Plasma Extrachromosomal Circular DNA is a Pathophysiological Hallmark of Short‐term Intensive Insulin Therapy for Type 2 Diabetes

Abstract Background Extrachromosomal circular DNA (eccDNA) has emerged as a promising biomarker for disease diagnosis and prognosis prediction. However, its role in type 2 diabetes remains unexplored. Objective To investigate the characteristics and dynamics of circulating eccDNAs in newly diagnosed type 2 diabetes mellitus (T2DM) patients undergoing short‐term intensive insulin therapy (SIIT), a highly effective treatment for inducing long‐term glycemic remission. Methods We conducted Circle‐Seq analysis on plasma samples from 35 T2DM patients at three time points: pre‐SIIT, post‐SIIT, and 1‐year post‐SIIT. Our analysis encompassed the characterization of eccDNA features, including GC content, eccDNA length distribution, genomic distribution, and the genes in eccDNAs. Results Following SIIT, we observed an increase in plasma eccDNA load, suggesting metabolic alterations during therapy. Notably, a correlation was identified between eccDNA profiles and glycemia in T2DM, both quantitatively and genetically. Our analysis also revealed the frequent presence of metabolism‐related genes within T2DM plasma eccDNAs, some of which spanned gene exons and/or fractions. Conclusion This study represents the first report of cell‐free eccDNA in T2DM and underscores a compelling association between cell‐free eccDNA and profound glycemic changes. These findings highlight the potential of eccDNAs as crucial players in the context of T2DM and glycemic control.