Dapagliflozin Enhances Fat Oxidation and Ketone Production in Patients With Type 2 Diabetes

Abstract

Objective: Insulin resistance is associated with mitochondrial dysfunction and decreased ATP synthesis. Treatment of individuals with type 2 diabetes mellitus (T2DM) with sodium-glucose transporter 2 inhibitors (SGLT2i) improves insulin sensitivity. However, recent reports have demonstrated development of ketoacidosis in subjects with T2DM treated with SGLT2i. The current study examined the effect of improved insulin sensitivity with dapagliflozin on 1) mitochondrial ATP synthesis and 2) substrate oxidation rates and ketone production.

Research design and methods: The study randomized 18 individuals with T2DM to dapagliflozin (n = 9) or placebo (n = 9). Before and after 2 weeks, subjects received an insulin clamp with tritiated glucose, indirect calorimetry, and muscle biopsies.

Results: Dapagliflozin reduced fasting plasma glucose (167 ± 13 to 128 ± 6 mg/dL) and increased insulin-stimulated glucose disposal by 36% (P < 0.01). Glucose oxidation decreased (1.06 to 0.80 mg/kg ⋅ min, P < 0.05), whereas nonoxidative glucose disposal (glycogen synthesis) increased (2.74 to 4.74 mg/kg ⋅ min, P = 0.03). Dapagliflozin decreased basal glucose oxidation and increased lipid oxidation and plasma ketone concentration (0.05 to 0.19 mmol/L, P < 0.01) in association with an increase in fasting plasma glucagon (77 ± 8 to 94 ± 13, P < 0.01). Dapagliflozin reduced the ATP synthesis rate, which correlated with an increase in plasma ketone concentration.

Conclusions: Dapagliflozin improved insulin sensitivity and caused a shift from glucose to lipid oxidation, which, together with an increase in glucagon-to-insulin ratio, provide the metabolic basis for increased ketone production.

Figure 1

Top panel: Effect in individuals with T2DM of dapagliflozin treatment for 2 weeks on ATP synthesis from glutamate (G)/malate (M), pyruvate (Pyr), succinate (SUC) plus rotenone (Rot), and 0.5 μmol/L and 1.0 μmol/L PC. *P < 0.001 vs. baseline. Bottom panel: Correlation between the change in whole-body insulin sensitivity (TGD/SSPI) and the change in ATP synthesis with PC. SSPI, steady-state plasma insulin concentration.

Figure 2

Correlation between ATP synthesis and plasma ketone concentration (Conc) in subjects with T2DM. G, glutamate; M, malate; Pyr, pyruvate; Rot, rotenone; Suc, succinate.

Figure 3

Schematic representation of the effect of SGLT2 inhibition on the stimulation of hepatic ketogenesis and ATP synthesis. A more detailed discussion is presented in the text. AcAc, acetoacetyl; OAA, oxaloacetic acid; PEP, phosphoenolpyruvic acid.