β-Cell Dedifferentiation in HOMA-βlow and HOMA-βhigh Subjects

• Published in: The journal of clinical endocrinology and metabolism Vol. 110; no. 5; p. e1430
• Main Authors: Kang, Fuyun, Zhang, Zhuo, Fu, Hui, Sun, Jiajun, Zhang, Jun, Wang, Qidi
• Format: Journal Article
• Language: English
• Published: United States 22.04.2025
• Subjects: Adult; Aged; Aldehyde Oxidoreductases - metabolism; Cell Dedifferentiation - physiology; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - pathology; Female; Glucose Transporter Type 2 - metabolism; Homeostasis - physiology; Humans; Insulin Resistance - physiology; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; Insulin-Secreting Cells - physiology; Male; Middle Aged; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Bach2; HOMA-β; β-cell dedifferentiation; type 2 diabetes
• ISSN: 1945-7197
• DOI: 10.1210/clinem/dgae538

β-Cell dedifferentiation ratio is increased in type 2 diabetes; but its direct link to in vivo β-cell function in human remains unclear. The present study was designed to investigate whether β-cell dedifferentiation in situ was closely associated with β-cell function in vivo and to identify targets crucial for β-cell dedifferentiation/function in human. We acquired homeostasis model assessment of β-cell function (HOMA-β) values, calculated the number of hormone-negative endocrine cells, and evaluated important markers and novel candidates for β-cell dedifferentiation/function on paraneoplastic pancreatic tissues from 13 patients with benign pancreatic cystic neoplasm or intrapancreatic accessory spleen. Both the β-cell dedifferentiation ratio and the dedifferentiation marker (Aldh1a3) were inversely related to in vivo β-cell function (HOMA-β) and in situ β-cell functional markers Glut2 and Ucn3 in humans. Moreover, the islets from HOMA-βlow subjects were manifested as (1) increased β-cell dedifferentiation ratio, (2) enriched dedifferentiation maker Aldh1a3, and (3) lower expression of Glut2 and Ucn3 compared with those from HOMA-βhigh subjects. We found that basic leucine zipper transcription factor 2 (Bach2) expression was significantly induced in islets from HOMA-βlow patients and was positively correlated with the ratio of β-cell dedifferentiation in humans. Our findings emphasize the contribution of β-cell dedifferentiation to β-cell dysfunction in humans. Bach2 induction in β-cells with higher frequency of dedifferentiation observed in HOMA-βlow subjects reinforces its distinctive role as a pharmaceutical target of β-cell dedifferentiation for the treatment of people with diabetes.