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

Abstract

OBJECTIVEInsulin 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 METHODSThe 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.RESULTSDapagliflozin 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.CONCLUSIONSDapagliflozin 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.

Determinants of the increase in ketone concentration during SGLT2 inhibition in NGT, IFG and T2DM patients

“…In addition to lowering plasma glucose concentration, SGLT2 inhibitors exert multiple other metabolic actions in T2DM individuals . They improve insulin sensitivity and beta cell function, stimulate an increase in basal rate of hepatic glucose production, lower fasting plasma insulin (FPI) concentration, stimulate glucagon secretion and switch fuel consumption from glucose to fat oxidation . Some of these metabolic actions of SGLT2 inhibitors can affect ketone production in T2DM patients.…”

Pioglitazone prevents the increase in plasma ketone concentration associated with dapagliflozin in insulin‐treated T2DM patients: Results from the Qatar Study

“…Thus, we could hypothesize only concerning the potential mechanism(s) by which pioglitazone prevents an increase in plasma ketone concentration (Figure ). Previous studies from our group and others have demonstrated an increase in plasma FFA concentration and total body fat oxidation following initiation of SGLT2i therapy.…”

“…We and others have shown that, in addition to lowering plasma glucose concentration, SGLT2i exert multiple other metabolic actions in T2DM patients including improved insulin sensitivity, enhanced beta cell function, and increased plasma free fatty acid (FFA) concentration, total body fat oxidation and ketone production. Although, in absolute terms, the increase in plasma ketone concentration is small, from approximately 0.2 mM to approximately 0.4 mM, it occurs in the vast majority (>90%) of patients receiving SGLT2i therapy,, and in 10% to 20% of patients the plasma ketone level exceeds the upper limit of the normal range .…”

Emerging use of combination therapies for the management of type 2 diabetes &ndash; focus on saxagliptin and dapagliflozin

“…This was associated with a 116% increase in ketone bodies and a 49% increase in free fatty acids,90 demonstrating the increased lipid catabolism seen in human beings with prolonged SGLT2 inhibitor use 91. This shift from glucose to fat oxidation has also been demonstrated in patients on dapagliflozin after only 2 weeks,92 and this likely accounts for the small changes seen in lipid levels.…”