Update in Type 1 Diabetes

Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Mail Stop B140, P.O. Box 6511, Aurora, Colorado 80045-6511, USA.
Journal of Clinical Endocrinology &amp Metabolism (Impact Factor: 6.21). 08/2007; 92(7):2403-7. DOI: 10.1210/jc.2007-0339
Source: PubMed


Type 1 diabetes is a heterogeneous disorder characterized by severe beta-cell loss. The great majority of patients have type 1A or immune-mediated diabetes.
There has been recent progress in defining the genetics, pathogenesis, and natural history of the disease. In addition, there is a major effort to develop immunotherapies to prevent the disorder and to cure the disease with islet transplantation, and there is potential for dramatic improvement in care with introduction of continuous glucose monitoring devices. The discovery of "metabolic memory" underscores the importance of excellent metabolic control. With comprehensive care, major microvascular complications (e.g. blindness and renal failure) are preventable for most patients.
The existence of multiple "competing" technologies to deal with this devastating disorder holds promise of improved outcomes.

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    • "Type 1 diabetes (T1D) is an autoimmune disease characterized by destruction of the insulin-producing β-cells in the pancreatic islets. Although its etiology is not yet understood, strong genetic and environmental components appear to modulate individual disease susceptibility in patients and in animal models [1]. The cytotoxic T lymphocyte antigen-4 gene (CTLA4) and the gene encoding CD28 have been mapped to chromosome 2q33. "
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    ABSTRACT: In the past decade, a number of case-control studies have been carried out to investigate the relationship between the CTLA4 gene polymorphisms and type 1 diabetes (T1D). However, these studies have yielded contradictory results. To investigate this inconsistency, we performed a meta-analysis of all available studies dealing with the relationship between the CTLA4 polymorphism and T1D. In total, 58 association studies on two CTLA4 polymorphisms (G49A and C60T) and risk of T1D, including a total of 30,723 T1D cases and 45,254 controls were included. In a combined analysis, the summary per-allele odds ratio (OR) for T1D of the G49A and C60T polymorphism was 1.42 [95% confidence interval (CI): 1.31-1.53, P<10(-5)] and 1.23 (95% CI: 1.18-1.29, P<10(-5)), respectively. Significant results were also observed using dominant or recessive genetic model. In the subgroup analysis by ethnicity and sample size, significantly increased risks were also found for these polymorphisms. This meta-analysis demonstrated that the G49A and C60T polymorphism of CTLA4 is a risk factor associated with increased T1D susceptibility, but these associations vary in different ethnic populations.
    PLoS ONE 01/2014; 9(1):e85982. DOI:10.1371/journal.pone.0085982 · 3.23 Impact Factor
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    • "Broken down of immune tolerance often leads to auto-reactive T-cell activation, which is pivotal for the development of autoimmune diseases, including Type 1 diabetes (T1D) [1], [2]. Foxp3+ regulatory T cells (Treg) play a critical role in maintaining self-tolerance, and co-transfer of Treg with pathogenic effector cells can prevent autoimmune disease development [3]–[5]. "
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    ABSTRACT: Foxp3(+) regulatory T cells (Treg) play a crucial role in regulating immune tolerance. The use of Treg to restore immune tolerance is considered an attractive novel approach to inhibit autoimmune disease, including type 1 diabetes (T1D), and to prevent rejection of organ transplants. In view of the goal of developing autologous Treg-based cell therapy for patients with long-term (>15 years) T1D, it will be necessary to expand a sufficient amount of functional Treg in vitro in order to study and compare Treg from T1D patients and healthy subjects. Our results have demonstrated that there is a comparable frequency of Treg in the peripheral blood lymphocytes (PBLs) of patients with long-term T1D relative to those in healthy subjects; however, Th1 cells, but not Th17 cells, were increased in the T1D patients. Further, more Treg in PBLs from T1D patients than from healthy subjects expressed the CD45RO(+) memory cell phenotype, suggesting they were antigen-experienced cells. After isolation, Treg from both T1D patients and healthy subjects were successfully expanded with high purity. Although there was no difference in Helios expression on Treg in PBLs, in vitro expansion led to fewer Helios-expressing Treg from T1D patients than healthy subjects. While more Th1-like Treg expressing IFN-γ or TNF-α were found in the PBLs of T1D patients than healthy controls, there was no such difference in the expanded Treg. Importantly, expanded Treg from both subject groups were able to suppress autologous or allogeneic CD8(+) effector T cells equally well. Our findings demonstrate that a large number of ex vivo expanded functional Treg can be obtained from long-term T1D patients, although fewer expanded Treg expressed a high level of Helios. Thus, based on the positive outcomes, these potent expanded Treg from diabetic human patients may be useful in treating T1D or preventing islet graft rejection.
    PLoS ONE 02/2013; 8(2):e56209. DOI:10.1371/journal.pone.0056209 · 3.23 Impact Factor
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    • "Type 1 diabetes is a complex polygenic disease for which there is a small number of genes with large effects (i.e., HLA) and a large number of genes with small effects (Todd et al. 2007; Barrett et al. 2009). Risk of T1D progression is conferred by specific HLA DR/DQ alleles (e.g., DRB1 Ã 03-DQB1 Ã 0201 [DR3] or DRB1 Ã 04-DQB1 Ã 0302 [DR4]) (Eisenbarth 2007). In addition, HLA alleles such as DQB1 Ã 0602 are associated with dominant protection from T1D in multiple populations (Pugliese et al. 1999). "
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    ABSTRACT: Type 1 diabetes mellitus (T1D) is an autoimmune disease encompassing the T-cell-mediated destruction of pancreatic β cells and the production of autoantibodies against islet proteins. In humoral autoimmunity in T1D, the detection of islet autoantibodies and the examination of their associations with genetic factors and cellular autoimmunity constitute major areas in both basic research and clinical practice. Although insulin is a key autoantigen and may be primus inter pares in importance among T1D autoantigens, an abundant body of research has also revealed other autoantigens associated with the disease process. Solid evidence indicates that autoantibodies against islet targets serve as key markers to enroll newly diagnosed T1D patients and their family members in intervention trials aimed at preventing or halting the disease process. The next challenge is perfecting mechanistic bioassays to be used as end points for disease amelioration following immunomodulatory therapies aimed at blocking immune-mediated β-cell injury and, in turn, preserving β-cell function in type 1 diabetes mellitus.
    Cold Spring Harbor Perspectives in Medicine 10/2012; 2(10). DOI:10.1101/cshperspect.a012831 · 9.47 Impact Factor
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