PMID- 38212723 OWN - NLM STAT- MEDLINE DCOM- 20240115 LR - 20240115 IS - 1689-1392 (Electronic) IS - 1425-8153 (Print) IS - 1425-8153 (Linking) VI - 29 IP - 1 DP - 2024 Jan 12 TI - Increased serum extrachromosomal circular DNA SORBS1(circle) level is associated with insulin resistance in patients with newly diagnosed type 2 diabetes mellitus. PG - 12 LID - 10.1186/s11658-023-00530-0 [doi] LID - 12 AB - BACKGROUND: Extrachromosomal circular DNAs (eccDNAs) exist in human blood and somatic cells, and are essential for oncogene plasticity and drug resistance. However, the presence and impact of eccDNAs in type 2 diabetes mellitus (T2DM) remains inadequately understood. METHODS: We purified and sequenced the serum eccDNAs obtained from newly diagnosed T2DM patients and normal control (NC) subjects using Circle-sequencing. We validated the level of a novel circulating eccDNA named sorbin and SH3-domain- containing-1(circle97206791-97208025) (SORBS1(circle)) in 106 newly diagnosed T2DM patients. The relationship between eccDNA SORBS1(circle) and clinical data was analyzed. Furthermore, we explored the source and expression level of eccDNA SORBS1(circle) in the high glucose and palmitate (HG/PA)-induced hepatocyte (HepG2 cell) insulin resistance model. RESULTS: A total of 22,543 and 19,195 eccDNAs were found in serum samples obtained from newly diagnosed T2DM patients and NC subjects, respectively. The T2DM patients had a greater distribution of eccDNA on chromosomes 1, 14, 16, 17, 18, 19, 20 and X. Additionally, 598 serum eccDNAs were found to be upregulated, while 856 eccDNAs were downregulated in T2DM patients compared with NC subjects. KEGG analysis demonstrated that the genes carried by eccDNAs were mainly associated with insulin resistance. Moreover, it was validated that the eccDNA SORBS1(circle) was significantly increased in serum of newly diagnosed T2DM patients (106 T2DM patients vs. 40 NC subjects). The serum eccDNA SORBS1(circle) content was positively correlated with the levels of glycosylated hemoglobin A1C (HbA1C) and homeostasis model assessment of insulin resistance (HOMA-IR) in T2DM patients. Intracellular eccDNA SORBS1(circle) expression was significantly enhanced in the high glucose and palmitate (HG/PA)-induced hepatocyte (HepG2 cell) insulin resistance model. Moreover, the upregulation of eccDNA SORBS1(circle) in the HG/PA-treated HepG2 cells was dependent on generation of apoptotic DNA fragmentation. CONCLUSIONS: These results provide a preliminary understanding of the circulating eccDNA patterns at the early stage of T2DM and suggest that eccDNA SORBS1(circle) may be involved in the development of insulin resistance. CI - (c) 2024. The Author(s). FAU - Kong, Xiang AU - Kong X AUID- ORCID: 0000-0003-1734-5171 AD - Anhui Provincial Key Laboratory of Non-Coding RNA Basic and Clinical Transformation, Wannan Medical College, Wuhu, 241002, China. AD - Geriatric Endocrinology Unit, Department of Gerontology, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu, 241001, China. AD - Central Laboratory of Yijishan Hospital, Wuhu, 241001, China. FAU - Wan, Shu-Jun AU - Wan SJ AD - Anhui Provincial Key Laboratory of Non-Coding RNA Basic and Clinical Transformation, Wannan Medical College, Wuhu, 241002, China. AD - Central Laboratory of Yijishan Hospital, Wuhu, 241001, China. FAU - Chen, Tian-Bing AU - Chen TB AD - Anhui Provincial Key Laboratory of Non-Coding RNA Basic and Clinical Transformation, Wannan Medical College, Wuhu, 241002, China. AD - Central Laboratory of Yijishan Hospital, Wuhu, 241001, China. FAU - Jiang, Lan AU - Jiang L AD - Anhui Provincial Key Laboratory of Non-Coding RNA Basic and Clinical Transformation, Wannan Medical College, Wuhu, 241002, China. AD - Central Laboratory of Yijishan Hospital, Wuhu, 241001, China. FAU - Xing, Yu-Jie AU - Xing YJ AD - Anhui Provincial Key Laboratory of Non-Coding RNA Basic and Clinical Transformation, Wannan Medical College, Wuhu, 241002, China. AD - Geriatric Endocrinology Unit, Department of Gerontology, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu, 241001, China. FAU - Bai, Ya-Ping AU - Bai YP AD - Anhui Provincial Key Laboratory of Non-Coding RNA Basic and Clinical Transformation, Wannan Medical College, Wuhu, 241002, China. FAU - Hua, Qiang AU - Hua Q AD - Department of Endocrinology, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu, 241001, China. FAU - Yao, Xin-Ming AU - Yao XM AD - Department of Endocrinology, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu, 241001, China. FAU - Zhao, Yong-Li AU - Zhao YL AD - Department of Endocrinology, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu, 241001, China. FAU - Zhang, Hong-Mei AU - Zhang HM AD - Department of Endocrinology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200092, China. FAU - Wang, De-Guo AU - Wang DG AD - Geriatric Endocrinology Unit, Department of Gerontology, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, Wuhu, 241001, China. wangdeguo@medmail.com.cn. FAU - Su, Qing AU - Su Q AD - Department of Endocrinology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200092, China. suqing@xinhuamed.com.cn. FAU - Lv, Kun AU - Lv K AD - Anhui Provincial Key Laboratory of Non-Coding RNA Basic and Clinical Transformation, Wannan Medical College, Wuhu, 241002, China. lvkun315@126.com. AD - Central Laboratory of Yijishan Hospital, Wuhu, 241001, China. lvkun315@126.com. LA - eng GR - 81970699/National Natural Science Foundation of China/ PT - Journal Article DEP - 20240112 PL - England TA - Cell Mol Biol Lett JT - Cellular & molecular biology letters JID - 9607427 RN - 9007-49-2 (DNA) RN - 0 (DNA, Circular) RN - 0 (Palmitates) RN - IY9XDZ35W2 (Glucose) RN - 0 (SORBS1 protein, human) RN - 0 (Microfilament Proteins) SB - IM MH - Humans MH - *Insulin Resistance/genetics MH - *Diabetes Mellitus, Type 2/genetics MH - DNA MH - DNA, Circular/genetics MH - Palmitates MH - Glucose MH - Microfilament Proteins/genetics PMC - PMC10785328 OTO - NOTNLM OT - Extrachromosomal circular DNAs OT - Insulin resistance OT - SORBS1 OT - T2DM COIS- Not applicable. EDAT- 2024/01/12 00:42 MHDA- 2024/01/15 12:43 PMCR- 2024/01/12 CRDT- 2024/01/11 23:35 PHST- 2023/07/04 00:00 [received] PHST- 2023/12/21 00:00 [accepted] PHST- 2024/01/15 12:43 [medline] PHST- 2024/01/12 00:42 [pubmed] PHST- 2024/01/11 23:35 [entrez] PHST- 2024/01/12 00:00 [pmc-release] AID - 10.1186/s11658-023-00530-0 [pii] AID - 530 [pii] AID - 10.1186/s11658-023-00530-0 [doi] PST - epublish SO - Cell Mol Biol Lett. 2024 Jan 12;29(1):12. doi: 10.1186/s11658-023-00530-0.