oxyntomodulin and glucagon-(19-29)

Topics: Amino Acid Sequence; Animals; Endopeptidases; Female; Gastric Mucosa; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Intestine, Small; Islets of Langerhans; Male; Molecular Sequence Data; Muscle, Smooth; Organ Specificity; Peptide Biosynthesis; Peptide Fragments; Peptides; Protein Precursors; Protein Processing, Post-Translational

Topics: Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Multigene Family; Peptide Fragments; Peptides; Protein Precursors

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.

Topics: Calcium; Calcium Channels; Cell Line; Cholinergic Agonists; Cyclic AMP; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose; Insulin; Insulin Antagonists; Insulin Secretion; Ion Transport; Islets of Langerhans; Membrane Potentials; Peptide Fragments; Peptides; Pertussis Toxin; Virulence Factors, Bordetella

Miniglucagon, or glucagon-[19-29], is partially processed from glucagon in its target tissues where it modulates the glucagon action. In the islets of Langerhans, the glucagon-producing A cells contain miniglucagon at a significant level (2-5% of the glucagon content). We studied a possible control of insulin release by miniglucagon using as a model the MIN6 cell line. Miniglucagon, in the 10(-14) to 10(-9) M range, inhibited insulin release induced by glucose, glucagon, tGLP-1, or glibenclamide by 85-100% with an IC50 close to 1 pM. While no change in the cyclic AMP content was noted, Ca2+ influx was reduced in parallel with the inhibition of insulin release. Use of pharmacological modulators of L-type voltage-sensitive Ca2+ channels and bacterial toxins indicates that miniglucagon blocks insulin release by closing this type of channel via a pertussis toxin-sensitive G protein. Miniglucagon is a novel, possibly physiologically relevant, local regulator of islet function.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Animals; Calcium; Calcium Channels; Calcium Channels, L-Type; Cell Line; Cell Membrane; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose; Glyburide; Homeostasis; Insulin; Insulin Secretion; Islets of Langerhans; Kinetics; Membrane Potentials; Peptide Fragments; Peptides