2399-P: Defining the Phenotypic Characteristics of an ABCC8 Loss-of-Function Variant and Its Response to Diazoxide

Introduction and Objective: ABCC8 encodes the SUR1 subunit of the β-cell KATP channel, a key regulator of insulin secretion. The role of the rare ABCC8 R306C variant in diabetes is unclear. This study aimed to determine whether this variant is loss-of-function and causes diabetes, and to evaluate the therapeutic potential of diazoxide. Methods: In our previous study, ABCC8 p.R306C was found to be possibly loss-of-function and was associated with diabetes. Using CRISPR/CAS9, we generated global ABCC8 p.R306C knock-in (MU) mice and wildtype (WT) littermates. Mice were fed with normal diet (ND) or diet containing the KATP channel opener diazoxide (DIA) from 8 to 50 weeks of age. Plasma glucose tolerance test (GTT) and insulin levels, along with pancreatic and renal morphology, were evaluated in different animal groups. Results: MU mice fed with ND developed early hyperinsulinemia at the age of 8 weeks, while there was no difference in fasting blood glucose levels. Then they progressed to diabetes from 24-week to 50-week compared to WT mice. At 50 weeks, they exhibited pancreatic structural injury and early kidney damage, mirroring human variant carriers. Furthermore, mice fed with diet added DIA exhibited significantly lower insulin levels and reduced blood glucose compared to those fed with ND with the same genotype. DIA treatment also ameliorated pancreatic injury. Conclusion: We conclude that the ABCC8 p.R306C is loss-of-function and causative for diabetes. Diazoxide ameliorates the resulting hyperinsulinemia and hyperglycemia, supporting its potential as a treatment for diabetes caused by inactivate ABCC8 variants. Disclosure M. Li: None. X. Han: None. L. Zhou: None. L. Ji: None. Funding the Peking University People's Hospital Research and Development Fund (RDY2019-21 and RDJP2024-28), and the 2024 National Clinical Key Specialty Construction Program of China (Department of Endocrinology, Peking University People's Hospital) with support from the central government budget