Paradoxical maturity-onset diabetes of the young (MODY) arising from loss-of-function mutations in ATP-sensitive potassium channels.

Pancreatic β-cell KATP channel closure underlies electrical excitability and insulin release, but loss or inhibition of KATP channels can lead to paradoxical crossover from hyperinsulinism plus hypoglycemia, to glucose-intolerance or diabetes. We report genotype-phenotype information on a set of patients clinically diagnosed with maturity onset diabetes of the young (MODY), and carrying coding variants in the KATP regulatory subunit gene ABCC8. In contrast to the naïve prediction that diabetes should be associated with KATP gain-of-function (GOF, as in KATP-dependent neonatal diabetes) each mutation caused mild to severe loss-of-function (LOF), through distinct molecular mechanisms, suggesting the affected individuals may have crossed over to glucose intolerance from KATP channel LOF-dependent congenital hyperinsulinism (CHI). Our data provide definitive support for a paradoxical form of MODY in association with KATP channel LOF, genetically and mechanistically distinct from a late diagnosis of diabetes resulting from KATP GOF. To avoid confusion and inappropriate treatment efforts, we argue that diabetes driven by KATP-GOF and KATP-LOF mutations should be officially recognized as distinct diseases.