Gluconeogenesis, But Not Glycogenolysis, Contributes to the Increase in Endogenous Glucose Production by SGLT-2 Inhibition

OBJECTIVE Recent studies indicate that sodium-glucose cotransporter 2 (SGLT-2) inhibition increases endogenous glucose production (EGP), potentially counteracting the glucose-lowering potency, and stimulates lipid oxidation and lipolysis. However, the acute effects of SGLT-2 inhibition on hepatic glycogen, lipid, and energy metabolism have not yet been analyzed. We therefore investigated the impact of a single dose of dapagliflozin (D) or placebo (P) on hepatic glycogenolysis, hepatocellular lipid (HCL) content and mitochondrial activity (kATP). RESEARCH DESIGN AND METHODS Ten healthy volunteers (control [CON]: age 30 +/- 3 years, BMI 24 +/- 1 kg/m(2), HbA(1c) 5.2 +/- 0.1%) and six patients with type 2 diabetes mellitus (T2DM: age 63 +/- 4 years, BMI 28 +/- 1.5 kg/m(2), HbA(1c) 6.1 +/- 0.5%) were investigated on two study days (CON-P vs. CON-D and T2DM-P vs. T2DM-D). H-1/C-13/P-31 MRS was performed before, 90-180 min (MR1), and 300-390 min (MR2) after administration of 10 mg dapagliflozin or placebo. EGP was assessed by tracer dilution techniques. RESULTS Compared with CON-P, EGP was higher in CON-D (10.0 +/- 0.3 vs. 12.4 +/- 0.5 mu mol kg(-1) min(-1); P < 0.05) and comparable in T2DM-D and T2DM-P (10.1 +/- 0.7 vs. 10.4 +/- 0.5 mu mol kg(-1) min(-1); P = not significant [n.s.]). A strong correlation of EGP with glucosuria was observed (r = 0.732; P < 0.01). The insulin-to-glucagon ratio was lower after dapagliflozin in CON-D and T2DM-D compared with baseline (P < 0.05). Glycogenolysis did not differ between CON-P and CON-D (-3.28 +/- 0.49 vs. -2.53 +/- 0.56 mu mol kg(-1) min(-1); P = n.s.) or T2DM-P and T2DM-D (-0.74 +/- 0.23 vs. -1.21 +/- 0.33 mu mol kg(-1) min(-1); P = n.s.), whereas gluconeogenesis was higher after dapagliflozin in CON-P compared with CON-D (6.7 +/- 0.6 vs. 9.9 +/- 0.6 mu mol kg(-1) min(-1); P < 0.01) but not in T2DM. No significant changes in HCL and kATP were observed. CONCLUSIONS The rise in EGP after SGLT-2 inhibition is due to increased gluconeogenesis, but not glycogenolysis. Changes in glucagon and the insulin-to-glucagon ratio are not associated with an increased hepatic glycogen breakdown. HCL and kATP are not significantly affected by a single dose of dapagliflozin.