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Liang T, Jiang T, Liang Z, Li L, Chen Y, Chen T, Yang L, Zhang N, Dong B, Xie X, Gu B, Wu Q. Gut microbiota-driven BCAA biosynthesis via Staphylococcus aureus -expressed acetolactate synthase impairs glycemic control in type 2 diabetes in South China. Microbiol Res 2025; 296:128145. [PMID: 40138872 DOI: 10.1016/j.micres.2025.128145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Revised: 03/12/2025] [Accepted: 03/14/2025] [Indexed: 03/29/2025]
Abstract
An increase in branched-chain amino acid (BCAA) levels can result in insulin resistance at different stages of type 2 diabetes (T2D), however, the causes of this increase are unclear. We performed metagenomics and metabolomics profiling in patients with prediabetes (PDM), newly diagnosed diabetes (NDDM), and post-medication type 2 diabetes (P2DM) to investigate whether altered gut microbes and metabolites could explain the specific clinical characteristics of different disease stages of T2D. Here we identify acetolactate synthase (ALS) a BCAA biosynthesis enzyme in Staphylococcus aureus as a cause of T2D insulin resistance. Compared with healthy peoples, patients with PDM, NDDM, and P2DM groups, especially in P2DM group, have increased faecal numbers of S. aureus. We also demonstrated that insulin administration may be a risk factor for S. aureus infection in T2D. The presence of ALS-positive S. aureus correlated with the levels of BCAAs and was associated with an increased fasting blood glucose (FBG) and insulin resistance. Humanized microbiota transplantation experiment indicated that ALS contributes to disordered insulin resistance mediated by S. aureus. We also found that S. aureus phage can reduced the FBG levels and insulin resistance in db/db mice. The ALS-positive S. aureus are associated with insulin resistance in T2D, opening a new therapeutic avenue for the prevention or treatment of diabetes.
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Affiliation(s)
- Tingting Liang
- Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, China; Department of Clinical Laboratory Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.
| | - Tong Jiang
- Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, China
| | - Zhuang Liang
- Department of Rehabilitation Hospital Pain Ward, Xi'an Jiaotong University Affiliated Honghui Hospital, Xi'an, Shaanxi 710054, China
| | - Longyan Li
- Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, China
| | - Ya Chen
- Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, China
| | - Tong Chen
- Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, China
| | - Lingshuang Yang
- Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, China
| | - Ni Zhang
- Department of Clinical Laboratory Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Bo Dong
- Department of Rehabilitation Hospital Pain Ward, Xi'an Jiaotong University Affiliated Honghui Hospital, Xi'an, Shaanxi 710054, China.
| | - Xinqiang Xie
- Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, China.
| | - Bing Gu
- Department of Clinical Laboratory Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.
| | - Qingping Wu
- Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, China.
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González Campos E, Grover Páez F, Ramos Becerra CG, Balleza Alejandri LR, Suárez Rico DO, Cardona Muñoz EG, Pascoe González S, Ramos Zavala MG, Beltrán Ramírez A, García Galindo JJ, Cardona Müller D. Empagliflozin Leads to Faster Improvement in Arterial Stiffness Compared to Dapagliflozin: A Double-Blind Clinical. Life (Basel) 2025; 15:802. [PMID: 40430228 DOI: 10.3390/life15050802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2025] [Revised: 04/22/2025] [Accepted: 05/14/2025] [Indexed: 05/29/2025] Open
Abstract
(1) Background: Arterial stiffness, often measured by carotid-femoral pulse wave velocity (cf-PWV), is crucial in cardiovascular disease. Dapagliflozin has shown rapid effects on arterial stiffness, but there is limited evidence of empagliflozin's acute effects, especially in type 2 diabetes (T2D) patients. This study evaluated the acute effects of empagliflozin and dapagliflozin on arterial stiffness and blood pressure (BP). (2) Methods: A one-week double-blind randomized trial involved 30 T2D patients on stable metformin therapy. Participants received empagliflozin (25 mg/day), dapagliflozin (10 mg/day), or a placebo. Arterial stiffness was assessed via cf-PWV, and BP was measured with an automated sphygmomanometer. (3) Results: Both SGLT2 inhibitors significantly reduced cf-PWV compared to the placebo after one week (p < 0.05), with dapagliflozin showing a more pronounced effect. No significant differences were observed in BP changes. (4) Conclusion: Short-term treatment with SGLT2 inhibitors acutely reduces arterial stiffness in T2D patients, with empagliflozin demonstrating a stronger effect, supporting the potential vascular benefits of SGLT2 inhibitors beyond glucose control.
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Affiliation(s)
- Erick González Campos
- Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico
| | - Fernando Grover Páez
- Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico
- Arterial Stiffness Laboratory, Experimental and Clinical Therapeutics Institute, Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico
| | - Carlos Gerardo Ramos Becerra
- Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico
- Arterial Stiffness Laboratory, Experimental and Clinical Therapeutics Institute, Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico
| | | | - Daniel Osmar Suárez Rico
- Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico
| | - Ernesto Germán Cardona Muñoz
- Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico
- Arterial Stiffness Laboratory, Experimental and Clinical Therapeutics Institute, Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico
| | - Sara Pascoe González
- Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico
- Arterial Stiffness Laboratory, Experimental and Clinical Therapeutics Institute, Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico
| | - María Guadalupe Ramos Zavala
- Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico
- Arterial Stiffness Laboratory, Experimental and Clinical Therapeutics Institute, Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico
| | - Alberto Beltrán Ramírez
- Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico
| | | | - David Cardona Müller
- Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico
- Arterial Stiffness Laboratory, Experimental and Clinical Therapeutics Institute, Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico
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Yang S, Deng J, Weng X, Ma Z, Lin N, Xiao Y, Zuo R, Hu Y, Zheng C, Zeng X, Lin Q, Hou K. Reduced abundance of Fusobacterium signifies cardiovascular benefits of sodium glucose cotransporter 2 inhibitor in type 2 diabetes: a single arm clinical trial. Front Pharmacol 2025; 16:1600464. [PMID: 40406484 PMCID: PMC12095364 DOI: 10.3389/fphar.2025.1600464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2025] [Accepted: 04/23/2025] [Indexed: 05/26/2025] Open
Abstract
Background The sodium glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin has been demonstrated cardiovascular benefits in patients with type 2 diabetes mellitus (T2DM). However, the underlying mechanism remains poorly understood. Methods We conducted an 8-week, single-arm clinical trial, which enrolled 12 patients with inadequate glycemic control on metformin monotherapy. These patients were treated with SGLT2i dapagliflozin (10 mg/day). We assessed changes in clinical parameters pertinent to glucose metabolism and risk factors of cardiovascular disease (CVD), as well as alterations in the gut microbiota using macrogene sequencing. Results Improvements were observed in anthropometric parameters, glucose metabolism, blood lipid-related indices, inflammatory markers, and endothelial cell function-related parameters. Concurrently, SGLT2i led to changes in composition and functional pathways of the gut microbiota, manifested as increased abundance of probiotics and decreased abundance of harmful bacteria. Importantly, reduced abundance of Fusobacterium was correlated with improvements in various clinical indicators. Conclusion SGLT2i represents a superior initial therapeutic option for T2DM patients at risk of CVD. The cardiovascular benefits of SGLT2i may be attributed to shifts in the gut microbiota, particularly the reduced abundance of Fusobacterium.
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Affiliation(s)
- Shuhui Yang
- Department of Endocrine and Metabolic Diseases, Shantou Central Hospital, Shantou, China
| | - Jiankun Deng
- Department of Endocrine and Metabolic Diseases, Shantou Central Hospital, Shantou, China
| | - Xiaoxu Weng
- Department of Endocrine and Metabolic Diseases, Shantou Central Hospital, Shantou, China
| | - Zhaojie Ma
- Department of Endocrine and Metabolic Diseases, Shantou Central Hospital, Shantou, China
| | - Nie Lin
- Department of Endocrine and Metabolic Diseases, Shantou Central Hospital, Shantou, China
| | - Yili Xiao
- Department of Endocrine and Metabolic Diseases, Shantou Central Hospital, Shantou, China
| | - Rui Zuo
- School of Public Health, Shantou University, Shantou, China
| | - Yufei Hu
- School of Public Health, Shantou University, Shantou, China
| | - Canbin Zheng
- Department of Endocrine and Metabolic Diseases, Shantou Central Hospital, Shantou, China
| | - Xiaoshan Zeng
- Department of Endocrine and Metabolic Diseases, Shantou Central Hospital, Shantou, China
| | - Qimao Lin
- Department of Endocrine and Metabolic Diseases, Shantou Central Hospital, Shantou, China
| | - Kaijian Hou
- School of Public Health, Shantou University, Shantou, China
- Department of Endocrine and Metabolic Diseases, Longhu People’s Hospital, Shantou, China
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Kristensen DK, Mose FH, Buus NH, Duus CL, Mårup FH, Bech JN, Nielsen SF. SGLT2 inhibition improves endothelium-independent vasodilatory function in type 2 diabetes: A double-blind, randomized, placebo-controlled crossover trial. Diabetes Obes Metab 2025; 27:1123-1131. [PMID: 39610328 DOI: 10.1111/dom.16097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 11/05/2024] [Accepted: 11/17/2024] [Indexed: 11/30/2024]
Abstract
AIMS The objective of this study was to examine the effects of empagliflozin on endothelium-dependent and endothelium-independent vasodilatation and systemic hemodynamic parameters and to assess the role of the nitric oxide (NO) system in patients with type 2 diabetes (T2DM). MATERIALS AND METHODS In this double-blind, placebo-controlled cross over trial, patients with T2DM were treated with either empagliflozin 10 mg or matching placebo for 4 weeks. Following a 2-week washout, participants were crossed over to 4 weeks of the opposite treatment. Forearm blood flow (FBF) was measured after each treatment period using venous occlusion plethysmography. Acetylcholine and sodium nitroprusside (SNP) were infused into the brachial artery to assess endothelium-dependent and endothelium-independent vasodilatory function, respectively. Total peripheral resistance, 24-h blood pressure (BP) and biochemical markers of NO activity were measured as well. RESULTS Sixteen participants completed the trial. The mean age was 68 ± 8 years, and 69% were male. The SNP response increased by 21% (geometric mean ratio 1.21, 95% CI: 1.09; 1.33) during treatment with empagliflozin compared to placebo (p ≤ 0.001), but not during acetylcholine infusion (p = 0.290). Empagliflozin decreased 24-h systolic BP by 5 mmHg (95% CI: -9; -1 mmHg) (p = 0.015), diastolic BP by 2 mmHg (95% CI: -5; 0 mmHg) (p = 0.029) and systemic vascular resistance by 48 dyn×s/m5 (95% CI: -94; -1 dyn×s/m5) (p = 0.044). Furthermore, empagliflozin reduced plasma levels of nitrite and urinary levels of NOx. CONCLUSIONS Empagliflozin improves endothelium-independent vasodilation, reduces vascular resistance and lowers 24-h BP in patients with T2DM, whereas no change in endothelial-dependent vasodilation was observed. TRIAL REGISTRATION EU Clinical Trials Register number: 2019-004303-12 (https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-004303-12/DK).
