A Novel Diabetic Mouse Model for Real-Time Monitoring of Clock Gene Oscillation and Blood Pressure Circadian Rhythm

Abstract

Diabetic patients have an increased prevalence of blood pressure (BP) circadian rhythm disruption, which is associated with an increased risk of target organ damage and detrimental cardiovascular events. Limited information is available regarding the role of clock genes in the disruption of BP circadian rhythm in diabetes due to the lack of a diabetic animal model that allows real-time monitoring of clock gene oscillation. Here, we generated a novel diabetic db/db-mPer2 Luc mouse model by crossing type 2 diabetic db/db mice with mPer2 Luc knock-in mice. The daily rhythms of BP, heart rate, locomotor activity, and food and water intake were acquired by radiotelemetry or using metabolic chambers. The daily oscillation of mPer2 bioluminescence was recorded by LumiCycle in real-time in tissue explants and using the IVIS system in vivo. Our results show that db/db-mPer2 Luc mice are obese, diabetic, and glucose intolerant. The db/db-mPer2 Luc mice displayed a compromised BP daily rhythm, which was associated with disrupted daily rhythms in baroreflex sensitivity, locomotor activity, and metabolism, but not heart rate or food and water intake. The phase of the mPer2 daily oscillation was advanced to different extents in the explanted peripheral tissues from db/db-mPer2 Luc mice relative to control mice. In contrast, no phase shift was detected in mPer2 daily oscillations in the explanted SCN. Moreover, advanced phase shift of the mPer2 daily oscillation was detected in the liver, kidney and submandibular gland in vivo of db/db-mPer2 Luc mice. In conclusion, the diabetic db/db-mPer2 Luc mouse is a novel animal model that allows real-time monitoring of mPer2 circadian rhythms ex vivo and in vivo. The results from db/db-mPer2 Luc mice suggest that the desynchrony of mPer2 daily oscillation in peripheral tissues contributes to the loss of BP daily oscillation in diabetes.