MECHANISMS UNDERLYING THE INSULINOSTATIC EFFECT OF PEPTIDE YY IN MOUSE PANCREATIC-ISLETS

Peptide YY is an insulinostatic peptide which is released into the cir culation from the intestinal mucosa upon food intake. Peptide YY is al so 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 th at peptide YY (0.1 nmol/l-1 mu mol/l) inhibited glucose (11.1 mmol/l)- stimulated insulin secretion from incubated isolated islets, with a ma ximal inhibition of approximately 70 % observed at a dose of 1 nmol/1 (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). Fur thermore, peptide YY inhibited glucose-stimulated cyclic AMP formation (by 67 %, p < 0.05), and insulin secretion stimulated by dibutyryl cy clic AMP (p < 0.01). In contrast, the peptide was without effect both on the cytoplasmic Ca2+ concentration in dispersed mouse islet-cell su spensions as measured by the FURA 2-AM technique, and on insulin relea se in isolated islets, when stimulated by the protein kinase C-activat or 12-O-tetradecanoyl phorbol 13-acetate. Finally, in pre-labelled per ifused islets, peptide YY caused a small and transient increase in the Rb-86(+) 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 step s in the cyclic AMP cascade, that is, both the accumulation and the ac tion of the cyclic nucleotide. In contrast, the data suggest that prot ein kinase C, K+ channels, the cytoplasmic Ca2+ concentration or other processes directly regulating the exocytosis are not involved in the signal transduction underlying peptide YY-induced inhibition of insuli n secretion.