Metabolomics study reveals the alteration of fatty acid oxidation in the hearts of diabetic mice by empagliflozin

Zhang, Yingwei; Zhang, Zeyu; Li, Chundi; Tang, Donge; Dai, Yong

doi:10.1039/d2mo00036a

Cited by 10 publications

(10 citation statements)

References 35 publications

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“…Curiously, in diabetic recipients, there was observed lipotoxic cardiomyocyte dysfunction associated with peroxisome proliferator-activated receptors-g (PPAR-g) overexpression, which could be reduced with the SGLT2is [ 90 ]. In a recent study conducted by Zhang et al, empagliflozin targeted the mitochondrial fatty acid oxidation pathway, which is altered in db/db mice hearts [ 91 ]. SGLT2i has been reported to induce phospho-AMP-activated protein kinase alpha 2 (pAMPKalpha2), which is responsible for metabolic switching from fatty acids and maintenance of energy balance [ 88 ].…”

Section: Sglt-2is In Dc—the Overview Of Research Resultsmentioning

confidence: 99%

The Importance of SGLT-2 Inhibitors as Both the Prevention and the Treatment of Diabetic Cardiomyopathy

et al. 2022

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According to the 2021 report of the International Diabetes Federation (IDF), there have been approximately 573 million cases of type 2 diabetes mellitus (T2DM) among adults, which sets the disease as a major concern in healthcare worldwide. The development of T2DM is strongly promoted by unhealthy lifestyle factors associated with urbanization and western civilization. The disease is associated with a broad list of systemic complications that can result in premature death, disability and significantly reduced quality of life. The most dramatic in their consequences are cardiovascular complications of T2DM. Our work focuses on one such complication that is specific for diabetes, named diabetic cardiomyopathy (DC). In this condition cardiac dysfunction occurs despite the absence of underlying hypertension, coronary artery disease and valvular disease, which suggest a leading role for metabolic disturbances as a cause. We aimed to establish the role of relatively new hypoglycaemic drugs that have taken the medical world by storm with their broad pleiotropic effects—SGLT-2 inhibitors—in the prevention and treatment of DC at any stage.

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Section: Sglt-2is In Dc—the Overview Of Research Resultsmentioning

confidence: 99%

The Importance of SGLT-2 Inhibitors as Both the Prevention and the Treatment of Diabetic Cardiomyopathy

et al. 2022

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“…14,73,74 Our study illuminates a central role of the microbiome and metabolic and early proximal tubule reconfiguration. Whereas several studies have explored the long-term effects on other tissues, [75][76][77] we focused on relatively healthy mice at early time points to avoid dominating secondary omics signals from fibrosis, serum responses, and tissue decay that hamper mechanistic interpretation of omics data. 78 SGLT2i had larger effects on metabolism and kidney reconfiguration in nondiabetic mice than in hyperglycemic Akita mice.…”

Section: Discussionmentioning

confidence: 99%

Metabolic Communication by SGLT2 Inhibition

Billing,

Kim,

Gullaksen

et al. 2024

Circulation

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BACKGROUND: SGLT2 (sodium-glucose cotransporter 2) inhibitors (SGLT2i) can protect the kidneys and heart, but the underlying mechanism remains poorly understood. METHODS: To gain insights on primary effects of SGLT2i that are not confounded by pathophysiologic processes or are secondary to improvement by SGLT2i, we performed an in-depth proteomics, phosphoproteomics, and metabolomics analysis by integrating signatures from multiple metabolic organs and body fluids after 1 week of SGLT2i treatment of nondiabetic as well as diabetic mice with early and uncomplicated hyperglycemia. RESULTS: Kidneys of nondiabetic mice reacted most strongly to SGLT2i in terms of proteomic reconfiguration, including evidence for less early proximal tubule glucotoxicity and a broad downregulation of the apical uptake transport machinery (including sodium, glucose, urate, purine bases, and amino acids), supported by mouse and human SGLT2 interactome studies. SGLT2i affected heart and liver signaling, but more reactive organs included the white adipose tissue, showing more lipolysis, and, particularly, the gut microbiome, with a lower relative abundance of bacteria taxa capable of fermenting phenylalanine and tryptophan to cardiovascular uremic toxins, resulting in lower plasma levels of these compounds (including p-cresol sulfate). SGLT2i was detectable in murine stool samples and its addition to human stool microbiota fermentation recapitulated some murine microbiome findings, suggesting direct inhibition of fermentation of aromatic amino acids and tryptophan. In mice lacking SGLT2 and in patients with decompensated heart failure or diabetes, the SGLT2i likewise reduced circulating p-cresol sulfate, and p-cresol impaired contractility and rhythm in human induced pluripotent stem cell–engineered heart tissue. CONCLUSION: SGLT2i reduced microbiome formation of uremic toxins such as p-cresol sulfate and thereby their body exposure and need for renal detoxification, which, combined with direct kidney effects of SGLT2i, including less proximal tubule glucotoxicity and a broad downregulation of apical transporters (including sodium, amino acid, and urate uptake), provides a metabolic foundation for kidney and cardiovascular protection.

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“…A recent study demonstrated that dapagliflozin therapy mobilizes FFAs from adipose tissue and increases hepatic FFA oxidation in diabetic animals 83 . Empagliflozin was also able to increase lipid peroxidation in diabetic mice 84 . Moreover, dapagliflozin increased lipid peroxidation and ketone body levels in T2DM patients 85 .…”

Section: Pathophysiology Of Sglt2i‐induced Acidosismentioning

confidence: 99%

“…83 Empagliflozin was also able to increase lipid peroxidation in diabetic mice. 84 Moreover, dapagliflozin increased lipid peroxidation and ketone body levels in T2DM patients. 85 Therefore, induction and promotion of FFA beta-oxidation is the main link between SGLT2is and DKA.…”

Section: Linked Mechanisms Effects On Ketogenesis Referencesmentioning

confidence: 99%

New insights into cellular links between sodium–glucose cotransporter‐2 inhibitors and ketogenesis

Yaribeygi

Maleki

Butler

et al. 2022

J of Cellular Biochemistry

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Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are a newly developed class of highly effective antidiabetic therapies that normalize hyperglycemia via urinary glucose excretion. However, they may be accompanied by certain side effects that negatively impact their therapeutic benefits. SGLT2is induce a metabolic shift from glucose to fatty acids and thus increase lipolysis which, in turn, induces ketogenesis. The complete pathways linking SGLT2is to ketoacidosis have not yet been fully elucidated, though much is now known.Therefore, in this mechanistic study, we present the current knowledge and shed light upon the possible cellular pathways involved. A deeper understanding of the possible links between SGLT2is and ketogenesis could help to prevent adverse side effects in diabetic patients treated with these drugs.

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Metabolomics study reveals the alteration of fatty acid oxidation in the hearts of diabetic mice by empagliflozin

Abstract: Empagliflozin (Empa, SGLT2 inhibitor), is widely used in clinical situation for the management of diabetes. It has beneficial effects in reducing cardiac dysfunction and heart failure. However, rare studies had...

Cited by 10 publications

References 35 publications

The Importance of SGLT-2 Inhibitors as Both the Prevention and the Treatment of Diabetic Cardiomyopathy

The Importance of SGLT-2 Inhibitors as Both the Prevention and the Treatment of Diabetic Cardiomyopathy

Metabolic Communication by SGLT2 Inhibition

New insights into cellular links between sodium–glucose cotransporter‐2 inhibitors and ketogenesis

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