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J Biol Chem, Vol. 274, Issue 16, 10869-10876, April 16, 1999

Miniglucagon (Glucagon 19-29), a Potent and Efficient Inhibitor of Secretagogue-induced Insulin Release through a Ca²⁺ Pathway

Stéphane Dalle, Paul Smith, Philippe Blache, Dung Le-Nguyen, Laurence Le Brigand, François Bergeron, Frances M. Ashcroft, and Dominique Bataille

From INSERM U376, CHU Arnaud-de-Villeneuve, 34295 Montpellier, France and the  University Laboratory of Physiology, Oxford University, Parks Road, Oxford OX1 3PT, United Kingdom

Using the MIN6 B-cell line, we investigated the hypothesis that miniglucagon, the C-terminal (19-29) fragment processed from glucagon and present in pancreatic A cells, modulates insulin release, and we analyzed its cellular mode of action. We show that, at concentrations ranging from 0.01 to 1000 pM, miniglucagon dose-dependently (ID₅₀ = 1 pM) inhibited by 80-100% the insulin release triggered by glucose, glucagon, glucagon-like peptide-1-(7-36) amide (tGLP-1), or glibenclamide, but not that induced by carbachol. Miniglucagon had no significant effects on cellular cAMP levels. The increase in ⁴⁵Ca²⁺ 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 experiments indicated that miniglucagon induces membrane hyperpolarization, probably by opening potassium channels, which terminated glucose-induced electrical 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 closing, via hyperpolarization, voltage-dependent Ca²⁺ channels linked to a pathway involving a pertussis toxin-sensitive G protein.

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