CALCITONIN-GENE-RELATED PEPTIDE AND ISLET AMYLOID POLYPEPTIDE STIMULATE INSULIN-SECRETION IN RINM5F CELLS THROUGH A COMMON RECEPTOR-COUPLEDTO A GENERATION OF CAMP

The question as to whether the homologous peptides CGRP and IAPP can r egulate 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 concen trations. The maximal stimulatory effects on insulin secretion were ob tained with 1.0 mu M of chicken CGRP (cCGRP), human alpha-CGRP (h alph a-CGRP) and human IAPP (hIAPP) which caused 246+/-22, 302+/-63 and 224 +/-14 percent increases of control levels, respectively (p<0.001). Sim ilarly, maximal accumulations of cAMP were obtained with 1.0 mu M of c CGRP, 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 ( U-CGRP and hIAPP appear to be mediated by the cAMP pathway. Chicken CG RP, the most potent peptide tested, displayed a correlated dose respon se stimulation of intracellular cAMP and insulin release within the co ncentration range of 10-1000nM. The EC(50) values of cCGRP for cAMP ac cumulation and insulin release were similar (20nM and 10nM respectivel y). The stimulatory effect of IAPP on cAMP was not additive with that of cCGRP suggesting that IAPP action was mediated by CGRP receptors. T his hypothesis was further sustained by a preferential inhibition of I -125[His]h (U-CGRP binding to RINm5F cells by cCGRP as compared to IAP P. We conclude that CGRP and IAPP, through a direct action on a chicke n CGRP preferring receptor present in beta cells, stimulated insulin b y a cAMP mediated pathway.