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Affiliation(s)
- Didde Kidmose Kristensen
- University Clinic in Nephrology and Hypertension, Gødstrup Hospital, Herning, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark
| | - Frank Holden Mose
- University Clinic in Nephrology and Hypertension, Gødstrup Hospital, Herning, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark
| | - Niels Henrik Buus
- Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark
- Department of Renal Medicine, Aarhus University Hospital, Aarhus N, Denmark
| | | | - Frederik Husum Mårup
- Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark
- Department of Renal Medicine, Aarhus University Hospital, Aarhus N, Denmark
| | - Jesper Nørgaard Bech
- University Clinic in Nephrology and Hypertension, Gødstrup Hospital, Herning, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark
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Rykova EY, Klimontov VV, Shmakova E, Korbut AI, Merkulova TI, Kzhyshkowska J. Anti-Inflammatory Effects of SGLT2 Inhibitors: Focus on Macrophages. Int J Mol Sci 2025; 26:1670. [PMID: 40004134 PMCID: PMC11854991 DOI: 10.3390/ijms26041670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 02/04/2025] [Accepted: 02/06/2025] [Indexed: 02/21/2025] Open
Abstract
A growing body of evidence indicates that nonglycemic effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors play an important role in the protective effects of these drugs in diabetes, chronic kidney disease, and heart failure. In recent years, the anti-inflammatory potential of SGLT2 inhibitors has been actively studied. This review summarizes results of clinical and experimental studies on the anti-inflammatory activity of SGLT2 inhibitors, with a special focus on their effects on macrophages, key drivers of metabolic inflammation. In patients with type 2 diabetes, therapy with SGLT2 inhibitors reduces levels of inflammatory mediators. In diabetic and non-diabetic animal models, SGLT2 inhibitors control low-grade inflammation by suppressing inflammatory activation of tissue macrophages, recruitment of monocytes from the bloodstream, and macrophage polarization towards the M1 phenotype. The molecular mechanisms of the effects of SGLT2 inhibitors on macrophages include an attenuation of inflammasome activity and inhibition of the TLR4/NF-κB pathway, as well as modulation of other signaling pathways (AMPK, PI3K/Akt, ERK 1/2-MAPK, and JAKs/STAT). The review discusses the state-of-the-art concepts and prospects of further investigations that are needed to obtain a deeper insight into the mechanisms underlying the effects of SGLT2 inhibitors on the molecular, cellular, and physiological levels.
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Affiliation(s)
- Elena Y. Rykova
- Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (IC&G SB RAS), Lavrentjev Prospect 10, 630090 Novosibirsk, Russia; (E.Y.R.); (V.V.K.); (E.S.); (A.I.K.); (T.I.M.)
| | - Vadim V. Klimontov
- Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (IC&G SB RAS), Lavrentjev Prospect 10, 630090 Novosibirsk, Russia; (E.Y.R.); (V.V.K.); (E.S.); (A.I.K.); (T.I.M.)
- Research Institute of Clinical and Experimental Lymphology, Branch of the Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (RICEL—Branch of IC&G SB RAS), Timakov Str. 2, 630060 Novosibirsk, Russia
| | - Elena Shmakova
- Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (IC&G SB RAS), Lavrentjev Prospect 10, 630090 Novosibirsk, Russia; (E.Y.R.); (V.V.K.); (E.S.); (A.I.K.); (T.I.M.)
- Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, 634050 Tomsk, Russia
| | - Anton I. Korbut
- Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (IC&G SB RAS), Lavrentjev Prospect 10, 630090 Novosibirsk, Russia; (E.Y.R.); (V.V.K.); (E.S.); (A.I.K.); (T.I.M.)
- Research Institute of Clinical and Experimental Lymphology, Branch of the Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (RICEL—Branch of IC&G SB RAS), Timakov Str. 2, 630060 Novosibirsk, Russia
| | - Tatyana I. Merkulova
- Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (IC&G SB RAS), Lavrentjev Prospect 10, 630090 Novosibirsk, Russia; (E.Y.R.); (V.V.K.); (E.S.); (A.I.K.); (T.I.M.)
| | - Julia Kzhyshkowska
- Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (IC&G SB RAS), Lavrentjev Prospect 10, 630090 Novosibirsk, Russia; (E.Y.R.); (V.V.K.); (E.S.); (A.I.K.); (T.I.M.)
- Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, 634050 Tomsk, Russia
- Institute of Transfusion Medicine and Immunology, Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany
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Ni Y, Du H, Ke L, Zheng L, Nan S, Ni L, Pan Y, Fu Z, He Q, Jin J. Gut-kidney interaction reinforces dapagliflozin-mediated alleviation in diabetic nephropathy. Am J Physiol Cell Physiol 2025; 328:C452-C466. [PMID: 39740794 DOI: 10.1152/ajpcell.00651.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 12/02/2024] [Accepted: 12/18/2024] [Indexed: 01/02/2025]
Abstract
Intestinal microbiota are pathophysiologically involved in diabetic nephropathy (DN). Dapagliflozin, recognized for its blood glucose-lowering effect, has demonstrated efficacy in improving DN. However, the mechanisms beyond glycemic control that mediate the impact of dapagliflozin on DN remain unclear. Here, we investigated the effects of dapagliflozin on DN and gut microbiota, elucidating how it mitigates DN via the gut-kidney axis. Low-dose dapagliflozin markedly ameliorated renal inflammation and fibrosis and improved gut barrier function in high-fat diet (HFD)/streptozotocin (STZ)-induced DN mice and db/db mice without affecting blood glucose levels. These effects were associated with altered gut microbial composition and function. Eradication of the resident microbiota abolished the protective effects of dapagliflozin against kidney injury in DN mice. Moreover, dapagliflozin significantly altered microbial metabolites in DN mice, decreasing argininosuccinic acid (ASA) and palmitic acid (PA), while increasing S-allylcysteine (SAC) levels. ASA and PA increased the expression of renal inflammation- and fibrosis-related markers in HK-2 cells, whereas SAC ameliorated renal damage and altered the microbial composition in a manner similar to dapagliflozin in DN mice. Notably, Muribaculaceae and Desulfovibrionaceae were correlated with the alleviation of DN-associated renal dysfunction by low- and high-dose dapagliflozin treatments in DN mice. These findings demonstrate a potential application of dapagliflozin in managing DN by targeting the gut microbiota.NEW & NOTEWORTHY We demonstrated that dapagliflozin administration alleviated renal inflammation and fibrosis in vivo and in vitro, along with reshaping the gut microbiota composition and altering levels of key microbial metabolites, including argininosuccinic acid (ASA) and palmitic acid (PA), while increasing S-allylcysteine (SAC). Importantly, the genera Muribaculaceae and Desulfovibrionaceae emerged as pivotal microbial genera mediating the protective effects of dapagliflozin against diabetic nephropathy.
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Affiliation(s)
- Yinhua Ni
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, China
| | - Haimei Du
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, China
| | - Lehui Ke
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, China
| | - Liujie Zheng
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, China
| | - Sujie Nan
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, China
| | - Liyang Ni
- Laboratory of Food Biochemistry, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Yuxiang Pan
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, China
| | - Zhengwei Fu
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, China
| | - Qiang He
- Department of Nephrology, First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, China
- Zhejiang Key Laboratory of Research and Translation for Kidney Deficiency-Stasis-Turbidity Disease, Hangzhou, Zhejiang, China
| | - Juan Jin
- Department of Nephrology, First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, China
- Zhejiang Key Laboratory of Research and Translation for Kidney Deficiency-Stasis-Turbidity Disease, Hangzhou, Zhejiang, China
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da Silva RS, de Paiva IHR, Mendonça IP, de Souza JRB, Lucena-Silva N, Peixoto CA. Anorexigenic and anti-inflammatory signaling pathways of semaglutide via the microbiota-gut--brain axis in obese mice. Inflammopharmacology 2025; 33:845-864. [PMID: 39586940 DOI: 10.1007/s10787-024-01603-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 11/05/2024] [Indexed: 11/27/2024]
Abstract
Our study focused on a mouse model of obesity induced by a high-fat diet (HFD). We administered Semaglutide intraperitoneally (Ozempic ®-0.05 mg/Kg-translational dose) every seven days for six weeks. HFD-fed mice had higher blood glucose, lipid profile, and insulin resistance. Moreover, mice fed HFD showed high gut levels of TLR4, NF-kB, TNF-α, IL-1β, and nitrotyrosine and low levels of occludin, indicating intestinal inflammation and permeability, culminating in higher serum levels of IL-1β and LPS. Treatment with semaglutide counteracted the dyslipidemia and insulin resistance, reducing gut and serum inflammatory markers. Structural changes in gut microbiome were determined by 16S rRNA sequencing. Semaglutide reduced the relative abundance of Firmicutes and augmented that of Bacteroidetes. Meanwhile, semaglutide dramatically changed the overall composition and promoted the growth of acetate-producing bacteria (Bacteroides acidifaciens and Blautia coccoides), increasing hypothalamic acetate levels. Semaglutide intervention increased the number of hypothalamic GLP-1R+ neurons that mediate endogenous action on feeding and energy. In addition, semaglutide treatment reversed the hypothalamic neuroinflammation HDF-induced decreasing TLR4/MyD88/NF-κB signaling and JNK and AMPK levels, improving the hypothalamic insulin resistance. Also, semaglutide modulated the intestinal microbiota, promoting the growth of acetate-producing bacteria, inducing high levels of hypothalamic acetate, and increasing GPR43+ /POMC+ neurons. In the ARC, acetate activated the GPR43 and its downstream PI3K-Akt pathway, which activates POMC neurons by repressing the FoxO-1. Thus, among the multifactorial effectors of hypothalamic energy homeostasis, possibly higher levels of acetate derived from the intestinal microbiota contribute to reducing food intake.
