Background: Inhibitors of the sodium-glucose cotransporter 2 (SGLT2) slow the progression of diabetic kidney disease, possibly by reducing the proximal tubule transport workload with subsequent improvement of renal oxygenation. We aimed to test this hypothesis in individuals with type 1 diabetes and albuminuria. Methods: A randomised, double-blind, placebo-controlled, crossover trial with a single 50 mg dose of the SGLT2 inhibitor dapagliflozin and placebo in random order, separated by a two-week washout period. Magnetic resonance imaging (MRI) was used to assess renal R 2 * (a low value corresponds to a high tissue oxygenation), renal perfusion (arterial spin labelling) and renal artery flow (phase contrast imaging) at baseline, three-and six hours from tablet ingestion. Exploratory outcomes, including baroreflex sensitivity, peripheral blood oxygen saturation, peripheral blood mononuclear cell mitochondrial oxygen consumption rate, and biomarkers of inflammation were evaluated at baseline and 12 h from medication. The study is registered in the EU Clinical Trials Register (EudraCT 2019À004,557À92), on ClinicalTrials.gov (NCT04193566), and is completed. Findings: Between February 3, 2020 and October 23, 2020, 31 individuals were screened, and 19 eligible individuals were randomised. Three dropped out before receiving any of the interventions and one dropped out after receiving only placebo. We included 15 individuals (33% female) in the per-protocol analysis with a mean age of 58 (SD 14) years, median urinary albumin creatinine ratio of 46 [IQR 21À58] mg/g and an eGFR of 73 (32) ml/min/1¢73m 2 . The mean changes in renal cortical R 2 * from baseline to six hours were for dapagliflozin -1¢1 (SD 0¢7) s À1 and for placebo +1¢3 (0¢7) s À1 , resulting in a difference between interventions of -2¢3 s À1 [95% CI -4¢0 to -0¢6]; p = 0¢012. No between-intervention differences were found in any other MRI outcomes, physiological parameters or exploratory outcomes. There were no adverse events. Interpretation: A single dose of 50 mg dapagliflozin acutely improved renal cortical R 2 * without changing renal perfusion or blood flow. This suggests improved renal cortical oxygenation due to a reduced tubular transport workload in the proximal tubules. Such improved oxygenation may in part explain the long-term beneficial renal effects seen with SGLT2 inhibitors, but it remains to be determined whether the observed effects can be achieved with lower doses, with chronic treatment and if they occur in type 2 diabetes as well.

We used magnetic resonance imaging (MRI) to study kidney energetics in persons with and without type 1 diabetes (T1D). In a cross-sectional study 15 persons with T1D and albuminuria and 15 non-diabetic controls (CONs) underwent multiparametric MRI (3 Tesla Philips Scanner) to quantify renal cortical and medullary oxygenation (R2*, higher values correspond to higher deoxyhaemoglobin concentration), renal perfusion (arterial spin labelling) and renal artery blood flow (phase contrast). Analyses were adjusted for age, sex, systolic blood pressure, plasma hemoglobin, body mass index, and estimated glomerular filtration rate (eGFR). Participants with T1D had a higher median [Q1; Q3] urine albumin creatinine ratio (UACR) than CONs (46 [21; 58] vs. 4 [3; 6] mg/g; p<0.0001) and a lower mean±SD eGFR (73±32 ml/min/1.73m2 vs. 88±15 ml/min/1.73m2; p = 0.12), although not significantly. Mean medullary R2* was lower in T1D (34±6 s–1vs. 38±5 s–1; p<0.01) corresponding to a higher oxygenation. R2* was not different in the cortex. Cortical perfusion was lower in T1D (163±40 vs. 224±49 ml/100g/min; p<0.001). Renal artery blood flow was lower in T1D than in CONs (360±130 vs. 430±113 ml/min; p = 0.05). In T1D, lower cortical oxygenation and renal artery blood flow were both associated with higher UACR and lower eGFR (p<0.05). Participants with T1D and albuminuria exhibited higher medullary oxygenation than CONs, despite lower cortical perfusion and renal artery blood flow. This might reflect perturbed kidney energetics leading to a higher setpoint of medullary oxygenation in T1D. Lower cortical oxygenation and renal artery blood flow were associated with higher UACR and lower eGFR in T1D.

Background Cardiac Rubidium‐82 (82Rb) positron emission tomography/computed tomography (PET/CT) provides a measure of the myocardial blood flow and the myocardial flow reserve, which reflects the function of both large epicardial arteries and the myocardial microcirculation. Knowledge on changes in the myocardial microvascular function over time is lacking. Methods In this cohort study, we recruited 60 persons with type 2 diabetes and 30 non‐diabetic controls, in 2013; all free of overt cardiovascular disease. All underwent a cardiac 82Rb PET/CT scan. In 2019, all survivors (n = 82) were invited for a repeated cardiac 82Rb PET/CT scan using the same protocol, and 29 with type 2 diabetes and 19 controls participated. Results Median duration between visits was 6.2 years (IQR: 6.1–6.3). In the total cohort, the mean age was 66.4 years (SD: 9.3) and 33% were females. The myocardial flow reserve was lower in persons with type 2 diabetes compared to controls (p = 0.002) but there was no temporal change in the myocardial flow reserve in participants with type 2 diabetes: mean change: −0.22 (95% CI: −0.47 to 0.02) nor in controls: −0.12 (−0.49 to 0.25) or when comparing type 2 diabetes to controls: mean difference: −0.10 (95% CI: −0.52 to 0.31). The temporal reduction in stress‐induced myocardial blood flow did not differ within the groups but was more pronounced in type 2 diabetes compared to controls: mean difference: −0.30 (95% CI: −0.55 to −0.04). Conclusion The myocardial microvascular function was impaired in persons with type 2 diabetes compared to controls but did not change significantly in either of the groups when evaluated over 6 years.