Meghana Vankina

Introduction. The circadian rhythm is an endogenous rhythmic pattern that is present in most organisms. In mammals, the central brain clock is within the suprachiasmatic nucleus and consists of a 24-hour autoregulatory feedback loop¹. Disruption of circadian rhythms has been linked to various cardio-metabolic disorders such as diabetes¹. Diabetes has been shown to be associated with both the disruption of clock genes and circadian misalignment². Studies have shown that shift-work is associated with the disruption of the circadian clock. This contributes to insulin sensitivity and glucose intolerance, which in turn can manifest as type II diabetes³. The prevalence of type II diabetes is significantly higher in shift workers than those working regular hours. Additionally, night-shift work has been associated with disruption in circadian clock genes and an increase in metabolic disorders³. Endoplasmic reticulum stress (ERS) and the disruption of circadian clock genes are thought to disrupt glucose homeostasis in night-shift workers. Methods. Peripheral blood mononuclear cells, serum, and plasma were obtained from 40 subjects, 20 day workers and 20 night workers. The day workers worked from 0700 h to 1900h and night workers worked from 1900 h until 0700 h. Blood samples collected at 0700 h and 1900 h were used to assess gene expression of genes related to the circadian cycle and ERS⁴. Results. The peripheral circadian clock elements that are most sensitive to night shift work are CRY1 and BMAL1⁴. NRF2 is an important oxidative stress regulator in many cells. Night workers showed a significant reduction in NRF2 mRNA levels at both times⁴. The loss of NRF2 function in some cells was associated with altered circadian rhythms, demonstrating that NRF2 may be required for normal circadian rhythm timing. Conclusion. There has been increasing evidence that demonstrates the interplay of ERS and circadian clock genes on glucose homeostasis disruption in night shift workers. ERS activation impairs regulation of the circadian clock mainly by an ATF4-dependent mechanism^4,5. Rev-erb-alpha is a circadian transcriptional repressor that has been implicated in glucose homeostasis and diabetes⁶. SR9009 and SR9011 are Rev-erb agonists that have therapeutic potential⁷. However, this has yet to be translated to clinical trials due to drug safety issues and suboptimal pharmacokinetics. Other potential therapeutics include early time restricted feeding (eTRF). eTRF protects from glucose intolerance and insulin resistance in clock-deficient mice⁸. Since eTRF also aligns with one’s circadian clock, there is promising potential of testing eTRF to improve insulin sensitivity in shift workers.

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5. Gao L, Chen H, Li C, et al. ER stress activation impairs the expression of circadian clock and clock-controlled genes in NIH3T3 cells via an ATF4-dependent mechanism. Cell Signal. 2019;57:89-101. doi:10.1016/j.cellsig.2019.01.008
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8. Sutton EF, Beyl R, Early KS, Cefalu WT, Ravussin E, Peterson CM. Early Time-Restricted Feeding Improves Insulin Sensitivity, Blood Pressure, and Oxidative Stress Even without Weight Loss in Men with Prediabetes. Cell Metab. 2018;27(6):1212-1221.e3. doi:10.1016/j.cmet.2018.04.010