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Affiliation(s)
- Rodrigo Soares da Silva
- Laboratory of Ultrastructure, Laboratório de Ultraestrutura, Aggeu Magalhães Institute (IAM), FIOCRUZ, Av. Moraes Rego S/N, Recife, PE, CEP 50670-420, Brazil
- Postgraduate Program in Biological Sciences/Center of Biosciences, Federal University of Pernambuco (UFPE), Recife, PE, Brazil
| | - Igor Henrique Rodrigues de Paiva
- Laboratory of Ultrastructure, Laboratório de Ultraestrutura, Aggeu Magalhães Institute (IAM), FIOCRUZ, Av. Moraes Rego S/N, Recife, PE, CEP 50670-420, Brazil
- Postgraduate Program in Biological Sciences/Center of Biosciences, Federal University of Pernambuco (UFPE), Recife, PE, Brazil
| | - Ingrid Prata Mendonça
- Laboratory of Ultrastructure, Laboratório de Ultraestrutura, Aggeu Magalhães Institute (IAM), FIOCRUZ, Av. Moraes Rego S/N, Recife, PE, CEP 50670-420, Brazil
- Postgraduate Program in Biological Sciences/Center of Biosciences, Federal University of Pernambuco (UFPE), Recife, PE, Brazil
| | | | - Norma Lucena-Silva
- Laboratory of Immunogenetics, Aggeu Magalhães Institute (IAM), Recife, PE, Brazil
| | - Christina Alves Peixoto
- Laboratory of Ultrastructure, Laboratório de Ultraestrutura, Aggeu Magalhães Institute (IAM), FIOCRUZ, Av. Moraes Rego S/N, Recife, PE, CEP 50670-420, Brazil.
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Ao N, Du J, Jin S, Suo L, Yang J. The cellular and molecular mechanisms mediating the protective effects of sodium-glucose linked transporter 2 inhibitors against metabolic dysfunction-associated fatty liver disease. Diabetes Obes Metab 2025; 27:457-467. [PMID: 39508115 DOI: 10.1111/dom.16043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 10/16/2024] [Accepted: 10/16/2024] [Indexed: 11/08/2024]
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD), formerly known as nonalcoholic fatty liver disease (NAFLD), is a common, highly heterogeneous condition that affects about a quarter of the world's population, with no approved drug therapy. Current evidence from preclinical research and a number of small clinical trials indicates that SGLT2 inhibitors could also be effective for MAFLD. MAFLD is associated with a higher risk of chronic liver disease and multiple extrahepatic events, especially cardiovascular disease (CVD) and chronic kidney disease (CKD). MAFLD is considered a more appropriate terminology than NAFLD because it captures the complex bidirectional interplay between fatty liver and metabolic dysfunctions associated with disease progression, such as obesity and type 2 diabetes mellitus (T2DM). SGLT2 inhibitors are antidiabetic drugs that block glucose reabsorption in the kidney proximal tubule. In this article, we reviewed current clinical evidence supporting the potential use of SGLT2 inhibitors as a drug therapy for MAFLD and discussed the possible cellular and molecular mechanisms involved. We also reviewed the clinical benefits of SGLT2 inhibitors against MAFLD-related comorbidities, especially CVD, CKD and cardiovascular-kidney-metabolic syndrome (CKM). The broad beneficial effects of SGLT2 inhibitors support their use, likely in combination with other drugs, as a therapy for MAFLD.
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Affiliation(s)
- Na Ao
- Department of Endocrinology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Jian Du
- Department of Endocrinology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Shi Jin
- Department of Endocrinology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Linna Suo
- Department of Endocrinology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Jing Yang
- Department of Endocrinology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
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9
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Kansakar U, Nieves Garcia C, Santulli G, Gambardella J, Mone P, Jankauskas SS, Lombardi A. Exogenous Ketones in Cardiovascular Disease and Diabetes: From Bench to Bedside. J Clin Med 2024; 13:7391. [PMID: 39685849 DOI: 10.3390/jcm13237391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 11/22/2024] [Accepted: 11/28/2024] [Indexed: 12/18/2024] Open
Abstract
Ketone bodies are molecules produced from fatty acids in the liver that act as energy carriers to peripheral tissues when glucose levels are low. Carbohydrate- and calorie-restricted diets, known to increase the levels of circulating ketone bodies, have attracted significant attention in recent years due to their potential health benefits in several diseases. Specifically, increasing ketones through dietary modulation has been reported to be beneficial for cardiovascular health and to improve glucose homeostasis and insulin resistance. Interestingly, although excessive production of ketones may lead to life-threatening ketoacidosis in diabetic patients, mounting evidence suggests that modest levels of ketones play adaptive and beneficial roles in pancreatic beta cells, although the exact mechanisms are still unknown. Of note, Sodium-Glucose Transporter 2 (SGLT2) inhibitors have been shown to increase the levels of beta-hydroxybutyrate (BHB), the most abundant ketone circulating in the human body, which may play a pivotal role in mediating some of their protective effects in cardiovascular health and diabetes. This systematic review provides a comprehensive overview of the scientific literature and presents an analysis of the effects of ketone bodies on cardiovascular pathophysiology and pancreatic beta cell function. The evidence from both preclinical and clinical studies indicates that exogenous ketones may have significant beneficial effects on both cardiomyocytes and pancreatic beta cells, making them intriguing candidates for potential cardioprotective therapies and to preserve beta cell function in patients with diabetes.
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Affiliation(s)
- Urna Kansakar
- Department of Molecular Pharmacology, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Neuroimmunology and Inflammation (INI), Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Crystal Nieves Garcia
- Department of Medicine, Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Gaetano Santulli
- Department of Molecular Pharmacology, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Neuroimmunology and Inflammation (INI), Albert Einstein College of Medicine, New York, NY 10461, USA
- Department of Medicine, Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Jessica Gambardella
- Department of Molecular Pharmacology, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Neuroimmunology and Inflammation (INI), Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Pasquale Mone
- Department of Molecular Pharmacology, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Neuroimmunology and Inflammation (INI), Albert Einstein College of Medicine, New York, NY 10461, USA
- Department of Medicine and Health Sciences, University of Molise, 86100 Campobasso, Italy
- Casa di Cura Montevergine, 83013 Mercogliano, Avellino, Italy
| | - Stanislovas S Jankauskas
- Department of Molecular Pharmacology, Division of Cardiology, Wilf Family Cardiovascular Research Institute, Einstein Institute for Neuroimmunology and Inflammation (INI), Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Angela Lombardi
- Department of Medicine, Fleischer Institute for Diabetes and Metabolism (FIDAM), Einstein-Mount Sinai Diabetes Research Center (ES-DRC), Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, USA
- Department of Clinical and Molecular Medicine, School of Medicine and Psychology, Sapienza University, 00189 Rome, Italy
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10
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Tan JS, Wei Y, Chong L, Yang Y, Hu S, Wang Y. SGLT2 inhibitors as a potential therapeutic option for pulmonary hypertension: mechanisms and clinical perspectives. Crit Rev Clin Lab Sci 2024; 61:709-725. [PMID: 38847284 DOI: 10.1080/10408363.2024.2361012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 04/29/2024] [Accepted: 05/24/2024] [Indexed: 11/27/2024]
Abstract
Pulmonary arterial hypertension (PAH), one subtype of pulmonary hypertension (PH), is a life-threatening condition characterized by pulmonary arterial remodeling, elevated pulmonary vascular resistance, and blood pressure in the pulmonary arteries, leading to right heart failure and increased mortality. The disease is marked by endothelial dysfunction, vasoconstriction, and vascular remodeling. The role of Sodium-Glucose Co-Transporter-2 (SGLT2) inhibitors, a class of medications originally developed for diabetes management, is increasingly being explored in the context of cardiovascular diseases, including PAH, due to their potential to modulate these pathophysiological processes. In this review, we systematically examine the burgeoning evidence from both basic and clinical studies that describe the effects of SGLT2 inhibitors on cardiovascular health, with a special emphasis on PAH. By delving into the complex interactions between these drugs and the potential pathobiology that underpins PH, this study seeks to uncover the mechanistic underpinnings that could justify the use of SGLT2 inhibitors as a novel therapeutic approach for PAH. We collate findings that illustrate how SGLT2 inhibitors may influence the normal function of pulmonary arteries, possibly alleviating the pathological hallmarks of PAH such as inflammation, oxidative stress, aberrant cellular proliferation, and so on. Our review thereby outlines a potential paradigm shift in PAH management, suggesting that these inhibitors could play a crucial role in modulating the disease's progression by targeting the potential dysfunctions that drive it. This comprehensive synthesis of existing research underscores the imperative need for further clinical trials to validate the efficacy of SGLT2 inhibitors in PAH and to integrate them into the therapeutic agents used against this challenging disease.
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Affiliation(s)
- Jiang-Shan Tan
- Emergency Center, Fuwai Hospital, State Key Laboratory of Cardiovascular Disease of China, National Clinical Research Center of Cardiovascular Diseases, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yixiao Wei
- Peking University Health Science Center, Beijing, China
| | - Lingtao Chong
- Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yanmin Yang
- Emergency Center, Fuwai Hospital, State Key Laboratory of Cardiovascular Disease of China, National Clinical Research Center of Cardiovascular Diseases, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Song Hu
- Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yimeng Wang
- Emergency Center, Fuwai Hospital, State Key Laboratory of Cardiovascular Disease of China, National Clinical Research Center of Cardiovascular Diseases, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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11
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Coll E, Cigarran S, Portolés J, Cases A. Gut Dysbiosis and Its Role in the Anemia of Chronic Kidney Disease. Toxins (Basel) 2024; 16:495. [PMID: 39591250 PMCID: PMC11598790 DOI: 10.3390/toxins16110495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 11/07/2024] [Accepted: 11/14/2024] [Indexed: 11/28/2024] Open
Abstract
The gut dysbiosis present in chronic kidney disease (CKD) has been associated with anemia. Factors such as the accumulation of gut-derived uremic toxins, increased gut barrier permeability-induced inflammation, and a reduced intestinal production of short-chain fatty acids (SCFAs), all associated with changes in the intestinal microbiota composition in CKD, may lead to the development or worsening of anemia in renal patients. Understanding and addressing these mechanisms related to gut dysbiosis in CKD patients can help to delay the development of anemia and improve its control in this population. One approach is to avoid or reduce the use of drugs linked to gut dysbiosis in CKD, such as phosphate binders, oral iron supplementation, antibiotics, and others, unless they are indispensable. Another approach involves introducing dietary changes that promote a healthier microbiota and/or using prebiotics, probiotics, or symbiotics to improve gut dysbiosis in this setting. These measures can increase the presence of SCFA-producing saccharolytic bacteria and reduce proteolytic bacteria, thereby lowering the production of gut-derived uremic toxins and inflammation. By ameliorating CKD-related gut dysbiosis, these strategies can also improve the control of renal anemia and enhance the response to erythropoiesis-stimulating agents (ESAs) in ESA-resistant patients. In this review, we have explored the relationship between gut dysbiosis in CKD and renal anemia and propose feasible solutions, both those already known and potential future treatments.
