Glibenclamide but not other sulphonylureas stimulates release of neuropeptide Y from perifused rat islets and hamster insulinoma cells

Abstract

We have studied the effects of first and second generation sulphonylureas on the release of insulin and neuropeptide tyrosine (NPY) from hamster insulinoma tumour (HIT-T15) cells and isolated rat islets. In the presence of 5-5 mmol/l glucose all sulphonylureas stimulated insulin release from the HIT cells (P<0.01 ANOVA, n ≥ 4) but only glibenclamide (GLIB, 10 μmol/l) stimulated the release of NPY (mean ± S.E.M. control 11.1 ± 1.3 vs GLIB 28.4 ± 4.1 fmol/h per 106 cells, P<0001, n = 16). In isolated perifused rat islets both glibenclamide (10 μmol/l) (control 3.5 ± 0.3 vs GLIB 6.3 ± 0.2 fmol/min per islet, P<0.01, n=6) and tolbutamide (50 μmol/l) (control 4.7 ± 0.1 vs TOLB 6.7 ± 0.3 fmol/min per islet, P<0.01, n=6) enhanced glucose (8 mmol/l)-stimulated insulin release. However, only glibenclamide stimulated the release of NPY from the islets (control 3.4 ± 0.8 vs GLIB 24.5 ± 5 attomol/min per islet, P<0.01, n=6). Similar results were obtained in islets isolated from dexamethasone-treated rats. Glibenclamide treatment of HIT cells showed a prompt insulin release (10 min) while NPY secretion was slower (60 min), suggesting that internalization of the sulphonylurea is required to stimulate NPY release. Glibenclamide, the most common oral therapeutic agent in type 2 diabetes mellitus, is associated with release of the autocrine insulin secretion inhibitor, NPY.