Mechanism (s) responsible for the cardiac benefits of SGLT2 inhibitors remain unknown. Aim: To examine the effect of increased ketone concentration (with infusion of beta-hydroxybutyrate [BOHB]) on left ventricular (LV) function and myocardial glucose uptake (MGU) Methods: Two groups (12 per group) of T2DM with HFrEF (<45%) were studied. Group I (Age=60; BMI=32 kg/m2; A1c = 7.7%) received randomly a 6-hr BOHB infusion (Prime =1.5 mg/kg.min, then 0.75 mg/kg.min) or 6-hr HCO3 infusion (control) . Group II (Age=57; BMI=32 kg/m2; A1c=7%) received a 3-hr BOHB infusion at a higher rate. A cardiac MRI was performed before and after each infusion. Additionally, Group I underwent a PET study with 18FDG Results: Groups I and II achieved plasma ketone levels of 1.2 and 2.6 mmol/L respectively. In both groups, the BOHB infusion significantly (P<0.05) increased CO, stroke volume (SV) , and ejection fraction (EF) ; the increase in EF was greater in Group II vs. Group I (<0.001) (Figure 1) . NaHCO3 infusion had no effect on CO, SV, or EF. Myocardial glucose uptake was not altered by BOHB Conclusion: In patients with T2DM and HFrEF, increased plasma ketones significantly increases LV function and may be dose-dependent. These findings support the hypothesis that plasma ketones can provide an additional fuel for the heart, without interfering myocardial glucose metabolism and may be used therapeutically to improve cardiac function in HFrEF. Disclosure C.Solis-herrera: Speaker's Bureau; Novo Nordisk. Y.Qin: None. H.Honka: None. A.Moody: None. G.D.Clarke: None. C.L.Triplitt: Consultant; Bayer AG, Speaker's Bureau; Eli Lilly and Company, Novo Nordisk. E.Cersosimo: Research Support; AstraZeneca. R.A.Defronzo: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Intarcia Therapeutics, Inc., Novo Nordisk, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Merck & Co., Inc., Speaker's Bureau; AstraZeneca. Funding Merck and Co and The Max and Minnie Tomerlin Voelcker Foundation and

We previously have shown that both acute and chronic SGLT-2 inhibition increases endogenous glucose production (EGP) . However, the organ - liver versus kidney - responsible for the increase in EGP has not been identified. We assessed the effect of a single dose of Dapagliflozin or Placebo on renal glucose production in 13 T2DM (age=57.5±1.8 yrs, BMI = 30±1.4 kg/m2) and 9 NGT (age 42±2 3 yrs, BMI = 30±1.1 kg/m2) subjects. Renal glucose production was measured using arteriovenous balance technique across the kidney combined with [3-3H] glucose infusion and PAH infusion (for determination of renal blood flow) before and 4 hours after administration of Dapagliflozin (10 mg) and Placebo; thus, each subject served as their own control. EGP increased following DAPA in both T2DM (2.00±0.11 to 2.43±0.15, P<0.05) and NGT (1.72±0.11 to 2.1±0.16, p<0.05) , while it decreased after placebo in T2DM (2.02±0.12 vs. 1.15±0.06) and NGT (2.10±0.2 vs. 2.05±0.1) (both p<0.01, DAPA vs. placebo) . The fractional renal extraction of glucose (0.02± 0.004 vs. 2.99 ± 1.0, p=0.001 in T2DM, and 0.02± 0.004 vs. 1.62± 1.4 in NGT, p=NS) and renal glucose uptake (0.067 ± 0.02 vs. 0.347 ± 0.06 in T2DM and 0.08 ± 0.02 vs. 0.27 ± 0.08 mg/kg.min in NGT) were higher following DAPA vs. placebo (p<0.05) and were entirely explained by the increase in glucosuria. There was a small, non-significant increase (0.065 & 0.032 mg/kg.min, respectively) in renal glucose production (RGP) following dapagliflozin in T2DM and NGT compared to the 0.45 mg/kg.min increase in total body EGP. Conclusion: A single dose of Dapagliflozin significantly increases EGP which primarily is explained by an increase in hepatic glucose production. Disclosure X. Chen: None. C. Solis-herrera: Speaker’s Bureau; Novo Nordisk. D. Tripathy: None. A. A. Hansis-diarte: None. R. Chilton: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Nova Biomedical. E. Cersosimo: Research Support; AstraZeneca. R. A. Defronzo: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Intarcia Therapeutics, Inc., Novo Nordisk, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Merck & Co., Inc., Speaker’s Bureau; AstraZeneca. Funding Astra Zeneca

Background: Cardioprotective benefits of SGLT2 inhibitors (SGLT2i) are well established. However, their effects on cardiopulmonary function measured by CPET in patients with T2D and HFrEF continue to be largely unknown. Objective: Examine the effects of SGLT2i on cardiopulmonary function measured by cardiopulmonary exercise test (CPET) & 6MWT in patients with T2D & HFrEF. Methods: Six subjects with T2D with HFrEF (<40%) (Age=59±2.6, BMI=33.3±1.1, A1c=7.1±0.3, EF 28±4%) were randomized to empagliflozin 25mg (SGLT2i) vs. placebo in a 2:1 fashion for 12 weeks. Cardiac MRI, 6MWT, and CPET were performed pre- and post-intervention. Results: SGLT2i group showed an increase in EF. All subjects reached submaximal cardiovascular effort (RER≤1.10). The Ventilatory Anaerobic Threshold (VT, submaximal index of exercise capacity) showed a significant increase in VT time with SGLT2i (p=0.05). The rest of the parameters trended toward improvement including Ve/VCO2 slope and 6MWT. Conclusion: Subjects with T2D and HFrEF, treated with an SGLT2i had improved EF, a decrease in the worsening of the Ve/VCO2 slope (a predictor of mortality in HF patients), an increase in 6MWT, and significantly improved VT time (aerobic metabolism) compared to placebo. These findings may represent a novel mechanism of CV protection and warrants further investigation. Disclosure Y. Qin: None. C. L. Triplitt: Speaker's Bureau; Novo Nordisk. G. D. Clarke: None. E. Cersosimo: None. S. E. Espinoza: None. R. A. Defronzo: Advisory Panel; AstraZeneca, Bayer Inc., Boehringer-Ingelheim, Novo Nordisk, Research Support; AstraZeneca, Boehringer-Ingelheim, Merck & Co., Inc., Speaker's Bureau; AstraZeneca. C. Solis-herrera: None. F. M. Acosta: None. S. Neppala: None. T. M. Cortes: None. A. Stepanenko: None. A. Moody: None. N. D. Sanchez: None. M. Brown: None. L. A. Cruz moreno: None. Funding Doris Duke Charitable Foundation; Voelcker Foundation; National Institutes of Health

