Long-chain CoA esters activate human pancreatic beta-cell KATP channels:: potential role in Type 2 diabetes

Aims/hypothesis. The ATP-regulated potassium (K-ATP) channel in the pancreatic beta cell couples the metabolic state to electrical activity. The primary regulator of the K-ATP channel is generally accepted to be changes in ATP/ADP ratio, where ATP inhibits and ADP activates channel activity. Recently, we showed that long-chain CoA (LC-CoA) esters form a new class of potent K-ATP channel activators in rodents, as studied in inside-out patches. Methods. In this study we have investigated the effects of LC-CoA esters in human pancreatic beta cells using the inside-out and whole-cell configurations of the patch clamp technique. Results. Human K-ATP channels were potently activated by acyl-CoA esters with a chain length exceeding 12 carbons. Activation by LC-CoA esters did not require the presence of Mg2+ or adenine nucleotides. A detailed characterization of the concentration-dependent relationship showed an EC50 of 0.7+/-0.1 mumol/l. Furthermore, in the presence of an ATP/ADP ratio of 10 (1.1 mmol/l total adenine nucleotides), whole-cell K-ATP channel currents increased approximately six-fold following addition of 1 mumol/l LC-CoA ester. The presence of 1 mumol/l LC-CoA in the recording pipette solution increased beta-cell input conductance, from 0.5+/-0.2 nS to 2.5+/-1.3 nS. Conclusion/interpretation. Taken together, these results show that LC-CoA esters are potent activators of the K-ATP channel in human pancreatic beta cells. The fact that LC-CoA esters also stimulate K-ATP channel activity recorded in the whole-cell configuration, points to the ability of these compounds to have an important modulatory role of human beta-cell electrical activity under both physiological and pathophysiological conditions.