| 1. |
- Larsson, K, et al.
(författare)
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Genetic and perinatal factors as risk for childhood type 1 diabetes
- 2004
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Ingår i: Diabetes/Metabolism Research & Reviews. - : Wiley. - 1520-7552. ; 20:6, s. 429-437
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Forskningsöversikt (refereegranskat)abstract
- The mechanisms by which gestational infections, blood incompatibility, birth weight, mother's age and other prenatal or neonatal events increase the risk for type 1 diabetes are not understood. Studies so far have been retrospective, and there is a lack of population-based prospective studies. The possibility identifying children at type 1 diabetes risk among first-degree relatives has resulted in prospective studies aimed at identifying postnatal events associated with the appearance of autoantibody markers for type 1 diabetes and a possible later onset of diabetes. However, the majority (85%) of new onset type 1 diabetes children do not have a first-degree relative with the disease. Population-based studies are therefore designed to prospectively analyse pregnant mothers and their offspring. One such study is DiPiS (Diabetes Prediction in Skane), which is examining a total of about 10 000 pregnancies expected every year in the Skane (Scania) region of Sweden that has 1.1 million inhabitants. Blood samples from all mothers in this region are obtained during pregnancy and at the time of delivery. Cord blood is analysed for HLA high-risk alleles and for autoantibodies against the 65 kD isoform of glutamic acid decarboxylase (GADA), the protein tyrosine phosphatase-related IA-2 antigen (IA-2A) and insulin (IAA) as a measure of prenatal autoimmune exposure. Identifying high-risk children by genetic, autoimmune and gestational risk factors followed by prospective analyses will make it possible to test the hypothesis that gestational events may trigger beta cell autoimmunity as a prerequisite for childhood type 1 diabetes. Copyright (C) 2004 John Wiley Sons, Ltd.
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| 2. |
- Elding Larsson, Helena, et al.
(författare)
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Does immune-tolerance treatment with Alum-formulated GAD65 protect insulin-production in the pancreatic islet β cells?
- 2011
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Ingår i: Human Vaccines. - : Informa UK Limited. - 1554-8600 .- 1554-8619. ; 7:1, s. 45-49
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Forskningsöversikt (refereegranskat)abstract
- Type 1 diabetes is a serious chronic disease in which the pancreatic islet beta cells are destroyed by autoimmunity specifically directed to intracellular autoantigens. Still undefined environmental factors are likely to initiate the disease process. One of the autoantigens is glutamic acid decarboxylase (GAD65) and attempts are made to induce immunological tolerance against this autoantigen. Alum-formulated GAD65 (Diamyd (®)) has been given subcutaneously in two injections with one month apart to recent onset type 1 diabetes patients with positive GAD65 autoantibodies. The injections were found to preserve residual β-cell function without treatment related serious adverse events. Phase III studies in children with recent onset type 1 diabetes are ongoing along with a study (DIAPREV-IT) aimed at testing whether Diamyd (®) may prevent the clinical onset of diabetes in non-diabetic children with GAD65 autoantibodies and at least one more islet autoantibody. Future studies may include investigation of Diamyd (®) in combination with other immunomodulating autoantigens.
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| 3. |
- Lernmark, Åke
(författare)
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Environmental factors in the etiology of type 1 diabetes, celiac disease, and narcolepsy
- 2016
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Ingår i: Pediatric Diabetes. - : Hindawi Limited. - 1399-543X. ; 17:S22, s. 65-72
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Forskningsöversikt (refereegranskat)abstract
- The etiology of human leukocyte antigen (HLA)-associated organ-specific autoimmune diseases is incomplete. In type 1 diabetes and celiac disease, the strongest associations are with the HLA-DR3-DQ2 and DR4-DQ8 haplotypes, whereas the DQB1*06:02 allele has a strong negative association. In contrast, narcolepsy, especially as recently triggered by the Pandemrix® H1N1 vaccine (GlaxoKlineSmith (GSK), Brentford, Middlesex, UK), did not seem to develop without at least one copy of the latter allele. The overall hypothesis is that the role of these different HLA haplotypes, especially in Finland and Sweden, is related to the immune response to infectious agents that are common in these two populations. The high incidence of both type 1 diabetes and celiac disease in Scandinavia may be the result of the HLA-DR3-DQ2 and DR4-DQ8 haplotypes, and the DQB1*06:02 allele are common because they protected people from succumbing to common infections. The timing of dissecting the autoimmune response is critical to understand the possible role of environmental factors. First, an etiological trigger may be a common virus infecting beta cells or with antigens inducing beta-cell cross reactivity. Second, an autoimmune reaction may ensue, perhaps in response to beta-cell apoptosis or autophagy, resulting in autoantigen-specific T cells and autoantibodies. It is critical in at-risk children to dissect the immune response prior to the appearance of autoantibodies in order to identify cellular reactions in response to environmental factors that are able to induce an HLA-associated immune reaction.
