BPS2026 – Functional characterization of novel ABCC8 mutations causing loss-of-function of pancreatic KATP channels, but paradoxical diabetes phenotype

ATP sensitive potassium (K ATP ) channels play a critical role in regulating membrane excitability and insulin secretion in pancreatic β cells. Gain-of-function (GOF) mutations in the ABCC8 or KCNJ11 genes (encoding SUR1 and Kir6.2 subunits of the β cell K ATP channel) cause neonatal diabetes mellitus and loss of insulin secretion; loss-of-function (LOF) mutations cause congenital hyperinsulinism (CHI) and increased secretory response. We have recently reported multiple cases of a paradoxical form of maturity onset diabetes of the young (MODY) associated with K ATP LOF, in which patients may have crossed over to glucose intolerance from K ATP LOF-dependent CHI. Here, we have characterized multiple novel mutations in ABCC8 reported in individuals who similarly presented with a MODY diagnosis. Mutant channels were expressed in stable HEK293 cell lines and evaluated with the voltage-sensitive dye DiBAC(4)3 assay and inside-out patch clamp recordings. Novel mutants displayed significantly higher fluorescence than WT under basal conditions, and after activation with diazoxide or oligomycin, reflecting relative depolarization and hence lower K ATP channel activity than WT channels. Inside-out patch clamp recordings showed that reduced channel activity resulted variably from reduced channel density or from reduced Mg-nucleotides activation compared to WT. This study identifies additional mutations causing K ATP LOF in patients with diabetic phenotype, providing definitive support for a paradoxical form of MODY in association with K ATP LOF, genetically and mechanistically distinct from a late diagnosis of diabetes resulting from K ATP GOF. To avoid confusion and inappropriate treatment efforts, we argue that diabetes driven by K ATP -GOF and K ATP -LOF mutations should be officially recognized as distinct diseases.