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

Aim To evaluate whether beta cells continue to undergo death in the later stages of type 1 diabetes (T1D). 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. Materials and Methods 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 beta cell death in individuals with longstanding T1D, even in the absence of detectable C-peptide production, suggesting that therapies targeting beta cell survival could be beneficial among individuals with longstanding T1D.