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

ABSTRACT: AIM:To evaluate whether ? 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 ? cell death in individuals with longstanding T1D, even in the absence of detectable C-peptide production, suggesting that therapies targeting ? cell survival could be beneficial among individuals with longstanding T1D.

SUBMITTER: Neyman A

PROVIDER: S-EPMC6281817 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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

Neyman Anna A Nelson Jennifer J Tersey Sarah A SA Mirmira Raghavendra G RG Evans-Molina Carmella C Sims Emily K EK

Diabetes, obesity & metabolism 20180824 1

<h4>Aim</h4>To evaluate whether β cells continue to undergo death in the later stages of type 1 diabetes (T1D).<h4>Materials and methods</h4>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 subject ...[more]

PMID: 30073765

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Project description:BackgroundIdentification of islet β cell death prior to the onset of type 1 diabetes (T1D) or type 2 diabetes (T2D) might allow for interventions to protect β cells and reduce diabetes risk. Circulating unmethylated DNA fragments arising from the human INS gene have been proposed as biomarkers of β cell death, but this gene alone may not be sufficiently specific to report β cell death.ResultsTo identify new candidate genes whose CpG sites may show greater specificity for β cells, we performed unbiased DNA methylation analysis using the Infinium HumanMethylation 450 array on 64 human islet preparations and 27 non-islet human tissues. For verification of array results, bisulfite DNA sequencing of human β cells and 11 non-β cell tissues was performed on 5 of the top 10 CpG sites that were found to be differentially methylated. We identified the CHTOP gene as a candidate whose CpGs show a greater frequency of unmethylation in human islets. A digital PCR strategy was used to determine the methylation pattern of CHTOP and INS CpG sites in primary human tissues. Although both INS and CHTOP contained unmethylated CpG sites in non-islet tissues, they occurred in a non-overlapping pattern. Based on Naïve Bayes classifier analysis, the two genes together report 100% specificity for islet damage. Digital PCR was then performed on cell-free DNA from serum from human subjects. Compared to healthy controls (N = 10), differentially methylated CHTOP and INS levels were higher in youth with new onset T1D (N = 43) and, unexpectedly, in healthy autoantibody-negative youth who have first-degree relatives with T1D (N = 23). When tested in lean (N = 32) and obese (N = 118) youth, increased levels of unmethylated INS and CHTOP were observed in obese individuals.ConclusionOur data suggest that concurrent measurement of circulating unmethylated INS and CHTOP has the potential to detect islet death in youth at risk for both T1D and T2D. Our data also support the use of multiple parameters to increase the confidence of detecting islet damage in individuals at risk for developing diabetes.

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

Publications

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

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