New research by Patrick Schrauwen and colleagues shows that circadian misalignment, which is seen in people who undertake shift work, causes a substantial reduction in muscle insulin sensitivity. Furthermore, they demonstrate that the peroxisome proliferator-activated receptor (PPAR) pathway has a role in this effect.
Previous epidemiological studies found that people who work night shifts have an increased risk of developing type 2 diabetes mellitus. Additionally, animal models with liver-specific or muscle-specific disruption of clock genes (genes that regulate circadian rhythms) develop insulin resistance. However, the metabolic effect of circadian misalignment in skeletal muscle in humans is still unknown, which led the authors to investigate this effect.
Schrauwen and his team recruited 14 healthy lean young men, who underwent a 3-day circadian alignment (control) protocol and a 3.5-day circadian misalignment protocol where their behavioural cycle was shifted by 12 hours. Plasma levels of glucose and free fatty acids were measured after each protocol, which showed that both levels increased during the misalignment. “Importantly, we found that rapid day–night shift resulted in a ~23% reduction of insulin sensitivity, which was mainly accounted for by muscle insulin resistance,” explains Schrauwen.
Next, the researchers analysed mRNA expression levels from muscle biopsy samples taken after each protocol and demonstrated that during circadian misalignment the expression of core clock genes (BMAL1, CRY1 and PER2) kept the same expression pattern as in the control condition. This result suggested that the molecular clock in skeletal muscle is misaligned relative to behavioural conditions. Finally, further analyses revealed that genes with protein products involved in fatty acid metabolism and PPAR signalling had increased expression, suggesting that circadian misalignment upregulated lipid metabolism in the muscle.
As the current study is on healthy participants, the authors are interested in whether similar effects would be observed in people with metabolic disorders (such as diabetes mellitus and obesity).
Wefers, J. et al. Circadian misalignment induces fatty acid metabolism gene profiles and compromises insulin sensitivity in human skeletal muscle. Proc. Natl Acad. Sci. USA https://doi.org/10.1073/pnas.1722295115 (2018)
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Leong, I. Shift work causes insulin resistance. Nat Rev Endocrinol 14, 503 (2018). https://doi.org/10.1038/s41574-018-0074-5