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 , HbA 1c = 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.

Pharmacologically induced glycosuria elicits adaptive responses in glucose homeostasis and hormone release. In type 2 diabetes (T2D), along with decrements in plasma glucose and insulin levels and increments in glucagon release, sodium-glucose cotransporter 2 (SGLT2) inhibitors induce stimulation of endogenous glucose production (EGP) and a suppression of tissue glucose disposal (TGD). We measured fasting and postmeal glucose fluxes in 25 subjects without diabetes using a double glucose tracer technique; in these subjects and in 66 previously reported patients with T2D, we also estimated lipolysis (from [ 2 H 5 ]glycerol turnover rate and circulating free fatty acids, glycerol, and triglycerides), lipid oxidation (LOx; by indirect calorimetry), and ketogenesis (from circulating b-hydroxybutyrate concentrations). In both groups, empagliflozin administration raised EGP, lowered TGD, and stimulated lipolysis, LOx, and ketogenesis. The pattern of glycosuria-induced changes was similar in subjects without diabetes and in those with T2D but quantitatively smaller in the former. With chronic (4 weeks) versus acute (first dose) drug administration, glucose flux responses were attenuated, whereas lipid responses were enhanced; in patients with T2D, fasting b-hydroxybutyrate levels rose from 246 6 288 to 561 6 596 mmol/L (P < 0.01). We conclude that by shunting substantial amounts of carbohydrate into urine, SGLT2-mediated glycosuria results in a progressive shift in fuel utilization toward fatty substrates. The associated hormonal milieu (lower insulin-to-glucagon ratio) favors glucose release and ketogenesis.When large quantities of glucose are pharmacologically forced into urinary excretion, whole-body metabolism undergoes adaptive changes involving glucose fluxes, hormonal responses, fuel selection, and energy expenditure (1,2). In previous work (3), we used empagliflozin to investigate the physiological response to forced glycosuria in patients with type 2 diabetes (T2D). By combining a mixed meal with the double-tracer technique, we found that after acute or chronic empagliflozin administration endogenous glucose production (EGP) rose, tissue glucose disposal (TGD) decreased, and lipid utilization increased. The aims of the present work were to measure the full spectrum of changes in lipolysis, lipid levels, and substrate availability consequent upon empagliflozininduced glycosuria in patients with T2D and to test whether and to what extent these changes occur in subjects without diabetes. RESEARCH DESIGN AND METHODS PopulationSixty-six patients with T2D were recruited into the study; their inclusion criteria are detailed in Ferrannini et al. (3). Twenty-five subjects without diabetes (12 with normal glucose tolerance [NGT] and 13 with impaired glucose tolerance [IGT]) served as control subjects (Supplementary Table 1). The glucose and hormone data for the patients with T2D have been reported (3) and are repeated here for comparison purposes. The study (clinicaltrials.gov identifier NCT01248364; EudraCT number 2010-...

OBJECTIVE-To quantitate the separate impact of obesity and hyperlycemia on the incretin effect (i.e., the gain in ␤-cell function after oral glucose versus intravenous glucose). (75 g) and intravenous glucose administration was performed in 51 subjects (24 with normal glucose tolerance [NGT], 17 with impaired glucose tolerance [IGT], and 10 with type 2 diabetes) with a wide range of BMI (20 -61 kg/m 2 ). C-peptide deconvolution was used to reconstruct insulin secretion rates, and ␤-cell glucose sensitivity (slope of the insulin secretion/glucose concentration dose-response curve) was determined by mathematical modeling. The incretin effect was defined as the oral-tointravenous ratio of responses. In 8 subjects with NGT and 10 with diabetes, oral glucose appearance was measured by the double-tracer technique. RESEARCH DESIGN AND METHODS-Isoglycemic oralRESULTS-The incretin effect on total insulin secretion and ␤-cell glucose sensitivity and the GLP-1 response to oral glucose were significantly reduced in diabetes compared with NGT or IGT (P Յ 0.05). The results were similar when subjects were stratified by BMI tertile (P Յ 0.05). In the whole dataset, each manifestation of the incretin effect was inversely related to both glucose tolerance (2-h plasma glucose levels) and BMI (partial r ϭ 0.27-0.59, P Յ 0.05) in an independent, additive manner. Oral glucose appearance did not differ between diabetes and NGT and was positively related to the GLP-1 response (r ϭ 0.53, P Ͻ 0.01). Glucagon suppression during the oral glucose tolerance test was blunted in diabetic patients.CONCLUSIONS-Potentiation of insulin secretion, glucose sensing, glucagon-like peptide-1 release, and glucagon suppression are physiological manifestations of the incretin effect. Glucose tolerance and obesity impair the incretin effect independently of one another.