Abstract 084: Significant Roles of Hyperglycemia and Obesity in the Disruption of Blood Pressure Circadian Rhythm in Leptin-receptor Mutant Db/db Mice

Blood pressure (BP) exhibits 24-hour rhythm. Loss of BP oscillation has been found in up to 75% diabetic patients and is associated with increased risks of target organ injuries. However, the mechanisms underlying the disruption of BP circadian rhythm in diabetes remain poorly understood. We and others have demonstrated that type 2 diabetic db/db mice in C57/KsJ background have hypertension and severely disrupted BP circadian rhythm. Since these db/db mice were severely hyperglycemic (>600 mg/dL) as well as obese, it is unclear which factor or both contribute to the disruption of BP oscillation. Moreover, it is unclear whether clock genes are involved in the diabetes associated disruption of BP circadian rhythm. To address these specific questions, we cross bred the leptin receptor mutated db/db mice in the C57BL/KsJ background with PERIOD2::LUCIFERASE knock in mice in C57BL/6J background. At 4-5 months old, the blood glucose in these db/db -Per2 mice was higher than controls (320.3 vs 153 mg/dL) but was significantly lower than the C57/KsJ - db/db mice (608.5 mg/dL). However, the body weight of these db/db -per2 mice was significantly higher than both the C57/KsJ- db/db (66.4 vs 44.8 g) as well as control mice (33.9 g). The metabolic flexibility, which is represented by respiratory exchange ratio and measured using TSE LabMaster Indirect Calorimetry System, was significantly compromised in the db/db -per2 mice when compared to controls. We then determined the BP in the db/db -per2 mice using radiotelemetry under 12: 12 light: dark cycle. The circadian parameters of BP, including period length, amplitude and acrophase were calculated using Chronos-fit software. The results demonstrated that db/db -per2 mice have normal BP value but disrupted BP circadian rhythm, with decreased power of 24h oscillation, diminished amplitude and shifted acrophase. However, the extent of the disruption was significantly less than that we have reported in the C57/KsJ- db/db mice. By using LumiCycle, we are currently investigating the clock gene functions in various tissues including SCN, aorta, liver, and etc isolated from db/db -Per2 mice. In summary, we demonstrated that both hyperglycemia and obesity significantly contribute to the disruption in BP circadian rhythm in db/db mice.