Evidence for a circadian rhythm of insulin release from perifused rat pancreatic islets

Abstract

While there is strong evidence that circadian rhythms are generated in the mammalian suprachiasmatic nucleus (SCN) [1,2] and in the avian pineal gland [3,4], determinations of circadian rhythms in other isolated organs or cells are rare. Only few in vitro investigations of insect tissues or mammalian cells or organs such as intestine, adrenals [5±7], heart cell networks and liver cells [8,9] have shown the existence of circadian rhythms in culture [10,11]. In addition it has been shown that cultured mammalian retina possesses a genetically programmed circadian oscillator which regulates the synthesis of melatonin in this tissue. These observations suggest that all vertebrate photoreceptive structures synthesize melatonin under the control of circadian oscillators [12]. A circadian rhythm is an oscillation with a period duration of approximately 24 h (range 20 to 28 h). Ultradian rhythms are oscillations with periods of less than 20 h.Various investigators have postulated oscillations of insulin secretion in a range of seconds [13] or periods between 9 and 14 min under both in vivo and in vitro conditions [14] or clonal pancreatic beta cells with periods of 5 to 8 min superimposed on 15 to Diabetologia (1998) Summary This study aims to analyse a circadian rhythm of insulin secretion from 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 system, adapted to the specific conditions of pancreatic islets. To determine rhythmicity of insulin secretion, 30-min fractions were collected continuously for investigative periods of 44 to 112 h. Insulin secretion in 10 experiments was analysed by using the MacAnova-program for period length (t), the c 2 -periodogram for test of significance (p < 0.001), and additionally the empirical cosine adaptation for amplitude and goodness-of-fit. Thereby a circadian pattern was observed with periods (t) 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 circadian insulin secretion phase-response studies show phase-shifts with approximately 9 h phase advance. Thereafter the circadian period was maintained, while the amplitude was enhanced. From this it is concluded that an endogenous circadian oscillator is located within the pancreatic islets of the rat that regulates circadian insulin secretion of the insulin-producing beta cells. The pacemaker is remarkably stable, because its periodicity is not affected by factors altering insulin secretion. In agreement with inhibitory influences of melatonin (range 0.5 nmol/l to 5 mmol/l) on the insulin response in vitro, the phaseresponses support the contention that pancreatic beta cells may be targets for melatonin action. [Diabetologia (1998)

The role of melatonin in diabetes: therapeutic implications

“…The existence of MT2 receptor on the pancreatic β-cell is accomplished by application of melatonin as isolated islets of rats has phase-shifting effects on the insulin rhythm (34). Moreover, molecular and immunocytochemical studies confirmed the presence of the melatonin receptors MT1 and MT2 in the islets of Langerhans and also in human pancreatic tissue (35).…”

“…Since the intake of food induces insulin secretion, the amount of insulin in plasma follow the daily rhythm in feeding and may exhibit a daily rhythm as well. In contrast, mouse and human pancreatic islet cells have been found to possess circadian activity as well (34,67,68). This concept gives emphasis to the presence of a circadian regulation over pancreatic function.…”

Melatonin receptors in pancreatic islets: good morning to a novel type 2 diabetes gene

“…The system is hierarchical, the suprachiasmatic nucleus in the hypothalamus being the 'master clock', with additional clock activities in numerous peripheral tissues. In fact, there is some evidence for a circadian rhythm in pancreatic islets [5]. The peripheral clocks are all thought to signal back to the 'master clock' in the suprachiasmatic nucleus.…”

“…That insulin secretion is controlled by circadian mechanisms is supported by studies of humans with circadian misalignment, who are reported to show profound perturbations of plasma glucose and insulin levels [8]. The concept is supported by the assumption that there is a circadian clock in pancreatic islets [5]. While it is clear that insulin secretion exhibits a circadian rhythm, it is unclear whether secretion increases or decreases during the night [41,42].…”

Implication des mutations du récepteur de la mélatonine MT2dans la survenue du diabète de type 2

“…En revanche, les taux plasmatiques de MLT sont élevés pendant la nuit et bas pendant la journée. Une étude sur des îlots de Langerhans du pancréas de rat a montré qu'un traitement par la MLT avance la phase de la sécrétion de l'insuline d'environ 9 h, ce qui suggère que la MLT peut influencer directement l'horloge du pancréas [17]. Des études récentes chez la souris ont montré qu'une perturbation des rythmes circadiens est responsable de la survenue de maladies métaboliques, dont le DT2 [18].…”