Background: Circadian rhythms are fundamental to regulating metabolic
processes and cardiovascular functions. Phosphorylated PERIOD2 (PER2) is a key
factor in determining the period of the mammalian circadian clock. Moreover,
casein kinase 1 (CK1) primes the PER2 phosphoswitch and
its stability. While diabetes contributes to the disorder of the circadian
system, changes in PER2 forms and their regulatory mechanisms during diabetes
remain unclear. In this study, we examined the impact of diabetes on PER2 and
CK1 signaling in the heart to determine the potential mechanism
between them. Methods: A Type-1 diabetic rat model was established by
intraperitoneally injecting rats with streptozotocin. General characteristics,
cardiac function, histology, serum biochemistry, apoptosis index and circadian
rhythm were analyzed in controls and diabetic rats treated with or without
PF-670462 (a CK1 inhibitor). A high-glucose model was created with
H9c2 cells and treated with PF-670462 and PER2 siRNA. Cell viability, LDH
release, dead/live rate and histology were determined to assess cellular
injuries. RT-PCR and Western blot were used to evaluate the expression of PER2,
CK1, phosphorylated PER2, and immunofluorescence (IF) was employed to
determine PER2’s location. Results: STZ-induced diabetes prolonged PER’s
period and upregulated the expression of CK1 and phosphorylated PER2
compared to the controls. Inhibiting CK1 and PER2 with PF-670462
downregulated the phosphorylation at Ser662 and the nuclear entry of PER2 in high
glucose conditions. In addition, pharmacologically or genetically suppressing
PER2 mitigated high-glucose-instigated myocardial injury. Conclusions:
Diabetes compromised PER2 in association with activated CK1
signaling. Targeting CK1-regulated PER2 alleviates myocardial
injuries in the presence of high glucose.