EFFECTS OF STEROID AND LACTOGENIC HORMONES ON ISLETS OF LANGERHANS - A NEW HYPOTHESIS FOR THE ROLE OF PREGNANCY STEROIDS IN THE ADAPTATION OF ISLETS TO PREGNANCY

Adaptive changes that occur in islets of Langerhans during pregnancy i nclude enhanced insulin secretion, insulin synthesis, beta-cell prolif eration, gap-junctional coupling among beta-cells, and glucose oxidati on. We have determined that elevated lactogenic activity is directly r esponsible for these changes in beta-cell function. Recently, we showe d that two of the principal adaptive characteristics (insulin secretio n and beta-cell proliferation) of rat pregnancy peaked on day 15 and r eturned to control levels by day 20. As placental lactogen remains ele vated during late gestation, it was of interest to determine whether p regnancy steroids could reverse the effects of lactogen on islets. In this study, rat islets were cultured with progesterone, estradiol, rat PRL (rPRL), or combinations of these hormones (progesterone and rPRL, estradiol and rPRL, or progesterone and estradiol and rPRL). Insulin secretion was examined for 8 days, and beta-cell proliferation by 2-br omo-5'-deoxyuridine (BrdU) incorporation on days 4 and 8. rPRL treatme nt resulted in a time-dependent increase in insulin secretion that was 3-fold greater than that from control islets by day 8. Progesterone a nd estradiol had minimal effects on insulin secretion. Estradiol had n o effect on the increased insulin secretion observed with rPRL during the first 6 days and a small inhibitory effect on days 7 and 8. Althou gh progesterone treatment had no effect on the increased insulin secre tion induced by rPRL during the first 3 days, it subsequently resulted in a decline in insulin secretion to that from control islets. The co mbination of progesterone and estradiol was more effective than either steroid by itself in reversing the effects of rPRL on insulin secreti on. Similar results were obtained in the BrdU labeling experiments: 1) a 7-fold increase in the number of BrdU-labeled nuclei per islet was observed after culture in the presence of rPRL; and 2) estradiol had a small inhibitory effect on the increased BrdU labeling observed with rPRL; however, 3) progesterone completely reversed the effect of rPRL on islet beta-cell division. These results demonstrate that progestero ne counterregulates the effects of PRL on insulin secretion and islet beta-cell division. The temporal changes observed in islets in vitro u nder the influence of PRL and progesterone mimic those seen in islets during pregnancy. We conclude that progesterone, which increases in th e later stages of gestation, is the primary hormone responsible for co unteracting the stimulatory effects of elevated lactogenic activity on islets during late pregnancy.