Mechanisms underlying the insulinostatic effect of peptide YY in mouse pancreatic islets

Abstract

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/1-1 ~tmol/1) inhibited glucose (11.1 mmol/1)-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/1) inhibited insulin secretion in response to 11.1 mmol/1 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 Ca 2 + concentration in dispersed mouse isletcell 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 Ca 2 +. We conclude that peptide YY inhibits glucosestimulated 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 Ca 2 + concentration or other processes directly regulating the exocytosis are not involved in the signal transduction underlying peptide YY-induced inhibition of insulin secretion. [Diabetologia (1994) [4,5]. Recently, PYY has been localized to the alpha cells in both the mouse and the rat pancreas [6,7], where it is co-stored with glucagon in the secretory granules [8]. The peptide has previously been demonstrated to inhibit stimulated insulin secretion under in vivo conditions in the rat [9], dog [10,11] and mouse [8], and in vitro in the perfused isolated rat pancreas and in isolatedrat islets [12]. This suggests that PYY participates in the regulation of insulin secretion.In the present study, we have examined possible mechanisms underlying the inhibitory effect of PYY

Low serum PYY is linked to insulin resistance in first-degree relatives of subjects with type 2 diabetes

“…Intravenously administe no eVect on basal plasma insulin levels, but cose-stimulated insulin secretion in mice (B 1989;Szecowka et al, 1983). In vitro studi that PYY dose-dependently inhibits gluco but not basal insulin secretion (Karlsson 1996;Nieuwenhuizen et al, 1994). Studies u islets isolated from rats suggest that this is a of PYY on islets (Bertrand et al, 1992).…”

The role of peptide YY in regulating glucose homeostasis

“…Intravenously administered PYY inhibits glucose-stimulated insulin secretion as well as carbachol-and arginine-induced glucagon secretion in mice [12] and [45]. In vitro studies also demonstrate that PYY dose-dependently inhibits glucose-stimulated but not basal insulin secretion [38]. This is supported by work on isolated mouse islets where PYY antiserum potentiates glucoseinduced insulin secretion in culture [25].…”

“…One study has suggested that PYY inhibits insulin secretion by inhibiting the accumulation and action of cyclic AMP [38]. However, as adenylate cyclase inhibition is a feature of all Y receptor subtypes, it was not determined which Y receptor subtype was involved in the PYY-mediated inhibition of insulin secretion [38].…”

“…This suggests that PYY may indirectly attenuate the stimulatory effect of glucagon on insulin secretion [25]. Considering PYY and glucagon are co-localized in the secretory granules of islet alpha cells, it is possible that PYY acts as a paracrine regulator of insulin secretion [38]. However, it is still unclear whether PYY is coreleased with glucagon [25].…”

Neuroendocrine Control of Hepatic Gluconeogenesis

“…Recent evidence reveals an emerging role of PYY involved in glucose homeostasis. In vitro study has showed that PYY inhibits glucose stimulated insulin secretion from the isolated islets by inhibiting the accumulation and action of cAMP [56]. In vivo evidence also suggests that deiciency of PYY in mice signiicantly increases body weight and fat mass.…”