Metabolite-Regulated ATP-Sensitive K+ Channel in Human Pancreatic Islet Cells

Abstract

In patch-clamped surface cells of human islets, we identified an inwardly rectifying, voltage-independent K+ channel that may be a crucial link between substrate metabolism and depolarization-induced insulin secretion. It is the major channel open at rest. It closes on exposure of the cell to secretagogue concentrations of glucose or other metabolic fuels and oral hypoglycemic sulfonylureas but reopens on addition of either a metabolic inhibitor that prevents substrate utilization or the hyperglycemic sulfonamide diazoxide. Onset of electrical activity coincides with channel closure by the secretagogues. In excised patches, the activity of this channel is inhibited at its cytoplasmic surface by ATP. These results suggest that in humans, as in rodents, 1) rises in cytoplasmic ATP levels during substrate metabolism trigger K+-channel closure and cell depolarization and 2) clinically useful sulfonamides modulate glucose-induced insulin secretion, in part by affecting a readily identifiable resting conductance pathway for K+.

Insulin Secretagogues, But Not Glucose, Stimulate an Increase in [Ca2+]i in the Fetal Rat β-cell

“…4, Table 1), thus demonstrating that membrane depolarization results in an increase in [Ca 2+ ]j. The response to arginine was abolished by diazoxide, a specific K + ATP channel activator in fJ-cells that prevents the membrane from depolarizing (33,45). Exposure of the fetal islets to 300 |xmol/l diazoxide, in the absence of arginine, did not cause a significant decrease in [Ca 2+ ]i from the resting levels during a 5-min exposure.…”

“…Leucine is also metabolized to ATP, thereby increasing the ATP:ADP ratio and closing the K + ATP channels in (U-cells (31)(32)(33)(34), leading to an increase in [Ca 2+ ]j. Exposure of the fetal islets (from 16 days gestation onward) to a 5-min pulse .…”

Cardioprotection by glucose-insulin-potassium: dependence on KATPchannel opening and blood glucose concentration before ischemia

“…The previous and present results support the contention that glucose, a known regulator of pancreatic K ATP channels (2), impairs activation of myocardial K ATP channels. Increasing glucose concentration within a physiological range from 3 to 6.5 mM is sufficient to close K ATP channels within 1-3 min in pancreatic islet cells (23). This effect occurs concomitantly with increases in ATP concentration generated by oxidative substrate metabolism.…”

Action of imipramine on activated ATP-sensitive K+ channels in interstitial cells of Cajal from murine small intestine

“…ATP-sensitive K + channels are found in a number of tissues including pancreatic B cells, smooth muscle cells and neuronal cells (Misler et al, 1989;Standen et al, 1989;Mourre et al, 1990). Generally, it is considered that ATP-sensitive K + channels stabilize the resting membrane potential and determines cell excitability.…”