781-P: Beyond Glucosuria: Urine Metabolome Signature Associated with Dapagliflozin in Wild-Type Mice

Background: Glucosuria is a hallmark feature of diabetes. When blood glucose exceeds 200 mg/dl, the amounts reaching the renal tubule overwhelm the capacity of glucose transport and cause glucosuria. SGLT2 inhibitors (SGLT2i) prevent reclamation of glucose from the renal filtrate, leading to glucosuria as well. While SGLT2i promote weight loss and provide cardiovascular protection, those effects are not explained by their glycosuric effect.

Hypothesis:Factors initiated by SGLT-2 blockade lead to excretion of substrates other than glucose, thus creating a unique signature of urine metabolome in SGLT2i-treated mice that may help identify renal responses to SGLT2 inhibition and correspond with system-wide beneficial effects.

Methods: To study SGLT2i effects on the urine metabolome, we used C57BL/6 age-matched male mice. Mice were fasted for three hours and then given either Dapagliflozin (Dapa) or PBS via oral gavage. Capillary glucose was checked prior to gavage. Five hours later, capillary glucose levels were checked again and urine samples were collected for untargeted metabolomics.

Results: Dapa reduced post-gavage glucose by an average Δ of 62.5 mg/dl (p=0.0001). No significant reduction was noted in glucose in the PBS group (Δ=9.2 mg/dl, p=0.52). Glucose was present in the urine of all mice treated with Dapa. Dapa treatment was associated with a unique signature of urine metabolome, with 17 metabolites significantly altered compared to control (P<0.05). While hyperoxaluria has been linked to progression of CKD, mice treated with Dapa had lower level of Oxaluria. Enrichment analysis identified metabolism of Phenylalanine and unsaturated fatty acids to be most affected.

Conclusion: Dapa is associated with excretion of metabolites other than glucose that generates a unique signature of urinary metabolome. Identification of renal response to SGLT2i may help further understand mechanisms of cardiovascular protection and weight loss mediated by SGLT2i.