Summary
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 μmol/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/ 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). 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. In contrast, the data suggest that protein 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 insulin secretion.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Abbreviations
- PYY:
-
Peptide YY
- TPA:
-
12-O-tetradecanoylphorbol 13-acetate
References
Taylor IL (1989) Peptide YY: the ileo-colonic, gastric, and pancreatic inhibitor. Biol Bull 177: 187–191
Böttcher G, Ekblad E, Ekman R, Håkanson R, Sundler F (1993) Peptide YY: a neuropeptide in the gut. Immunocytochemical and immunochemical evidence. Neuroscience 55: 281–290
Tatemoto K, Carlquist M, Mutt V (1982) Neuropeptide Y — a novel brain peptide with structural similarities to peptide YY and pancreatic polypeptide. Nature 296: 659–660
Ahrén B, Östenson CG, Efendic S (1991) Other islet peptides. In: Samols E (ed) The endocrine pancreas. Raven Press, New York, pp 153–173
Petterson M, Ahrén B (1990) Insulin secretion in rats: effects of neuropeptide Y and noradrenaline. Diabetes Res 13: 35–42
Böttcher G, Sjöberg J, Ekman R, Håkanson R, Sundler F (1993) Peptide YY in the mammalian pancreas: immunocytochemical localization and immunochemical characterization. Regul Pept 43: 115–130
Böttcher G, Ekman R, Lundqvist G, Ahrén B, Sundler F (1994) Pancreatic peptide YY in alloxan diabetic mice. Pancreas (in press)
Böttcher G, Ahrén B, Lundquist I, Sundler F (1989) Peptide YY: intrapancreatic localization and effects on insulin and glucagon secretion in the mouse. Pancreas 4: 282–288
Szecowka J, Tatemoto K, Rajamäki G, Efendic S (1983) Effects of PYY and PP on endocrine pancreas. Acta Physiol Scand 119: 123–126
Greeley GH, Lluis F, Gomez G, Ishizuka J, Holland B, Thompson JC (1988) Peptide YY antagonizes β-adrenergic-stimulated release of insulin in dogs. Am J Physiol 254: E513-E517
Guo YS, Singh P, Draviam E, Greeley GH, Thompson JC (1989) Peptide YY inhibits the insulinotropic action of gastric inhibitory polypeptide. Gastroenterology 96: 690–694
Bertrand G, Gross R, Roye M, Ahrén B, Ribes G (1992) Evidence for a direct inhibitory effect of PYY on insulin secretion in rats. Pancreas 7: 595–600
Prentki M, Matschinsky FM (1987) Ca2+, cAMP, and phospholipid-derived messengers in coupling mechanisms of insulin secretion. Physiol Rev 67: 1185–1248
Rajan AS, Aguilar-Bryan L, Nelson DA et al. (1990) Ion channels and insulin secretion. Diabetes Care 13: 340–363
Farese RV, Standaert ML, Arnold T et al. (1992) The role of protein kinase C in insulin action. Cell Signal 4: 133–143
Lacy PE, Kostianovski M (1967) Method for the isolation of intact islets of Langerhans from the rat pancreas. Diabetes 16: 35–39
Skoglund G, Lundquist I, Ahrén B (1988) Selective α-adrenoceptor activation by clonidine: effects on 45Ca2+ efflux and insulin secretion from isolated rat islets. Acta Physiol Scand 132: 289–296
Ahrén B, Karlsson S, Linskog S (1990) Cholinergic regulation of the endocrine pancreas (1990) In: Aquilonius S-M, Gillberg P-G (ed) Progress in brain research 84. Elsevier, Amsterdam pp. 209–218
Fridolf T, Karlsson S, Ahrén B (1992) The effects of CCK-8 on the cytoplasmic free calcium concentration in isolated rat islet cells. Biochem Biophys Res Commun 192: 878–882
Grynkiewics G, Poenie M, Tsien R (1985) A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem 260: 3440–3450
Henquin JC (1987) Regulation of insulin release by ionic and electrical events in B cells. Hormone Res 27: 168–178
Nilsson T, Arkhammar P, Rorsman P, Berggren PO (1989) Suppression of insulin release by galanin and somatostatin is mediated by a G-protein: an effect involving repolarization and reduction in cytoplasmic free Ca2+ concentration. J Biol Chem 264: 973–980
Malaisse WJ, Boschero AC, Kawazu S, Hutton JC (1978) The stimulus secretion coupling of glucose-induced insulin release. XXVII. Effects of glucose on K+ fluxes in isolated islets. Pflügers Arch 373: 237–242
Henquin JC (1980) The potassium permeability of pancreatic islet cells: mechanisms of control and influence on insulin release. Horm Metab Res 10 [Suppl]: 66–73
Trube G, Rorsman P, Ohno-Shosaku T (1986) Opposite effects of tolbutamide and diazoxide on the ATP-dependent K+ channel in mouse pancreatic β-cells. Pflügers Arch 407: 493–499
Henquin JC, Meissner HP (1982) Opposite effects of tolbutamide and diazoxide on 86Rb+ fluxes and membrane potential in pancreatic beta cells. Biochem Pharmacol 31: 1407–1415
Drews G, Debuyser A, Nenquin M, Henquin JC (1990) Galanin and epinephrine act on distinct receptors to inhibit insulin release by the same mechanisms including an increase in K+ permeability of the B-cell membrane. Endocrinology 126: 1646–1653
Goldsmith BA, Abrams TW (1992) cAMP modulates multiple K+ currents, increased spike duration and excitability in Aplysia sensory neurons. Proc Natl Acad Sci USA 89: 11481–11485
Henquin JC, Meissner HP (1984) The ionic, electrical, and secretory effects of endogenous cyclic adenosine monophosphate in mouse pancreatic B cells: studies with forskolin. Endocrinology 115: 1125–1134
Michel MC (1991) Receptors for neuropeptide Y: multiple subtypes and multiple second messengers. Trends Pharmacol Sci 12: 389–394
Wahlestedt C, Regunathan S, Reis DJ (1991) Identification of cultured cells selectively expressing Y1-, Y2-, or Y3-type receptors for neuropeptide Y/peptide YY. Life Sci 50: 7–12
Yoshinaga K, Mochizuki T, Yanaihara N et al. (1992) Structural requirements of peptide YY for biological activity at enteric sites. Am J Physiol 263: G695-G701
Lu M, Wheeler MB, Leng XH, Boyd III AE (1993) The role of the free cytosolic calcium transduction by gastric inhibitory polypeptide and glucagon-like peptide I(7–36). Endocrinology 132: 94–100
Taylor IL (1985) Distribution and release of peptide YY in dog measured by specific radioimmunoassay. Gastroenterology 88: 731–737
Adrian TE, Ferri G-L, Bacarese-Hamilton AJ, Fuessls HS, Pollak JM, Bloom SR (1985) Human distribution and release of a putative new gut hormone, peptide YY. Gastroenterology 89: 1070–1077
Adrian TE, Sagor GR, Savage AP, Bacarese-Hamilton AJ, Hall GM, Bloom SR (1986) Peptide YY kinetics and effects on blood pressure and circulating pancreatic and gastrointestinal hormones and metabolites in man. J Clin Endocrinol Metab 63: 803–807
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Nieuwenhuizen, A.G., Karlsson, S., Fridolf, T. et al. Mechanisms underlying the insulinostatic effect of peptide YY in mouse pancreatic islets. Diabetologia 37, 871–878 (1994). https://doi.org/10.1007/BF00400941
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00400941