Mechanism of the insulin-releasing action of alpha-ketoisocaproate and related alpha-keto acid anions.
Alpha-ketoisocaproate directly inhibits the ATP-sensitive K(+) channel (K(ATP) channel) in pancreatic beta-cells, but it is unknown whether direct K(ATP) channel inhibition contributes to insulin release by alpha-ketoisocaproate and related alpha-keto acid anions, which are generally believed to act via beta-cell metabolism. In membranes from HIT-T15 beta-cells and COS-1 cells expressing sulfonylurea receptor 1, alpha-keto acid anions bound to the sulfonylurea receptor site of the K(ATP) channel with affinities increasing in the order alpha-ketoisovalerate < alpha-ketovalerate < alpha-ketoisocaproate < alpha-ketocaproate < beta-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 beta-cells). These findings were compared with the insulin secretion stimulated in isolated mouse islets by alpha-keto acid anions (10 mM). When all K(ATP) channels were closed by the sulfonylurea glipizide, alpha-keto acid anions amplified the insulin release in the order beta-phenylpyruvate < alpha-ketoisovalerate < alpha-ketovalerate approximately alpha-ketocaproate < alpha-ketoisocaproate. The differences in amplification apparently reflected special features of the metabolism of the individual alpha-keto acid anions. In islets with active K(ATP) channels, the first peak of insulin secretion triggered by alpha-keto acid anions was similar for alpha-ketoisocaproate, alpha-ketocaproate, and beta-phenylpyruvate but lower for alpha-ketovalerate and insignificant for alpha-ketoisovalerate. This difference from the above orders indicates that direct K(ATP) channel inhibition is not involved in the secretory responses to alpha-ketoisovalerate and alpha-ketovalerate, moderately contributes to initiation of insulin secretion by alpha-ketoisocaproate and alpha-ketocaproate, and is a major component of the insulin-releasing property of beta-phenylpyruvate.
Heissig
Henrike
H
Institute of Pharmacology and Toxicology, Technical University of Braunschweig, Mendelssohnstrasse 1, D-38106 Braunschweig, Germany.
Urban
Karin A
KA
Hastedt
Katja
K
Zünkler
Bernd J
BJ
Panten
Uwe
U
D018528:ATP-Binding Cassette Transporters / Q000187:drug effects; D000818:Animals; D000838:Anions; D001549:Benzamides / Q000494:pharmacology; D019556:COS Cells; D006224:Cricetinae; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D007651:Keto Acids / Q000494:pharmacology*; D051379:Mice; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects; D011955:Receptors, Drug / Q000187:drug effects; D064233:Sulfonylurea Receptors
D018528:ATP-Binding Cassette Transporters; D000838:Anions; D001549:Benzamides; D007328:Insulin; D007651:Keto Acids; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; C013082:alpha-ketoisocaproic acid; C030516:meglitinide