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Affiliation(s)
- Elisabet Coll
- Servei de Nefrologia, Fundacio Puigvert, 08025 Barcelona, Spain
- Anemia Working Group of the Spanish Society of Nephrology, 39008 Santander, Spain; (J.P.); (A.C.)
| | | | - Jose Portolés
- Anemia Working Group of the Spanish Society of Nephrology, 39008 Santander, Spain; (J.P.); (A.C.)
- Ressearch Net RICORS 2030 Instituto de Salud Carlos III ISCIII, 28029 Madrid, Spain
- Nephrology Department, Hospital Universitario Puerta de Hierro Majadahonda, 28222 Madrid, Spain
- Medicine Department, Facultad de Medicina, Research Institute Puerta de Hierro Segovia de Arana (IDIPHISA), Universidad Autónoma de Madrid, 28029 Madrid, Spain
| | - Aleix Cases
- Anemia Working Group of the Spanish Society of Nephrology, 39008 Santander, Spain; (J.P.); (A.C.)
- Nephrology Unit, Hospital Clinic, 08036 Barcelona, Spain
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12
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Hershenson R, Nardi-Agmon I, Leshem-Lev D, Kornowski R, Eisen A. The effect of empagliflozin on circulating endothelial progenitor cells in patients with diabetes and stable coronary artery disease. Cardiovasc Diabetol 2024; 23:386. [PMID: 39468546 PMCID: PMC11520434 DOI: 10.1186/s12933-024-02466-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Accepted: 10/10/2024] [Indexed: 10/30/2024] Open
Abstract
BACKGROUND Diabetes mellitus (DM) is associated with premature atherosclerotic disease, coronary artery disease (CAD) and chronic heart failure (HF), leading to increased morbidity and mortality. Sodium-Glucose Co-transporter 2 Inhibitors (SGLT2i) exhibit cardioprotective benefits beyond glucose lowering, reducing the risk of major cardiovascular events (MACE) and HF hospitalizations in patients with DM and CAD. Endothelial progenitor cells (EPCs) are bone marrow-derived cells involved in vascular repair, mobilized in response to vascular injury. The number and function of circulating EPCs (cEPCs) are negatively affected by cardiovascular risk factors, including DM. This study aimed to examine the response of cEPCs to SGLT2i treatment in DM patients with stable CAD. METHODS A prospective single-center study included patients with DM and stable CAD who were started on an SGLT2i (empagliflozin). Peripheral blood samples were collected at baseline, 1 month, and 3 months to evaluate cEPC levels and function by flow cytometry, immunohistochemistry and MTT assays. RESULTS Eighteen patients were included in the study (median age 73, (IQR 69, 77) years, 67% male). After 1 month of treatment with empagliflozin, there was no significant change in cEPCs level or function. However, following 3 months of treatment, a significant increase was observed both in cell levels (CD34(+)/VEGFR-2(+): from 0.49% (IQR 0.32, 0.64) to 1.58% (IQR 0.93, 1.82), p = 0.0006; CD133(+)/VEGFR-2(+): from 0.38% (IQR 0.27, 0.6) to 0.82% (IQR 0.7, 1.95), p = 0.0001) and in cell function (from 0.25 CFUs (IQR 0, 0.5) at baseline, to 2 CFUs (IQR 1, 2) at 3 months, p = 0.0012). CONCLUSIONS Empagliflozin treatment in patients with DM and stable CAD increases cEPC levels and function, implying a cardioprotective mechanism. These findings highlight the potential of SGLT2i in treating cardiovascular diseases, warranting further research to explore these effects and their long-term implications.
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Affiliation(s)
- Roy Hershenson
- Department of Cardiology, Rabin Medical Center, 39 Jabotinsky St., 49100, Petah Tikva, Israel.
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
| | - Inbar Nardi-Agmon
- Department of Cardiology, Rabin Medical Center, 39 Jabotinsky St., 49100, Petah Tikva, Israel
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva, Israel
| | - Dorit Leshem-Lev
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva, Israel
| | - Ran Kornowski
- Department of Cardiology, Rabin Medical Center, 39 Jabotinsky St., 49100, Petah Tikva, Israel
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Alon Eisen
- Department of Cardiology, Rabin Medical Center, 39 Jabotinsky St., 49100, Petah Tikva, Israel
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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Piperis C, Marathonitis A, Anastasiou A, Theofilis P, Mourouzis K, Giannakodimos A, Tryfou E, Oikonomou E, Siasos G, Tousoulis D. Multifaceted Impact of SGLT2 Inhibitors in Heart Failure Patients: Exploring Diverse Mechanisms of Action. Biomedicines 2024; 12:2314. [PMID: 39457625 PMCID: PMC11504660 DOI: 10.3390/biomedicines12102314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 10/02/2024] [Accepted: 10/09/2024] [Indexed: 10/28/2024] Open
Abstract
Heart failure (HF) is a growing concern due to the aging population and increasing prevalence of comorbidities. Despite advances in treatment, HF remains a significant burden, necessitating novel therapeutic approaches. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have emerged as a promising treatment option, demonstrating benefits across the entire spectrum of HF, regardless of left ventricular ejection fraction (LVEF). This review explores the multifaceted mechanisms through which SGLT2is exert cardioprotective effects, including modulation of energy metabolism, reduction of oxidative stress, attenuation of inflammation, and promotion of autophagy. SGLT2is shift myocardial energy substrate utilization from carbohydrates to more efficient fatty acids and ketone bodies, enhancing mitochondrial function and reducing insulin resistance. These inhibitors also mitigate oxidative stress by improving mitochondrial biogenesis, reducing reactive oxygen species (ROS) production, and regulating calcium-signaling pathways. Inflammation, a key driver of HF progression, is alleviated through the suppression of proinflammatory cytokines and modulation of immune cell activity. Additionally, SGLT2is promote autophagy, facilitating the clearance of damaged cellular components and preserving myocardial structure and function. Beyond their glucose-lowering effects, SGLT2is provide significant benefits in patients with chronic kidney disease (CKD) and HF, reducing the progression of CKD and improving overall survival. The pleiotropic actions of SGLT2is highlight their potential as a cornerstone in HF management. Further research is needed to fully elucidate their mechanisms and optimize their use in clinical practice.
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Affiliation(s)
- Christos Piperis
- 3rd Department of Cardiology, Thoracic Diseases General Hospital “Sotiria”, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.P.); (A.M.); (A.A.); (K.M.); (A.G.); (E.T.); (E.O.); (G.S.)
| | - Anastasios Marathonitis
- 3rd Department of Cardiology, Thoracic Diseases General Hospital “Sotiria”, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.P.); (A.M.); (A.A.); (K.M.); (A.G.); (E.T.); (E.O.); (G.S.)
| | - Artemis Anastasiou
- 3rd Department of Cardiology, Thoracic Diseases General Hospital “Sotiria”, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.P.); (A.M.); (A.A.); (K.M.); (A.G.); (E.T.); (E.O.); (G.S.)
| | - Panagiotis Theofilis
- 1st Department of Cardiology, “Hippokration” General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Konstantinos Mourouzis
- 3rd Department of Cardiology, Thoracic Diseases General Hospital “Sotiria”, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.P.); (A.M.); (A.A.); (K.M.); (A.G.); (E.T.); (E.O.); (G.S.)
| | - Alexios Giannakodimos
- 3rd Department of Cardiology, Thoracic Diseases General Hospital “Sotiria”, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.P.); (A.M.); (A.A.); (K.M.); (A.G.); (E.T.); (E.O.); (G.S.)
| | - Elsi Tryfou
- 3rd Department of Cardiology, Thoracic Diseases General Hospital “Sotiria”, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.P.); (A.M.); (A.A.); (K.M.); (A.G.); (E.T.); (E.O.); (G.S.)
| | - Evangelos Oikonomou
- 3rd Department of Cardiology, Thoracic Diseases General Hospital “Sotiria”, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.P.); (A.M.); (A.A.); (K.M.); (A.G.); (E.T.); (E.O.); (G.S.)
| | - Gerasimos Siasos
- 3rd Department of Cardiology, Thoracic Diseases General Hospital “Sotiria”, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.P.); (A.M.); (A.A.); (K.M.); (A.G.); (E.T.); (E.O.); (G.S.)
| | - Dimitris Tousoulis
- 1st Department of Cardiology, “Hippokration” General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece;
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14
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Yuan F, Zhang T, Jia S, Zhao J, Wan B, Liu G. Fine mapping-based multi-omics analysis interprets the gut-lung axis function of SGLT2 inhibitors. Front Cell Infect Microbiol 2024; 14:1447327. [PMID: 39318474 PMCID: PMC11420167 DOI: 10.3389/fcimb.2024.1447327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 08/21/2024] [Indexed: 09/26/2024] Open
Abstract
Background Currently, Sodium-glucose cotransporter 2 (SGLT2) inhibitors demonstrate additional effects beyond glucose control on the gut microbiota and circulating metabolites. The gut microbiota and metabolites have been found to be useful in elucidating potential biological mechanisms of pulmonary diseases. Therefore, our study aims to investigate the effects of gut microbiota and metabolites mediating SGLT2 inhibition in 10 pulmonary diseases through Mendelian randomization (MR) research. Methods We conducted a two-sample, two-step MR study to assess the association between SGLT2 inhibition and 10 pulmonary diseases and to investigate the mediating effects of gut microbiota and metabolite. Gene-fine mapping and annotation of mediators by FUMA and Magma analyses were performed, and causal associations of mapped genes with diseases were assessed by muti-omics MR analyses. Possible side effects of SGLT2 inhibition were assessed by PheWAS analysis. Results SGLT2 inhibition was linked to a reduced risk of T2DM, Interstitial lung disease (ILD), Pneumoconiosis, Pulmonary tuberculosis, and Asthma(OR=0.457, 0.054, 0.002, 0.280, 0.706). The family Enterobacteriaceae and order Enterobacteriales were associated with SGLT2 inhibition and ILD(95% CI:0.079-0.138). The family Alcaligenaceae and X-12719 were linked to pneumoconiosis (95% CI: 0.042-0.120, 0.050-0.099). The genus Phascolarctobacterium was connected to pulmonary tuberculosis (95% CI: 0.236-0.703).The degree of unsaturation (Fatty Acids), ratio of docosahexaenoic acid to total fatty acids, and 4-androsten-3beta,17beta-diol disulfate 2, were associated with asthma(95% CI: 0.042-0.119, 0.039-0.101, 0.181-0.473). Furthermore, Fuma and Magma analyses identified target genes for the four diseases, and proteomic MR analysis revealed six overlapping target genes in asthma. PheWAS analysis also highlighted potential side effects of SGLT2 inhibition. Conclusions This comprehensive study strongly supports a multi-omics association between SGLT2 inhibition and reduced risk of interstitial lung disease, tuberculosis, pneumoconiosis, and asthma. Four identified gut microbiota, four metabolites, sixteen metabolic pathways, and six target genes appear to play a potential role in this association. The results of the comprehensive phenome-wide association analysis also identified the full effect of SGLT2 inhibitors.
