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

Multidirectional studies estimating the alterations of cellular immune system in the preclinical phase of type 1 diabetes mellitus create the possibilities for better understanding the mechanisms of the auto-aggression process leading to the pancreatic beta cells destruction and insulin-dependent diabetes mellitus development. In the present review we analyse the recent studies concerning the alterations of the cellular immune markers (ex. peripheral blood lymphocytes subsets, cytokines production or adhesion molecules expression, etc...), which could reflect an early stages of autoimmune process and better identify people at risk of type 1 diabetes mellitus. In summary we suggest that the measurements of new immune markers of prediabetes, together with the estimation of the pancreatic auto-antibodies, genetic risk and age of the studied subjects give the possibility for the better early diagnosis of the people at high risk of type 1 diabetes mellitus development. There is an increasing hope that these markers are useful for the estimation of the efficacy of the preventive therapeutic procedures aiming to type 1 diabetes mellitus protection.
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PMID:[Immune markers in preclinical phases of diabetes type 1. Role of cytokines, adhesion molecules and peripheral blood lymphocyte subpopulations in the pathogenesis and prediction of insulin-dependent diabetes]. 1139 99

Type 1 diabetes (also known as insulin-dependent diabetes mellitus or juvenile-onset diabetes) is usually caused by T cell-mediated autoimmunity, with a prediabetic state characterized by the production of autoantibodies specific for proteins expressed by pancreatic beta cells. The nonobese patient with diabetes (NOD) mouse is a spontaneous model of type 1 diabetes with a strong genetic component that maps to the major histocompatibility complex (MHC) region of the genome. A specific proteasome defect has been identified in NOD mouse in select lymphocytic and monocytic lineages that results from down-regulation of expression of the proteasome subunit LMP2, which is encoded by a gene in the MHC genomic region. This defect prevents the proteolytic processing required for the production and activation of the transcription factor nuclear factor-kappaB (NF-kappaB), which plays important roles in immune and inflammatory responses, as well as increases the susceptibility of the affected cells to apoptosis induced by tumor necrosis factor-alpha (TNF-alpha). The novel role of the proteasome in dysfunction in autoimmunity is presented and documented to be both tissue and developmental stage specific. We propose a role of the proteasome as a step in disease pathogenesis and tissue targeting.
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PMID:Defective function of the proteasome in autoimmunity: involvement of impaired NF-kappaB activation. 1146 44

The clinical presentation of type 1 diabetes is preceded by an asymptomatic latent period characterized by the presence of diabetes-associated autoantibodies in the peripheral circulation, reflecting beta-cell damage. This prediabetic period may last for months and years. Several studies observing genetically susceptible subjects from birth have shown that insulin autoantibodies (IAA) are the first or among the first autoantibodies to appear in young children, implying that insulin may be the primary autoantigen in most cases of childhood type 1 diabetes. About 12-16% of siblings of children with type 1 diabetes have been observed to test positive for at least one diabetes-associated autoantibody, whereas the risk of diabetes among siblings has been estimated to be 6-8%. In parallel, close to 4% of Finnish schoolchildren tested positive for at least one diabetes-associated autoantibody; the lifetime risk of type 1 diabetes in the Finnish population has been estimated to be close to 1%. These observations suggest that only 25-50% of those with signs of beta-cell autoimmunity eventually progress to clinical type 1 diabetes. Accordingly there is a considerable proportion of children in whom beta-cell autoimmunity remains subclinical or is aborted. Positivity for only one diabetes-associated autoantibody may actually represent innocent beta-cell autoimmunity, while positivity for two or more autoantibodies seems to mark a point of no return. The autoimmune response is very dynamic in the early phase of prediabetes, with spreading from one antigen to another and from one epitope to another within a given antigen. In addition both isotype spreading and switching can be observed in early prediabetes. This indicates that the early prediabetic process may be a suitable target for immunomodulation aimed at delaying or preventing progression to clinical diabetes.
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PMID:Natural course of preclinical type 1 diabetes. 1197 15

The patient was an infant with transient hyperglycemia and decreased endogenous insulin secretion on intravenous glucose tolerance test (IVGTT) with the appearance of IA-2 autoantibodies (IA-2Ab), and we speculated that he was in the prediabetes stage. To our knowledge, this is the first case reported to be diagnosed as type 1 diabetes prior to clinical onset in Japan.
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PMID:Early detection of infantile pre-type 1 diabetes case with transient hyperglycemia. 1206 51

