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Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve hard renal outcomes in type 2 diabetes. This is possibly explained by the fact that SGLT2i normalize the measured glomerular filtration rate (mGFR) by increasing renal vascular resistance, as was shown in young people with type 1 diabetes and glomerular hyperfiltration. Therefore, we compared the renal hemodynamic effects of dapagliflozin with gliclazide in type 2 diabetes. The mGFR and effective renal plasma flow were assessed using inulin and para-aminohippurate clearances in the fasted state, during clamped euglycemia (5 mmol/L) and during clamped hyperglycemia (15 mmol/L). Filtration fraction and renal vascular resistance were calculated. Additionally, factors known to modulate renal hemodynamics were measured. In 44 people with type 2 diabetes on metformin monotherapy (Hemoglobin A1c 7.4%, mGFR 113 mL/min), dapagliflozin versus gliclazide reduced mGFR by 5, 10, and 12 mL/min in the consecutive phases while both agents similarly improved Hemoglobin A1c (-0.48% vs -0.65%). Dapagliflozin also reduced filtration fraction without increasing renal vascular resistance, and increased urinary adenosine and prostaglandin concentrations. Gliclazide did not consistently alter renal hemodynamic parameters. Thus, beyond glucose control, SGLT2i reduce mGFR and filtration fraction in type 2 diabetes. The fact that renal vascular resistance was not increased by dapagliflozin suggests that this is due to post-glomerular vasodilation rather than pre-glomerular vasoconstriction.

Sodium–glucose transporter (SGLT)2 inhibitors increase plasma magnesium and plasma phosphate and may cause ketoacidosis, but the contribution of improved glycemic control to these observations as well as effects on other electrolytes and acid–base parameters remain unknown. Therefore, our objective was to compare the effects of SGLT2 inhibitors dapagliflozin and sulfonylurea gliclazide on plasma electrolytes, urinary electrolyte excretion, and acid–base balance in people with Type 2 diabetes (T2D). We assessed the effects of dapagliflozin and gliclazide treatment on plasma electrolytes and bicarbonate, 24-hour urinary pH and excretions of electrolytes, ammonium, citrate, and sulfate in 44 metformin-treated people with T2D and preserved kidney function. Compared with gliclazide, dapagliflozin increased plasma chloride by 1.4 mmol/l (95% CI 0.4–2.4), plasma magnesium by 0.03 mmol/l (95% CI 0.01–0.06), and plasma sulfate by 0.02 mmol/l (95% CI 0.01–0.04). Compared with baseline, dapagliflozin also significantly increased plasma phosphate, but the same trend was observed with gliclazide. From baseline to week 12, dapagliflozin increased the urinary excretion of citrate by 0.93 ± 1.72 mmol/day, acetoacetate by 48 μmol/day (IQR 17–138), and β-hydroxybutyrate by 59 μmol/day (IQR 0–336), without disturbing acid–base balance. In conclusion, dapagliflozin increases plasma magnesium, chloride, and sulfate compared with gliclazide, while reaching similar glucose-lowering in people with T2D. Dapagliflozin also increases urinary ketone excretion without changing acid–base balance. Therefore, the increase in urinary citrate excretion by dapagliflozin may reflect an effect on cellular metabolism including the tricarboxylic acid cycle. This potentially contributes to kidney protection.

OBJECTIVE: Kidney insulin clearance, proposed to be the main route of extra-hepatic insulin clearance, occurs in tubular cells following glomerular filtration and peritubular uptake, a process that may be impaired in people with type 2 diabetes (T2D) and/or impaired kidney function. Human studies that investigated kidney insulin clearance are limited by the invasive nature of the measurement. Instead, we evaluated relationships between whole-body insulin clearance, and gold-standard measured kidney function and insulin sensitivity in adults with T2D and normal kidney function.RESEARCH DESIGN AND METHODS: We determined insulin, inulin/iohexol and para-aminohippuric acid (PAH) clearances during a hyperinsulinemic-euglycemic clamp to measure whole-body insulin clearance and kidney function. Insulin sensitivity was expressed by glucose infusion rate (M value). Associations between whole-body insulin clearance, kidney function and insulin sensitivity were examined using univariable and multivariable linear regressions models.RESULTS: We investigated 44 predominantly male (77%) T2D adults aged 63 ± 7, with fat mass 34.5 ± 9 kg, lean body mass 63.0 ± 11.8 kg, and HbA1c 7.4 ± 0.6%. Average whole-body insulin clearance was 1188 ± 358 mL/min. Mean GFR was 110 ± 22 mL/min, mean ERPF 565 ± 141 mL/min, and M value averaged 3.9 ± 2.3 mg/min. Whole-body insulin clearance was positively correlated with lean body mass, ERPF and insulin sensitivity, but not with GFR. ERPF explained 6% of the variance when entered in a nested multivariable linear regression model op top of lean body mass (25%) and insulin sensitivity (15%).CONCLUSIONS: In adults with T2D and normal kidney function, whole-body insulin clearance was predicted best by lean body mass and insulin sensitivity, and to a lesser extent by ERPF. GFR was not associated with whole-body insulin clearance. In contrast to prior understanding, this suggests that in this population kidney insulin clearance may not play such a dominant role in whole-body insulin clearance.