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| 4. |
- Lernmark, Åke, et al.
(författare)
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Immune therapy in type 1 diabetes mellitus.
- 2013
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Ingår i: Nature Reviews Endocrinology. - : Springer Science and Business Media LLC. - 1759-5037 .- 1759-5029. ; 9:2, s. 92-103
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Forskningsöversikt (refereegranskat)abstract
- Type 1 diabetes mellitus (T1DM) is an autoimmune disorder directed against the β cells of the pancreatic islets. The genetic risk of the disease is linked to HLA-DQ risk alleles and unknown environmental triggers. In most countries, only 10-15% of children or young adults newly diagnosed with T1DM have a first-degree relative with the disease. Autoantibodies against insulin, GAD65, IA-2 or the ZnT8 transporter mark islet autoimmunity. These islet autoantibodies may already have developed in children of 1-3 years of age. Immune therapy in T1DM is approached at three different stages. Primary prevention is treatment of individuals at increased genetic risk. For example, one trial is testing if hydrolyzed casein milk formula reduces T1DM incidence in genetically predisposed infants. Secondary prevention is targeted at individuals with persistent islet autoantibodies. Ongoing trials involve nonautoantigen-specific therapies, such as Bacillus Calmette-Guérin vaccine or anti-CD3 monoclonal antibodies, or autoantigen-specific therapies, including oral and nasal insulin or alum-formulated recombinant human GAD65. Trial interventions at onset of T1DM have also included nonautoantigen-specific approaches, and autoantigen-specific therapies, such as proinsulin peptides. Although long-term preservation of β-cell function has been difficult to achieve in many studies, considerable progress is being made through controlled clinical trials and animal investigations towards uncovering mechanisms of β-cell destruction. Novel therapies that prevent islet autoimmunity or halt progressive β-cell destruction are needed.
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| 5. |
- Lernmark, Åke, et al.
(författare)
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Possible heterogeneity of initial pancreatic islet beta-cell autoimmunity heralding type 1 diabetes
- 2023
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Ingår i: Journal of Internal Medicine. - 1365-2796. ; 294:2, s. 145-158
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Forskningsöversikt (refereegranskat)abstract
- The etiology of type 1 diabetes foreshadows the pancreatic islet beta-cell autoimmune pathogenesis that heralds the clinical onset of type 1 diabetes. Standardized and harmonized tests of autoantibodies against insulin (IAA), glutamic acid decarboxylase (GADA), islet antigen-2 (IA-2A) and ZnT8 transporter (ZnT8A) allowed children to be followed from birth until the appearance of a first islet autoantibody. In the Environmental Determinants of Diabetes in the Young (TEDDY) study, a multicenter (Finland, Germany, Sweden and the US) observational study, children were identified at birth for the type 1 diabetes high risk HLA haplogenotypes DQ2/DQ8, DQ2/DQ2, DQ8/DQ8 and DQ4/DQ8. The TEDDY study was preceded by smaller studies in Finland, Germany, Colorado, Washington and Sweden. The aims were to follow children at increased genetic risk to identify environmental factors that trigger the first-appearing autoantibody (etiology) and progress to type 1 diabetes (pathogenesis). The larger TEDDY study found that the incidence rate of the first-appearing autoantibody was split into two patterns. IAA first peaked already during the first year of life and tapered off by 3-4 years of age. GADA first appeared by 2-3 years of age to reach a plateau by about 4 years. Prior to the first-appearing autoantibody, genetic variants were either common or unique to either pattern. A split was also observed in whole blood transcriptomics, metabolomics, dietary factors and exposures such as gestational life events and early infections associated with prolonged shedding of virus. An innate immune reaction prior to the adaptive response cannot be excluded. Clarifying the mechanisms by which autoimmunity is triggered to either insulin or GAD65 is key to uncovering the aetiology of autoimmune type 1 diabetes. This article is protected by copyright. All rights reserved.
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| 6. |
- Leslie, R David, et al.
(författare)
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Diabetes at the crossroads: relevance of disease classification to pathophysiology and treatment.
