Mapping the metabolic reprogramming induced by sodium-glucose cotransporter 2 inhibition
Aviram Kogot-Levin, Yael Riahi, Ifat Abramovich, Ofri Mosenzon, Bella Agranovich, Liat Kadosh, Rachel Ben-Haroush Schyr, Doron Kleiman, Liad Hinden, Erol Cerasi, Danny Ben-Zvi, Ernesto Bernal-Mizrachi, Joseph Tam, Eyal Gottlieb, Gil Leibowitz
Aviram Kogot-Levin, Yael Riahi, Ifat Abramovich, Ofri Mosenzon, Bella Agranovich, Liat Kadosh, Rachel Ben-Haroush Schyr, Doron Kleiman, Liad Hinden, Erol Cerasi, Danny Ben-Zvi, Ernesto Bernal-Mizrachi, Joseph Tam, Eyal Gottlieb, Gil Leibowitz
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Research Article Metabolism Therapeutics

Mapping the metabolic reprogramming induced by sodium-glucose cotransporter 2 inhibition

Abstract

Diabetes is associated with increased risk for kidney disease, heart failure, and mortality. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) prevent these adverse outcomes; however, the mechanisms involved are not clear. We generated a roadmap of the metabolic alterations that occur in different organs in diabetes and in response to SGLT2i. In vivo metabolic labeling with 13C-glucose in normoglycemic and diabetic mice treated with or without dapagliflozin, followed by metabolomics and metabolic flux analyses, showed that, in diabetes, glycolysis and glucose oxidation are impaired in the kidney, liver, and heart. Treatment with dapagliflozin failed to rescue glycolysis. SGLT2 inhibition increased glucose oxidation in all organs; in the kidney, this was associated with modulation of the redox state. Diabetes was associated with altered methionine cycle metabolism, evident by decreased betaine and methionine levels, whereas treatment with SGLT2i increased hepatic betaine along with decreased homocysteine levels. mTORC1 activity was inhibited by SGLT2i along with stimulation of AMPK in both normoglycemic and diabetic animals, possibly explaining the protective effects against kidney, liver, and heart diseases. Collectively, our findings suggest that SGLT2i induces metabolic reprogramming orchestrated by AMPK-mTORC1 signaling with common and distinct effects in various tissues, with implications for diabetes and aging.

Authors

Aviram Kogot-Levin, Yael Riahi, Ifat Abramovich, Ofri Mosenzon, Bella Agranovich, Liat Kadosh, Rachel Ben-Haroush Schyr, Doron Kleiman, Liad Hinden, Erol Cerasi, Danny Ben-Zvi, Ernesto Bernal-Mizrachi, Joseph Tam, Eyal Gottlieb, Gil Leibowitz

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Figure 1

Metabolic effects of treatment with SGLT2i in WT and Akita mice.

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Metabolic effects of treatment with SGLT2i in WT and Akita mice. (A–H) T...
(A–H) Two-month-old WT mice fed on regular chow were treated with or without dapagliflozin (10 mg/kg/day in drinking water for 2 weeks) compared with untreated controls. (A) IPGTT; glucose (1.5 g/kg) was given i.p. after a 4-hour fast. (B and C) Continuous measurement of blood glucose using FreeStyle Libre flash monitoring system. Average glucose levels and glucose variability (Stdev) during the dark and light periods before and after adding dapagliflozin and a representative plot are shown. (D) Insulin tolerance test; insulin (1 U/kg) was injected to mice after a 4-hour fast with consecutive measurements of blood glucose. Results are expressed as percentage of glucose levels at time 0. Blood glucose levels at baseline were 137.7 ± 18.4 and 127.1 ± 23.3 mg/dL in control and dapagliflozin treated mice, respectively. (E) Steady-state mTORC1 activity in muscle, evident by S6 phosphorylation; lanes were run on the same gel but were noncontiguous. (F and G) Insulin-stimulated AKT phosphorylation is shown in muscle and liver. Insulin (3 U/kg mice) was injected i.p. after an overnight fast. Gastrocnemius muscle and the liver were isolated and extracted after 5 minutes, and AKT phosphorylation was analyzed by Western blotting. Data represent the mean ± SEM of 3–8 mice per group. (H and I) Two-month-old Akita mice were fed on regular chow and treated without or with dapagliflozin (10 mg/kg/day in drinking water) for 1 week. (H) Overnight fasting blood glucose levels. (I) IPGTT was performed after an overnight fast. Data represent the mean ± SEM of 3–8 mice per group. Data were analyzed by unpaired 2-tailed Student’s t test (A–E) or by 2-way ANOVA (F–I). *P < 0.05, **P < 0.01, ***P < 0.001.