Introduction: Sodium-glucose cotransporter-2 inhibitors (SGLT2is) improve hard renal outcomes in type 2 diabetes (T2D) patients. An acute and reversible drop in eGFR that stabilizes over time, as with RAS inhibitors, suggests involvement of a beneficial renal hemodynamic mechanism. In hyperfiltering T1D patients, SGLT2i lowered GFR by increasing afferent arteriolar resistance, possibly by activating tubuloglomerular feedback. We studied the renal hemodynamic effects of SGLT2i dapagliflozin in T2D patients like those included in recent outcome trials. Methods: Forty-four T2D patients on metformin monotherapy, (62.9±7.0 years, HbA1c 7.38±0.63%, GFR 113±19 mL/min) were randomized to 12 weeks dapagliflozin 10mg (DAPA, n=24) or gliclazide 30mg (GLIC, n=20) QD to achieve glycemic equipoise. At baseline and week 12, GFR and renal plasma flow (RPF) were measured by gold-standard inulin and para-aminohippurate clearances. The measurements were performed 1) in the fasting state, 2) during clamped euglycemia (90 mg/dL) and 3) hyperglycemia (270 mg/dL). Renal vascular resistance (RVR) and filtration fraction (FF) were calculated using GFR, RPF, Ht and MAP. Afferent and efferent arteriolar resistances were estimated by Gomez’ equations. Results: HbA1C decreased similarly (0.47% with DAPA and 0.65% with GLIC; p=ns), while only DAPA significantly reduced MAP by approximately 6 mmHg. DAPA reduced GFR during all three conditions by 8.9 (p Conclusion: We confirm that SGLT2i induces beneficial renal hemodynamic changes in T2D beyond glycemic control that are characterized by reduced GFR and FF. However, in contrast to standing opinion, this is mediated by efferent arteriolar dilation rather than afferent arteriolar constriction. Disclosure E.J. van Bommel: None. M.A. Muskiet: Consultant; Self; Eli Lilly and Company, Novo Nordisk A/S, Sanofi. M.J. van Baar: None. M.H. Kramer: None. M. Nieuwdorp: Advisory Panel; Self; Caelus health. J.A. Joles: None. D.H. van Raalte: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Sanofi. Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Sanofi. Funding AstraZeneca Nederland BV

Introduction: Disease progression in type 2 diabetes (T2D) is due to a continuous loss of β-cell function, partly driven by chronic secretory stress on remaining islets caused by hyperglycemia. Beta-cell loss may be further enhanced by insulin secretagogues such as sulfonylureas. In contrast, sodium-glucose cotransporter-2 inhibitors (SGLT2is) may improve beta-cell function by reducing β-cell afterload by lowering blood glucose levels through glucosuria. Methods: Forty-four T2D patients treated with metformin (age 63 ± 7 years; HbA1c 7.3 ± 0.6%; GFR 113±19 mL/min) were randomized to dapagliflozin 10mg (DAPA, n=24) or gliclazide 30mg (GLIC, n=20) QD. At baseline and week 12, whole-body insulin sensitivity (M-value) and β-cell function were quantified by gold-standard hyperinsulinemic-euglycemic and hyperglycemic clamp with additional arginine stimulation. First-phase glucose-stimulated and arginine-stimulated incremental area under the C-peptide curves (iAUCCP) were calculated. iAUCCP multiplied by M-value rendered disposition indices (1st phase and ARG-DI; nmol.min/L.mg/kg.min). Results: HbA1C decreased similarly (-0.47% with DAPA and -0.65% with GLIC; p=ns). DAPA, but not GLIC, decreased fasting hyperinsulinemia (-18.4 pmol/l vs. +2.7 pmol/l, p=0.01). Neither treatment improved insulin sensitivity. GLIC significantly increased 1st phase DI from 0.75 ± 1.21 to 2.89 ± 3.25 (p Conclusion: In contrast to the secretagogue GLIC, DAPA lowered fasting insulin levels and did not further enhance C-peptide secretion in response to hyperglycemia. However, it did improve ARG-DI, which may reflect β-cell total secretory capacity. Thus, by lowering beta-cell afterload, DAPA may confer long-term β-cell benefit versus GLIC. Disclosure E.J.M. van Bommel: None. M.H. Muskiet: Consultant; Self; Eli Lilly and Company, Novo Nordisk A/S, Sanofi. M.J. van Baar: None. M.H. Kramer: None. M. Nieuwdorp: Advisory Panel; Self; Caelus health. C.B. Verchere: Advisory Panel; Self; Sirona Biochem. Board Member; Self; Integrated Nanotherapeutics. D.H. van Raalte: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Sanofi. Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Sanofi. Funding AstraZeneca Nederland BV