Paradoxical Maturity-Onset Diabetes of the Young Arising From Loss-of-Function Mutations in ATP-Sensitive Potassium Channels

Pancreatic β-cell ATP-sensitive K + (K ATP ) channel closure underlies electrical excitability and insulin release, but loss or inhibition of K ATP channels can lead to paradoxical crossover from hyperinsulinism plus hypoglycemia, to glucose intolerance or diabetes. We report genotype-phenotype information from a set of patients clinically diagnosed with maturity-onset diabetes of the young (MODY) and carrying coding variants in the K ATP regulatory subunit gene ABCC8. In contrast to the naive prediction that diabetes should be associated with K ATP gain-of-function (GOF; as in K ATP -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 K ATP channel LOF-dependent congenital hyperinsulinism. Our data provide definitive support for a paradoxical form of MODY associated with K ATP channel LOF that is genetically and mechanistically distinct from a late diagnosis of neonatal 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. Article Highlights Gain-of-function (GOF) ATP-sensitive K + (K ATP ) mutations cause neonatal diabetes mellitus. K ATP mutations are also associated with maturity-onset diabetes of the young (MODY), but the molecular cause is not clear. What are the molecular consequences of MODY-associated K ATP mutations? K ATP mutations from a large group of patients with MODY were all associated with loss-of-function (LOF) of different molecular etiologies. There are two distinct forms of K ATP -associated MODY resulting from GOF and LOF, respectively, with very different clinical and therapeutic implications.