Mechanisms underlying the insulinostatic effect of peptide YY in mouse pancreatic islets.
Peptide YY is an insulinostatic peptide which is released into the circulation from the intestinal mucosa upon food intake. Peptide YY is also co-stored with glucagon in the secretory granules of the pancreatic alpha cells. We examined the mechanisms underlying the insulinostatic effect of peptide YY in isolated mouse pancreatic islets. We found that peptide YY (0.1 nmol/l-1 mumol/l) inhibited glucose (11.1 mmol/l)-stimulated insulin secretion from incubated isolated islets, with a maximal inhibition of approximately 70% observed at a dose of 1 nmol/l (p < 0.001). Also in perifused islets the peptide (1 nmol/l) inhibited insulin secretion in response to 11.1 mmol/l glucose (p < 0.001). Furthermore, peptide YY inhibited glucose-stimulated cyclic AMP formation (by 67%, p < 0.05), and insulin secretion stimulated by dibutyryl cyclic AMP (p < 0.01). In contrast, the peptide was without effect both on the cytoplasmic Ca2+ concentration in dispersed mouse islet-cell suspensions as measured by the FURA 2-AM technique, and on insulin release in isolated islets, when stimulated by the protein kinase C-activator 12-O-tetradecanoyl phorbol 13-acetate. Finally, in pre-labelled perifused islets, peptide YY caused a small and transient increase in the 86Rb+ efflux (p < 0.001), but only in the absence of extracellular Ca2+. We conclude that peptide YY inhibits glucose-stimulated insulin secretion from isolated mouse islets by inhibiting two different steps in the cyclic AMP cascade, that is, both the accumulation and the action of the cyclic nucleotide.(ABSTRACT TRUNCATED AT 250 WORDS)
Nieuwenhuizen
A G
AG
Department of Medicine, University of Lund, Malmö General Hospital, Sweden.
Karlsson
S
S
Fridolf
T
T
Ahrén
B
B
D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005456:Fluorescent Dyes; D016257:Fura-2 / Q000031:analogs & derivatives; D005711:Gallopamil / Q000494:pharmacology; D005947:Glucose / Q000037:antagonists & inhibitors / Q000494:pharmacology; D005985:Glyceraldehyde / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D051379:Mice; D008815:Mice, Inbred Strains; D019894:Peptide YY; D010455:Peptides / Q000494:pharmacology*; D011189:Potassium Chloride / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D012413:Rubidium / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors
D005456:Fluorescent Dyes; D007328:Insulin; D010455:Peptides; C049925:fura-2-am; D019894:Peptide YY; D005985:Glyceraldehyde; D005711:Gallopamil; D003994:Bucladesine; D011189:Potassium Chloride; D002217:Carbachol; D000242:Cyclic AMP; D011493:Protein Kinase C; D005947:Glucose; D012413:Rubidium; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium; D016257:Fura-2