BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower glycemia by 
enhancing urinary glucose excretion. The physiologic response to 
pharmacologically induced acute or chronic glycosuria has not been investigated 
in human diabetes.
METHODS: We evaluated 66 patients with type 2 diabetes (62 ± 7 years, BMI = 31.6 
± 4.6 kg/m(2), HbA1c = 55 ± 8 mmol/mol, mean ± SD) at baseline, after a single 
dose, and following 4-week treatment with empagliflozin (25 mg). At each time 
point, patients received a mixed meal coupled with dual-tracer glucose 
administration and indirect calorimetry.
RESULTS: Both single-dose and chronic empagliflozin treatment caused glycosuria 
during fasting (median, 7.8 [interquartile range {IQR}, 4.4] g/3 hours and 9.2 
[IQR, 5.2] g/3 hours) and after meal ingestion (median, 29.0 [IQR, 12.5] g/5 
hours and 28.2 [IQR, 15.4] g/5 hours). After 3 hours of fasting, endogenous 
glucose production (EGP) was increased 25%, while glycemia was 0.9 ± 0.7 mmol/l 
lower (P < 0.0001 vs. baseline). After meal ingestion, glucose and insulin AUC 
decreased, whereas the glucagon response increased (all P < 0.001). While oral 
glucose appearance was unchanged, EGP was increased (median, 40 [IQR, 14] g and 
37 [IQR, 11] g vs. 34 [IQR, 11] g, both P < 0.01). Tissue glucose disposal was 
reduced (median, 75 [IQR, 16] g and 70 [IQR, 21] g vs. 93 [IQR, 18] g, P < 
0.0001), due to a decrease in both glucose oxidation and nonoxidative glucose 
disposal, with a concomitant rise in lipid oxidation after chronic 
administration (all P < 0.01). β Cell glucose sensitivity increased (median, 55 
[IQR, 35] pmol • min(-1) • m(-2) • mM(-1) and 55 [IQR, 39] pmol • min(-1) • 
m(-2) • mM(-1) vs. 44 [IQR, 32] pmol • min(-1) • m(-2) • mM(-1), P < 0.0001), 
and insulin sensitivity was improved. Resting energy expenditure rates and those 
after meal ingestion were unchanged.
CONCLUSIONS: In patients with type 2 diabetes, empagliflozin-induced glycosuria 
improved β cell function and insulin sensitivity, despite the fall in insulin 
secretion and tissue glucose disposal and the rise in EGP after one dose, 
thereby lowering fasting and postprandial glycemia. Chronic dosing shifted 
substrate utilization from carbohydrate to lipid. Trial registration. 
ClinicalTrials.Gov NCT01248364 (EudraCT no. 2010-018708-99). Funding. This study 
was funded by Boehringer Ingelheim.