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

Jin Hee Kim, Minyoung Lee, Soo Hyun Kim, So Ra Kim, Byung Wan Lee, Eun Seok Kang, Bong Soo Cha, Jin Won Cho, Yong ho Lee

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38 Citations (Scopus)


Aim: To investigate sodium-glucose cotransporter 2 inhibitor (SGLT2i)-induced changes in ketogenic enzymes and transporters in normal and diabetic mice models. Materials and methods: Normal mice were randomly assigned to receive either vehicle or SGLT2i (25 mg/kg/d by oral gavage) for 7 days. Diabetic mice were treated with vehicle, insulin (4.5 units/kg/d by subcutaneous injection) or SGLT2i (25 mg/kg/d by intra-peritoneal injection) for 5 weeks. Serum and tissues of ketogenic organs were analysed. Results: In both normal and diabetic mice, SGLT2i increased beta-hydroxybutyrate (BHB) content in liver, kidney and colon tissue, as well as in serum and urine. In these organs, SGLT2i upregulated mRNA expression of ketogenic enzymes, 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2 and 3-hydroxy-3-methylglutaryl-coenzyme A lyase. Similar patterns were observed in the kidney, ileum and colon for mRNA and protein expression of sodium-dependent monocarboxylate transporters (SMCTs), which mediate the cellular uptake of BHB and butyrate, an important substrate for intestinal ketogenesis. In diabetic mice under euglycaemic conditions, SGLT2i increased major ketogenic enzymes and SMCTs, while insulin suppressed ketogenesis. Conclusions: SGLT2i increased systemic and tissue BHB levels by upregulating ketogenic enzymes and transporters in the liver, kidney and intestine, suggesting the integrated physiological consequences for ketone body metabolism of SGLT2i administration.

Original languageEnglish
Pages (from-to)801-811
Number of pages11
JournalDiabetes, Obesity and Metabolism
Issue number4
Publication statusPublished - 2019 Apr

Bibliographical note

Funding Information:
This work was supported by the National Research Foundation of Korea (NRF) grant (NRF-2016R1A5A1010764) funded by the Korean Government (MSIP), and the grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI17C0913).

Publisher Copyright:
© 2018 John Wiley & Sons Ltd

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology


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