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, = 0.005). Similar trends were observed during clamped euglycemia ( = 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.

Sodium-glucose co-transporter-2 inhibitors: peculiar “hybrid” diuretics that protect from target organ damage and cardiovascular events

“…By indirect estimates of intrarenal hemodynamics, this study suggests a role of efferent arteriole dilatation rather than of afferent arteriole constriction, when patients, mostly treated with RAAS antagonists (75%), are also treated with SGLT2i. The authors confirm the increase in renal/urinary adenosine, following the activation of the tubule-glomerular feedback, previously found in T1DM subjects [15]. However, they hypothesize a vasodilatory action of adenosine on the efferent (postglomerular) arteriole through A2 adenosine receptor (A2AR), when the potential for preglomerular vasoconstriction is limited, such as in T2DM patients in which a much higher renal vascular resistance is already present.…”

“…This leads to glomerular hyperfiltration, because of the consequent reduction of the tubuleglomerular feedback. Empagliflozin was found to increase urine adenosine excretion in patients with type 1 diabetes mellitus (T1DM), documenting the increased activity of the macula densa in the regulation of renal hemodynamics, when SGLT2 is inhibited [15]. This results in a reduction of glomerular capillary pressure and BPdependent hyperfiltration.…”

Renal hemodynamic effects of sodium-glucose cotransporter 2 inhibitors in hyperfiltering people with type 1 diabetes and people with type 2 diabetes and normal kidney function

“…The fact that urinary adenosine, a key signaling factor of TGF and primarily known to cause afferent vasoconstriction, was increased after empagliflozin treatment further supports this hypothesis. 12 In addition to these observations in humans, empagliflozin was subsequently shown to lower GFR in a mouse model of T1D by decreasing afferent arteriolar diameteras measured in vivo with multiphoton microscopy-via adenosine-mediated stimulation of the A1 adenosine receptor (A1aR). 13 This study by Kidokoro et al 13 built on previous work by other groups showing that SGLT2 inhibition reduces hyperfiltration in different animal models of T1D and T2D.…”

“…This is supported by the fact that a rise in urinary adenosine excretion was observed in both populations. 12,16 As we have mentioned, adenosine is primarily known to cause afferent arteriolar constriction via stimulation of the A1aR. Yet, it can have different effects depending on the prevailing conditions.…”

Glucose and Blood Pressure-Dependent Pathways–The Progression of Diabetic Kidney Disease

“…The reduced sodium concentration at the macula densa level activates tubuloglomerular feedback (TGF) leading to increased intraglomerular pressure and hyperfiltration. Pharmacological SGLT2i reverses these pathophysiological changes, causing less sodium reabsorption in the proximal tubule, thus reducing sodium and fluid retention as well as systemic blood pressure with the increase in sodium and glucose concentration at the macula densa triggering adenosine release, which is a paracrine mediator of TGF downregulation [272,273]. Adenosine enhances arteriolar tone, resulting in reduced intraglomerular pressure, reduction in albuminuria, and amelioration of hyperfiltration.…”