Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are effective treatments for improving glucose control and reducing cardiovascular events in patients with T2D. In the present study we examined the metabolic effects of chronic treatment of the SGLT2i dapagliflozin in obese insulin resistant Zucker rats. Three different studies were performed with the aims to assess: 1) liver CoA intermediates, 2) whole-body FA metabolism using a constant infusion of 3H-palmitate and 3) tissue-specific rates of FA utilization and storage using 3H-labelled bromo-palmitate and 14C-labelled palmitate, respectively. Four weeks treatment with dapagliflozin (1 mg/kg/d p.o.) markedly increased glucosuria, reduced HbA1c and fasting plasma glucose and insulin levels and increased pancreatic insulin content compared to vehicle treated rats. Liver acetyl-CoA levels were increased while the malonyl-CoA/acetyl-CoA ratio was decreased following dapagliflozin treatment, suggestive of an increased liver FA oxidation. Treatment with dapagliflozin also increased liver HMG-CoA levels, an intermediate in ketone body formation, indicating that the acetyl-CoA is diverted to ketone body formation. This was supported by increased fasting plasma levels of the ketone body β-hydroxybutyrate in the dapagliflozin-treated rats compared to vehicle. Dapagliflozin treatment resulted in increased plasma FA levels and rates of whole-body FA oxidation. The increased whole-body FA oxidation was subsequently found to be driven by an increase in liver FA utilization.
In conclusion, dapagliflozin improves glucose homeostasis and enhances FA utilization in insulin resistant obese animals. These results suggest that dapagliflozin-induced glucose loss in urine signals a fasting state to the liver, which leads to an increased FA oxidation and ketone body production.
T. Kroon: Employee; Self; AstraZeneca. T. Hagstedt: None. A. Kjellstedt: None. A. Lindblom: Employee; Self; AstraZeneca. L. Löfgren: Employee; Self; AstraZeneca. J. Boucher: Employee; Self; AstraZeneca. M. Sörhede Winzell: Employee; Self; AstraZeneca. D. Linden: Employee; Self; AstraZeneca. K. Wallenius: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca.