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 islet beta-cell K(ATP) channels and increased insulin release. Using whole-cell patch-clamp recordings, iptakalim depolarized beta-cells, induced action potential firing and reduced pancreatic KATP channel currents. Using single-channel recordings, iptakalim reduced K(ATP) channel open-probability independently of intracellular ATP concentrations. We demonstrated that iptakalim elevated intracellular calcium 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 KATP channel opener, closes rat islet beta-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 islet 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.
28 Apr - 02 May 2007
European Society of Endocrinology