Department of Biology, College of Liberal Arts and Sciences, Tokyo Medical and Dental University, Ichikawa, Chiba, Japan.
Department of Clinical Engineering, Faculty of Health Sciences, Komatsu University, Komatsu, Ishikawa, Japan.
Front Endocrinol (Lausanne). 2023 May 23;14:1173113. doi: 10.3389/fendo.2023.1173113. eCollection 2023.
Melatonin, a neurohormone nocturnally produced by the pineal gland, is known to regulate the circadian rhythm. It has been recently reported that variants of melatonin receptors are associated with an increased risk of hyperglycemia and type 2 diabetes, suggesting that melatonin may be involved in the regulation of glucose homeostasis. Insulin is a key hormone that regulates circulating glucose levels and cellular metabolism after food intake in many tissues, including the brain. Although cells actively uptake glucose even during sleep and without food, little is known regarding the physiological effects of nocturnal melatonin on glucose homeostasis. Therefore, we presume the involvement of melatonin in the diurnal rhythm of glucose metabolism, independent of insulin action after food intake. In the present study, goldfish () was used as an animal model, since this species has no insulin-dependent glucose transporter type 4 (GLUT4). We found that in fasted individuals, plasma melatonin levels were significantly higher and insulin levels were significantly lower during the night. Furthermore, glucose uptake in the brain, liver, and muscle tissues also significantly increased at night. After intraperitoneal administration of melatonin, glucose uptake by the brain and liver showed significantly greater increases than in the control group. The administration of melatonin also significantly decreased plasma glucose levels in hyperglycemic goldfish, but failed to alter insulin mRNA expression in Brockmann body and plasma insulin levels. Using an insulin-free medium, we demonstrated that melatonin treatment increased glucose uptake in a dose-dependent manner in primary cell cultures of goldfish brain and liver cells. Moreover, the addition of a melatonin receptor antagonist decreased glucose uptake in hepatocytes, but not in brain cells. Next, treatment with N1-acetyl-5-methoxykynuramine (AMK), a melatonin metabolite in the brain, directly increased glucose uptake in cultured brain cells. Taken together, these findings suggest that melatonin is a possible circadian regulator of glucose homeostasis, whereas insulin acquires its effect on glucose metabolism following food intake.
褪黑素是一种由松果体夜间产生的神经激素，已知其可调节昼夜节律。最近有报道称，褪黑素受体的变异与高血糖和 2 型糖尿病的风险增加有关，这表明褪黑素可能参与了葡萄糖稳态的调节。胰岛素是一种关键的激素，可调节进食后许多组织（包括大脑）中的循环葡萄糖水平和细胞代谢。尽管细胞在睡眠和没有食物的情况下仍积极摄取葡萄糖，但对于夜间褪黑素对葡萄糖稳态的生理影响知之甚少。因此，我们假设褪黑素参与了葡萄糖代谢的昼夜节律，而与进食后胰岛素的作用无关。在本研究中，我们使用金鱼（）作为动物模型，因为这种物种没有胰岛素依赖性葡萄糖转运蛋白 4（GLUT4）。我们发现，在禁食个体中，夜间褪黑素水平显著升高，胰岛素水平显著降低。此外，脑、肝和肌肉组织中的葡萄糖摄取也在夜间显著增加。腹腔内给予褪黑素后，脑和肝的葡萄糖摄取增加幅度明显大于对照组。褪黑素的给予还显著降低了高血糖金鱼的血浆葡萄糖水平，但未能改变布罗克曼体和血浆胰岛素水平的胰岛素 mRNA 表达。使用无胰岛素的培养基，我们证明褪黑素处理以剂量依赖性方式增加了金鱼脑和肝细胞原代培养物中的葡萄糖摄取。此外，添加褪黑素受体拮抗剂可降低肝细胞中的葡萄糖摄取，但不能降低脑细胞中的葡萄糖摄取。接下来，用 N1-乙酰-5-甲氧基色胺（AMK）处理，一种大脑中的褪黑素代谢物，可直接增加培养脑细胞中的葡萄糖摄取。综上所述，这些发现表明褪黑素可能是葡萄糖稳态的一种昼夜节律调节剂，而胰岛素在进食后才对葡萄糖代谢产生作用。
