Institute of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Grosse Steinstrasse 52, 06097 Halle, Germany.
Diabetologia. 2011 Jul;54(7):1831-40. doi: 10.1007/s00125-011-2138-0. Epub 2011 Apr 15.
AIMS/HYPOTHESIS: It is well documented that melatonin influences insulin secretion mediated by G-protein-coupled melatonin receptor isoforms MT1 and MT2, which are present in rat and human pancreatic islets, as well as in rat insulinoma cells. Recent investigations have proven that hyperinsulinaemic Goto-Kakizaki (GK) rats, which are a rat model of type 2 diabetic rats, and humans have decreased melatonin plasma levels, whereas a streptozotocin-induced rat model of diabetes developed reduced insulin levels combined with increased melatonin levels.
Plasma levels of glucose, insulin and melatonin as well as RNA expression of pineal Aanat, Hiomt (also known as Asmt), insulin receptor, adrenoceptor β1 and the clock genes Per1 and Bmal1 (also known as Arntl) were determined in male and female LEW.1AR1-iddm rats as well as in insulin-substituted LEW.1AR1-iddm rats.
Severe hypoinsulinaemia in diabetic LEW.1AR1-iddm rats was associated with decreased body weight and increased melatonin plasma levels combined with mainly elevated expression of Aanat, Hiomt, pineal insulin receptor and adrenoceptor β1. The changes were normalised by insulin substitution. Diurnal profiles of plasma melatonin and of antagonistic clock genes Per1 and Bmal1 were maintained in diabetic and insulin-substituted rats.
CONCLUSIONS/INTERPRETATION: The assumed causal relation between elevated melatonin and reduced insulin levels in LEW.1AR1-iddm rats is supported by the observation that insulin substitution normalised these changes. Further support for this interpretation comes from the observation that in GK rats an increase of plasma insulin was combined with a decrease of plasma noradrenaline (norepinephrine), the most important activator of melatonin synthesis. These relationships between the noradrenergic and insulin pathway support the existence of melatonin-insulin antagonism.
目的/假设：有大量文献证明褪黑素通过 G 蛋白偶联型褪黑素受体亚型 MT1 和 MT2 影响胰岛素分泌，MT1 和 MT2 存在于大鼠和人胰岛以及大鼠胰岛素瘤细胞中。最近的研究证明，作为 2 型糖尿病大鼠模型的高胰岛素血症 Goto-Kakizaki（GK）大鼠和人类的血浆褪黑素水平降低，而链脲佐菌素诱导的糖尿病大鼠模型则表现出胰岛素水平降低伴褪黑素水平升高。
测定雄性和雌性 LEW.1AR1-iddm 大鼠以及胰岛素替代治疗的 LEW.1AR1-iddm 大鼠的血糖、胰岛素和褪黑素的血浆水平以及松果腺 Aanat、Hiomt（也称为 Asmt）、胰岛素受体、肾上腺素能受体β1 和时钟基因 Per1 和 Bmal1（也称为 Arntl）的 RNA 表达。
糖尿病 LEW.1AR1-iddm 大鼠严重的胰岛素缺乏症与体重下降和褪黑素血浆水平升高有关，同时主要表现为 Aanat、Hiomt、松果腺胰岛素受体和肾上腺素能受体β1 的表达增加。胰岛素替代治疗可使这些变化恢复正常。糖尿病和胰岛素替代治疗大鼠的血浆褪黑素和拮抗时钟基因 Per1 和 Bmal1 的昼夜节律图谱保持不变。
结论/解释：LEW.1AR1-iddm 大鼠中升高的褪黑素和降低的胰岛素水平之间的因果关系假设得到了支持，因为观察到胰岛素替代治疗可使这些变化正常化。进一步支持这一解释的是，在 GK 大鼠中，血浆胰岛素增加与血浆去甲肾上腺素（肾上腺素）减少有关，而去甲肾上腺素是促进褪黑素合成的最重要激活剂。这些去甲肾上腺素和胰岛素途径之间的关系支持褪黑素-胰岛素拮抗作用的存在。
