AbstractAims/hypothesis. The circulating concentrations of endothelin-1 (ET-1), a peptide derived from endothelium, are increased in hypertension and diabetes. Endothelin-1 has recently been shown to be an insulinotropic agent. The mechanism of action of endothelin-1 on the endocrine pancreas has not yet been clarified. Methods. We investigated the action of endothelin-1 on the insulin secretion, the binding of 125I-ET-1 to beta cells as well as its effects on purified beta and non-beta cells from normal rats. The expression of endothelin receptors in alpha- and beta-cell lines and in normal rat islets was also studied. Results. First, we studied the effects of endothelin-1 on insulin secretion from beta-cell lines (INS-1, TC3 and MIN6). At all endothelin-1 concentrations applied (1 pmol/l to 1 mol/l) no change in insulin secretion was found. Ligand-binding experiments on TC3 cells showed no specific binding of 125I-ET-1. A prominent expression of ETA-receptor mRNA in an alpha-cell line (TC1.9) and in normal rat islets was found whereas no expression was found in INS-1 cells. No influence of endothelin-1(1 mol/l) on insulin secretion stimulated by glucose was detected from purified beta cells. Endothelin-1-(100 nmol/l) increased, however, both insulin and glucagon secretion from a mixture of purified beta and non-beta cells indicating that alpha cells seem to have a key role for the action of ET-1 on insulin secretion. Conclusion/interpretation. The insulinotropic impact of endothelin-1 is not caused by a direct action on the beta cells but seems to be mediated by a paracrine action, probably secondary to enhanced release of glucagon from the endothelin receptor positive alpha cells. [Diabetologia (1999) 42: 13021307]