β cell death and dysfunction during type 1 diabetes development in at-risk individuals

J Clin Invest. 2015 Mar 2;125(3):1163-73. doi: 10.1172/JCI78142. Epub 2015 Feb 2.

Abstract

Role 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.

Background: The 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.

Methods: Here, 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.

Results: In 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.

Conclusion: We 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 registration: Clinicaltrials.gov NCT00097292.

Funding: Funding was from the NIH, the Juvenile Diabetes Research Foundation, and the American Diabetes Association.

Publication types

  • Observational Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Death
  • Child
  • DNA Methylation
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / metabolism
  • Diabetes Mellitus, Type 1 / pathology*
  • Diabetes Mellitus, Type 1 / prevention & control
  • Disease Progression
  • Glucose Intolerance
  • Humans
  • Insulin / genetics
  • Insulin-Secreting Cells / physiology*
  • Prospective Studies
  • Risk

Substances

  • Insulin

Associated data

  • ClinicalTrials.gov/NCT00097292

Grant support