Closure by iptakalim, a cardiovascular K_ATP channel opener, of rat pancreatic β-cell K_ATP channels and its molecular basis

Diabetes mellitus is a group of diseases characterized by high levels of blood glucose resulting from defects in insulin production, insulin action, or both. Diabetes patients usually have accompanying cardiovascular disorders. Sulfonylureas have been the leading oral antihyperglycemic agents for type 2 diabetes treatment, which currently still constitute the most popular anti-diabetic drugs. Nevertheless, concern has arisen over the side effects of sulfonylureas on the cardiovascular system. Here we report that iptakalim, a novel cardiovascular ATP-sensitive potassium (K_ATP) channel opener, closed rat pancreatic β-cell K_ATP channels and increased insulin release. Using whole-cell patch-clamp recordings, iptakalim depolarized β-cells, induced action potential firing and reduced pancreatic K _ATP channel currents. Using single-channel recordings, iptakalim reduced K_ATP channel open-probability independently of intracellular ATP concentrations. We demonstrated that iptakalim elevated intracellular Ca²⁺ concentrations and increased insulin release as revealed by fluorescence imaging (fura-2) and biochemical measurements, respectively. In addition, iptakalim significantly inhibited the open-probability of recombinant Kir6.2/SUR1 and Kir6.2FL4A (a trafficking mutant of the Kir6.2) channels expressed in transfected human embryonic kidney (HEK) 293 cells. Collectively, iptakalim, a cardiovascular K_ATP channel opener, closes rat pancreatic β-cell K_ATP channels, which may result from direct inhibition of the Kir6.2 subunit. Therefore, iptakalim bi-directionally regulates K_ATP channels in cardiovascular and pancreatic tissues, and this unique pharmacological property suggests iptakalim could be used as a new therapeutic strategy for the treatment of type 2 diabetes with the potential benefit in alleviating cardiac and/or vascular disorders frequently associated with diabetes.