Saturated and cis/trans unsaturated acyl CoA esters differentially regulate wild-type and polymorphic β-cell ATP-sensitive K+ channels

Abstract

Metabolic regulation of pancreatic β-cell ATP-sensitive K+ channel (KATP channel) function plays a key role in the process of glucose-stimulated insulin secretion (GSIS). Modulation of KATP channel activity by long-chain acyl CoAs represents an important endogenous regulatory mechanism. Elevated acyl CoA levels have been reported in obese and type 2 diabetic individuals and may contribute to reduced β-cell excitability and impaired GSIS. Recent studies suggest that the composition of dietary fat may influence the effects of high-fat feeding on impaired GSIS. Therefore, we examined the effects of side-chain length and the degree of saturation of various acyl CoAs on KATP channel activity. Macroscopic currents from either wild-type or polymorphic (Kir6.2[E23K/I337V]) recombinant β-cell KATP channels were measured in inside-out patches by exposing the inner surface of the membrane to acyl CoAs at physiological nanomolar concentrations. Acyl CoAs increased both wild-type and polymorphic KATP channel activity with the following rank order of efficacy: C18:0, C18: 1trans ∼ C18:1cis, C20:4 = C16:0, C16:1, and C18:2. A significant correlation exists between activation and acyl CoA hydrophobicity, suggesting that both side-chain length and degree of saturation are critical determinants of KATP channel activation. Our observations reveal a plausible mechanism behind the disparate effects of acyl CoA saturation on KATP channel activation and suggest that dietary fat composition may determine the severity of impaired GSIS via differential activation of β-cell KATP channels. © 2005 by the American Diabetes Association.