Statistics show that approximately 537 million adults worldwide had diabetes in 2021, and this number is expected to rise to 783 million by 2045. Sleep disorders are highly prevalent among patients with type 2 diabetes, affecting between 42% and 76.8% of them. These sleep disturbances are increasingly regarded as significant complications of type 2 diabetes. As a result, finding evidence-based methods to enhance the sleep quality of these patients has become an urgent issue.
The n-3 polyunsaturated fatty acids (PUFA) rich in deep-sea fish oil are believed to promote sleep. However, their specific benefits for patients with type 2 diabetes and the underlying molecular mechanisms remain unclear.
On May 9, 2025, an important research achievement was published in Cell Reports Medicine, a sub-journal of Cell. The research team discovered that marine n-3 polyunsaturated fatty acids can slow down the progression of sleep disorders by regulating the central circadian rhythms in patients with type 2 diabetes.
The regulation of sleep involves multiple aspects, including homeostatic pressure, wakefulness-dependent regulation, and circadian rhythms. The central biological clock located in the suprachiasmatic nucleus (SCN) controls the entire sleep process in a 24-hour cycle through feedback loops driven by genes such as Clock, Bmal1, Rorα, Per, and Rev-erb. These genes play a crucial role in maintaining sleep homeostasis.
In patients with type 2 diabetes, reduced expression of biological clock genes is associated with insulin resistance, impaired β-cell function, and elevated glycated hemoglobin levels. The decreased expression of Bmal1, Per1, and Per2 genes in white blood cells of these patients may further exacerbate sleep-wake disorders. Notably, RORα plays a key role in both the upstream regulation of the SCN and glucose metabolism. It influences sleep patterns through interactions with Bmal1 transcription, making it a potential target for regulating circadian rhythms in the treatment of type 2 diabetes.
Dietary fat intake is closely linked to the balance of sleep and circadian rhythms. In the general population, there is a negative correlation between the consumption of oily fish and the Pittsburgh Sleep Quality Index (PSQI) score (a higher score indicates poorer sleep quality), suggesting that n-3 polyunsaturated fatty acids in deep-sea fish oil may be beneficial for sleep and circadian rhythm regulation. However, a previous meta-analysis concluded that n-3 polyunsaturated fatty acids have no effect on sleep, and no previous studies have focused on diabetic patients, who are prone to sleep disorders.
The research team’s previous studies have confirmed that marine n-3 polyunsaturated fatty acids can improve the balance of glucose and lipid metabolism in diabetic mice. In addition to metabolic regulation, n-3 polyunsaturated fatty acids also participate in circadian rhythm regulation as non-photic synchronizers and may enhance insulin secretion through GPR120 and promote phase shifts of the liver’s biological clock. However, the specific mechanisms by which n-3 polyunsaturated fatty acids affect the central biological clock rhythms in diabetic patients have remained unknown.
In this latest study, the research team conducted a 14-month randomized controlled trial (RCT) to investigate whether long-term fish oil consumption can improve the sleep quality of patients with type 2 diabetes. Meanwhile, they used docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) in hypothalamic neurons and combined molecular docking and RORα gene knockout experiments to study their effects on the central biological clock and circadian rhythm oscillations, aiming to clarify the underlying mechanisms.
The study results showed a significant association between regular fish oil consumption and improved sleep quality among 27,549 patients with type 2 diabetes. The RCT also demonstrated that fish oil supplements could not only improve the sleep parameters of these patients but also upregulate the expression of central biological clock genes such as Clock, Bmal1, and Per2. In in vitro experiments, DHA and EPA were able to restore the rhythmic oscillations of key biological clock genes in hypothalamic neurons damaged by palmitic acid. Further research revealed that n-3 polyunsaturated fatty acids regulate the oscillations of the circadian biological clock by acting on RORα and promote the translocation of BMAL1 into the cell nucleus.
This study reached several important conclusions. First, there is a correlation between fish oil use and improved sleep quality among a large number of type 2 diabetes patients. Second, fish oil can slow down sleep disorders and regulate the expression of biological clock genes in these patients. Third, n-3 polyunsaturated fatty acids regulate the circadian rhythm oscillations of hypothalamic neurons by acting on RORα. Fourth, n-3 polyunsaturated fatty acids can restore the rhythmic oscillations of BMAL1 and enhance its nuclear translocation.
Overall, this study indicates that marine n-3 polyunsaturated fatty acids, as a dietary intervention, have great potential in improving the sleep health of patients with type 2 diabetes.
