Mechanism of the insulin-releasing action of alpha-ketoisocaproate and related alpha-keto acid anions

Mol Pharmacol. 2005 Oct;68(4):1097-105. doi: 10.1124/mol.105.015388. Epub 2005 Jul 13.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / drug effects
  • Animals
  • Anions
  • Benzamides / pharmacology
  • COS Cells
  • Cricetinae
  • Insulin / metabolism*
  • Insulin Secretion
  • Islets of Langerhans / drug effects*
  • Islets of Langerhans / metabolism
  • Keto Acids / pharmacology*
  • Mice
  • Potassium Channels / drug effects
  • Potassium Channels / metabolism*
  • Potassium Channels, Inwardly Rectifying / drug effects
  • Receptors, Drug / drug effects
  • Sulfonylurea Receptors

Substances

  • ATP-Binding Cassette Transporters
  • Anions
  • Benzamides
  • Insulin
  • Keto Acids
  • Potassium Channels
  • Potassium Channels, Inwardly Rectifying
  • Receptors, Drug
  • Sulfonylurea Receptors
  • alpha-ketoisocaproic acid
  • meglitinide