Insulin secretagogues (sulfonylureas and glinides) increase insulin secretion by closing the ATP-sensitive K ؉ channel (K ATP channel) in the pancreatic -cell membrane. K ATP channels subserve important functions also in the heart. First, K ATP channels in coronary myocytes contribute to the control of coronary blood flow at rest and in hypoxia. Second, K ATP channels in the sarcolemma of cardiomyocytes (sarcK ATP channels) are required for adaptation of the heart to stress. In addition, the opening of sarcK ATP channels and of K ATP channels in the inner membrane of mitochondria (mitoK ATP channels) plays a central role in ischemic preconditioning. Opening of sarcK ATP channels also underlies the STsegment elevation of the electrocardiogram, the primary diagnostic tool for initiation of lysis therapy in acute myocardial infarction. Therefore, inhibition of cardiovascular K ATP channels by insulin secretagogues is considered to increase cardiovascular risk. Electrophysiological experiments have shown that the secretagogues differ in their selectivity for the pancreatic over the cardiovascular K ATP channels, being either highly selective (ϳ1,000؋; short sulfonylureas such as nateglinide and mitiglinide), moderately selective (10 -20؋; long sulfonylureas such as glibenclamide [glyburide]), or essentially nonselective (<2؋; repaglinide). New binding studies presented here give broadly similar results. In clinical studies, these differences are not yet taken into account. The hypothesis that the in vitro selectivity of the insulin secretagogues is of importance for the cardiovascular outcome of diabetic patients with coronary artery disease needs to be tested. Diabetes 53 (Suppl. 3):S156 -S164, 2004 I nsulin secretagogues are widely prescribed in the treatment of type 2 diabetes. They close the ATPsensitive K ϩ channel (K ATP channel) in the membrane of the pancreatic -cell, thereby depolarizing the cell and triggering insulin secretion. K ATP channels are gated by intracellular nucleotides with ATP inducing channel closure and MgADP channel opening. The -cell is special in that physiological changes in plasma glucose change the intracellular ATP and ADP concentrations such that the channel opens and closes; hence, the channel functions as the glucose sensor in this cell (1-3). K ATP channel subtypes are found in many cell types. The generation of mice in which the genes for the K ATP channel subunits were deleted have shed new light on the diverse functions of the K ATP channels in various tissues in physiological and pathophysiological conditions (1). In brain, K ATP channels are involved in actions as diverse as the control of glucose homeostasis and the regulation of neuronal excitability in hypoxia (1); however, the insulin secretagogues do not cross the blood-brain barrier easily enough to affect these channels at therapeutic plasma levels (4). In several vascular beds, the K ATP channel in the vascular myocytes is involved in the regulation of vessel tone; opening is triggered in particular by stimuli inc...
ATP-sensitive K ϩ (K ATP ) channels are composed of pore-forming subunits (Kir6.x) and of regulatory subunits, the sulfonylurea receptors (SURx). Subtypes of K ATP channels are expressed in different organs. The sulfonylureas and glinides (insulinotropes) close the K ATP channel in pancreatic -cells and stimulate insulin secretion. The insulinotrope binding site of the pancreatic channel (Kir6.2/SUR1) consists of two overlapping (sub)-sites, site A, located on SUR1 and containing Ser1237 (which in SUR2 is replaced by Tyr1206), and site B, formed by SUR1 and Kir6.2. Insulinotropes bind to the A-, B-, or A ϩ B-site(s) and are grouped accordingly. A-ligands are highly selective in closing the pancreatic channel, whereas B-ligands are nonselective and insensitive to the mutation S1237Y. We have examined the binding of insulinotropes representative of the three groups in [ 3 H]glibenclamide competition experiments to determine the contribution of Kir6.x to binding affinity, the effect of the mutation Y1206S in site A of SUR2, and the subtype selectivity of the compounds. The results show that the bipartite nature of the SUR1 binding site applies also to SUR2. Kir6.2 as part of the B-site may interact directly or allosterically with structural elements common to all insulinotropes, i.e., the negative charge and/or the adjacent phenyl ring. The B-site confers a moderate subtype selectivity on B-ligands. The affinity of B-ligands is altered by the mutation SUR2(Y1206S), suggesting that the mutation affects the binding chamber of SUR2 as a whole or subsite A, including the region where the subsites overlap.Sulfonylureas and glinides (termed here insulinotropes) are used in the therapy of type 2 diabetes. They act by closing the ATP-sensitive K ϩ (K ATP ) channel in pancreatic -cells, thereby inducing depolarization, Ca 2ϩ entry, and insulin secretion (Sturgess et al., 1985; for review, see Proks et al., 2002). K ATP channels are closed by intracellular ATP and opened by MgADP. They are composed of two types of subunits, inwardly rectifying K ϩ channels (Kir6.x), which form the pore of the channel, and sulfonylurea receptors (SURx), which serve as regulatory subunits (Fig. 1). SURs are members of the ATP-binding cassette protein superfamily and carry binding sites for nucleotides, sulfonylureas, and the K ATP channel openers. Both Kir6.x and SURx are encoded by two genes, giving rise to two subtypes each; in addition, alternative splicing of SUR2 results in two major isoforms, SUR2A and SUR2B, which differ in the last 42 amino acids. The K ATP channels in pancreatic -cells have the composition Kir6.2/SUR1, in cardiomyocytes Kir6.2/SUR2A, and in vascular myocytes Kir6.1/SUR2B (Aguilar-Bryan and Bryan, 1999;Gribble and Reimann, 2003;Seino and Miki, 2003). K ATP channels subserve important functions not only in the pancreatic -cells (in which they link the secretion of insulin to the plasma glucose level) but also in other tissues (Seino and Miki, 2003). Hence, the selectivity of the insulinotropes for the panc...
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