Calcitonin gene-related peptide and islet amyloid polypeptide stimulate insulin secretion in RINm5F cells through a common receptor coupled to a generation of cAMP.

The question as to whether the homologous peptides CGRP and IAPP can regulate insulin secretion in RINm5F cells was addressed. Chicken CGRP displayed a reproducible inhibitory effect on insulin secretion within 0.1 and 1 nM concentrations and a stimulatory effect at higher concentrations. The maximal stimulatory effects on insulin secretion were obtained with 1.0 microM of chicken CGRP (cCGRP), human alpha-CGRP (h alpha-CGRP) and human IAPP (hIAPP) which caused 246 +/- 22, 302 +/- 63 and 224 +/- 14 percent increases of control levels, respectively (p < 0.001). Similarly, maximal accumulations of cAMP were obtained with 1.0 microM of cCGRP, h alpha-CGRP and hIAPP with the respective percent increases of control levels of 587 +/- 24, 436 +/- 41 and 410 +/- 25 (p < 0.005). Thus the stimulatory effects on insulin secretion in RINm5F cells by cCGRP, h alpha-CGRP and hIAPP appear to be mediated by the cAMP pathway. Chicken CGRP, the most potent peptide tested, displayed a correlated dose response stimulation of intracellular cAMP and insulin release within the concentration range of 10-1000nM. The EC50 values of cCGRP for cAMP accumulation and insulin release were similar (20nM and 10nM respectively). The stimulatory effect of IAPP on cAMP was not additive with that of cCGRP suggesting that IAPP action was mediated by CGRP receptors. This hypothesis was further sustained by a preferential inhibition of 125I[His]h alpha-CGRP binding to RINm5F cells by cCGRP as compared to IAPP. We conclude that CGRP and IAPP, through a direct action on a chicken CGRP preferring receptor present in beta cells, stimulated insulin by a cAMP mediated pathway.