Increased Melatonin Signaling Is a Risk Factor for Type 2 Diabetes.
Increased Melatonin Signaling Is a Risk Factor for Type 2 Diabetes.
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DOI：
10.1016/j.cmet.2016.04.009
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发表时间：
2016-06
期刊：
影响因子：
29
通讯作者：
T. Tuomi;C. Nagorny;Pratibha Singh;H. Bennet;Qian Yu;Ida Alenkvist;B. Isomaa;Bjarne Östman
中科院分区：
文献类型：
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作者：
T. Tuomi;C. Nagorny;Pratibha Singh;H. Bennet;Qian Yu;Ida Alenkvist;B. Isomaa;Bjarne Östman
2 型糖尿病 (T2D) 是一种全球流行病。全基因组关联研究 (GWAS) 已识别出超过 100 种与该疾病相关的遗传变异，其中包括褪黑激素受体 1 b 基因 (MTNR1B) 中的常见变异。在这里，我们证明了风险 G 等位基因携带者的人类胰岛中 MTNR1B 表达增加，这可能导致胰岛素释放减少，增加 T2D 风险。因此，在胰岛素分泌细胞中，褪黑激素降低了 cAMP 水平，而 MTNR1B 过度表达则加剧了褪黑激素对胰岛素释放的抑制作用。相反，受体被破坏的小鼠会分泌更多的胰岛素。在一项人类基因型回忆研究中，褪黑素治疗减少了风险 G 等位基因携带者的胰岛素分泌，并更广泛地提高了血糖水平。因此，我们的数据支持这样一个模型：胰岛中褪黑激素信号增强会减少胰岛素分泌，导致高血糖和未来患 T2D 的风险更大。研究结果还表明，褪黑激素在生理上可以抑制夜间胰岛素的释放。
Type 2 diabetes (T2D) is a global pandemic. Genome-wide association studies (GWASs) have identified >100 genetic variants associated with the disease, including a common variant in the melatonin receptor 1 b gene (MTNR1B). Here, we demonstrate increasedMTNR1Bexpression in human islets from risk G-allele carriers, which likely leads to a reduction in insulin release, increasing T2D risk. Accordingly, in insulin-secreting cells, melatonin reduced cAMP levels, andMTNR1Boverexpression exaggerated the inhibition of insulin release exerted by melatonin. Conversely, mice with a disruption of the receptor secreted more insulin. Melatonin treatment in a human recall-by-genotype study reduced insulin secretion and raised glucose levels more extensively in risk G-allele carriers. Thus, our data support a model where enhanced melatonin signaling in islets reduces insulin secretion, leading to hyperglycemia and greater future risk of T2D. The findings also imply that melatonin physiologically serves to inhibit nocturnal insulin release.