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

Abstract

Results of the present study demonstrate that SGLT2 inhibition exerts different metabolic effects in non-diabetic individuals as compared to diabetic 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 . Because of the reduction in daily insulin dose, the increase in plasma ketone concentration associated with the initiation of SGLT2i therapy was highest in patients receiving insulin therapy.…”

“…Under certain clinical conditions, acute illness for example, SGLT2i therapy has led to the development of clinically significant diabetic ketoacidosis despite a normal/near normal plasma glucose concentration, that is, euglycaemic ketoacidosis . We have shown previously that the magnitude of increase in the plasma ketone concentration following empagliflozin administration is strongly and inversely associated with the magnitude of decrease in plasma glucose and insulin concentrations and is strongly correlated with the increase in plasma FFA concentration . Because pioglitazone is a strong inhibitor of lipolysis and lowers plasma FFA concentration independent of plasma insulin concentration, we hypothesized that the combination of pioglitazone and SGLT2i will prevent the increase in plasma ketone concentration.…”

Sodium‐glucose cotransporter 2 inhibitors regulate ketone body metabolism via inter‐organ crosstalk

“…Patients with diabetes have different ketone body homeostasis compared with non‐diabetics . In the former, baseline serum BHB levels were elevated compared with the latter, who also have a higher rate of ketone utilization and production . Conditions such as type 2 diabetes, characterized by a deprivation of glucose utilization, lower insulin‐to‐glucagon ratio, and increased circulating FFAs by accelerated lipolysis, can enhance ketogenesis .…”

SGLT2 inhibitors: hypotheses on the mechanism of cardiovascular protection

“…12 Glucagon release by pancreatic -cells is increased following SGLT2 inhibition, which may be beneficial in heart failure through its ionotropic effects, 13 but also increases availability of circulating ketones, thereby providing organs that are critically challenged by hypoxia or ischaemia are provided with an advantageous energy substrate in which to synthesise ATP with reduced oxygen consumption as compared to glucose or fat, as postulated by Ferrannini and others. 14,15 Very little experimental data is currently available to support this hypothesis as an explanation for the advantageous outcomes in EMPA-REG and CANVAS, but it presents an intriguing avenue for further exploration.…”