Type 1 (insulin-dependent) diabetes mellitus is an autoimmune disease that has no cure. Closed-loop insulin administration strategies and approaches for replacement of the insulin-producing beta cells may offer improved treatments, which could delay or prevent diabetes complications. In the long run, however, prevention of type 1 diabetes in susceptible individuals represents the best chance for reducing the toll of the disease. Prevention of type 1 diabetes will require reliable methods for early diagnosis of predisposition to the disease, using improved genetic and serological screening on a wide scale. Identification of the primary antigenic target(s) for autoimmunity will allow intervention in prediabetes stages aimed at the induction of antigen-specific tolerance. In addition to manipulation of the immune system, the susceptibility of beta cells to autoimmunity could be reduced. A number of genes have been shown to increase beta-cell resistance to immune effector molecules in animal models and cultured beta-cell lines. These genes could be used for preventive gene therapy of type 1 diabetes mellitus if expressed in beta cells prior to the onset of autoimmune destruction. This prospect depends on the development of safe and efficient vectors, and approaches for cell-specific targeting of these vectors to beta cells in vivo.
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PMID:Preventing type 1 diabetes mellitus: the promise of gene therapy. 1208 47

Diabetes mellitus is a heterogeneous disorder. Evidence for heterogeneity is based on measuring endogenous insulin level since some forty years ago. Insulin is lacking at the time of diagnosis in most patients, whose disease started rapidly, with classical symptoms, and who are mainly children, adolescents or young adults. In the majority of middle-aged, obese diabetics, insulin levels are frequently high at diagnosis. Since insulin measuring from sera became a routine laboratory test these two main types were nominated as insulin-dependent, and insulin non-dependent types (IDDM and NIDDM). The aim of the recent classification was, that different diabetic subgroups should be based on etiologic evidence. (Previous classification was based mainly due to the current therapy!). To avoid confusing nominations, the recent classification recommended to abandon the acronyms, IDDM and NIDDM, and only type-1 and type-2 should be used In the third subgroup-other diabetic groups--there are selected many disorders, whose etiology is mostly clear. As fourth subgroup gestational diabetes preserved its previous place. There are some differential-diagnostic problems in between type-1 and type-2 subgroups, especially between lean body weight type-2 and-the newly discovered latent-onset diabetes in adults (LADA). Diagnostic criteria of diabetes and prediabetic states are being changed according to epidemiological data, because type-2 patients die frequently from cardio-cerebrovascular fatal disorders, and elevated blood sugar values-especially postprandially-contribute to it. Thresholds of blood sugar values for diagnosing diabetes are therefore decreasing, and a new category: impaired fasting glucose (IFG, blood sugar: 6, 1-7.0 mmol/l) was introduced. Impaired glucose tolerance (IGT) remained as prediabetic state. IGT + IFG are nominated as impaired glucoregulation. These two categories cover different populations. Oral glucose loading test in most problematic cases should be carried out. The clinical importance of postprandial hyperglycaemia (postprandial state) is discussed. As a new clinical concept, the Metabolic Syndrome seems to replace type-2 diabetes in the majority of these patients, even in the impaired glucose tolerance (IGT) state. Diabetics, carrying the features of this syndrome need holistic care.
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PMID:[New diagnostic and classification system in diabetic syndrome]. 1250 59

Type 1 diabetes mellitus affects about 1 in 300 people in North America and Europe. Epidemiological studies indicate that the incidence and thus prevalence of type 1 diabetes is rising worldwide. Intervention in autoimmune type 1a diabetes could occur at the time of diagnosis or, preferably, prior to clinical presentation during the 'prediabetic' period (e.g. prevention). Prediabetes is best recognised by the detection of islet autoantibodies in the serum. Promising intervention strategies include monoclonal antibody therapies (e.g. anti-CD3, anti-CD25, anti-CD52 or anti-CD20 monoclonal antibodies), immunosuppression (e.g. calcineurin inhibitors, B7 blockade, glucocorticoids, sirolimus (rapamycin), azathioprine or mycophenolate mofetil), immunomodulatory therapies (e.g. plasmapheresis, intravenous immunoglobulin, cytokine administration, adoptive cellular gene therapy) and tolerisation interventions (e.g. autoantigen administration or avoidance, altered peptide ligand or peptide-based therapies). To date, islet and pancreas transplantation have essentially been reserved for patients with long-standing diabetes who have complications and are also in need of a concurrent kidney transplant. None of the therapies attempted to date has produced long-term remissions in new-onset type 1 diabetes patients and no therapies have been shown to prevent the disease. Nevertheless, with advances in our understanding of basic immunology and the cellular and molecular mechanisms of tolerance induction and maintenance, successful intervention therapies will be developed. The balance between safety and efficacy is critical. Higher rates of adverse events might be more tolerable in new-onset type 1 diabetes patients if the therapy is extremely effective at inducing a permanent remission. However, therapies must not harm the beta-cells themselves or any organ system that is a potential target of diabetes complications, such as the nervous system, retina, cardiovascular system or kidney. In the treatment of prediabetes, successful therapies should provide a level of safety similar to that of currently used vaccines and a high level of efficacy.
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PMID:Prevention strategies for type 1 diabetes mellitus: current status and future directions. 1253 19

