DELAYED RECTIFIER K-CELLS ASSOCIATED WITH IMPAIRED GLUCOSE RESPONSIVENESS( CHANNEL OVEREXPRESSION IN TRANSGENIC ISLETS AND BETA)

Glucose stimulation of pancreatic beta-cell insulin secretion is close ly coupled to alterations in ion channel conductances and intracellula r Ca2+ ([Ca2+](i)). To further examine this relationship after augment ation of voltage-dependent K+ channel expression, transgenic mice were produced which specifically overexpress a human insulinoma-derived, t etraethylammonium (TEA)-insensitive delayed rectifier K+ channel in th eir pancreatic beta-cells as shown by immunoblot of isolated islets an d immunohistochemical analysis of pancreas sections. Whole-cell curren t recordings confirmed the presence of high amplitude TEA-resistant K currents in transgenic islet cells, whose expression correlated with hyperglycemia and hypoinsulinemia. Stable overexpression of the channe l in insulinoma cells attenuated glucose-activated increases in [Ca2+] (i) and prevented the induction of TEA-dependent [Ca2+](i) oscillation s. These results, employing the first ion channel transgenic mouse, de monstrate the importance of membrane potential regulation in excitatio n-secretion coupling in the pancreatic beta-cells.