Diabetes Metab Syndr.  2025  Aug  20.  pii:  S1871-4021(25)00101-8. [Epub  ahead  of  print]19(7): 103284
Divya Joshi, 
Marie Pigeyre, 
Muhammad Usman Ali, 
Renee de Mutsert, 
Femke Rutters, 
David Campbell, 
Jean-Pierre Despres, 
Sayem Borhan, 
Talha Rafiq, 
Romy Slebe, 
Denis Blondin, 
Andre Carpentier, 
Joris Hoeks, 
Andries Kalsbeek, 
Patrick Schrauwen, 
Chun-Xia Yi, 
Parminder Raina.
 
  
BACKGROUND: Misalignment of the endogenous circadian system may contribute to the risk of type 2 diabetes. This systematic review and meta-analysis examined the association between clock gene polymorphisms and glycemic parameters and type 2 diabetes.
METHODS: Embase, Medline, and Web of Science databases were searched from inception to August 20, 2024. Empirical studies examining the association between core clock gene polymorphisms and type 2 diabetes and glycemic parameters, and studies examining non-core clock genes with information on environmental factors were included. A multi-level meta-analytical approach was used, and a weighted odds ratio was reported (PROSPERO, CRD42022337706).
RESULTS: In total, 37 studies comprising 535,063 participants were included. CRY2 was associated with higher fasting blood glucose (OR: 1.07, 95 % CI: 1.03-1.11) and impaired glucose tolerance (OR: 1.02, CI: 1.00-1.04). Polymorphisms in MTNR1B were associated with a greater risk of type 2 diabetes. CLOCK was associated with lower risk of type 2 diabetes (OR: 0.94, CI: 0.89-1.00), and PER3 was associated with lower fasting insulin (OR: 0.94, CI: 0.91-0.97) and lower risk of insulin resistance (OR: 0.92, CI: 0.88-0.95). These associations reflect pooled variant-level effects within genes, and the effects of certain variants were modified by diet, alcohol consumption, physical activity, sleep, and length of daylight.
CONCLUSIONS: Specific polymorphisms in circadian genes, including CRY2, MTNR1B, CLOCK, and PER3, were associated with glycemic parameters and type 2 diabetes risk. These associations may be influenced by lifestyle and environmental factors, and interventions targeting circadian alignment could potentially modify diabetes risk, although further research is needed.
Keywords:  Chronotype; Circadian rhythm; Clock genes; Type 2 diabetes