Genetics, pathogenesis and clinical interventions in type 1 diabetes.
Ontology highlight
ABSTRACT:
SUBMITTER: Bluestone JA
PROVIDER: S-EPMC4959889 | biostudies-literature | 2010 Apr
REPOSITORIES: biostudies-literature
Publications
Genetics, pathogenesis and clinical interventions in type 1 diabetes.
Bluestone Jeffrey A JA Herold Kevan K Eisenbarth George G
Nature 20100401 7293
Type 1 diabetes is an autoimmune disorder afflicting millions of people worldwide. Once diagnosed, patients require lifelong insulin treatment and can experience numerous disease-associated complications. The last decade has seen tremendous advances in elucidating the causes and treatment of the disease based on extensive research both in rodent models of spontaneous diabetes and in humans. Integrating these advances has led to the recognition that the balance between regulatory and effector T c ...[more]
Similar Datasets
Project description:With rapidly increasing prevalence, diabetes has become one of the major causes of mortality worldwide. According to the latest studies, genetic information makes substantial contributions towards the prediction of diabetes risk and individualized antidiabetic treatment. To date, approximately 70 susceptibility genes have been identified as being associated with type 2 diabetes (T2D) at a genome-wide significant level (P < 5 × 10(-8)). However, all the genetic loci identified so far account for only about 10% of the overall heritability of T2D. In addition, how these novel susceptibility loci correlate with the pathophysiology of the disease remains largely unknown. This review covers the major genetic studies on the risk of T2D based on ethnicity and briefly discusses the potential mechanisms and clinical utility of the genetic information underlying T2D.
| S-EPMC4016836 | biostudies-literature
Project description:A large proportion of heritability of type 2 diabetes (T2D) has been attributed to inherent genetics. Recent genetic studies, especially genome-wide association studies (GWAS), have identified a multitude of variants associated with T2D. It is thus reasonable to question if these findings may be utilized in a clinical setting. Here we briefly review the identification of risk loci for T2D and discuss recent efforts and propose future work to utilize these loci in clinical setting-for the identification of individuals who are at particularly high risks of developing T2D and for the stratification of specific health-care approaches for those who would benefit most from such interventions.
| S-EPMC4488669 | biostudies-literature
Project description:Type 1 diabetes is an autoimmune disease, hence the rationale for immunotherapy to halt disease progression. Based on knowledge gained from other autoimmune diseases and from transplantation, the first immunointervention trials used immunosuppressive drugs, e.g., cyclosporin, in patients with recently diagnosed type 1 diabetes. Although remarkable, the effect vanished following drug withdrawal. Efforts were then devoted to devise strategies to induce/restore self-tolerance and avoid chronic immunosuppression. Various approaches were identified from work in spontaneous models of autoimmune diabetes, including the use of ?-cell autoantigens and monoclonal antibodies directed at relevant immune molecules such as costimulatory ligands, T-cell receptor molecules such as CD3, and B cells. Phase II and phase III trials were launched, results of which are now available. Although the endeavor is challenging, the experience gained indicates that immunotherapy appears as the real hope of inducing long-term remission of the disease provided the treatment is started early and that protocols are adapted based on lessons from the past.
| S-EPMC3405831 | biostudies-literature
Project description:To provide an overview of the genetics of type 2 diabetes in the context of recent progress in the understanding of the genetic architecture of the disease and its applicability to the pathogenesis of the disease as well as efforts to individualize therapy in type 2 diabetes. Efforts are underway to understand how these loci alter measurable physiologic processes in nondiabetic humans. However, it is important to understand the potential pitfalls in such studies and the limitations underlying measurement of insulin secretion and action using qualitative methodologies.The availability of large population-based cohorts and the ease with which large numbers of common genetic variants can be genotyped has enabled the discovery of multiple loci and pathways associated with type 2 diabetes. Recent efforts examining quantitative traits such as fasting glucose concentrations have led to the discovery of other genes likely to be important in the development of diabetes.The past 4 years have witnessed a significant increase in our understanding of genetic predisposition to type 2 diabetes. Hopefully more progress will be made in applying this knowledge to the pathophysiology of type 2 diabetes in the coming years.
