Abstract
Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to increase ketone bodies in patients with type 2 diabetes; however, the underlying mechanisms have not been fully elucidated. Here we examined the effect of the SGLT2 inhibitor dapagliflozin (1 mg/kg/day, formulated in a water, PEG400, ethanol, propylene glycol solution, 4 weeks) on lipid metabolism in obese Zucker rats. Fasting FFA metabolism was assessed in the anesthetized state using a [9,10-3H(N)]-palmitic acid tracer by estimating rates of plasma FFA appearance (Ra), whole-body FFA oxidation (Rox), and nonoxidative disposal (Rst). In the liver, clearance (Kβ-ox) and flux (Rβ-ox) of FFA into β-oxidation were estimated using [9,10-3H]-(R)-bromopalmitate/[U-14C]palmitate tracers. As expected, dapagliflozin induced glycosuria and a robust antidiabetic effect; treatment reduced fasting plasma glucose and insulin, lowered glycated hemoglobin, and increased pancreatic insulin content compared with vehicle controls. Dapagliflozin also increased plasma FFA, Ra, Rox, and Rst with enhanced channeling toward oxidation versus storage. In the liver, there was also enhanced channeling of FFA to β-oxidation, with increased Kβ-ox, Rβ-ox and tissue acetyl-CoA, compared with controls. Finally, dapagliflozin increased hepatic HMG-CoA and plasma β-hydroxybutyrate, consistent with a specific enhancement of ketogenesis. Since ketogenesis has not been directly measured, we cannot exclude an additional contribution of impaired ketone body clearance to the ketosis. In conclusion, this study provides evidence that the dapagliflozin-induced increase in plasma ketone bodies is driven by the combined action of FFA mobilization from adipose tissue and diversion of hepatic FFA toward β-oxidation.
Highlights
Sodium-glucose cotransporter 2 (SGLT2) inhibitors including dapagliflozin, are established treatments for patients with type 2 diabetes leading to improved glucose control as well as decreased risk of cardiovascular events and development of kidney disease [1,2,3,4,5,6,7]
In the obese Zucker rats, dapagliflozin treatment (1 mg/kg/day, oral gavage) for 4 weeks increased glucosuria compared to the vehicle group (Fig. 1a), consistent with expected inhibition of SGLT2
Consistent with effects seen in multiple clinical trials in patients with type 2 diabetes [23], in the current study, SGLT2 inhibitor treatment improved glucose control in the obese Zucker rat
Summary
SGLT2 inhibitors including dapagliflozin, are established treatments for patients with type 2 diabetes leading to improved glucose control as well as decreased risk of cardiovascular events and development of kidney disease [1,2,3,4,5,6,7]. The improved cardiovascular and renal outcome data for this class of drugs has resulted in a change in standard of care recommendations, placing SGLT2 inhibitors after lifestyle interventions and metformin treatment for patients with combined diabetes and heart failure or chronic kidney disease [8]. The increased ketone body levels might result from a systemic increase in FFA mobilization driven by the established treatment-induced reductions in plasma glucose and insulin. While involvement of enhanced FFA mobilization seems likely, data directly assessing this mechanism is currently lacking in the literature
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