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The SGLT2 Inhibitor Dapagliflozin Increases the Oxidation of Ingested Fatty Acids to Ketones in Type 2 Diabetes

Roselle A Herring1,2, Fariba Shojaee-Moradie1, Mary Stevenage1

  • 1Centre for Endocrinology, Diabetes and Research, Royal Surrey NHS Foundation Trust, Guildford, U.K.

Diabetes Care
|March 21, 2022
PubMed
Abstract

Insights

The SGLT2 inhibitor dapagliflozin increases ketogenesis in type 2 diabetes by promoting a liver-based metabolic switch, not by increasing lipolysis. This enhances ketone production from meal-derived fatty acids.

Area of Science:

  • Endocrinology
  • Metabolic Diseases
  • Pharmacology

Background:

  • Sodium-glucose cotransporter 2 (SGLT2) inhibitors like dapagliflozin are used to manage type 2 diabetes.
  • Increased ketogenesis has been observed with SGLT2 inhibitor treatment, but the underlying mechanism requires elucidation.

Purpose of the Study:

  • To investigate the mechanism by which dapagliflozin treatment increases ketogenesis in individuals with type 2 diabetes.
  • To determine the contribution of meal-derived fatty acids and lipolysis to dapagliflozin-induced ketogenesis.

Main Methods:

  • A double-blind, placebo-controlled, crossover study design was employed.
  • Participants ingested [U-13C]palmitate to measure ketogenesis and stable isotopes for glucose flux and lipolysis.
  • Blood samples were collected over 480 minutes post-ingestion.

Main Results:

  • Dapagliflozin treatment led to higher plasma β-hydroxybutyrate (BOHB) concentrations and increased ketone enrichment from ingested palmitate.
  • Peripheral glucose uptake was lower, and glucose excretion was higher with dapagliflozin.
  • Nonesterified fatty acids (NEFAs) were elevated, but lipolysis and endogenous glucose production remained unchanged.

Conclusions:

  • Dapagliflozin treatment enhances ketogenesis, with meal-derived fatty acids contributing to increased ketone production.
  • The rise in BOHB suggests a liver-specific metabolic switch promoting ketogenesis, independent of significant changes in lipolysis.

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