Recent genetic studies have highlighted the potential involvement of melatonin receptor 1 (MT₁) and melatonin receptor 2 (MT₂) in the pathogenesis of type 2 diabetes. Here, we report that mice lacking MT₁ (MT₁ KO) tend to accumulate more fat mass than WT mice and exhibit marked systemic insulin resistance. Additional experiments revealed that the main insulin signaling pathway affected by the loss of MT₁ was the activation of phosphatidylinositol‐3‐kinase (PI3K). Transcripts of both catalytic and regulatory subunits of PI3K were strongly downregulated within MT₁ KO mice. Moreover, the suppression of nocturnal melatonin levels within WT mice, by exposing mice to constant light, resulted in impaired PI3K activity and insulin resistance during the day, similar to what was observed in MT₁ KO mice. Inversely, administration of melatonin to WT mice exposed to constant light was sufficient and necessary to restore insulin‐mediated PI3K activity and insulin sensitivity. Hence, our data demonstrate that the activation of MT₁ signaling at night modulates insulin sensitivity during the day via the regulation of the PI3K transcription and activity. Lastly, we provide evidence that decreased expression of MTNR1A (MT₁) in the liver of diabetic individuals is associated with poorly controlled diabetes.

中文翻译：

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褪黑激素受体 1 型信号的夜间激活通过调节 PI3K 活性来调节昼夜胰岛素敏感性

最近的遗传研究强调了褪黑激素受体 1 (MT ₁ ) 和褪黑激素受体 2 (MT ₂ ) 在 2 型糖尿病发病机制中的潜在参与。在这里，我们报告说，缺乏 MT ₁ (MT ₁ KO) 的小鼠往往比 WT 小鼠积累更多的脂肪量，并表现出明显的全身胰岛素抵抗。其他实验表明，受 MT ₁缺失影响的主要胰岛素信号通路是磷脂酰肌醇 3 激酶 (PI3K) 的激活。PI3K 的催化亚基和调节亚基的转录本在 MT _{1 中}被强烈下调KO老鼠。此外，通过将小鼠暴露在恒定光照下抑制 WT 小鼠的夜间褪黑激素水平，导致白天 PI3K 活性和胰岛素抵抗受损，类似于在 MT ₁ KO 小鼠中观察到的情况。相反，向暴露于恒定光照的 WT 小鼠施用褪黑激素对于恢复胰岛素介导的 PI3K 活性和胰岛素敏感性是足够且必要的。因此，我们的数据表明，夜间MT ₁信号传导的激活通过调节 PI3K 转录和活性来调节白天的胰岛素敏感性。最后，我们提供证据表明糖尿病个体肝脏中MTNR1A (MT ₁ ) 的表达降低与糖尿病控制不佳有关。