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

Research output: Contribution to journalArticle

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Abstract

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
Volume21
Issue number4
DOIs
Publication statusPublished - 2019 Apr

Fingerprint

Sodium-Glucose Transport Proteins
Ketone Bodies
3-Hydroxybutyric Acid
Enzymes
Kidney
Colon
Hydroxymethylglutaryl-CoA Synthase
Sodium
Insulin
Messenger RNA
Butyrates
Liver
Subcutaneous Injections
Serum
Ileum
Intestines
Urine

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

Kim, Jin Hee ; Lee, Minyoung ; Kim, Soo Hyun ; Kim, So Ra ; Lee, Byung Wan ; Kang, Eun Seok ; Cha, Bong Soo ; Cho, Jin Won ; Lee, Yong ho. / Sodium-glucose cotransporter 2 inhibitors regulate ketone body metabolism via inter-organ crosstalk. In: Diabetes, Obesity and Metabolism. 2019 ; Vol. 21, No. 4. pp. 801-811.
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Sodium-glucose cotransporter 2 inhibitors regulate ketone body metabolism via inter-organ crosstalk. / Kim, Jin Hee; Lee, Minyoung; Kim, Soo Hyun; Kim, So Ra; Lee, Byung Wan; Kang, Eun Seok; Cha, Bong Soo; Cho, Jin Won; Lee, Yong ho.

In: Diabetes, Obesity and Metabolism, Vol. 21, No. 4, 04.2019, p. 801-811.

Research output: Contribution to journalArticle

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T1 - Sodium-glucose cotransporter 2 inhibitors regulate ketone body metabolism via inter-organ crosstalk

AU - Kim, Jin Hee

AU - Lee, Minyoung

AU - Kim, Soo Hyun

AU - Kim, So Ra

AU - Lee, Byung Wan

AU - Kang, Eun Seok

AU - Cha, Bong Soo

AU - Cho, Jin Won

AU - Lee, Yong ho

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N2 - 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.

AB - 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.

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U2 - 10.1111/dom.13577

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