Persistent elevations in circulating INS DNA among subjects with longstanding type 1 diabetes

Aim To evaluate whether β cells continue to undergo death in the later stages of type 1 diabetes (T1D). Materials and Methods Fasting banked sera from a cross‐section of 90 participants in the T1D Exchange Registry with longstanding T1D (median duration of 9 years) were analysed. Subjects were determined to be C‐peptide (−) or (+) based on mixed‐meal tolerance testing. Results were compared with 54 adult non‐diabetic controls. Stimulated samples were assayed in a subset of subjects. Levels of unmethylated and methylated preproinsulin ( INS ) DNA were analysed using digital droplet PCR. Results Fasting and stimulated circulating unmethylated INS DNA levels were increased among both C‐peptide (−) and C‐peptide (+) subjects with longstanding T1D compared with non‐diabetic controls ( P < 0.01). Consistent with prior reports, unmethylated INS DNA values correlated with methylated INS DNA values, which were also elevated among T1D subjects ( P < 0.001). There was wide variation in the effects of mixed‐meal stimulation on DNA levels, with fasting values in the highest quartiles decreasing with stimulation ( P < 0.05). Conclusions These results could reflect ongoing β cell death in individuals with longstanding T1D, even in the absence of detectable C‐peptide production, suggesting that therapies targeting β cell survival could be beneficial among individuals with longstanding T1D.