Endothelin-1 stimulates insulin secretion by direct action on the islets of Langerhans in mice.
Endothelin-1 (ET-1), a potent endothelium-derived vasoconstrictor peptide, is secreted in response to insulin. Elevated circulating ET-1 levels have been found in patients with diabetes mellitus and vascular dysfunction. The question arises whether ET-1 acts as a direct modulator of insulin secretion. To test this, we studied the effects of ET-1 on isolated mouse islets of Langerhans. ET-1 (1 nmol/l-1 mumol/l) dose-dependently stimulated insulin secretion from islets incubated in the presence of 16.7 mmol/l glucose (p < 0.05). The effect of ET-1 is glucose-dependent since no potentiation was found at 3.3 mmol/l glucose. Furthermore, ET-1 induced a large, transient increase in glucose-stimulated insulin secretion during islet perifusion in the presence (p < 0.001), but not in the absence, of extracellular Ca2+. The rate of 45Ca(2+)-efflux from 45Ca(2+)-prelabelled islets was transiently stimulated by ET-1 during perifusion at 16.7 mmol/l glucose in the presence of extracellular Ca2+ (p < 0.001). A short-lived increase in 45Ca(2+)-efflux was also observed in the absence of extracellular Ca2+ (p < 0.05). It is suggested that the effects of ET-1 on insulin secretion are critically dependent on influx via Ca(2+)-channels. In addition, ET-1 transiently enhanced 86Rb(+)-efflux from 86Rb(+)-prelabelled islets both in the presence (p < 0.001) and in the absence (p < 0.001) of extracellular Ca2+ suggesting that ET-1 does not elicit insulin secretion by inhibition of the potassium permeability. Our study provides evidence that ET-1 stimulates insulin secretion via a direct effect on the islets of Langerhans.
Gregersen
S
S
Department of Endocrinology and Metabolism, Aarhus University Hospital, Denmark.
Thomsen
J L
JL
Brock
B
B
Hermansen
K
K
D000704:Analysis of Variance; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D002478:Cells, Cultured; D004533:Egtazic Acid / Q000494:pharmacology; D019332:Endothelin-1 / Q000494:pharmacology*; D005260:Female; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D007700:Kinetics; D051379:Mice; D008815:Mice, Inbred Strains; D013997:Time Factors
D019332:Endothelin-1; D007328:Insulin; D004533:Egtazic Acid; D002217:Carbachol; D005947:Glucose; D002118:Calcium