Endothelin-1 stimulates insulin secretion by direct action on the islets of Langerhans in mice

Summary

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 Μmol/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 ⁴⁵Ca²⁺-efflux from ⁴⁵Ca²⁺-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 ⁴⁵Ca²⁺-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 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.