Improved renal oxygenation is proposed as a potential reno-protective mechanism of SGLT2 inhibitors in T2DM. Bold-MRI studies in nondiabetic subjects showed no effect with dapagliflozin and improved renal cortical oxygenation with empagliflozin in T1DM. No studies have examined renal oxygenation in T2DM. We examined the effect of dapagliflozin (10 mg) on renal oxygen delivery and oxygen consumption in 7 T2DM (age=58±3 yrs, BMI = 30±1.8 kg/m2) and 7 NGT (age = 47±3.4 yrs, BMI = 28.6±1.6kg/m2) subjects who received a single dose of dapagliflozin or placebo. Renal vein (SvO2) and radial artery (SaO2) hemoglobin saturation were measured with i-STAT point of care analyzer and renal blood flow with PAH infusion before and 4 hours after dapagliflozin/placebo. At baseline arterial (CaO2, 19 ± 0.8 vs 19 ± 0.7 ml/dl, p=NS) and renal venous (CvO2, 16 ± 0.9 vs 18 ± 0.7 ml/dl, p=NS) oxygen Content were similar in DAPA and PLAC. Thus, there was no difference in renal oxygen delivery (478 ± 29 vs 533 ±27 ml/min/m2) between DAPA and PLAC groups. Following DAPA/PLAC renal plasma flow did not change, and there was no change in arterial (CaO2) (19 ± 0.8 vs 18.2 ± 0.7 ml/dl, p=NS) or renal venous (CvO2) (16 ± 0.9 vs 15.5 ± 0.9 ml/dl) oxygen content in DAPA or PLAC groups. Renal oxygen consumption following DAPA (67 ± 10 vs 78 ±13 ml/min/m2, p=NS) and PLAC (42 ± 8 vs 50 ± 6 ml/min/m2, p=NS) groups were not different versus baseline. Conclusion: A single acute dose of dapagliflozin does not alter renal oxygen delivery or consumption in T2DM or NGT subjects. Disclosure D. Tripathy: None. X. Chen: None. R. Chilton: None. A.A. Hansis-Diarte: None. M. Salehi: None. C. Solis-Herrera: None. E. Cersosimo: None. R.A. DeFronzo: Speaker's Bureau; AstraZeneca. Advisory Panel; AstraZeneca, Bayer Inc., Boehringer-Ingelheim, Novo Nordisk. Research Support; AstraZeneca, Boehringer-Ingelheim, Merck & Co., Inc. Funding AstraZeneca

Background: The CV benefits of SGLT2i are well established. However, how skeletal muscle (SkM) bioenergetics respond to SGLT2i in T2D and HFrEF remains largely unknown. Objective: To explore the effects of empagliflozin on SkM bioenergetics (phosphorus metabolites & myocellular lipid content) at rest and post-exercise (31P & 1H MRS) and cardiac function (MRI). Methods: Subjects with T2D & HFrEF (<40%) (n=6) were randomized 2:1 to empagliflozin 25mg (SGLT2i) or placebo for 12 wks (Age=59±2.6, BMI=33.3±1.1, A1c=7.1±0.3, EF 28±4%). A cardiac MRI, & static/dynamic 31P & 1H SkM by MRS, were performed before & after treatment. Results: In the empagliflozin group, SkM 31P MRS at rest, showed decrease in phosphodiesterase [PDE]. 31P MRS post-exercise, showed significant improvement in Phosphocreatinine (PCr) recovery, expressed by the K value. 1H MRS showed a reduction of saturated intramyocellular lipids (IMCL-CH2:CH3 ratio). Conclusion: Empagliflozin in subjects with T2D and HFrEF had beneficial effects in SkM energy utilization and muscle recovery post-exercise as determined by a decrease in PDE and increase in K value. Additionally, empagliflozin decreased saturated IMCL, which could be expected to improve mitochondrial function and energy utilization. If similar findings were to occur in cardiac muscle, this could provide a novel mechanism for the beneficial CV effects of SGLT2i. Disclosure Y. Qin: None. N. D. Sanchez: None. A. Moody: None. F. M. Acosta: None. S. Neppala: None. M. Brown: None. H. Honka: None. L. A. Cruz Moreno: None. C. L. Triplitt: Speaker's Bureau; Novo Nordisk. G. D. Clarke: None. E. Cersosimo: None. R. A. DeFronzo: Speaker's Bureau; AstraZeneca. Advisory Panel; AstraZeneca, Bayer Inc., Boehringer-Ingelheim, Novo Nordisk. Research Support; AstraZeneca, Boehringer-Ingelheim, Merck & Co., Inc. C. Solis-Herrera: None. Funding Doris Duke Charitable Foundation; Voelcker Foundation; National Institutes of Health