title: Urinary adenosine excretion in type 1 diabetes.
abstract: In experimental models of diabetes, augmented sodium-glucose cotransport-2 (SGLT2) activity diminishes sodium (Na+) delivery at the macula densa. As a result, less vasoconstrictive adenosine is generated, leading to afferent arteriolar vasodilatation and hyperfiltration. The measurement and significance of urinary adenosine in humans has not been examined extensively in states of renal hemodynamic impairment like that of diabetes. Our aim was to validate a method for urine adenosine quantification in humans and perform an exploratory post hoc analysis to determine whether urinary adenosine levels change dynamically in response to natriuresis in patients with type 1 diabetes (T1D) before and after treatment with the SGLT2 inhibitor (SGLT2i) empagliflozin. We hypothesized that SGLT2i, which reduces renal hyperfiltration through increased Na+delivery to the macula densa, would increase urinary adenosine excretion. Urine adenosine corrected for creatinine was measured using our validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method in 40 healthy participants and 40 patients with T1D. In the T1D cohort, measurements were performed during clamped euglycemic and hyperglycemic conditions before and following 8 wk of SGLT2i therapy. Urinary adenosine was detectable in healthy subjects (0.32 ± 0.11 µmol/mmol Cr) and patients with T1D. In response to SGLT2i, urine adenosine increased during clamped hyperglycemia (0.40 ± 0.11 vs. 0.45 ± 0.12 µmol/mmol Cr,P= 0.005). Similar trends were observed during clamped euglycemia (P= 0.08). In conclusion, SGLT2i increases urinary adenosine excretion under clamped hyperglycemic conditions in patients with T1D. The potentially protective role of SGLT2i against glomerular hyperfiltration and its mediation by adenosine in diabetes merits further study.
authors.affiliation: Division of Nephrology, Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada.|Department of Physiology, University of Toronto, Toronto, Onatario, Canada.
authors.forename: Harindra
authors.initials: H
authors.lastname: Rajasekeran
authors.affiliation: Division of Nephrology, Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada.|Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Yuliya
authors.initials: Y
authors.lastname: Lytvyn
authors.affiliation: Departments of Clinical Biochemistry and Laboratory Medicine and Pathobiology, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bozovic
authors.affiliation: Division of Nephrology, Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada.|Division of Endocrinology and Metabolism, Department of Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Lovshin
authors.affiliation: Departments of Clinical Biochemistry and Laboratory Medicine and Pathobiology, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Eleftherios
authors.initials: E
authors.lastname: Diamandis
authors.affiliation: Division of Nephrology, Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Cattran
authors.affiliation: Division of Cardiology, Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada; and.
authors.forename: Mansoor
authors.initials: M
authors.lastname: Husain
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Perkins
authors.affiliation: Division of Endocrinology, Department of Medicine, Saint Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Advani
authors.affiliation: Division of Nephrology, Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Heather N
authors.initials: HN
authors.lastname: Reich
authors.affiliation: Departments of Clinical Biochemistry and Laboratory Medicine and Pathobiology, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Vathany
authors.initials: V
authors.lastname: Kulasingam
authors.affiliation: Division of Nephrology, Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada; david.cherney@uhn.ca.|Department of Physiology, University of Toronto, Toronto, Onatario, Canada.
authors.forename: David Z I
authors.initials: DZI
authors.lastname: Cherney
mesh_terms: D000241:Adenosine / Q000652:urine*; D000328:Adult; D001559:Benzhydryl Compounds / Q000627:therapeutic use; D016022:Case-Control Studies; D002853:Chromatography, Liquid; D003922:Diabetes Mellitus, Type 1 / Q000175:diagnosis / Q000188:drug therapy / Q000503:physiopathology / Q000652:urine*; D005260:Female; D005960:Glucosides / Q000627:therapeutic use; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D065667:Renal Elimination / Q000187:drug effects; D015203:Reproducibility of Results; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D053719:Tandem Mass Spectrometry; D013997:Time Factors; D016896:Treatment Outcome; D016482:Urinalysis / Q000379:methods*; D055815:Young Adult
chemical_list: D001559:Benzhydryl Compounds; D005960:Glucosides; D007004:Hypoglycemic Agents; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C570240:empagliflozin; D000241:Adenosine
keywords: diabetic chronic kidney disease; liquid chromatography-tandem mass spectrometry; urinary adenosine