%0 Journal Article
%T A KATP Channel-Dependent Pathway within ¦Á Cells Regulates Glucagon Release from Both Rodent and Human Islets of Langerhans
%A Patrick E. MacDonald
%A Yang Zhang De Marinis
%A Reshma Ramracheya
%A Albert Salehi
%A Xiaosong Ma
%A Paul R. V. Johnson
%A Roger Cox
%A Lena Eliasson
%A Patrik Rorsman
%J PLOS Biology
%D 2012
%I Public Library of Science (PLoS)
%R 10.1371/journal.pbio.0050143
%X Glucagon, secreted from pancreatic islet ¦Á cells, stimulates gluconeogenesis and liver glycogen breakdown. The mechanism regulating glucagon release is debated, and variously attributed to neuronal control, paracrine control by neighbouring ¦Â cells, or to an intrinsic glucose sensing by the ¦Á cells themselves. We examined hormone secretion and Ca2+ responses of ¦Á and ¦Â cells within intact rodent and human islets. Glucose-dependent suppression of glucagon release persisted when paracrine GABA or Zn2+ signalling was blocked, but was reversed by low concentrations (1¨C20 ¦ÌM) of the ATP-sensitive K+ (KATP) channel opener diazoxide, which had no effect on insulin release or ¦Â cell responses. This effect was prevented by the KATP channel blocker tolbutamide (100 ¦ÌM). Higher diazoxide concentrations (¡Ý30 ¦ÌM) decreased glucagon and insulin secretion, and ¦Á- and ¦Â-cell Ca2+ responses, in parallel. In the absence of glucose, tolbutamide at low concentrations (<1 ¦ÌM) stimulated glucagon secretion, whereas high concentrations (>10 ¦ÌM) were inhibitory. In the presence of a maximally inhibitory concentration of tolbutamide (0.5 mM), glucose had no additional suppressive effect. Downstream of the KATP channel, inhibition of voltage-gated Na+ (TTX) and N-type Ca2+ channels (¦Ø-conotoxin), but not L-type Ca2+ channels (nifedipine), prevented glucagon secretion. Both the N-type Ca2+ channels and ¦Á-cell exocytosis were inactivated at depolarised membrane potentials. Rodent and human glucagon secretion is regulated by an ¦Á-cell KATP channel-dependent mechanism. We propose that elevated glucose reduces electrical activity and exocytosis via depolarisation-induced inactivation of ion channels involved in action potential firing and secretion.
%U http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.0050143