Miniglucagon (glucagon 19-29), a potent and efficient inhibitor of secretagogue-induced insulin release through a Ca2+ pathway

Using the MIN6 B-cell line, we investigated the hypothesis that miniglucago n, the C-terminal (19-29) fragment processed from glucagon and present in p ancreatic A cells, modulates insulin release, and we analyzed its cellular mode of action. We show that, at concentrations ranging from 0.01 to 1000 p hr, miniglucagon dose-dependently (ID50 = 1 pM) inhibited by 80-100% the in sulin release triggered by glucose, glucagon, glucagonlike peptide-1-(7-36) amide (tGLP-1), or glibenclamide, but not that induced by carbachol, Minig lucagon had no significant effects on cellular cAMP levels. The increase in Ca-45(2+) uptake induced by depolarizing agents (glucose or extracellular K+), by glucagon, or by the Ca2+ channel agonist Bay K-8644 was blocked by miniglucagon at the doses active on insulin release. Electrophysiological e xperiments indicated that miniglucagon induces membrane hyperpolarization, probably by opening potassium channels, which terminated glucose-induced el ectrical activity. Pretreatment with pertussis toxin abolished the effects of miniglucagon on insulin release. It is concluded that miniglucagon is a highly potent and efficient inhibitor of insulin release by dosing, via hyp erpolarization, voltage-dependent Ca2+ channels linked to a pathway involvi ng a pertussis toxin-sensitive G protein.