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

Abstract

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/m², HbA_1c 5.2 ± 0.1%) and six patients with type 2 diabetes mellitus (T2DM: age 63 ± 4 years, BMI 28 ± 1.5 kg/m², HbA_1c 6.1 ± 0.5%) were investigated on two study days (CON-P vs. CON-D and T2DM-P vs. T2DM-D). ¹H/¹³C/³¹P 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 μmol kg^-1 min^-1; P < 0.05) and comparable in T2DM-D and T2DM-P (10.1 ± 0.7 vs. 10.4 ± 0.5 μmol 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 μmol kg^-1 min^-1; P = n.s.) or T2DM-P and T2DM-D (-0.74 ± 0.23 vs. -1.21 ± 0.33 μmol 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 μmol 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.

Trial registration: ClinicalTrials.gov NCT02558270.