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 miniglucagon, the C-terminal () 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.
Dalle
S
S
INSERM U376, CHU Arnaud-de-Villeneuve, 34295 Montpellier, France.
Smith
P
P
Blache
P
P
Le-Nguyen
D
D
Le Brigand
L
L
Bergeron
F
F
Ashcroft
F M
FM
Bataille
D
D
D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects* / Q000378:metabolism; D002460:Cell Line; D018679:Cholinergic Agonists / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D005934:Glucagon / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1; D004763:Glucagon-Like Peptides; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D007329:Insulin Antagonists / Q000494:pharmacology*; D000078790:Insulin Secretion; D017136:Ion Transport; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology; D037342:Pertussis Toxin; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D015220:Calcium Channels; D018679:Cholinergic Agonists; D007328:Insulin; D007329:Insulin Antagonists; D010446:Peptide Fragments; D010455:Peptides; D010566:Virulence Factors, Bordetella; D004763:Glucagon-Like Peptides; C039265:glucagon (19-29); D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000242:Cyclic AMP; D037342:Pertussis Toxin; D005947:Glucose; C051322:glucagon-like peptide 1 (7-37); D002118:Calcium