Pancreatic islets of Langerhans are enveloped by peri-islet Schwann cells (pSC), which express glial fibrillary acidic protein (GFAP) and S100beta. pSC-autoreactive T- and B-cell responses arise in 3- to 4-week-old diabetes-prone non-obese diabetic (NOD) mice, followed by progressive pSC destruction before detectable beta-cell death. Humans with probable prediabetes generate similar autoreactivities, and autoantibodies in islet-cell autoantibody (lCA) -positive sera co-localize to pSC. Moreover, GFAP-specific NOD T-cell lines transferred pathogenic peri-insulitis to NOD/severe combined immunodeficient (NOD/SCID) mice, and immunotherapy with GFAP or S100beta prevented diabetes. pSC survived in rat insulin promoter Iymphocytic choriomeningitis virus (rip-LCMV) glycoprotein/CD8+ T-cell receptor(gp) double-transgenic mice with virus-induced diabetes, suggesting that pSC death is not an obligate consequence of local inflammation and beta-cell destruction. However, pSC were deleted in spontaneously diabetic NOD mice carrying the CD8+/8.3 T-cell receptor transgene, a T cell receptor commonly expressed in earliest islet infiltrates. Autoimmune targeting of pancreatic nervous system tissue elements seems to be an integral, early part of natural type 1 diabetes.
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PMID:Autoimmune islet destruction in spontaneous type 1 diabetes is not beta-cell exclusive. 1256 31

The clinical manifestation of type 1 diabetes mellitus is preceded by an asymptomatic prodromal period called prediabetes or preclinical diabetes. It may last from a few months to several years, during which the autoimmune destruction of the insulin-producing beta-cells in the pancreas progresses. The genes on the human leukocyte antigen (HLA) and insulin gene region are major genetic determinants for genetic disease susceptibility, while dietary compounds and viral infections are the most likely environmental factors contributing to the etiopathogenesis. T cells are thought to be the effector cells for the beta-cell destruction, and glutamic acid decarboxylase, insulinoma-associated protein 2 and insulin represent the three major autoantigens. Autoantibodies are early detectable markers of an ongoing disease process and are used to diagnose prediabetes. Among first-degree relatives of patients with type 1 diabetes, the risk for clinical disease can be graded from <5% in those with one or no antibodies to >90% in individuals who carry the HLA-DQB1*02/0302 risk genotype and are positive for multiple autoantibodies. beta-Cell function may also be tested in autoantibody-positive individuals and low first-phase insulin response is highly predictive for rapid progression to the clinical disease. However, dynamic course and individual variation of the disease process complicates the disease prediction, and it is not known whether all individuals with signs of prediabetes will inevitably progress to clinical type 1 diabetes. Until clinically applicable prevention for the condition exists, the screening for the risk markers of type 1 diabetes should actively be undertaken only in the context of research projects. Several major national and international multicenter studies are ongoing to test the potential of various agents (e.g. insulin and nicotinamide) or early elimination of dietary compounds (e.g. cow's milk proteins) to delay or prevent the onset of clinical type 1 diabetes.
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PMID:Prediabetes in children: natural history, diagnosis, and preventive strategies. 1266 17

We set out to study the association between human leukocyte antigen-defined genetic disease susceptibility and the stage of preclinical type 1 diabetes and whether genetic predisposition affects the natural course of preclinical diabetes in initially nondiabetic siblings of affected children. A total of 701 initially unaffected siblings were graded into four stages of preclinical type 1 diabetes based on the initial number of disease-associated autoantibodies detectable close to the time of diagnosis of the index case: no prediabetes (no antibodies), early (one antibody specificity), advanced (two antibodies), and late prediabetes (three or more antibodies). Another classification system covering 659 siblings was based on a combination of the initial number of antibodies and the first-phase insulin response (FPIR) to iv glucose: no prediabetes (no antibodies), early (one antibody specificity, normal FPIR), advanced (two or more antibodies, normal FPIR), and late prediabetes (at least one antibody, reduced FPIR). Genetic susceptibility to type 1 diabetes was defined by human leukocyte antigen identity and DR and DQ genotypes. There was a higher proportion of siblings with late prediabetes initially among those with strong genetic disease susceptibility than among those with decreased genetic predisposition (16.7% vs. 0.5%; P < 0.001 for DQB1 genotypes according to the first classification), whereas there was a higher proportion of siblings with no signs of prediabetes among those with genotypes conferring decreased risk (91.2% vs. 70.4% among those with high-risk DQB1 genotypes; P < 0.001 according to the first classification). Autoantibodies alone were more sensitive in the prediction of future diabetes in siblings than when combined with genetic susceptibility. Genetic susceptibility played a role in whether the initial prediabetic stage progressed (progression in 29.6% of the high-risk siblings compared with 6.6% of the siblings with DQB1 genotypes conferring decreased risk; P < 0.001 according to the first classification) and whether overt type 1 diabetes became manifest or not. Genetic susceptibility has an impact on both the initiation and progression of the autoimmune process leading to clinical diabetes in siblings of affected children.
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PMID:Genetic modification of risk assessment based on staging of preclinical type 1 diabetes in siblings of affected children. 1278 73

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