The insulinotropic effect of endothelin-1 is mediated by glucagon release from the islet alpha cells

Aims/hypothesis. The circulating concentrations of endothelin-l (ET-1), a p eptide derived from endothelium, are increased in hypertension and diabetes . Endothelin-l has recently been shown to be an insulinotropic agent. The m echanism of action of endothelin-1 on the endocrine pancreas has not yet be en clarified. Methods. We investigated the action of endothelin-l on the insulin secretio n, the binding of I-125-ET-1 to beta cells as well as its effects on purifi ed beta and non-beta cells from normal rats. The expression of endothelin r eceptors in alpha- and beta-cell lines and in normal rat islets was also st udied. Results. First, we studied the effects of endothelin-l on insulin secretion from beta-cell lines (INS-1, beta TC3 and MIN6). At all endothelin-l conce ntrations applied (1 pmol/l to 1 mu mol/l) no change in insulin secretion w as found. Ligand-binding experiments on beta TC3 cells showed no specific b inding of I-125-ET-1. A prominent expression of ETA-receptor mRNA in an alp ha-cell line (alpha TC1.9) and in normal rat islets was found whereas no ex pression was found in INS-1 cells. No influence of endothelin-l(1 mu mol/l) on insulin secretion stimulated by glucose was detected from purified beta cells. Endothelin-1-(100 nmol/l) increased, however, both insulin and gluc agon secretion from a mixture of purified beta and non-beta cells indicatin g that alpha cells seem to have a key role for the action of ET-1 on insuli n secretion. Conclusion/interpretation. The insulinotropic impact of endothelin-l 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 t he endothelin receptor positive alpha cells.