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

Abstract

Diabetes is associated with increased risk for kidney and liver diseases, congestive heart failure, and mortality. Urinary glucose excretion using sodiumglucose cotransporter 2 (SGLT2) inhibitors prevents these adverse outcomes, however the mechanisms involved are not clear. Herein, we generated a roadmap of the metabolic alterations that occur in the kidney, liver, and heart in diabetes and in response to SGLT2 inhibition. We performed in vivo metabolic labeling with 13 C-glucose in normoglycemic and diabetic mice treated with or without the SGLT2 inhibitor dapagliflozin, followed by simultaneous metabolomics and metabolic flux analyses in different organs and the plasma.We found that in diabetes, glycolysis and glucose oxidation are impaired in the kidney, liver, and heart. Treatment with dapagliflozin failed to rescue glycolysis and further inhibited pyruvate kinase activity in the liver. SGLT2 inhibition increased glucose oxidation in all organs; in the kidney, this effect was associated with modulation of the redox state, which may protect against oxidative stress. In addition, 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.

Kidney single-cell transcriptomes uncover SGLT2i-induced metabolic reprogramming via restoring glycolysis and fatty acid oxidation

“…Our findings are consistent with prior studies that showed reduced glycolysis in diabetes (23, 31). In addition, a mouse study elucidated the impaired glycolysis in diabetic mice by labeling with 13 C-glucose characterized by increased glucose influx in diabetic mice (25). However, in this study, SGLT2i failed to reverse the dysfunction, which may be due to insufficient duration of treatment with SGLT2i.…”

“…However, in another mouse model of type 1 diabetes, treatment with an SGLT2i failed to rescue glycolysis. SGLT2 inhibition increases glucose oxidation in multiple organs (25). Thus, the role of SGLT2i in glycolysis is still under debate.…”

Effect of dapagliflozin on proteomics and metabolomics of serum from patients with type 2 diabetes

“…SGLT2i reduce glucose load by increasing glycosuria, thereby causing changes in glucose metabolism. SGLT2i inhibit hepatic glycolysis by inhibiting pyruvate kinase [ 76 ]. Animal experiments have also demonstrated that the down-regulation of Phosphoenolpyruvate carboxykinase (PEPCK) and Glucose-6-phosphatase (G6Pase) activities by Adenosine 5 ‘-monophosphate (AMP)-activated protein kinase/ cAMP-response element binding protein (AMPK/CREB) signaling pathway can inhibit hepatic gluconeogenesis, and the activation of AMPK/ Glycogen synthase kinase 3β (GSK3β) signaling pathway in vivo can promote glycogen synthesis [ 77 ].…”

Duality of Branched-Chain Amino Acids in Chronic Cardiovascular Disease: Potential Biomarkers versus Active Pathophysiological Promoters

“…Among these pathways, the most extensively studied is the activation of the mTOR signaling pathway by leucine [ 26 , 35 ]. mTOR, a serine–threonine protein kinase, is a member of the PI3K-related kinase (PIKK) family and functions as the catalytic component for two separate complexes known as mTORC1 and mTORC2 [ 36 , 37 , 38 ]. Besides controlling the production of proteins by overseeing the messenger ribonucleic acid (mRNA) translation process, the intracellular mTOR molecule serves as a critical regulator in various essential cellular processes, including cell growth, cell division, autophagy, and glucose balance [ 39 ].…”

“…The majority of the energy is normally produced through fatty acid oxidation in the mitochondria, with a return to the fetal pattern of cardiac development in a pathological state, in which anaerobic glycolytic metabolism, with its high use of ketones and lactate and a decrease in fatty acid use, is characteristic [ 50 , 55 ]. This alternative adaptive mechanism is only beneficial in the short-term, extended use of glucose, causing a deficiency in ATP production commonly observed in various cardiac diseases [ 37 , 56 , 57 , 58 ]. ATP generation through the tricarboxylic acid (TCA) cycle in the mitochondria after fatty acid breakdown, together with the electrons generated and transferred through the electron transport chain (ETC), leads to the creation of a proton gradient and energy production [ 50 , 59 , 60 ].…”