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

Jin Hee Kim1,2, Minyoung Lee2,3, Soo Hyun Kim2

  • 1Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.

Diabetes, Obesity & Metabolism
|November 9, 2018
PubMed
Abstract

Insights

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) boost ketone production in mice by increasing ketogenic enzymes and transporters in the liver, kidney, and intestine. This highlights SGLT2i

Area of Science:

  • Metabolic Physiology
  • Pharmacology
  • Endocrinology

Background:

  • Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are used to manage type 2 diabetes.
  • The impact of SGLT2i on ketone body metabolism is not fully understood.
  • Ketogenesis is a critical metabolic pathway involving the liver, kidney, and intestine.

Purpose of the Study:

  • To investigate the effects of SGLT2i on ketogenic enzymes and transporters.
  • To compare SGLT2i effects with insulin in diabetic models.
  • To elucidate the physiological consequences of SGLT2i on ketone metabolism.

Main Methods:

  • Utilized normal and diabetic mouse models.
  • Administered SGLT2i or insulin via oral gavage or injection.
  • Analyzed serum and tissue samples from ketogenic organs for enzyme and transporter expression.

Main Results:

  • SGLT2i increased beta-hydroxybutyrate (BHB) levels in serum and multiple tissues (liver, kidney, colon).
  • Upregulation of ketogenic enzymes (3-hydroxy-3-methylglutaryl-coenzyme A synthase 2, 3-hydroxy-3-methylglutaryl-coenzyme A lyase) and sodium-dependent monocarboxylate transporters (SMCTs) was observed.
  • Insulin suppressed ketogenesis in diabetic mice, contrasting with SGLT2i's ketogenic effects.

Conclusions:

  • SGLT2i enhances systemic and tissue BHB levels by upregulating key ketogenic enzymes and transporters.
  • These findings suggest integrated physiological effects of SGLT2i on ketone body metabolism.
  • SGLT2i promotes ketogenesis, while insulin has an inhibitory effect in diabetic conditions.
Keywords:
antidiabetic drugempagliflozinsodium-glucose cotransporter 2 inhibitors

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