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Affiliation(s)
- Fengqin Yuan
- Department of Infection Control, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China
| | - Tianlong Zhang
- Department of Critical Care Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China
| | - Sixiang Jia
- Department of Cardiology, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China
| | - Jianqiang Zhao
- Department of Cardiology, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China
| | - Binbin Wan
- Department of Immunization Planning, Yiwu Center for Disease Control and Prevention, Yiwu, Zhejiang, China
| | - Gang Liu
- Department of Infection Control, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China
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15
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Kirtipal N, Seo Y, Son J, Lee S. Systems Biology of Human Microbiome for the Prediction of Personal Glycaemic Response. Diabetes Metab J 2024; 48:821-836. [PMID: 39313228 PMCID: PMC11449821 DOI: 10.4093/dmj.2024.0382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Accepted: 08/29/2024] [Indexed: 09/25/2024] Open
Abstract
The human gut microbiota is increasingly recognized as a pivotal factor in diabetes management, playing a significant role in the body's response to treatment. However, it is important to understand that long-term usage of medicines like metformin and other diabetic treatments can result in problems, gastrointestinal discomfort, and dysbiosis of the gut flora. Advanced sequencing technologies have improved our understanding of the gut microbiome's role in diabetes, uncovering complex interactions between microbial composition and metabolic health. We explore how the gut microbiota affects glucose metabolism and insulin sensitivity by examining a variety of -omics data, including genomics, transcriptomics, epigenomics, proteomics, metabolomics, and metagenomics. Machine learning algorithms and genome-scale modeling are now being applied to find microbiological biomarkers associated with diabetes risk, predicted disease progression, and guide customized therapy. This study holds promise for specialized diabetic therapy. Despite significant advances, some concerns remain unanswered, including understanding the complex relationship between diabetes etiology and gut microbiota, as well as developing user-friendly technological innovations. This mini-review explores the relationship between multiomics, precision medicine, and machine learning to improve our understanding of the gut microbiome's function in diabetes. In the era of precision medicine, the ultimate goal is to improve patient outcomes through personalized treatments.
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Affiliation(s)
- Nikhil Kirtipal
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea
| | - Youngchang Seo
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea
| | - Jangwon Son
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Bucheon, Korea
| | - Sunjae Lee
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea
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16
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Troise D, Mercuri S, Infante B, Losappio V, Cirolla L, Netti GS, Ranieri E, Stallone G. mTOR and SGLT-2 Inhibitors: Their Synergistic Effect on Age-Related Processes. Int J Mol Sci 2024; 25:8676. [PMID: 39201363 PMCID: PMC11354721 DOI: 10.3390/ijms25168676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 07/31/2024] [Accepted: 08/02/2024] [Indexed: 09/02/2024] Open
Abstract
The aging process contributes significantly to the onset of chronic diseases, which are the primary causes of global mortality, morbidity, and healthcare costs. Numerous studies have shown that the removal of senescent cells from tissues extends lifespan and reduces the occurrence of age-related diseases. Consequently, there is growing momentum in the development of drugs targeting these cells. Among them, mTOR and SGLT-2 inhibitors have garnered attention due to their diverse effects: mTOR inhibitors regulate cellular growth, metabolism, and immune responses, while SGLT-2 inhibitors regulate glucose reabsorption in the kidneys, resulting in various beneficial metabolic effects. Importantly, these drugs may act synergistically by influencing senescence processes and pathways. Although direct studies on the combined effects of mTOR inhibition and SGLT-2 inhibition on age-related processes are limited, this review aims to highlight the potential synergistic benefits of these drugs in targeting senescence.
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Affiliation(s)
- Dario Troise
- Nephrology, Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
- Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, 14152 Stockholm, Sweden
| | - Silvia Mercuri
- Nephrology, Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
| | - Barbara Infante
- Nephrology, Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
| | - Vincenzo Losappio
- Nephrology, Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
| | - Luciana Cirolla
- Nephrology, Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
| | - Giuseppe Stefano Netti
- Unit of Clinical Pathology, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
| | - Elena Ranieri
- Unit of Clinical Pathology, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
| | - Giovanni Stallone
- Nephrology, Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
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17
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Mylonas N, Nikolaou PE, Karakasis P, Stachteas P, Fragakis N, Andreadou I. Endothelial Protection by Sodium-Glucose Cotransporter 2 Inhibitors: A Literature Review of In Vitro and In Vivo Studies. Int J Mol Sci 2024; 25:7274. [PMID: 39000380 PMCID: PMC11242615 DOI: 10.3390/ijms25137274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 06/26/2024] [Accepted: 06/30/2024] [Indexed: 07/16/2024] Open
Abstract
Endothelial dysfunction often precedes the development of cardiovascular diseases, including heart failure. The cardioprotective benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2is) could be explained by their favorable impact on the endothelium. In this review, we summarize the current knowledge on the direct in vitro effects of SGLT2is on endothelial cells, as well as the systematic observations in preclinical models. Four putative mechanisms are explored: oxidative stress, nitric oxide (NO)-mediated pathways, inflammation, and endothelial cell survival and proliferation. Both in vitro and in vivo studies suggest that SGLT2is share a class effect on attenuating reactive oxygen species (ROS) and on enhancing the NO bioavailability by increasing endothelial nitric oxide synthase activity and by reducing NO scavenging by ROS. Moreover, SGLT2is significantly suppress inflammation by preventing endothelial expression of adhesion receptors and pro-inflammatory chemokines in vivo, indicating another class effect for endothelial protection. However, in vitro studies have not consistently shown regulation of adhesion molecule expression by SGLT2is. While SGLT2is improve endothelial cell survival under cell death-inducing stimuli, their impact on angiogenesis remains uncertain. Further experimental studies are required to accurately determine the interplay among these mechanisms in various cardiovascular complications, including heart failure and acute myocardial infarction.
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Affiliation(s)
- Nikolaos Mylonas
- Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimioupolis, Zografou, 15771 Athens, Greece; (N.M.); (P.E.N.)
| | - Panagiota Efstathia Nikolaou
- Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimioupolis, Zografou, 15771 Athens, Greece; (N.M.); (P.E.N.)
| | - Paschalis Karakasis
- Second Department of Cardiology, Aristotle University of Thessaloniki, Hippokration General Hospital of Thessaloniki, 54642 Thessaloniki, Greece; (P.K.); (P.S.); (N.F.)
| | - Panagiotis Stachteas
- Second Department of Cardiology, Aristotle University of Thessaloniki, Hippokration General Hospital of Thessaloniki, 54642 Thessaloniki, Greece; (P.K.); (P.S.); (N.F.)
| | - Nikolaos Fragakis
- Second Department of Cardiology, Aristotle University of Thessaloniki, Hippokration General Hospital of Thessaloniki, 54642 Thessaloniki, Greece; (P.K.); (P.S.); (N.F.)
- Outpatient Department of Cardiometabolic Medicine, Second Department of Cardiology, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece
| | - Ioanna Andreadou
- Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimioupolis, Zografou, 15771 Athens, Greece; (N.M.); (P.E.N.)
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Dardano A, Bianchi C, Garofolo M, Del Prato S. The current landscape for diabetes treatment: Preventing diabetes-associated CV risk. Atherosclerosis 2024; 394:117560. [PMID: 38688748 DOI: 10.1016/j.atherosclerosis.2024.117560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 04/11/2024] [Accepted: 04/18/2024] [Indexed: 05/02/2024]
Abstract
Despite the risk of atherosclerosis has progressively declined over the past few decades, subjects with type 2 diabetes mellitus (T2DM) continue to experience substantial excess of atherosclerotic cardiovascular disease (ASCVD)-related events. Therefore, there is urgent need to treat ASCVD disease in T2DM earlier, more intensively, and with greater precision. Many factors concur to increase the risk of atherosclerosis, and multifactorial intervention remains the basis for effective prevention or reduction of atherosclerotic events. The role of anti-hyperglycemic medications in reducing the risk of ASCVD in subjects with T2DM has evolved over the past few years. Multiple cardiovascular outcome trials (CVOTs) with new and emerging glucose-lowering agents, namely SGLT2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP1-RA), have demonstrated significant reductions of major cardiovascular events and additional benefits. This robust evidence has changed the landscape for managing people with T2DM. In addition to glycemic and ancillary extra-glycemic properties, SGLT2i and GLP1-RA might exert favorable effects on subclinical and clinical atherosclerosis. Therefore, the objective of this review is to discuss the available evidence supporting anti-atherosclerotic properties of SGLT2i and GLP1-RA, with a quick nod to sotagliflozin and tirzepatide.
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Affiliation(s)
- Angela Dardano
- Department of Clinical and Experimental Medicine, University of Pisa, Italy; Section of Diabetes and Metabolic Diseases, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Cristina Bianchi
- Section of Diabetes and Metabolic Diseases, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Monia Garofolo
- Department of Clinical and Experimental Medicine, University of Pisa, Italy
| | - Stefano Del Prato
- Interdisciplinary Research Center "Health Science", Sant'Anna School of Advanced Studies, Pisa, Italy.
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Kim HL, Jo SH. Arterial Stiffness and Heart Failure With Preserved Ejection Fraction. J Korean Med Sci 2024; 39:e195. [PMID: 38887204 PMCID: PMC11182699 DOI: 10.3346/jkms.2024.39.e195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Accepted: 05/20/2024] [Indexed: 06/20/2024] Open
Abstract
Heart failure with preserved ejection fraction (HFpEF) is prevalent and associated with a poor prognosis, imposing a significant burden on society. Arterial stiffness is increasingly recognized as a crucial factor in the pathophysiology of HFpEF, affecting diagnosis, management, and prognosis. As a hallmark of vascular aging, arterial stiffness contributes to increased afterload on the left ventricle (LV), leading to diastolic dysfunction, a key feature of HFpEF. Elevated arterial stiffness is linked with common cardiovascular risk factors in HFpEF, such as hypertension, diabetes and obesity, exacerbating the progression of disease. Studies have demonstrated that patients with HFpEF exhibit significantly higher levels of arterial stiffness compared to those without HFpEF, highlighting the value of arterial stiffness measurements as both diagnostic and prognostic tools. Moreover, interventions aimed at reducing arterial stiffness, whether through pharmacological therapies or lifestyle modifications, have shown potential in improving LV diastolic function and patient outcomes. Despite these advancements, the precise mechanisms by which arterial stiffness contributes to HFpEF are still not fully understood, necessitating the need for further research.