- 2016
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 59:1, s. 13-20
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Forskningsöversikt (refereegranskat)abstract
- Diabetes is not a single homogeneous disease but composed of many diseases with hyperglycaemia as a common feature. Four factors have, historically, been used to identify this diversity: the age at onset; the severity of the disease, i.e. degree of loss of beta cell function; the degree of insulin resistance and the presence of diabetes-associated autoantibodies. Our broad understanding of the distinction between the two major types, type 1 diabetes mellitus and type 2 diabetes mellitus, are based on these factors, but it has become apparent that they do not precisely capture the different disease forms. Indeed, both major types of diabetes have common features, encapsulated by adult-onset autoimmune diabetes and maturity-onset diabetes of the young. As a result, there has been a repositioning of our understanding of diabetes. In this review, drawing on recent literature, we discuss the evidence that autoimmune type 1 diabetes has a broad clinical phenotype with diverse therapeutic options, while the term non-autoimmune type 2 diabetes obscures the optimal management strategy because it encompasses substantial heterogeneity. Underlying these developments is a general progression towards precision medicine with the need for precise patient characterisation, currently based on clinical phenotypes but in future augmented by laboratory-based tests. Key points • The need to clarify diabetes classification, which is currently imprecise in distinguishing major disease types, using laboratory tests • The importance of predictors of disease progression, including genetic, immune and metabolic features • The potential for predicting therapeutic responses to provide a more personalised approach to therapy.
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| 7. |
- Regnell, Simon, et al.
(författare)
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Hepatic steatosis in type 1 diabetes
- 2011
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Ingår i: Review of Diabetic Studies. - 1613-6071. ; 8:4, s. 454-467
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Forskningsöversikt (refereegranskat)abstract
- Islet autoimmunity in type 1 diabetes results in the loss of the pancreatic β-cells. The consequences of insulin deficiency in the portal vein for liver fat are poorly understood. Under normal conditions, the portal vein provides 75% of the liver blood supply. Recent studies suggest that non-alcoholic fatty liver disease (NAFLD) may be more common in type 1 diabetes than previously thought, and may serve as an independent risk marker for some chronic diabetic complications. The pathogenesis of NAFLD remains obscure, but it has been hypothesized that hepatic fat accumulation in type 1 diabetes may be due to lipoprotein abnormalities, hyperglycemia-induced activation of the transcription factors carbohydrate response element-binding protein (ChREBP) and sterol regulatory element-binding protein 1c (SREBP-1c), upregulation of glucose transporter 2 (GLUT2) with subsequent intrahepatic fat synthesis, or a combination of these mechanisms. Novel approaches to non-invasive determinations of liver fat may clarify the consequences for liver metabolism when the pancreas has ceased producing insulin. This article aims to review the factors potentially contributing to hepatic steatosis in type 1 diabetes, and to assess the feasibility of using liver fat as a prognostic and/or diagnostic marker for the disease. It provides a background and a case for possible future studies in the field.
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| 8. |
- Uibo, Raivo, et al.
(författare)
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GAD65 Autoimmunity-Clinical Studies
- 2008
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Ingår i: Advances in Immunology. - 0065-2776. ; 100, s. 39-78
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Forskningsöversikt (refereegranskat)abstract
- Type 1 diabetes (TID) in children and particularly in teenagers and adults is strongly associated with autoreactivity to the Mr 65,000 isoform of glutamic acid decarboxylase (GAD65). Autoantibodies to GAD65 are common at the time of clinical diagnosis and may be present for years prior to the onset of hyperglycemia. GAD65 autoantibodies predict conversion to insulin dependence when present in patients classified with type 2 diabetes nowadays more often referred to as patients with latent autoimmune diabetes in the adult (LADA) or type 1,5 diabetes. Analyses of T cells with HLA DRB1*0401-tetramers with GAD65-specific peptides as well as of anti-idiotypic GAD65 autoantibodies suggest that GAD6S auto-reactivity is common. The immunological balance is disturbed and the appearance of GAD65 autoantibodies represents markers of autoreactive loss of pancreatic beta cells. Extensive experimental animal research. in particular of the Non-obese diabetic (NOD) mouse, showed that GAD65 therapies reduce insulitis and prevent spontaneous diabetes. Recombinant human GAD65 produced by current Good Manufacturing Practice (cGMP) and formulated with alum was found to be safe in Phase I and 11 placebo-controlled, double-blind, randomized clinical trials. The approach to modulate GAD65 autoreactivity with subcutaneous immunotherapy (SCIT) showed promise as alum-formulated GAD65 induced a dose-dependent reduction in the disappearance rate of endogenous residual C-peptide production. Additional controlled clinical trials are needed to uncover the mechanisms by which subcutaneous injections of recombinant human GAD65 may alter GAD6S autoreactivity.
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