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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    • "The disease occurs following an impairment of the mass and/or function of the insulin-producing pancreatic beta-cells [2e4]. The natural history of the disease and the underlying causes are still a matter of debate [5] [6], and the molecular and cellular mechanisms of the disease are not fully understood. This unsatisfactory situation is largely due to the lack of non-invasive techniques that would allow to monitor the onset and the progression of diabetes, specifically by imaging. "
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    ABSTRACT: The monitoring of diabetes mellitus, as it develops and becomes clinically evident, remains a major challenge for diagnostic imaging in clinical practice. Here we present a novel approach to beta-cell imaging by targeting the sulphonylurea receptor subtype 1 (SUR1), using multivalent derivatives of the anti-diabetic drug glibenclamide. Since glibenclamide has a high affinity for SUR1 but does not contain a suitable functional group to be linked to an imaging probe, we have synthesized 11 glibenclamide derivatives and evaluated their affinity to SUR1 in MIN6 cells. The most promising compound has been used to obtain multivalent glibenclamide-polyamidoamine (PAMAM) derivatives, containing up to 15 sulphonylurea moieties per dendrimer. The remaining functional groups on the dendrimers can consecutively be used for labeling with reporter groups for different imaging modalities, thus allowing for multifunctional imaging, and for the modification of pharmacokinetic properties. We synthesized fluorochrome-labeled multivalent probes, that demonstrate in cellular assays affinities to SUR1 in the nanomolar range, superior to native glibenclamide. The probes specifically label MIN6 cells, but not HeLa or PANC-1 cells which do not express SUR1. A very low cytotoxicity of the multivalent probes is demonstrated by the persistent release of insulin from MIN6 cells exposed to high glucose concentrations. Furthermore, the probes display positive labeling of beta-cells of primary mouse and human islet-cells ex vivo and of islets of Langerhans in vivo. The data document that multivalent probes based on glibenclamide derivatives provide a suitable platform for further developments of cell-specific probes, and can be adapted for multiple imaging modalities, including those that are now used in the clinics.
    Biomaterials 10/2015; 75:1-12. DOI:10.1016/j.biomaterials.2015.10.006 · 8.56 Impact Factor
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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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