Nocturnal activation of melatonin receptor type 1 signaling modulates diurnal insulin sensitivity via regulation of PI3K activity

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.