2. Academic Validation
  3. Sidt2 inhibits islet β-cell dedifferentiation by regulating insulin secretion

Sidt2 inhibits islet β-cell dedifferentiation by regulating insulin secretion

  • J Biol Chem. 2025 Jul 30;301(9):110544. doi: 10.1016/j.jbc.2025.110544.
Jing Gu 1,  Meng-Xiang Qi 2,  Rui-Xi Zhang 3,  Ying-Ying Song 3,  Xing Hu 3,  Hai-Jun Liu 4,  Ya-Ting Zhang 2,  Wen-Xiu Wu 2,  Ya-Jun Wu 2,  Jia-Hao Xu 2,  Jun-Hao Wang 2,  Jing-Rong Li 2,  Miao-Miao Liu 2,  Wen-Jun Pei 4,  Yao Zhang 5,  Li-Zhuo Wang 6,  Jia-Lin Gao 7
Affiliations

Affiliations

  • 1 Department of Endocrinology and Genetic Metabolism, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, PR China; Institute of Endocrine and Metabolic Diseases, Department of Endocrinology and Genetic Metabolism, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, PR China; Department of Endocrinology, Kunshan Fourth People's Hospital, Kunshan, PR China.
  • 2 Anhui Province Key Laboratory of Biological Macro-molecules Research, Wannan Medical College, Wuhu, PR China.
  • 3 Department of Endocrinology and Genetic Metabolism, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, PR China; Institute of Endocrine and Metabolic Diseases, Department of Endocrinology and Genetic Metabolism, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, PR China.
  • 4 Department of Biochemistry and Molecular Biology, Wannan Medical Collage, Wuhu, PR China.
  • 5 Department of Biochemistry and Molecular Biology, Wannan Medical Collage, Wuhu, PR China; School of Clinical Medicine, Wannan Medical College, Wuhu, PR China.
  • 6 Anhui Province Key Laboratory of Biological Macro-molecules Research, Wannan Medical College, Wuhu, PR China; Department of Biochemistry and Molecular Biology, Wannan Medical Collage, Wuhu, PR China. Electronic address: 20110043@wnmc.edu.cn.
  • 7 Department of Endocrinology and Genetic Metabolism, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, PR China; Institute of Endocrine and Metabolic Diseases, Department of Endocrinology and Genetic Metabolism, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, PR China; Department of Biochemistry and Molecular Biology, Wannan Medical Collage, Wuhu, PR China; Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, PR China. Electronic address: gaojialin-ktz@wnmc.edu.cn.
PMID: 40749831 DOI: 10.1016/j.jbc.2025.110544
Abstract

β-cell dedifferentiation plays an important role in the pathogenesis of type 2 diabetes mellitus (T2DM). SID1 transmembrane family member 2 (Sidt2) is a lysosomal membrane protein known to regulate hepatic steatosis and lipid metabolism. However, its role in pancreatic β-cell dedifferentiation remains unclear. In this study, we found that Sidt2 expression was significantly decreased in diabetic mice and patients, correlating with impaired glucose metabolism. Through in-vitro and in-vivo experiments, we observed that the loss of Sidt2 accelerated β-cell dedifferentiation, as evidenced by an increase in the number of α cells and a marked reduction in key β-cell markers, such as pancreatic and duodenal homeobox 1 (Pdx1), V-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA), and glucose transporter 2 (GLUT2). Moreover, Sidt2 deficiency disrupted islet function, leading to impaired Insulin secretion. Further analyses revealed that the dedifferentiation of β cells induced by Sidt2 deficiency was independent of the Forkhead box protein O1 (FOXO1) pathway, a known regulator of β-cell identity. Instead, the primary mechanism appeared to be related to defects in Insulin secretion. In conclusion, our study identified a novel regulatory mechanism of β-cell dedifferentiation and Insulin secretion mediated by Sidt2. These findings enhance our understanding of the molecular mechanisms underlying β-cell dedifferentiation and offer new perspectives on the pathogenesis of T2DM, supporting the potential of targeting Sidt2 as an innovative therapeutic strategy to preserve β-cell function and to treat this disease.

Keywords

Sidt2; diabetes; insulin secretion; islet β-cell dedifferentiation; islet β-cell identity.

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