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Affiliation(s)
- Hack-Lyoung Kim
- Division of Cardiology, Department of Internal Medicine, Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea
| | - Sang-Ho Jo
- Division of Cardiology, Department of Internal Medicine, Hallym University Sacred Heart Hospital, Anyang, Korea.
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Wang L, Wang Y, Xu H, Li W. Effect of dapagliflozin on ferroptosis through the gut microbiota metabolite TMAO during myocardial ischemia-reperfusion injury in diabetes mellitus rats. Sci Rep 2024; 14:13851. [PMID: 38879701 PMCID: PMC11180094 DOI: 10.1038/s41598-024-64909-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Accepted: 06/14/2024] [Indexed: 06/19/2024] Open
Abstract
Dapagliflozin (DAPA) demonstrates promise in the management of diabetic mellitus (DM) and cardiomyopathy. Trimethylamine N-oxide (TMAO) is synthesized by the gut microbiota through the metabolic conversion of choline and phosphatidylcholine. Ferroptosis may offer novel therapeutic avenues for the management of diabetes and myocardial ischemia-reperfusion injury (IRI). However, the precise mechanism underlying ferroptosis in cardiomyocytes and the specific role of TMAO generated by gut microbiota in the therapeutic approach for DM and myocardial IRI utilizing DAPA need to be further explored. Nine male SD rats with specific pathogen-free (SPF) status were randomly divided equally into the normal group, the DM + IRI (DIR) group, and the DAPA group. The diversity of the gut microbiota was analyzed using 16S rRNA gene sequencing. Additionally, the Wekell technique was employed to measure the levels of TMAO in the three groups. Application of network pharmacology to search for intersection targets of DAPA, DIR, and ferroptosis, and RT-PCR experimental verification. Ultimately, the overlapping targets that were acquired were subjected to molecular docking analysis with TMAO. The changes of Bacteroidetes and Firmicutes in the gut microbiota of DIR rats were most significantly affected by DAPA. Escherichia-Shigella and Prevotella_9 within the phylum Bacteroidetes could be identified as the primary effects of DAPA on DIR. Compared with the normal group, the TMAO content in the DIR group was significantly increased, while the TMAO content in the DAPA group was decreased compared to the DIR group. For the network pharmacology analysis, DAPA and DIR generated 43 intersecting target genes, and then further intersected with ferroptosis-related genes, resulting in 11 overlapping target genes. The mRNA expression of ALB, HMOX1, PPARG, CBS, LCN2, and PPARA decreased in the DIR group through reverse transcription polymerase chain reaction (RT-PCR) validation, while the opposite trend was observed in the DAPA group. The docking score between TMAO and DPP4 was - 5.44, and the MM-GBSA result of - 22.02 kcal/mol. It epitomizes the finest docking performance among all the target genes with the lowest score. DAPA could reduce the levels of metabolite TMAO produced by gut microbiota, thereby regulating related target genes to decrease ferroptosis in DIR cardiomyocytes.
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Affiliation(s)
- Lian Wang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
- College of Medicine, Wuhan University of Science and Technology, Wuhan, 430070, Hubei, China
| | - Yao Wang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Heng Xu
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Wenyuan Li
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.
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Balleza Alejandri LR, Grover Páez F, González Campos E, Ramos Becerra CG, Cardona Muñóz EG, Pascoe González S, Ramos Zavala MG, Reynoso Roa AS, Suárez Rico DO, Beltrán Ramírez A, García Galindo JJ, Cardona Müller D, Galán Ruíz CY. Empagliflozin and Dapagliflozin Improve Endothelial Function in Mexican Patients with Type 2 Diabetes Mellitus: A Double-Blind Clinical Trial. J Cardiovasc Dev Dis 2024; 11:182. [PMID: 38921682 PMCID: PMC11204032 DOI: 10.3390/jcdd11060182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 06/06/2024] [Accepted: 06/10/2024] [Indexed: 06/27/2024] Open
Abstract
AIM To assess the acute effect of empagliflozin versus dapagliflozin administration on flow-mediated vasodilation in patients with type 2 diabetes mellitus. DESIGN A double-blind clinical trial, at the Experimental and Clinical Therapeutics Institute, University Health Sciences Center, at the Universidad de Guadalajara, in inpatients with T2D according to the 2023 ADA criteria. METHODS Thirty patients (15 males and 15 females), aged between 35 and 65 years, were included in this study, according to the 2023 ADA criteria. The eligible patients were randomly assigned to three groups: empagliflozin 25 mg once daily, dapagliflozin 10 mg once daily, or placebo once daily. Anthropometric parameters were taken using validated techniques. FMD was measured using a high-resolution semiautomatic ultrasound UNEX-EF 38G (UNEX Co., Ltd., Nagoya, Japan). Arterial tension was determined with the OMRON electronic digital sphygmomanometer (HEM 907 XL, Kyoto, Japan). RESULTS The group of patients who received empagliflozin had a significantly lower baseline flow-mediated dilation (FMD) compared to the group receiving dapagliflozin (p = 0.017); at the end of this study, the empagliflozin group achieved a comparable FMD to the dapagliflozin group (p = 0.88). CONCLUSION After the treatment period, the empagliflozin and dapagliflozin groups achieved similar FMD, suggesting a class effect.
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Affiliation(s)
- Luis Ricardo Balleza Alejandri
- Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico; (L.R.B.A.); (E.G.C.); (C.G.R.B.); (E.G.C.M.); (S.P.G.); (M.G.R.Z.); (A.S.R.R.); (D.O.S.R.); (A.B.R.); (J.J.G.G.); (D.C.M.); (C.Y.G.R.)
| | - Fernando Grover Páez
- Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico; (L.R.B.A.); (E.G.C.); (C.G.R.B.); (E.G.C.M.); (S.P.G.); (M.G.R.Z.); (A.S.R.R.); (D.O.S.R.); (A.B.R.); (J.J.G.G.); (D.C.M.); (C.Y.G.R.)
- Arterial Stiffness Laboratory, Department of Physiology, Experimental and Clinical Therapeutics Institute, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico
| | - Erick González Campos
- Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico; (L.R.B.A.); (E.G.C.); (C.G.R.B.); (E.G.C.M.); (S.P.G.); (M.G.R.Z.); (A.S.R.R.); (D.O.S.R.); (A.B.R.); (J.J.G.G.); (D.C.M.); (C.Y.G.R.)
| | - Carlos G. Ramos Becerra
- Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico; (L.R.B.A.); (E.G.C.); (C.G.R.B.); (E.G.C.M.); (S.P.G.); (M.G.R.Z.); (A.S.R.R.); (D.O.S.R.); (A.B.R.); (J.J.G.G.); (D.C.M.); (C.Y.G.R.)
- Arterial Stiffness Laboratory, Department of Physiology, Experimental and Clinical Therapeutics Institute, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico
| | - Ernesto Germán Cardona Muñóz
- Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico; (L.R.B.A.); (E.G.C.); (C.G.R.B.); (E.G.C.M.); (S.P.G.); (M.G.R.Z.); (A.S.R.R.); (D.O.S.R.); (A.B.R.); (J.J.G.G.); (D.C.M.); (C.Y.G.R.)
- Arterial Stiffness Laboratory, Department of Physiology, Experimental and Clinical Therapeutics Institute, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico
| | - Sara Pascoe González
- Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico; (L.R.B.A.); (E.G.C.); (C.G.R.B.); (E.G.C.M.); (S.P.G.); (M.G.R.Z.); (A.S.R.R.); (D.O.S.R.); (A.B.R.); (J.J.G.G.); (D.C.M.); (C.Y.G.R.)
- Arterial Stiffness Laboratory, Department of Physiology, Experimental and Clinical Therapeutics Institute, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico
| | - María Guadalupe Ramos Zavala
- Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico; (L.R.B.A.); (E.G.C.); (C.G.R.B.); (E.G.C.M.); (S.P.G.); (M.G.R.Z.); (A.S.R.R.); (D.O.S.R.); (A.B.R.); (J.J.G.G.); (D.C.M.); (C.Y.G.R.)
- Arterial Stiffness Laboratory, Department of Physiology, Experimental and Clinical Therapeutics Institute, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico
| | - Africa Samantha Reynoso Roa
- Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico; (L.R.B.A.); (E.G.C.); (C.G.R.B.); (E.G.C.M.); (S.P.G.); (M.G.R.Z.); (A.S.R.R.); (D.O.S.R.); (A.B.R.); (J.J.G.G.); (D.C.M.); (C.Y.G.R.)
- Arterial Stiffness Laboratory, Department of Physiology, Experimental and Clinical Therapeutics Institute, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico
| | - Daniel Osmar Suárez Rico
- Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico; (L.R.B.A.); (E.G.C.); (C.G.R.B.); (E.G.C.M.); (S.P.G.); (M.G.R.Z.); (A.S.R.R.); (D.O.S.R.); (A.B.R.); (J.J.G.G.); (D.C.M.); (C.Y.G.R.)
| | - Alberto Beltrán Ramírez
- Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico; (L.R.B.A.); (E.G.C.); (C.G.R.B.); (E.G.C.M.); (S.P.G.); (M.G.R.Z.); (A.S.R.R.); (D.O.S.R.); (A.B.R.); (J.J.G.G.); (D.C.M.); (C.Y.G.R.)
| | - Jesús Jonathan García Galindo
- Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico; (L.R.B.A.); (E.G.C.); (C.G.R.B.); (E.G.C.M.); (S.P.G.); (M.G.R.Z.); (A.S.R.R.); (D.O.S.R.); (A.B.R.); (J.J.G.G.); (D.C.M.); (C.Y.G.R.)
| | - David Cardona Müller
- Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico; (L.R.B.A.); (E.G.C.); (C.G.R.B.); (E.G.C.M.); (S.P.G.); (M.G.R.Z.); (A.S.R.R.); (D.O.S.R.); (A.B.R.); (J.J.G.G.); (D.C.M.); (C.Y.G.R.)
