Shift to Fatty Substrate Utilization in Response to Sodium–Glucose Cotransporter 2 Inhibition in Subjects Without Diabetes and Patients With Type 2 Diabetes

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, 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 nondiabetic subjects (ND) using a double-glucose-tracer technique; in these subjects and in 66 previously reported T2D patients, we also estimated lipolysis (from [ 2 H 5 ]-glycerol turnover rate and circulating free fatty acids, glycerol, and triglycerides), lipid oxidation (by indirect calorimetry) and ketogenesis (from circulating s-hydroxybutyrate concentrations). In both groups, empagliflozin administration raised EGP and lowered TGD, stimulated lipolysis, lipid oxidation, and ketogenesis. The pattern of glycosuria-induced changes was similar in ND and T2D, but quantitatively smaller in the former. With chronic (4 weeks) vs acute (first dose) drug administration, glucose flux responses were attenuated whereas lipid responses were enhanced; in T2D, fasting β-hydroxybutyrate levels rose from 246±288 to 561±596 µmol/L (p