Permanent neonatal diabetes-causing insulin mutations have dominant negative effects on beta cell identity

• Main Authors: Yuwei Zhang (Author), Lina Sui (Author), Qian Du (Author), Leena Haataja (Author), Yishu Yin (Author), Ryan Viola (Author), Shuangyi Xu (Author), Christian Ulrik Nielsson (Author), Rudolph L. Leibel (Author), Fabrizio Barbetti (Author), Peter Arvan (Author), Dieter Egli (Author)
• Format: Book
• Published: Elsevier, 2024-02-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 2212-8778; 10.1016/j.molmet.2024.101879
• Keywords: Insulin; ER stress; iPS cells; Gene correction; Cell therapy; Beta cell de-differentiation; Internal medicine; RC31-1245
• Source: Molecular Metabolism, Vol 80, Iss , Pp 101879- (2024)

Objective: Heterozygous coding sequence mutations of the INS gene are a cause of permanent neonatal diabetes (PNDM), requiring insulin therapy similar to T1D. While the negative effects on insulin processing and secretion are known, how dominant insulin mutations result in a continued decline of beta cell function after birth is not well understood. Methods: We explored the causes of beta cell failure in two PNDM patients with two distinct INS mutations using patient-derived iPSCs and mutated hESCs. Results: we detected accumulation of misfolded proinsulin and impaired proinsulin processing in vitro, and a dominant-negative effect of these mutations on beta-cell mass and function after transplantation into mice. In addition to anticipated ER stress, we found evidence of beta-cell dedifferentiation, characterized by an increase of cells expressing both Nkx6.1 and ALDH1A3, but negative for insulin and glucagon. Conclusions: These results highlight a novel mechanism, the loss of beta cell identity, contributing to the loss and functional failure of human beta cells with specific insulin gene mutations.