Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 125, Issue 3, Pages 1163-1173Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI78142
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Categories
Funding
- NIH [DP3DK101122, R01DK057846, R41DK095639, U01DK085466, R03DK102469]
- JDRF [2012-546]
- NIH through National Institute of Diabetes and Digestive and Kidney Diseases
- NIH through National Institute of Allergy and Infectious Diseases
- NIH through Eunice Kennedy Shriver National Institute of Child Health and Human Development [U01 DK061010, U01 DK061016, U01 DK061034, U01 DK061036, U01 DK061040, U01 DK061041, U01 DK061042, U01 DK061055, U01 DK061058, U01 DK084565, U01 DK085453, U01 DK085461, U01 DK085463, U01 DK085499, U01 DK085505, U01 DK085509, HHSN267200800019C]
- National Center for Research Resources [UL1 RR024131, UL1 RR024139, UL1 RR024153, UL1 RR024975, UL1 RR024982, UL1 RR025744, UL1 RR025761, UL1 RR025780, UL1 RR029890, UL1 RR031986, P30 DK017047]
- General Clinical Research Center [M01 RR00400]
- JDRF
- American Diabetes Association
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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 beta 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 beta cell death with an assay that detects beta 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 beta 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 beta cell killing as the result of T1D-associated autoimmunity. Together, the data support the concept that beta cell killing occurs sporadically during the years prior to diagnosis of T1D and is more intense in the peridiagnosis period.
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