Abstract
Pancreatic β-cell ATP-sensitive K+ (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 from 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 naive 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. Our data provide definitive support for a paradoxical form of MODY associated with KATP channel LOF that is genetically and mechanistically distinct from a late diagnosis of neonatal 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. ARTICLE HIGHLIGHTS: Gain-of-function (GOF) ATP-sensitive K+ (KATP) mutations cause neonatal diabetes mellitus. KATP 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 KATP mutations? KATP 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 KATP-associated MODY resulting from GOF and LOF, respectively, with very different clinical and therapeutic implications.