Genetic and clinical insights into acute kidney injury in maturity-onset diabetes of the young caused by the ABCC8 c.2500C>T mutation: Potential risk factors associated with SGLT2 inhibitors

Jing Zou; Xiang Chen; Hong-Ping Yu; Ying Chen; Kai-Ying He; Dan-Dan Ruan; Juan Zhu; Qian Chen; Jian-Hui Zhang; Li Zhang; Yu-Mian Gan; Mei-Zhu Gao; Li Chen; Ji-Xing Liang; Tian-Min Wu; Li-Sheng Liao; Jie-Wei Luo

doi:10.3892/etm.2025.12914

Genetic and clinical insights into acute kidney injury in maturity-onset diabetes of the young caused by the ABCC8 c.2500C>T mutation: Potential risk factors associated with SGLT2 inhibitors

Exp Ther Med. 2025 Jun 26;30(2):164. doi: 10.3892/etm.2025.12914. eCollection 2025 Aug.

Authors

Jing Zou¹, Xiang Chen², Hong-Ping Yu¹, Ying Chen¹, Kai-Ying He³, Dan-Dan Ruan¹, Juan Zhu³, Qian Chen¹, Jian-Hui Zhang¹, Li Zhang¹, Yu-Mian Gan¹, Mei-Zhu Gao¹, Li Chen¹, Ji-Xing Liang⁴, Tian-Min Wu⁵, Li-Sheng Liao⁶, Jie-Wei Luo¹

Affiliations

¹ Department of Traditional Chinese Medicine and Neurology, Shengli Clinical Medical College of Fujian Medical University, Fuzhou University Affiliated Provincial Hospital, Fuzhou, Fujian 350001, P.R. China.
² The First Clinical Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China.
³ Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China.
⁴ Department of Endocrinology, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, Fujian 350001, P.R. China.
⁵ Department of Traditional Chinese Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian 350005, P.R. China.
⁶ Department of Hematology, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, Fujian 350001, P.R. China.

Abstract

Mature-onset diabetes of the young (MODY) is an autosomal dominant genetic disease that is typically diagnosed during childhood or early adolescence. The primary pathogenesis of MODY involves gene mutations that impair insulin synthesis and/or secretion by islet β cells, rendering the condition independent of insulin resistance. A family with the MODY-12 phenotype caused by an ATP-binding cassette subfamily C member 8 (ABCC8) gene mutation was investigated in the present study. Clinical data were collected from all family members, and second-generation gene sequencing and Sanger sequencing were performed. The suspected pathogenic mutation was validated by Sanger sequencing, and the three-dimensional structure of the pathogenic variant protein was predicted and simulated using the Swiss-Model platform. Five individuals with MODY-12, including the proband, were identified in this family. Second-generation gene sequencing confirmed that all family members carried the ABCC8 c.2500C>T (p.Arg834Cys) mutation. Structural modeling revealed that the replacement of arginine at position 834 in the wild-type protein with cysteine results in the formation of an additional hydrogen bond with the surrounding amino acids. In addition, the ABCC8 c.2500C>T carriers in this family experienced recurrent diabetic ketoacidosis and acute kidney involvement (AKI) phenotypes, and all patients had a history of sodium-glucose transporter 2 inhibitor (SGLT2i) use. We hypothesize that AKI in these patients may be pseudo-AKI associated with the use of SGLT2is. However, the proband exhibited symptoms indicative of rapidly progressing diabetic nephropathy. This study demonstrates that clinicians managing patients with MODY should be aware of the risk of acute and serious complications, particularly as SGLT2i may induce pseudo-AKI, which could ultimately compromise patients' long-term renal prognosis.

Keywords: ABCC8; acute renal failure; diabetic ketoacidosis; mature-onset diabetes of the young; sodium-glucose cotransporter 2 inhibitor.