Abstract| Volume 40, ISSUE 5, SUPPLEMENT , S64, October 2016

The Effect of SGLT2 Inhibition on Urinary Adenosine Excretion in Patients with Type 1 Diabetes

      Augmented renal proximal tubular sodium-glucose cotransport-2 (SGLT2) activity promotes hyperfiltration, due to diminished sodium (Na+) delivery at the macula densa (MD), leading to afferent arteriolar vasodilatation and hyperfiltration. While experimental models have shown that reduced MD-derived adenosine causes afferent vasodilatation, the role of adenosine in humans is unknown. Our aims were to 1) develop a urine adenosine assay in humans with type 1 diabetes (T1D); 2) to determine if the SGLT2 inhibitor (SGLT2i) empagliflozin, which reduces hyperfiltration through increased Na+ delivery to the MD, increases urinary adenosine excretion. In this post-hoc analysis, urine adenosine corrected for creatinine was measured using liquid chromatography with tandem mass spectrometry (LC-MS/MS) in 40 patients with T1D who participated in an 8-week study examining the effect of SGLT2i on renal function. The operating characteristics for the novel LC-MS/MS adenosine assay were excellent. In response to SGLT2i, urine adenosine increased under clamped hyperglycemic conditions (p=0.0005, Figure 1). Urine adenosine can be detected in patients with T1D using LC-MS/MS. SGLT2i increases urine adenosine excretion—an effect that may contribute to the regulation of renal hemodynamic function.
      Figure 1
      Figure 1Urinary adenosine excretion within type 1 diabetes patients under clamped hyperglycemic and euglycemic conditions, pre- and post-SGLT2 inhibition treatment. Significant adenosine release was observed under the hyperglycemic context (p=0.0005), with a similar effect observed under euglycemia. V3, pre-SGLT2i euglycemic day; V4, pre-SGLT2i hyperglycemic day; V12, post-SGLT2i euglycemic day; V13, post-SGLT2i hyperglycemic day].
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