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Immune therapy and ?-cell death in type 1 diabetes.

ABSTRACT: Type 1 diabetes (T1D) results from immune-mediated destruction of insulin-producing ?-cells. The killing of ?-cells is not currently measurable; ?-cell functional studies routinely used are affected by environmental factors such as glucose and cannot distinguish death from dysfunction. Moreover, it is not known whether immune therapies affect killing. We developed an assay to identify ?-cell death by measuring relative levels of unmethylated INS DNA in serum and used it to measure ?-cell death in a clinical trial of teplizumab. We studied 43 patients with recent-onset T1D, 13 nondiabetic subjects, and 37 patients with T1D treated with FcR nonbinding anti-CD3 monoclonal antibody (teplizumab) or placebo. Patients with recent-onset T1D had higher rates of ?-cell death versus nondiabetic control subjects, but patients with long-standing T1D had lower levels. When patients with recent-onset T1D were treated with teplizumab, ?-cell function was preserved (P < 0.05) and the rates of ?-cell were reduced significantly (P < 0.05). We conclude that there are higher rates of ?-cell death in patients with recent-onset T1D compared with nondiabetic subjects. Improvement in C-peptide responses with immune intervention is associated with decreased ?-cell death.

SUBMITTER: Lebastchi J

PROVIDER: S-EPMC3636605 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Immune therapy and β-cell death in type 1 diabetes.

Lebastchi Jasmin J Deng Songyan S Lebastchi Amir H AH Beshar Isabel I Gitelman Stephen S Willi Steven S Gottlieb Peter P Akirav Eitan M EM Bluestone Jeffrey A JA Herold Kevan C KC

Diabetes 20130219 5

Type 1 diabetes (T1D) results from immune-mediated destruction of insulin-producing β-cells. The killing of β-cells is not currently measurable; β-cell functional studies routinely used are affected by environmental factors such as glucose and cannot distinguish death from dysfunction. Moreover, it is not known whether immune therapies affect killing. We developed an assay to identify β-cell death by measuring relative levels of unmethylated INS DNA in serum and used it to measure β-cell death i ...[more]

PMID: 23423576

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Project description:UnlabelledRole of the funding source: Funding from the NIH was used for support of the participating clinical centers and the coordinating center. The funding source did not participate in the collection or the analysis of the data.BackgroundThe β cell killing that characterizes type 1 diabetes (T1D) is thought to begin years before patients present clinically with metabolic decompensation; however, this primary pathologic process of the disease has not been measured.MethodsHere, we measured β cell death with an assay that detects β cell-derived unmethylated insulin (INS) DNA. Using this assay, we performed an observational study of 50 participants from 2 cohorts at risk for developing T1D from the TrialNet Pathway to Prevention study and of 4 subjects who received islet autotransplants.ResultsIn at-risk subjects, those who progressed to T1D had average levels of unmethylated INS DNA that were elevated modestly compared with those of healthy control subjects. In at-risk individuals that progressed to T1D, the observed increases in unmethylated INS DNA were associated with decreases in insulin secretion, indicating that the changes in unmethylated INS DNA are indicative of β cell killing. Subjects at high risk for T1D had levels of unmethylated INS DNA that were higher than those of healthy controls and higher than the levels of unmethylated INS DNA in the at-risk progressor and at-risk nonprogressor groups followed for 4 years. Evaluation of insulin secretory kinetics also distinguished high-risk subjects who progressed to overt disease from those who did not.ConclusionWe conclude that a blood test that measures unmethylated INS DNA serves as a marker of active β cell killing as the result of T1D-associated autoimmunity. Together, the data support the concept that β cell killing occurs sporadically during the years prior to diagnosis of T1D and is more intense in the peridiagnosis period.Trial registrationClinicaltrials.gov NCT00097292.FundingFunding was from the NIH, the Juvenile Diabetes Research Foundation, and the American Diabetes Association.

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Immune therapy and ?-cell death in type 1 diabetes.

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Immune therapy and β-cell death in type 1 diabetes.

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