| S-EPMC2953639 | biostudies-literature
Project description:BACKGROUND:Type 1 diabetes, a multifactorial disease with a strong genetic component, is caused by the autoimmune destruction of pancreatic ? cells. The major susceptibility locus maps to the HLA class II genes at 6p21, although more than 40 non-HLA susceptibility gene markers have been confirmed. CONTENT:Although HLA class II alleles account for up to 30%-50% of genetic type 1 diabetes risk, multiple non-MHC loci contribute to disease risk with smaller effects. These include the insulin, PTPN22, CTLA4, IL2RA, IFIH1, and other recently discovered loci. Genomewide association studies performed with high-density single-nucleotide-polymorphism genotyping platforms have provided evidence for a number of novel loci, although fine mapping and characterization of these new regions remain to be performed. Children born with the high-risk genotype HLADR3/4-DQ8 comprise almost 50% of children who develop antiislet autoimmunity by the age of 5 years. Genetic risk for type 1 diabetes can be further stratified by selection of children with susceptible genotypes at other diabetes genes, by selection of children with a multiple family history of diabetes, and/or by selection of relatives that are HLA identical to the proband. SUMMARY:Children with the HLA-risk genotypes DR3/4-DQ8 or DR4/DR4 who have a family history of type 1 diabetes have more than a 1 in 5 risk for developing islet autoantibodies during childhood, and children with the same HLA-risk genotype but no family history have approximately a 1 in 20 risk. Determining extreme genetic risk is a prerequisite for the implementation of primary prevention trials, which are now underway for relatives of individuals with type 1 diabetes.
| S-EPMC4874193 | biostudies-literature
Project description:Type 1 diabetes (T1D) results from immune-mediated loss of pancreatic beta cells leading to insulin deficiency. It is the most common form of diabetes in children, and its incidence is on the rise. This article reviews the current knowledge on the genetics of T1D. In particular, we discuss the influence of HLA and non-HLA genes on T1D risk and disease progression through the preclinical stages of the disease, and the development of genetic scores that can be applied to disease prediction. Racial/ethnic differences, challenges and future directions in the genetics of T1D are also discussed.
| S-EPMC5918237 | biostudies-literature
Project description:ContextOver the last few months, genome-wide association studies have contributed significantly to our understanding of the genetic architecture of type 2 diabetes. If and how this information will impact clinical practice is not yet clear.Evidence acquisitionPrimary papers reporting genome-wide association studies in type 2 diabetes or establishing a reproducible association for specific candidate genes were compiled. Further information was obtained from background articles, authoritative reviews, and relevant meeting conferences and abstracts.Evidence synthesisAs many as 17 genetic loci have been convincingly associated with type 2 diabetes; 14 of these were not previously known, and most of them were unsuspected. The associated polymorphisms are common in populations of European descent but have modest effects on risk. These loci highlight new areas for biological exploration and allow the initiation of experiments designed to develop prediction models and test possible pharmacogenetic and other applications.ConclusionsAlthough substantial progress in our knowledge of the genetic basis of type 2 diabetes is taking place, these new discoveries represent but a small proportion of the genetic variation underlying the susceptibility to this disorder. Major work is still required to identify the causal variants, test their role in disease prediction and ascertain their therapeutic implications.
| S-EPMC2626447 | biostudies-literature
Project description:The global epidemic of type 2 diabetes mellitus (T2D) is one of the most challenging problems of the 21(st) century leading cause of and the fifth death worldwide. Substantial evidence suggests that T2D is a multifactorial disease with a strong genetic component. Recent genome-wide association studies (GWAS) have successfully identified and replicated nearly 75 susceptibility loci associated with T2D and related metabolic traits, mostly in Europeans, and some in African, and South Asian populations. The GWAS serve as a starting point for future genetic and functional studies since the mechanisms of action by which these associated loci influence disease is still unclear and it is difficult to predict potential implication of these findings in clinical settings. Despite extensive replication, no study has unequivocally demonstrated their clinical role in the disease management beyond progression to T2D from impaired glucose tolerance. However, these studies are revealing new molecular pathways underlying diabetes etiology, gene-environment interactions, epigenetic modifications, and gene function. This review highlights evolving progress made in the rapidly moving field of T2D genetics that is starting to unravel the pathophysiology of a complex phenotype and has potential to show clinical relevance in the near future.
