ENDOTHELIN-1 STIMULATES INSULIN-SECRETION BY DIRECT ACTION ON THE ISLETS OF LANGERHANS IN MICE

Endothelin-1 (ET-1), a potent endothelium-derived vasoconstrictor pept ide, is secreted in response to insulin. Elevated circulating ET-1 lev els have been found in patients with diabetes mellitus and vascular dy sfunction. 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 mu mol/l) dos e-dependently stimulated insulin secretion from islets incubated in th e presence of 16.7 mmol/l glucose (p < 0.05). The effect of ET-1 is gl ucose-dependent since no potentiation was found at 3.3 mmol/l glucose. Furthermore, ET-1 induced a large, transient increase in glucose-stim ulated insulin secretion during islet perifusion in the presence (p < 0.001), but not in the absence, of extracellular Ca2+. The rate of Ca- 45(2+)-efflux from Ca-45(2+)-prelabelled islets was transiently stimul ated 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 Ca-45(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 Ca2+-channels. In addition, ET-1 t ransiently enhanced Rb-86(+)-efflux from Rb-86(+)-prelabelled islets b oth in the presence (p < 0.001) and in the absence (p < 0.001) of extr acellular Ca2+ suggesting that ET-1 does not elicit insulin secretion by inhibition of the potassium permeability. Our study provides eviden ce that ET-1 stimulates insulin secretion via a direct effect on the i slets of Langerhans.