TY - JOUR T1 - Blocking Kir6.2 channels with SpTx1 potentiates glucose-stimulated insulin secretion from murine pancreatic β cells and lowers blood glucose in diabetic mice JF - bioRxiv DO - 10.1101/2022.01.16.476512 SP - 2022.01.16.476512 AU - Yajamana Ramu AU - Jayden Yamakaze AU - Yufeng Zhou AU - Toshinori Hoshi AU - Zhe Lu Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/01/17/2022.01.16.476512.abstract N2 - ATP-sensitive K+ (KATP) channels in pancreatic β cells comprise pore-forming subunits (Kir6.2) and modulatory sulfonylurea receptor subunits (SUR1). The ATP sensitivity of these channels enables them to couple metabolic state to insulin secretion in β cells. Antidiabetic sulfonylureas such as glibenclamide target SUR1 and indirectly suppress Kir6.2 activity. Glibenclamide acts as both primary and secondary secretagogues to trigger insulin secretion and potentiate glucose-stimulated insulin secretion, respectively. We tested whether blocking Kir6.2 itself causes the same effects as glibenclamide, and found that the Kir6.2 pore-blocker SpTx1 acts as a strong secondary, but not a primary, secretagogue. SpTx1 triggered a transient rise of plasma insulin and lowered the elevated blood glucose of diabetic mice over-expressing Kir6.2 but did not affect those of non-diabetic mice. This proof-of-concept study suggests that blocking Kir6.2 may serve as an effective treatment for diabetes and other diseases stemming from Kir6.2 hyperactivity that cannot be suppressed with sulfonylureas.Competing Interest StatementThe authors have declared no competing interest. ER -