Leptin-stimulated K(ATP) channel trafficking: A new paradigm for β-cell stimulus-secretion coupling?

Insulin secretion from pancreatic β-cells is initiated by the closure of ATP-sensitive K(+) channels (K(ATP)) in response to high concentrations of glucose, and this action of glucose is counteracted by the hormone leptin, an adipokine that signals through the Ob-R(b) receptor to increase K(ATP) channel activity. Despite intensive investigations, the molecular basis for K(ATP) channel regulation remains uncertain, particularly from the standpoint of whether fluctuations in plasma membrane K(ATP) channel content underlie alterations of K(ATP) channel activity in response to glucose or leptin. Surprisingly, newly published findings reveal that leptin stimulates AMP-activated protein kinase (AMPK) in order to promote trafficking of K(ATP) channels from cytosolic vesicles to the plasma membrane of β-cells. This action of leptin is mimicked by low concentrations of glucose that also activate AMPK and that inhibit insulin secretion. Thus, a new paradigm for β-cell stimulus-secretion coupling is suggested in which leptin exerts a tonic inhibitory effect on β-cell excitability by virtue of its ability to increase plasma membrane K(ATP) channel density and whole-cell K(ATP) channel current. One important issue that remains unresolved is whether high concentrations of glucose suppress AMPK activity in order to shift the balance of membrane cycling so that K(ATP) channel endocytosis predominates over vesicular K(ATP) channel insertion into the plasma membrane. If so, high concentrations of glucose might transiently reduce K(ATP) channel density/current, thereby favoring β-cell depolarization and insulin secretion. Such an AMPK-dependent action of glucose would complement its established ability to generate an increase of ATP/ADP concentration ratio that directly closes K(ATP) channels in the plasma membrane.