- Arterial Stiffness Laboratory, Department of Physiology, Experimental and Clinical Therapeutics Institute, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico
| | - Claudia Yanette Galán Ruíz
- Department of Physiology, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico; (L.R.B.A.); (E.G.C.); (C.G.R.B.); (E.G.C.M.); (S.P.G.); (M.G.R.Z.); (A.S.R.R.); (D.O.S.R.); (A.B.R.); (J.J.G.G.); (D.C.M.); (C.Y.G.R.)
- Arterial Stiffness Laboratory, Department of Physiology, Experimental and Clinical Therapeutics Institute, University Health Sciences Center, Universidad de Guadalajara, Guadalajara 44340, Mexico
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Afsar B, Afsar RE, Lentine KL. The impact of sodium-glucose cotransporter inhibitors on gut microbiota: a scoping review. J Diabetes Metab Disord 2024; 23:497-508. [PMID: 38932911 PMCID: PMC11196485 DOI: 10.1007/s40200-024-01435-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Accepted: 04/10/2024] [Indexed: 06/28/2024]
Abstract
Studies consistently showed that sodium-glucose cotransporter inhibitors (SGLTi) have cardiovascular and renal benefits, independent of their glucose lowering effects. Recent studies showed that SGLTi might influence gut microbiota. We performed a narrative review of publications focusing on use of SGLTi and changes in gut microbiota. Most studies showed that use of SGLTi re-shapes gut microbiota. These studies are heterogeneous regarding in study designs, doses and types of drugs used (SGLT1i vs. SGLT2i, or SGLT1/2i in combination) and the methods used to determine gut microbiota. However, existing data showed that SGLTi might alter food fermentation and gut permeability, which might translate into clinical outcomes. Thus the objective of this review is to summarize and discuss the updated data regarding SGLTi and changes in gut microbiota for the first time and suggest further study points that needs to be discovered. Graphical Abstract
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Affiliation(s)
- Baris Afsar
- Suleyman Demirel University, School of Medicine, Department of Nephrology, Isparta, Turkey
| | - Rengin Elsurer Afsar
- Suleyman Demirel University, School of Medicine, Department of Nephrology, Isparta, Turkey
- Saint Louis University, School of Medicine, Division of Nephrology, St. Louis, MO USA
| | - Krista L. Lentine
- Saint Louis University, School of Medicine, Division of Nephrology, St. Louis, MO USA
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Marrone G, Cornali K, Di Lauro M, Ceravolo MJ, Di Marco L, Manca di Villahermosa S, Mitterhofer AP, Noce A. Innovative Treatments to Counteract Endothelial Dysfunction in Chronic Kidney Disease Patients. Biomedicines 2024; 12:1085. [PMID: 38791047 PMCID: PMC11117580 DOI: 10.3390/biomedicines12051085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 05/02/2024] [Accepted: 05/09/2024] [Indexed: 05/26/2024] Open
Abstract
In chronic kidney disease (CKD) patients, several risk factors contribute to the development of endothelial dysfunction (ED), which can be described as an alteration in the cell structure or in the function of the endothelium. Among the well-known CKD-related risk factors capable of altering the production of endothelium-derived relaxing factors, we include asymmetric dimethylarginine increase, reduced dimethylarginine dimethylamine hydrolase enzyme activity, low-grade chronic systemic inflammation, hyperhomocysteinemia, oxidative stress, insulin resistance, alteration of calcium phosphorus metabolism, and early aging. In this review, we also examined the most important techniques useful for studying ED in humans, which are divided into indirect and direct methods. The direct study of coronary endothelial function is considered the gold standard technique to evaluate if ED is present. In addition to the discussion of the main pharmacological treatments useful to counteract ED in CKD patients (namely sodium-glucose cotransporter 2 inhibitors and mineralocorticoid receptor antagonist), we elucidate innovative non-pharmacological treatments that are successful in accompanying the pharmacological ones. Among them, the most important are the consumption of extra virgin olive oil with high intake of minor polar compounds, adherence to a plant-dominant, low-protein diet (LPD), an adaptive physical activity program and, finally, ketoanalogue administration in combination with the LPD or the very low-protein diet.
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Affiliation(s)
- Giulia Marrone
- Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy (K.C.); (L.D.M.); (S.M.d.V.); (A.P.M.)
| | - Kevin Cornali
- Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy (K.C.); (L.D.M.); (S.M.d.V.); (A.P.M.)
| | - Manuela Di Lauro
- Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy (K.C.); (L.D.M.); (S.M.d.V.); (A.P.M.)
| | - Maria Josè Ceravolo
- Nephrology and Dialysis Unit, Department of Systems Medicine, University Hospital of Rome Tor Vergata, 00133 Rome, Italy
| | - Luca Di Marco
- Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy (K.C.); (L.D.M.); (S.M.d.V.); (A.P.M.)
| | - Simone Manca di Villahermosa
- Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy (K.C.); (L.D.M.); (S.M.d.V.); (A.P.M.)
- Nephrology and Dialysis Unit, Department of Systems Medicine, University Hospital of Rome Tor Vergata, 00133 Rome, Italy
| | - Anna Paola Mitterhofer
- Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy (K.C.); (L.D.M.); (S.M.d.V.); (A.P.M.)
- Nephrology and Dialysis Unit, Department of Systems Medicine, University Hospital of Rome Tor Vergata, 00133 Rome, Italy
| | - Annalisa Noce
- Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy (K.C.); (L.D.M.); (S.M.d.V.); (A.P.M.)
- Nephrology and Dialysis Unit, Department of Systems Medicine, University Hospital of Rome Tor Vergata, 00133 Rome, Italy
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Zhang R, Xie Q, Lu X, Fan R, Tong N. Research advances in the anti-inflammatory effects of SGLT inhibitors in type 2 diabetes mellitus. Diabetol Metab Syndr 2024; 16:99. [PMID: 38735956 PMCID: PMC11089742 DOI: 10.1186/s13098-024-01325-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 03/28/2024] [Indexed: 05/14/2024] Open
Abstract
Diabetes mellitus is one of the most significant global burden diseases. It is well established that a chronic, systemic, low-grade inflammatory condition is strongly correlated with type 2 diabetes mellitus (T2D) and the development of target-organ damage (TOD). Sodium-glucose cotransporter inhibitors (SGLTis), novel oral drugs for the treatment of diabetes, act mainly by reducing glucose reabsorption in proximal renal tubules and/or the intestine. Several high-quality clinical trials and large observational studies have revealed that SGLTis significantly improve cardiovascular and renal outcomes in T2D patients. Increasing evidence suggests that this is closely related to their anti-inflammatory properties, which are mainly manifested by a reduction in plasma concentrations of inflammatory biomarkers. This review analyses the potential mechanisms behind the anti-inflammatory effects of SGLTis in diabetes and presents recent evidence of their therapeutic efficacy in treating diabetes and related TOD.
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Affiliation(s)
- Ruining Zhang
- Department of Endocrinology, Center for Diabetes and Metabolism Research, West China Hospital of Sichuan University, Chengdu, China
| | - Qingxing Xie
- Department of Endocrinology, Center for Diabetes and Metabolism Research, West China Hospital of Sichuan University, Chengdu, China
| | - Xi Lu
- Department of Endocrinology, Center for Diabetes and Metabolism Research, West China Hospital of Sichuan University, Chengdu, China
| | - Rongping Fan
- Department of Endocrinology, Center for Diabetes and Metabolism Research, West China Hospital of Sichuan University, Chengdu, China
| | - Nanwei Tong
- Department of Endocrinology, Center for Diabetes and Metabolism Research, West China Hospital of Sichuan University, Chengdu, China.
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Alsereidi FR, Khashim Z, Marzook H, Gupta A, Al-Rawi AM, Ramadan MM, Saleh MA. Targeting inflammatory signaling pathways with SGLT2 inhibitors: Insights into cardiovascular health and cardiac cell improvement. Curr Probl Cardiol 2024; 49:102524. [PMID: 38492622 DOI: 10.1016/j.cpcardiol.2024.102524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 03/13/2024] [Indexed: 03/18/2024]
Abstract
Sodium-glucose cotransporter 2 (SGLT2) inhibitors have attracted significant attention for their broader therapeutic impact beyond simply controlling blood sugar levels, particularly in their ability to influence inflammatory pathways. This review delves into the anti-inflammatory properties of SGLT2 inhibitors, with a specific focus on canagliflozin, empagliflozin, and dapagliflozin. One of the key mechanisms through which SGLT2 inhibitors exert their anti-inflammatory effects is by activating AMP-activated protein kinase (AMPK), a crucial regulator of both cellular energy balance and inflammation. Activation of AMPK by these inhibitors leads to the suppression of pro-inflammatory pathways and a decrease in inflammatory mediators. Notably, SGLT2 inhibitors have demonstrated the ability to inhibit the release of cytokines in an AMPK-dependent manner, underscoring their direct influence on inflammatory signaling. Beyond AMPK activation, SGLT2 inhibitors also modulate several other inflammatory pathways, including the NLRP3 inflammasome, expression of Toll-like receptor 4 (TLR-4), and activation of NF-κB (Nuclear factor kappa B). This multifaceted approach contributes to their efficacy in reducing inflammation and managing associated complications in conditions such as diabetes and cardiovascular disorders. Several human and animal studies provide support for the anti-inflammatory effects of SGLT2 inhibitors, demonstrating protective effects on various cardiac cells. Additionally, these inhibitors exhibit direct anti-inflammatory effects by modulating immune cells. Overall, SGLT2 inhibitors emerge as promising therapeutic agents for targeting inflammation in a range of pathological conditions. Further research, particularly focusing on the molecular-level pathways of inflammation, is necessary to fully understand their mechanisms of action and optimize their therapeutic potential in inflammatory diseases.
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Affiliation(s)
- Fatmah R Alsereidi
- Cardiovascular Research Group, Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Zenith Khashim
- Department of Physiology and Biomedical Engineering, Mayo Clinic Rochester, Rochester, MN, United States
| | - Hezlin Marzook
- Cardiovascular Research Group, Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Anamika Gupta
- Cardiovascular Research Group, Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Ahmed M Al-Rawi
- Cardiovascular Research Group, Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Mahmoud M Ramadan
- Cardiovascular Research Group, Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates; Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Cardiology, Faculty of Medicine, Mansoura University, 35516 Egypt
| | - Mohamed A Saleh
- Cardiovascular Research Group, Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates; Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516 Egypt.
