Abstract P327: Real-Time Analysis of Blood Glucose Dynamics by a Glucose Telemetry System in Canagliflozin-Treated Diabetic Mice

Abstract

SGLT2 inhibitors lower blood glucose (BG) levels and have the potential to reduce cardiovascular and renal complications of type 2 diabetes mellitus (T2DM). Since BG levels can vary significantly during a treatment regime, hemoglobin A1c is often utilized as a stable indicator of BG status but dynamic measurements of BG may provide greater insights. A blood glucose telemetry systems was used to investigate BG dynamics in canagliflozin (CANA, an SGLT inhibitor)-treated T2DM mice. Male New Zealand Obese mice were fed a high fat diet to induce diabetes. When the mice exhibited a BG of ~350 mg/dl, the mice were treated with vehicle for 5 days followed by 10 mg/kg/day CANA for 5 days by daily oral gavage (single dosing/day). BG levels were monitored continuously via implanted telemetry devices. Chronic treatment (6 weeks) was also performed to investigate blood pressure monitored by a telemetry system and to assess kidney injury. During vehicle treatment for 5 days, BG levels in the mice averaged 336.7 mg/dl. Lower BG levels during early morning compared to night time (active time) were observed during vehicle treatment. BG levels demonstrated a large variation over 24 hours during the vehicle treatment (maximum minus minimum BG: 368.5 mg/dl on day 5). CANA rapidly reduced BG levels within 3 hours following treatment (214.8±25.4 mg/dl), and the lowered BG was sustained until the next dosing. The average 24-hour BG was gradually suppressed during the CANA treatment reaching 170.1 mg/dl on the last day of CANA treatment. Moreover, CANA reduced the variation of BG (maximum minus minimum BG: 214.8 mg/dl on day 5 of CANA treatment). In mice receiving chronic treatment, CANA started lowering systolic blood pressure on week 2 and significant suppression was observed on week 6 (vehicle: 157.9±2.2 vs. CANA: 124.7±7.6 mmHg). The development of kidney injury, especially renal tubular fibrosis and inflammation, was attenuated by CANA. These findings demonstrate that CANA treatment results in rapid and sustained reductions of both BG levels and BG variability which precede the reduction of blood pressure. The temporal dissociation between the lowering of BG and of arterial pressure levels by CANA suggests hyperglycemia-induced factors mediate the development of hypertension in T2DM.