What question did this study set out to answer?

To investigate the effects of novel ABCC8 mutations on pancreatic KATP channels and their paradoxical association with diabetes.

February 21, 2026

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

Key Points

To investigate the effects of novel ABCC8 mutations on pancreatic KATP channels and their paradoxical association with diabetes.
Characterized novel ABCC8 mutations in stable HEK293 cell lines
Evaluated channel activity using DiBAC(4)3 fluorescence assay
Conducted inside-out patch clamp recordings to assess channel functionality
Novel ABCC8 mutations linked to diminished KATP channel activity were identified
Mutant channels showed increased fluorescence under basal conditions indicating reduced activity
Results suggest a distinct diabetic phenotype associated with KATP loss-of-function mutations

Abstract

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.

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