cytokines does not add information on the role that they may play in the pathogenesis of IDDM.
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PMID:Cytokines in sera from insulin-dependent diabetic patients at diagnosis. 193 94

The inbred non-obese diabetic (NOD) mouse is a spontaneous model for insulin-dependent diabetes mellitus (IDDM). As in man and BB rats, IDDM in the NOD mouse has an autoimmune aetiology. The disease is controlled by several genes, one of which, Idd-1, has been mapped to the major histocompatibility complex (MHC) on chromosome 17. However, Idd-1 has not yet been identified. To facilitate the identification of Idd-1 we have further analysed the MHC region for restriction fragment length polymorphisms and we find that the NOD mouse has a distinct haplotype: H-2K1nod Kd A beta nod A alpha d E beta nod TNF-alpha beta. In addition, the NOD mouse shows some similarities with the H-2b haplotype in the Q region, in that either the Q7 or the Q9 gene seems to be like that in the b-haplotype and that the Qa2 antigen is expressed, while other parts of this region are distinct from the b- as well as the d- haplotype. In contrast, the sister strain, the non-obese normal (NON) mouse, derived from the same cataract-prone line of mice as the NOD mouse, has an MHC Class I region indistinguishable from the b-haplotype, but the MHC Class II region is distinct from the NOD mouse as well as the b-, d- and k-haplotype.
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PMID:Restriction fragment length polymorphisms in the major histocompatibility complex of the non-obese diabetic mouse. 197 42

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


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