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Mechanism of the Insulin-Releasing Action of -Ketoisocaproate and Related -Keto Acid Anions

Institute of Pharmacology and Toxicology, Technical University of Braunschweig, Braunschweig, Germany (H.H., K.A.U., K.H., U.P.); and Federal Institute for Drugs and Medical Devices, Bonn, Germany (B.J.Z.)

-Ketoisocaproate directly inhibits the ATP-sensitive K⁺ channel (K_ATP channel) in pancreatic -cells, but it is unknown whether direct K_ATP channel inhibition contributes to insulin release by -ketoisocaproate and related -keto acid anions, which are generally believed to act via -cell metabolism. In membranes from HIT-T15 -cells and COS-1 cells expressing sulfonylurea receptor 1, -keto acid anions bound to the sulfonylurea receptor site of the K_ATP channel with affinities increasing in the order -ketoisovalerate < -ketovalerate < -ketoisocaproate < -ketocaproate < -phenylpyruvate. Patch-clamp experiments revealed a similar order for the K_ATP channel-inhibitory potencies of the compounds (applied at the cytoplasmic side of inside-out patches from mouse -cells). These findings were compared with the insulin secretion stimulated in isolated mouse islets by -keto acid anions (10 mM). When all K_ATP channels were closed by the sulfonylurea glipizide, -keto acid anions amplified the insulin release in the order -phenylpyruvate < -ketoisovalerate < -ketovalerate -ketocaproate < -ketoisocaproate. The differences in amplification apparently reflected special features of the metabolism of the individual -keto acid anions. In islets with active K_ATP channels, the first peak of insulin secretion triggered by -keto acid anions was similar for -ketoisocaproate, -ketocaproate, and -phenylpyruvate but lower for -ketovalerate and insignificant for -ketoisovalerate. This difference from the above orders indicates that direct K_ATP channel inhibition is not involved in the secretory responses to -ketoisovalerate and -ketovalerate, moderately contributes to initiation of insulin secretion by -ketoisocaproate and -ketocaproate, and is a major component of the insulin-releasing property of -phenylpyruvate.

Address correspondence to: Dr. Uwe Panten, Institute of Pharmacology and Toxicology, Technical University of Braunschweig, Mendelssohnstrasse 1, D-38106 Braunschweig, Germany. E-mail: u.panten{at}tu-bs.de

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