EVIDENCE FOR THE PARACRINE ACTION OF ISLET-DERIVED CORTICOTROPIN-LIKEPEPTIDES ON THE REGULATION OF INSULIN RELEASE

In view of recent evidence for the endogenous synthesis of proopiomela nocortin (POMC) by pancreatic islets, we have assessed (1) the release of POMC-derived corticotropin (ACTH)-like peptides (ACTH-LP) from iso lated perifused rat islets, and (2) the potential paracrine modulatory effect on insulin output of these putative secretagogues. Islets peri fused at a glucose concentration of 3.3 mmol/L secreted ACTH-LP at 0.1 5 +/- 0.005 ng/islet/10 min, which was increased by 17-fold at 16.7 mm ol/L glucose. Islets statically incubated with different concentration s of medium glucose plus synthetic (1-39)ACTH at 55 pmol/L showed a si gnificant increase of insulin release at 8 (by 79%) and 46 (by 119%) m mol/L glucose, but not at 4 mmol/L. To determine the possible cis-dire cted effects of these endogenously released islet ACTH-LP on insulin s ecretion, we either blocked their biological action by immunoneutraliz ation with an ACTH-specific antiserum or prevented their receptor inte raction by addition of the ACTH-inhibiting polypeptide (CIP) to the in cubation medium. In the presence of 16.7 mmol/L glucose, the rate of i nsulin output decreased by approximately 25% upon exposure to the anti serum and by approximately 50% in the presence of CIP. The foregoing o bservations would therefore suggest that both (1) the elaboration of A CTH-LP by isolated perifused islets and (2) the stimulation of islet i nsulin release by exogenous (1-39)ACTH in static incubation occur as a function of glucose concentration in the incubation medium, and that (3) the newly-secreted endogenous ACTH-LP operate in a cia mode to enh ance islet insulin output in a manner analogous to that of exogenously added ACTH species. These results strongly support the view that isle t-elaborated ACTH-LP are important physiological paracrine modulators of insulin secretion. (C) 1996 by W.B. Saunders Company.