The insulinotropic effect of endothelin-1 is mediated by glucagon release from the islet alpha cells.
OBJECTIVE
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 (125)I-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, betaTC3 and MIN6). At all endothelin-1 concentrations applied (1 pmol/l to 1 micromol/l) no change in insulin secretion was found. Ligand-binding experiments on betaTC3 cells showed no specific binding of (125)I-ET-1. A prominent expression of ET(A)-receptor mRNA in an alpha-cell line (alphaTC1.9) and in normal rat islets was found whereas no expression was found in INS-1 cells. No influence of endothelin-1(1 micromol/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.


CONCLUSIONS
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: 1302-1307]
Brock
B
B
Department of Endocrinology and Metabolism, Aarhus University Hospital, Aarhus University, Aarhus, Denmark.
Gregersen
S
S
Kristensen
K
K
Thomsen
J L
JL
Buschard
K
K
Kofod
H
H
Hermansen
K
K
D000818:Animals; D002460:Cell Line; D019332:Endothelin-1 / Q000494:pharmacology*; D005934:Glucagon / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D019332:Endothelin-1; D007328:Insulin; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; D005934:Glucagon