Systemic Glucose Homeostasis Requires Pancreatic but Not Neuronal ATP-sensitive Potassium Channels

The adenosine triphosphate (ATP)-sensitive potassium (KATP) channels, composed of Kir6.2 and sulfonylurea receptor 1 (SUR1) subunits, are essential for glucose homeostasis. While the role of pancreatic KATP channels in regulating insulin secretion is well-documented, the specific contributions of neuronal KATP channels remain unclear due to challenges in precisely targeting neuronal subpopulations. In this study, we utilized a Kir6.2 conditional knockout mouse model to distinguish the roles of KATP channels in different cell types. Our findings demonstrate that deletion of neuronal KATP channels does not impair glucose homeostasis, as glucose-sensing neurons retained their responsiveness despite the absence of functional KATP channels. In contrast, the deletion of KATP channels in pancreatic β cells led to significant hyperglycemia and glucose intolerance, indicating unstable blood glucose levels under varying physiological conditions. Importantly, we showed that restoring KATP channel function exclusively in pancreatic β cells within a global Kir6.2 knockout background effectively reversed glucose regulation defects. This underscores the critical role of pancreatic KATP channels in maintaining systemic glucose homeostasis. Our results challenge the previous hypothesis that neuronal KATP channels are essential for glucose regulation, suggesting that their primary function may be neuroprotective rather than homeostatic. These findings highlight pancreatic KATP channels as key regulators of glucose balance and potential therapeutic targets for correcting glucose dysregulation.