We discovered numerous congenital diabetes (CD), insulin release-inhibiting mutations in ABCC8/KCNJ11 genes coding for the pancreatic beta-cell (SUR1/Kir6.2)4 KATP channel (Diabetes 53:2719; N Engl J Med 355:456; Diabetes 56:1737; J Biol Chem 283:8778; reviewed in Endocr Rev 29:265). Based on FEBS Lett 445:131; 459:367 and subsequent structure-activity analyses and mechanistic models of KATP channels (reviewed in J Mol Cell Cardiol 39:79), Babenko predicted three possible mechanisms of KATP hyperactivation by mutations in ABCC8 and started testing the hypothesis (DK077827 R01 project ABCC8/KCNJ11 Mechanisms and Diabetes). Following the analysis described in N Engl J Med 355:456 and J Biol Chem 283:8778, we established that the majority of CD mutations which map to the canonical ABC exporter core increase the open channel probability (Po) in intact cells by enhancing the MgATP/ADP-dependent stimulatory action of SUR1 on the channel, without affecting its maximal Po in the absence of nucleotides (Pomax) or its Mg-independent sensitivity to inhibitory ATP, IC50(ATP). This is called the A-type mechanism of KATP hyperactivation. The majority of CD mutations which map to the non-canonical, TMD0-L0 “gatekeeper” (J Biol Chem 278:41577) domain of SUR1 increase Pomax and apparent IC50(ATP). Single-channel kinetics analysis reveals that this effect is due to reciprocal changes in the rates of channel transitions to and from its long-lived closed state with the lowest apparent Kd(ATP) for the inhibitory nucleotide. This establishes the second, or B-type, mechanism of KATP hyperactivity. Although our search for the third, Kd(ATP)-increasing type mutations in ABCC8 continues, we are in the position to conclude that A/B-mechanisms cause the majority of CD-KATP cases and our refined Sav1866/MsbA / KcsA/Kir3.1/BacKir/Chimera-based models of KATP channels help correctly predict the principal effect of the majority of diabetogenic mutations in ABCC8/KCNJ11 on KATP gating.