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Mapping the metabolic reprogramming induced by sodium-glucose cotransporter 2 inhibition
Aviram Kogot-Levin1, Yael Riahi1, Ifat Abramovich2
1Diabetes Unit and Endocrine Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
JCI Insight
|February 22, 2023
Summary
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) reprogram metabolism in diabetes, enhancing glucose oxidation and modulating key signaling pathways. These metabolic shifts in organs like the kidney, liver, and heart may explain SGLT2i
Area of Science:
- Metabolic pathways and signaling in diabetes and its complications.
Background:
- Diabetes mellitus increases the risk of kidney disease, heart failure, and mortality.
- The precise mechanisms by which Sodium-glucose cotransporter 2 inhibitors (SGLT2i) confer protection remain incompletely understood.
Purpose of the Study:
- To elucidate the metabolic alterations in various organs during diabetes and in response to SGLT2 inhibition.
- To investigate the role of SGLT2i in metabolic reprogramming and its underlying signaling pathways.
Main Methods:
- In vivo metabolic labeling with 13C-glucose in normoglycemic and diabetic mice.
- Metabolomics and metabolic flux analyses in kidney, liver, and heart tissues.
- Assessment of AMPK and mTORC1 signaling pathway activity.
Main Results:
- Diabetes impairs glycolysis and glucose oxidation in the kidney, liver, and heart; SGLT2i did not restore glycolysis but increased glucose oxidation.
- SGLT2 inhibition modulated the renal redox state and altered hepatic methionine metabolism, decreasing homocysteine.
- SGLT2i inhibited mTORC1 activity and stimulated AMPK signaling across all studied organs.
Conclusions:
- SGLT2 inhibitors induce significant metabolic reprogramming orchestrated by AMPK-mTORC1 signaling.
- These adaptations occur with both common and distinct tissue-specific effects, offering a mechanistic explanation for their protective benefits in diabetes and potentially aging.
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