Abstract
Background: The need for minimally invasive biomarkers for the early diagnosis of type 2 diabetes (T2DM) prior to the clinical onset and monitoring of β-pancreatic cell loss is emerging. Here, we focused on studying circulating cell-free DNA (ccfDNA) as a liquid biopsy biomaterial for accurate diagnosis/monitoring of T2DM. Methods: ccfDNA levels were directly quantified in sera from 96 T2DM patients and 71 healthy individuals via fluorometry, and then fragment DNA size profiling was performed by capillary electrophoresis. Following this, ccfDNA methylation levels of five β-cell-related genes were measured via qPCR. Data were analyzed by automated machine learning to build classifying predictive models. Results: ccfDNA levels were found to be similar between groups but indicative of apoptosis in T2DM. INS (Insulin), IAPP (Islet Amyloid Polypeptide-Amylin), GCK (Glucokinase), and KCNJ11 (Potassium Inwardly Rectifying Channel Subfamily J member 11) levels differed significantly between groups. AutoML analysis delivered biosignatures including GCK, IAPP and KCNJ11 methylation, with the highest ever reported discriminating performance of T2DM from healthy individuals (AUC 0.927). Conclusions: Our data unravel the value of ccfDNA as a minimally invasive biomaterial carrying important clinical information for T2DM. Upon prospective clinical evaluation, the built biosignature can be disruptive for T2DM clinical management.
Highlights
Just under half a billion people are living with diabetes worldwide, and the number is projected to increase by 25% in 2030 and 51% in 2045 [1]
Receiver operating characteristic (ROC) curve analysis showed that GCK methylation could provide high discrimination between Type 2 Diabetes mellitus (T2DM) patients and healthy individuals (AUC 0.848) (Figure 4), while IAPP and KCNJ11 methylation could offer lower discrimination between groups
Were circulating cell-free DNA (ccfDNA) levels were significantly elevated in T2DM patients with or withoutlevels complicasignificantly elevated in patients with or without complications compared to healthy tions compared to healthy individuals, indicating that ccfDNA can be of significant individuals, ccfDNA can be of [33]
Summary
Just under half a billion people are living with diabetes worldwide, and the number is projected to increase by 25% in 2030 and 51% in 2045 [1]. As the number of people with T2DM worldwide keeps on rising, there is an emerging need for the development of minimally invasive biomarkers for the early diagnosis of diabetes as well as the development of monitoring potential, both of which could lead to better therapeutic decisions. Given the significant obstacle of directly accessing the pancreas for biopsy, special attention has been recently given to minimally invasive biomarkers for monitoring or diagnosing the disease early. Towards this direction, epigenetic information detected in circulating cell-free DNA (ccfDNA) is currently tested as a clinically valuable biomarker of β-cell death in Type 1 Diabetes Mellitus (T1DM) by several groups [5–12].
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