Endothelin-1 (ET-1)—potentiated insulin secretion: Involvement of protein kinase C and the ETA receptor subtype
S Gregersen, JL Thomsen, K Hermansen - Metabolism, 2000 - Elsevier
S Gregersen, JL Thomsen, K Hermansen
Metabolism, 2000•ElsevierEndothelin-1 (ET-1), a potent vasoconstrictor peptide of endothelial origin, is capable of
influencing hormone secretion from endocrine tissues, eg, pancreatic islet cells. We have
shown a direct stimulatory effect of ET-1 on insulin secretion from isolated mouse islets of
Langerhans. However, it is unknown as to whether the peptide acts through specific
receptors on the islet cells and which mechanisms are involved in this insulinotropic action.
We have therefore used the specific ETA receptor antagonist BQ123, the ETB receptor …
influencing hormone secretion from endocrine tissues, eg, pancreatic islet cells. We have
shown a direct stimulatory effect of ET-1 on insulin secretion from isolated mouse islets of
Langerhans. However, it is unknown as to whether the peptide acts through specific
receptors on the islet cells and which mechanisms are involved in this insulinotropic action.
We have therefore used the specific ETA receptor antagonist BQ123, the ETB receptor …
Endothelin-1 (ET-1), a potent vasoconstrictor peptide of endothelial origin, is capable of influencing hormone secretion from endocrine tissues, eg, pancreatic islet cells. We have shown a direct stimulatory effect of ET-1 on insulin secretion from isolated mouse islets of Langerhans. However, it is unknown as to whether the peptide acts through specific receptors on the islet cells and which mechanisms are involved in this insulinotropic action. We have therefore used the specific ETA receptor antagonist BQ123, the ETB receptor agonist BQ3020, and classic α- and β-adrenergic and cholinergic antagonists. ET-1 (100 nmol/L) stimulated insulin secretion from islets incubated at 8.3, 11.6, 16.7, and 25 mmol/L glucose (P < .05). At 3.3. mmol/L glucose, no alteration in insulin secretion was found. The cholinergic receptor antagonist atroine (5 μmol/L) or the adrenergic receptor antagonists propranolol (5 μmol/L) or phentolamine (5 μmol/L) did not affect ET-1 (100 nmol/L)-stimulated insulin secretion. BQ123 (10 pmol/L to 10 μmol/L) and BQ3020 (1 nmol/L to 1 μmol/L) had no effect on glucose (16.7 mmol/L)-stimulated insulin secretion, but BQ123 counteracted the stimulatory effect of ET-1 (100 nmol/L) at concentrations of 1 nmol/L to 10 μmol/L (P < .01). We also studied the relative role of protein kinase C (PKC) and a Worthmannin-sensitive pathway for ET-1—induced insulin secretion using 12-O-tetradecanoyl phorbol-13-acetate (PTA), Calphostin C, and Worthmannin, respectively. At 5.6 mmol/L glucose, ET-1 (100 nmol/L) had no effect per se, whereas in the presence of 1 μmol/L TPA, which acutely stimulates PKC, the peptide did potentiate insulin secretion (P < .05). Furthermore, the insulinotropic effect of ET-1 at 16.7 mmol/L glucose was counteracted by the PKC inhibitor Calphostin C (P < .05) and by downregulation of PKC by 24 hours of exposure of islets to TPA (0.5 μmol/L, P < .05). Wortmannin (1 μmol/L) did not alter ET-1—potentiated insulin secretion. In conclusion, our results suggest that ET-1 acts through specific ET-1 receptors, most likely the ETA subtype. Furthermore, PCK plays an essential role in the insulinotrpic action of ET-1 in mouse islets.
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