EVIDENCE FOR A CIRCADIAN-RHYTHM OF INSULIN RELEASE FROM PERIFUSED RATPANCREATIC-ISLETS

This study aims to analyse a circadian rhythm of insulin secretion fro m isolated rat pancreatic islets in vitro and its potential modulation by melatonin, the concentrations of which change in vivo inversely to that of insulin. The circadian rhythm was evaluated in a perifusion s ystem, adapted to the specific conditions of pancreatic islets. To det ermine rhythmicity of insulin secretion, 30-min fractions were collect ed continuously for investigative periods of 44 to 112 h. Insulin secr etion in 10 experiments was analysed by using the MacAnova-program for period length (tau), the chi(2)-periodogram for test of significance (p < 0.001). and additionally the empirical cosine adaptation for ampl itude and goodness-of-fit. Thereby a circadian pattern was observed wi th periods (tau) between 21.8 and 26.2 h. The period duration (mean +/ - SEM) was 23.59 +/- 0.503 h, the overall mean insulin release 1038 +/ - 13 pmol/l and the mean amplitude 88 +/- 17 pmol/l. Adding melatonin (10 nmol/l, t = 2 h) as a hormonal Zeitgeber during analysis of circad ian insulin secretion phase-response studies show phase-shifts with ap proximately 9 h phase advance. Thereafter the circadian period was mai ntained, while the amplitude was enhanced. From this it is concluded t hat an endogenous circadian oscillator is located within the pancreati c islets of the rat that regulates circadian insulin secretion of the insulin-producing beta cells. The pacemaker is remarkably stable, beca use its periodicity is not affected by factors altering insulin secret ion. In agreement with inhibitory influences of melatonin (range 0.5 n mol/l to 5 mu mol/l) on the insulin response in vitro, the phase-respo nses support the contention that pancreatic beta cells may be targets for melatonin action.