Immune Therapy and β-Cell Death in Type 1 Diabetes

  1. Kevan C. Herold1
  1. 1Departments of Immunobiology and Internal Medicine and Surgery, Yale University School of Medicine, New Haven, Connecticut
  2. 2Department of Pediatrics, University of California, San Francisco, San Francisco, California
  3. 3Department of Endocrinology, Children’s Hospital of Philadelphia, and Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
  4. 4Department of Internal Medicine, University of Colorado at Denver, Aurora, Colorado
  5. 5Diabetes and Obesity Center, Winthrop University Hospital, Mineola, New York
  6. 6Department of Internal Medicine, University of California, San Francisco, San Francisco, California
  1. Corresponding author: Kevan C. Herold, kevan.herold{at}yale.edu.

Abstract

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 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 β-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, β-cell function was preserved (P < 0.05) and the rates of β-cell were reduced significantly (P < 0.05). We conclude that there are higher rates of β-cell death in patients with recent-onset T1D compared with nondiabetic subjects. Improvement in C-peptide responses with immune intervention is associated with decreased β-cell death.

Footnotes

  • Received September 2, 2012.
  • Accepted November 23, 2012.

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  1. Diabetes vol. 62 no. 5 1676-1680
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