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, HbA1c 5.2 ± 0.1%) and six patients with type 2 diabetes mellitus (T2DM: age 63 ± 4 years, BMI 28 ± 1.5 kg/m2, HbA1c 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.

Energy expenditure due to gluconeogenesis in pathological conditions of insulin resistance

“…Medications to reduce glucose, such as insulin, sulfonylureas, and thiazolidinediones, are mainstays of treatment (19), and decrease GNG in human (20) and rodent studies (21)(22)(23), which may contribute to weight gain associated with these medications. Conversely, increased GNG with sodium glucose tranporter type 2 inhibitors may contribute to weight loss associated with these drugs (24,25). However, changes in GNG-associated EE f P < 0.05 for lipodystrophy vs. T2DM-NIH; g P < 0.05 for lipodystrophy vs. obesity; h P < 0.05 for T2DM-NIH vs. obesity.…”

Critical Reanalysis of the Mechanisms Underlying the Cardiorenal Benefits of SGLT2 Inhibitors and Reaffirmation of the Nutrient Deprivation Signaling/Autophagy Hypothesis

“… 76 , 210 After the induction of glycosuria, the activation of SIRT1, SIRT6, and PGC-1α supports blood glucose by promoting gluconeogenesis 76 , 221 —a distinctive metabolic signature of SGLT2 inhibitors (demonstrated clinically), which limits their antihyperglycemic response. 201 , 222 Activation of AMPK and PGC-1α promotes fatty acid oxidation and increased synthesis of SIRT1 and SIRT3 stimulates 3-hydroxy-3-methylglutaryl CoA synthase, the rate-limiting enzyme for ketone body formation. 223 As a result, AMPK, SIRT1, SIRT3, and PGC-1α act in concert to promote ketogenesis in the liver and the clinical finding of ketogenesis during starvation and after SGLT2 inhibition reflects enhanced nutrient deprivation signaling.…”

Cardiorenal protection of SGLT2 inhibitors—Perspectives from metabolic reprogramming

“…83 The direct metabolic effect of SGLT2 inhibitors was shown to induce a decrease in blood glucose levels, which elicited a decrease in insulin secretion and a rise in glucagon, as well as a paradoxical increase in endogenous glucose production (EGP). 84,85 The mechanisms underlying the increase in EPG are not completely understood, which may be attributed to (1) the increased glucagon levels and the glucagon-to-insulin ratio, 86 (2) the direct inhibition of SGLT2 in pancreatic a-cells to promote glucagon secretion, 87 (3) an increase in gluconeogenesis, 88,89 and (4) a neuronal loop between the kidney and liver to stimulate hepatic glucose production. 90,91 The increase in EPG potentially counteracts the glucose-lowering potency of SGLT2 inhibitors, thereby reducing the risk of hypoglycaemia.…”