Abstract: BACKGROUND: Disturbance of circadian rhythm aggravates insulin resistance and abnormal glucose and lipid metabolism, becoming an important inducement for diabetes and its complications. Regular aerobic exercise enhances insulin sensitivity through activation of the AMPK signaling pathway while upregulating silent information regulation 1 (SIRT1) expression to stabilize rhythmic oscillations of core clock genes.
OBJECTIVE: To explore the effect of treadmill exercise on metabolic abnormalities and cognitive dysfunction induced by circadian rhythm disturbance in diabetic mice, and analyze its underlying molecular mechanism. 
METHODS: The 8-week-old wild-type C57BL/6J and diabetic db/db mice were selected as normal controls and diabetic controls. Circadian rhythm disorder models were established by intermittent light (8-hour light/4-hour dark, lasting for 6 weeks), and divided into model and diabetes+model groups. Based on a 6-week treadmill exercise, mouse models were divided into model+exercise group and diabetes+model+exercise group. The detection indicators include body mass, serum melatonin, fasting blood glucose, homeostatic model assessment of insulin resistance, glucose tolerance test and insulin tolerance test, fat mass, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and Morris water maze behavioral performance, as well as BMAL1, CLOCK, Nrf2, superoxide dismutase 2, and mRNA expression levels of SIRT1 and glycogen synthase kinase 3β (GSK3β) in pancreatic tissues. 
RESULTS AND CONCLUSION: (1) Circadian rhythm disruption significantly exacerbated body mass gain, decreased serum melatonin levels, elevated fasting blood glucose, and abnormal lipid metabolism in db/db mice, while exercise intervention reduced these indicators, improved glucose tolerance and insulin sensitivity, significantly reduced the level of interleukin-4 and elevated the level of interferon-γ in mice with circadian rhythm disorders (P < 0.01). (2) Exercise downregulated the expression of the circadian core genes BMAL1 and CLOCK, activated the Nrf2-superoxide dismutase 2 antioxidant pathway, and regulated the SIRT1-GSK3 β signaling axis. (3) Exercise intervention decreased the escape latency and increased crossing platform frequency of db/db mice (P < 0.01). Overall, by regulating SIRT1-GSK3 β signal axis and antioxidant pathway, treadmill exercise can effectively improve metabolic abnormalities, immune imbalance and cognitive damage caused by circadian rhythm disorder in diabetic mice.

Key words: treadmill exercise, silent information regulation 1, glycogen synthase kinase 3β, diabetic mice, circadian rhythm disorder, metabolic abnormalities, cognitive dysfunction