| S-EPMC3521576 | biostudies-literature
Project description:Since fulminant type 1 diabetes was reported as a distinct subtype of type 1 diabetes in 2000, the Committee on Type 1 diabetes, Japan Diabetes Society has continuously recruited patients and conducted genomic research to elucidate the genetic basis of fulminant type 1 diabetes. The contribution of the human leukocyte antigen complex (HLA) to genetic susceptibility to fulminant type 1 diabetes was compared with that of other subtypes in 2009. The alleles and haplotypes associated with fulminant type 1 diabetes were found to be different from acute-onset and slowly progressive type 1 diabetes. DRB1*15:01-DQB1*06:02, a protective haplotype against acute-onset type 1 diabetes, does not provide protection against fulminant type 1 diabetes and DRB1*08:02-DQB1*03:02, a susceptible haplotype to acute-onset type 1 diabetes, does not confer susceptibility to fulminant type 1 diabetes. Recently, the first genome-wide association study (GWAS) of fulminant type 1 diabetes was performed in Japanese individuals. A strong association was observed with multiple single nucleotide polymorphisms (SNPs) in the HLA region, and the strongest association was observed with rs9268853 in the class II DR region. In addition, 11 SNPs outside the HLA region showed some evidence of association with the disease. In particular, rs11170445 in CSAD/lnc-ITGB7-1 on chromosome 12q13.13 showed an association at a genome-wide significance level. Fine mapping revealed that rs3782151 in CSAD/lnc-ITGB7-1 showed the lowest P value. CSAD/lnc-ITGB7-1 was found to be strongly associated with susceptibility to fulminant, but not classical, autoimmune type 1 diabetes, implicating this locus in the distinct phenotype of fulminant type 1 diabetes.
| S-EPMC7538480 | biostudies-literature
Project description:BackgroundDiabetes mellitus (DM) is one of the world's greatest health threats with rising prevalence. Global digitalization leads to new digital approaches in diabetes management, such as telemedical interventions. Telemedicine, which is the use of information and communication technologies, may provide medical services over spatial distances to improve clinical patient outcomes by increasing access to diabetes care and medical information.ObjectiveThis study aims to examine whether telemedical interventions effectively improve diabetes control using studies that pooled patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), and whether the benefits are greater in patients diagnosed with T2DM than in those diagnosed with T1DM. We analyzed the primary outcome glycated hemoglobin A1c (HbA1c) and the secondary outcomes fasting blood glucose (FBG), blood pressure (BP), body weight, BMI, quality of life (QoL), cost, and time saving.MethodsPublications were systematically identified by searching Cochrane Library, MEDLINE via PubMed, Web of Science Core Collection, Embase, and CINAHL databases for studies published between January 2008 and April 2020, considering systematic reviews (SRs), meta-analyses (MAs), randomized controlled trials (RCTs), and clinical trials (CTs). Study quality was assessed using the A Measurement Tool to Assess Systematic Reviews, Effective Public Health Practice Project, and National Institute for Health and Care Excellence qualitative checklist. We organized the trials by communication technologies in real-time video or audio interventions, asynchronous interventions, and combined interventions (synchronous and asynchronous communication).ResultsFrom 1116 unique citations, we identified 31 eligible studies (n=15 high, n=14 moderate, n=1 weak, and n=1 critically low quality). We selected 21 SRs and MAs, 8 RCTs, 1 non-RCT, and 1 qualitative study. Of the 10 trials, 3 were categorized as real-time video, 1 as real-time video and audio, 4 as asynchronous, and 2 as combined intervention. Significant decline in HbA1c levels based on pooled T1DM and T2DM patients data ranged from -0.22% weighted mean difference (WMD; 95% CI -0.28 to -0.15; P<.001) to -0.64% mean difference (95% CI -1.01 to -0.26; P<.001). The intervention effect on lowering HbA1c values might be significantly smaller for patients with T1DM than for patients with T2DM. Evidence on the impact on BP, body weight, FBG, cost effectiveness, and time saving was smaller compared with HbA1c but indicated potential in some publications.ConclusionsTelemedical interventions might be clinically effective in improving diabetes control overall, and they might significantly improve HbA1c concentrations. Patients with T2DM could benefit more than patients with T1DM regarding lowering HbA1c levels. Further studies with longer duration and larger cohorts are necessary.
| S-EPMC7935656 | biostudies-literature