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

Abstract

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.