β-cell dedifferentiation in HOMA-βlow and HOMA-βhigh subjects.

Context: β-cell dedifferentiation ratio is increased in type 2 diabetes; but its direct link to in vivo β-cell function in human remains unclear.

Objective: 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.

Methods: We acquired 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 (PCN) or intrapancreatic accessory spleen.

Results: Both β-cell dedifferentiation ratio and dedifferentiation marker (Aldh1a3) were inversely related with in vivo β-cell function (HOMA-β) and in situ β-cell functional markers Glut2 and Ucn3 in human. 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 to 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 human.

Conclusions: Our findings emphasize the contribution of β-cell dedifferentiation to β-cell dysfunction in human. The Bach2 induction in β-cells with higher frequency of dedifferentiation observed in HOMA-βlow subjects reinforce its distinctive role as a pharmaceutical target of β-cell dedifferentiation for the treatment of human diabetes.