A KATP Channel-Dependent Pathway within α Cells Regulates Glucagon Release from Both Rodent and Human Islets of Langerhans

• Published in: PLoS biology 2007-05, Vol.5 (6), p.e143
• Main Authors: MacDonald, Patrick E, Marinis, Yang Zhang De, Ramracheya, Reshma, Salehi, Albert, Ma, Xiaosong, Johnson, Paul R. V, Cox, Roger, Eliasson, Lena, Rorsman, Patrik
• Format: Article
• Language: English
• Subjects: Diabetes and Endocrinology; Homo (human); In Vitro; Physiology; Rattus (rat)
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.0050143

Glucagon, secreted from pancreatic islet α cells, stimulates gluconeogenesis and liver glycogen breakdown. The mechanism regulating glucagon release is debated, and variously attributed to neuronal control, paracrine control by neighbouring β cells, or to an intrinsic glucose sensing by the α cells themselves. We examined hormone secretion and Ca 2+ responses of α and β cells within intact rodent and human islets. Glucose-dependent suppression of glucagon release persisted when paracrine GABA or Zn 2+ signalling was blocked, but was reversed by low concentrations (1–20 μM) of the ATP-sensitive K + (K ATP ) channel opener diazoxide, which had no effect on insulin release or β cell responses. This effect was prevented by the K ATP channel blocker tolbutamide (100 μM). Higher diazoxide concentrations (≥30 μM) decreased glucagon and insulin secretion, and α- and β-cell Ca 2+ responses, in parallel. In the absence of glucose, tolbutamide at low concentrations (10 μM) were inhibitory. In the presence of a maximally inhibitory concentration of tolbutamide (0.5 mM), glucose had no additional suppressive effect. Downstream of the K ATP channel, inhibition of voltage-gated Na + (TTX) and N-type Ca 2+ channels (ω-conotoxin), but not L-type Ca 2+ channels (nifedipine), prevented glucagon secretion. Both the N-type Ca 2+ channels and α-cell exocytosis were inactivated at depolarised membrane potentials. Rodent and human glucagon secretion is regulated by an α-cell K ATP 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. Elevated glucose levels reduce electrical activity and the release of glucagon via inactivation of ion channels in pancreatic islet cells.