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26
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Aziz F, Tripolt NJ, Pferschy PN, Scharnagl H, Abdellatif M, Oulhaj A, Benedikt M, Kolesnik E, von Lewinski D, Sourij H. Ketone body levels and its associations with cardiac markers following an acute myocardial infarction: a post hoc analysis of the EMMY trial. Cardiovasc Diabetol 2024; 23:145. [PMID: 38678253 PMCID: PMC11055693 DOI: 10.1186/s12933-024-02221-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 03/30/2024] [Indexed: 04/29/2024] Open
Abstract
BACKGROUND Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have been suggested to exert cardioprotective effects in patients with heart failure, possibly by improving the metabolism of ketone bodies in the myocardium. METHODS This post hoc analysis of the EMMY trial investigated the changes in serum β-hydroxybutyrate (3-βOHB) levels after acute myocardial infarction (AMI) in response to 26-week of Empagliflozin therapy compared to the usual post-MI treatment. In addition, the association of baseline and repeated measurements of 3-βOHB with cardiac parameters and the interaction effects of Empagliflozin were investigated. Cardiac parameters included N-terminal pro-B-type natriuretic peptide (NT-proBNP), left ventricular ejection fraction (LVEF), left ventricle end-systolic volume (LVESV), left ventricle end-diastolic volume (LVEDV), and left ventricular filling pressure (E/é ratio). RESULTS The mean 3-βOHB levels increased from baseline (46.2 ± 3.0 vs. 51.7 ± 2.7) to 6 weeks (48.8 ± 2.2 vs. 42.0 ± 2.3) and 26 weeks (49.3 ± 2.2 vs. 35.8 ± 1.9) in the Empagliflozin group compared to a consistent decline in placebo over 26 weeks (pinteraction < 0.001). Baseline and longitudinal measurements of 3-βOHB were not significantly associated with NT-proBNP and E/é ratio. Baseline 3-βOHB value was negatively associated with LVEF (coefficient: - 0.464, 95%CI - 0.863;- 0.065, p = 0.023), while an increase in its levels over time was positively associated with LVEF (0.595, 0.156;1.035, 0.008). The baseline 3-βOHB was positively associated with LVESV (1.409, 0.186;2.632, 0.024) and LVEDV (0.640, - 1.170;- 2.449, 0.488), while an increase in its levels over time was negatively associated with these cardiac parameters (LVESV: - 2.099, - 3.443;- 0.755, 0.002; LVEDV: - 2.406, - 4.341;- 0.472, 0.015). Empagliflozin therapy appears to modify the association between 3-βOHB, LVEF (pinteraction = 0.090), LVESV (pinteraction = 0.134), and LVEDV (pinteraction = 0.168), particularly at 26 weeks; however, the results were not statistically significant. CONCLUSION This post hoc analysis showed that SGLT2i increased 3-βOHB levels after AMI compared to placebo. Higher baseline 3-βOHB levels were inversely associated with cardiac function at follow-up, whereas a sustained increase in 3-βOHB levels over time improved these markers. This highlights the importance of investigating ketone body metabolism in different post-MI phases. Although more pronounced effect of 3-βOHB on cardiac markers was observed in the SGLT2i group, further research is required to explore this interaction effect.
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Affiliation(s)
- Faisal Aziz
- Interdisciplinary Metabolic Medicine Trials Unit, Medical University of Graz, Graz, Austria
- Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria
| | - Norbert J Tripolt
- Interdisciplinary Metabolic Medicine Trials Unit, Medical University of Graz, Graz, Austria
- Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria
| | - Peter N Pferschy
- Interdisciplinary Metabolic Medicine Trials Unit, Medical University of Graz, Graz, Austria
- Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria
| | - Hubert Scharnagl
- Clinical Institute for Chemical and Medical Laboratory Analysis, Medical University of Graz, Graz, Austria
| | | | - Abderrahim Oulhaj
- Department of Public Health and Epidemiology, College of Medicine and Health Sciences, Khalifa University of Sciences and Technology, Abu Dhabi, United Arab Emirates
- Biotechnology Center, Khalifa University of Sciences and Technology, Abu Dhabi, United Arab Emirates
| | - Martin Benedikt
- Division of Cardiology, Medical University of Graz, Graz, Austria
| | - Ewald Kolesnik
- Division of Cardiology, Medical University of Graz, Graz, Austria
| | - Dirk von Lewinski
- Division of Cardiology, Medical University of Graz, Graz, Austria.
- Working Group Myocardial Energetics and Metabolism, Medical University of Graz, Graz, Austria.
| | - Harald Sourij
- Interdisciplinary Metabolic Medicine Trials Unit, Medical University of Graz, Graz, Austria.
- Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria.
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27
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Cui X, Buonfiglio F, Pfeiffer N, Gericke A. Aging in Ocular Blood Vessels: Molecular Insights and the Role of Oxidative Stress. Biomedicines 2024; 12:817. [PMID: 38672172 PMCID: PMC11048681 DOI: 10.3390/biomedicines12040817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 04/01/2024] [Accepted: 04/05/2024] [Indexed: 04/28/2024] Open
Abstract
Acknowledged as a significant pathogenetic driver for numerous diseases, aging has become a focal point in addressing the profound changes associated with increasing human life expectancy, posing a critical concern for global public health. Emerging evidence suggests that factors influencing vascular aging extend their impact to choroidal and retinal blood vessels. The objective of this work is to provide a comprehensive overview of the impact of vascular aging on ocular blood vessels and related diseases. Additionally, this study aims to illuminate molecular insights contributing to vascular cell aging, with a particular emphasis on the choroid and retina. Moreover, innovative molecular targets operating within the domain of ocular vascular aging are presented and discussed.
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Affiliation(s)
- Xiuting Cui
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany; (F.B.); (N.P.)
| | | | | | - Adrian Gericke
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany; (F.B.); (N.P.)
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28
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Mohebi R, Liu Y, Hansen MK, Yavin Y, Sattar N, Pollock CA, Butler J, Jardine M, Masson S, Heerspink HJ, Januzzi JL. Associations of Angiopoietin 2 and Vascular Endothelial Growth Factor-A Concentrations with Clinical End Points. Clin J Am Soc Nephrol 2024; 19:429-437. [PMID: 38099944 PMCID: PMC11020427 DOI: 10.2215/cjn.0000000000000389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Accepted: 12/11/2023] [Indexed: 01/09/2024]
Abstract
BACKGROUND Angiopoietin 2 regulates endothelial function partially mediated by vascular endothelial growth factor-A (VEGF-A) and may play a role in diabetic kidney disease (DKD). We assessed the association of angiopoietin 2 and VEGF-A with cardiorenal outcomes and investigated the effect of canagliflozin on angiopoietin 2 and VEGF-A concentrations. METHODS Two thousand five hundred sixty-five study participants with DKD and available plasma samples treated with canagliflozin or placebo in the Canagliflozin and Kidney Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial were included. Angiopoietin 2 and VEGF-A concentrations were measured at baseline, year 1, and year 3. The primary composite end point of the trial was a composite of kidney failure, doubling of the serum creatinine level, and kidney or cardiovascular death. RESULTS Patients with the highest baseline quartile of angiopoietin 2, but not VEGF-A, concentration had the highest risk clinical profile. Treatment with canagliflozin significantly lowered concentrations of angiopoietin 2 (adjusted geometric mean ratio: 0.94; 95% confidence interval, 0.92 to 0.95; P < 0.001), but not VEGF-A. In multivariable-adjusted modeling, each 50% increment in log baseline angiopoietin 2 concentrations was associated with a higher risk of primary composite outcome (hazard ratio, 1.27; 95% confidence interval, 1.13 to 1.43). Angiopoietin 2 change at year 1 compared with baseline explained 10% of the effect of canagliflozin on the primary composite outcome. VEGF-A concentrations were not associated with outcomes, alone or in combination with angiopoietin 2. CONCLUSIONS Higher angiopoietin 2 levels were associated with cardiorenal risk among individuals with DKD independent of VEGF-A. Canagliflozin lowered angiopoietin 2 concentrations. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy, NCT02065791 .
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Affiliation(s)
- Reza Mohebi
- Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Yuxi Liu
- Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | | | - Yshai Yavin
- Janssen Research & Development, LLC, Spring House, Pennsylvania
| | - Naveed Sattar
- BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
| | - Carol A. Pollock
- Kolling Institute, Royal North Shore Hospital University of Sydney, Sydney, New South Wales, Australia
| | - Javed Butler
- Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi
- Baylor Scott & White Institute, Dallas, Texas
| | - Meg Jardine
- The George Institute for Global Health, UNSW Sydney, Sydney, New South Wales, Australia
- NHMRC Clinical Trials Centre, University of Sydney, Sydney, New South Wales, Australia
- Concord Repatriation General Hospital, Sydney, New South Wales, Australia
| | - Serge Masson
- Roche Diagnostics International, Rotkreuz, Switzerland
| | - Hiddo J.L. Heerspink
- Department Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, The Netherlands
| | - James L. Januzzi
- Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- Heart Failure and Biomarker Trials, Baim Institute for Clinical Research, Boston, Massachusetts
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29
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Zhang L, Wang P, Huang J, Xing Y, Wong FS, Suo J, Wen L. Gut microbiota and therapy for obesity and type 2 diabetes. Front Endocrinol (Lausanne) 2024; 15:1333778. [PMID: 38596222 PMCID: PMC11002083 DOI: 10.3389/fendo.2024.1333778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Accepted: 03/06/2024] [Indexed: 04/11/2024] Open
Abstract
There has been a major increase in Type 2 diabetes and obesity in many countries, and this will lead to a global public health crisis, which not only impacts on the quality of life of individuals well but also places a substantial burden on healthcare systems and economies. Obesity is linked to not only to type 2 diabetes but also cardiovascular diseases, musculoskeletal disorders, and certain cancers, also resulting in increased medical costs and diminished quality of life. A number of studies have linked changes in gut in obesity development. Dysbiosis, a deleterious change in gut microbiota composition, leads to altered intestinal permeability, associated with obesity and Type 2 diabetes. Many factors affect the homeostasis of gut microbiota, including diet, genetics, circadian rhythms, medication, probiotics, and antibiotics. In addition, bariatric surgery induces changes in gut microbiota that contributes to the metabolic benefits observed post-surgery. Current obesity management strategies encompass dietary interventions, exercise, pharmacotherapy, and bariatric surgery, with emerging treatments including microbiota-altering approaches showing promising efficacy. While pharmacotherapy has demonstrated significant advancements in recent years, bariatric surgery remains one of the most effective treatments for sustainable weight loss. However, access to this is generally limited to those living with severe obesity. This underscores the need for non-surgical interventions, particularly for adolescents and mildly obese patients. In this comprehensive review, we assess longitudinal alterations in gut microbiota composition and functionality resulting from the two currently most effective anti-obesity treatments: pharmacotherapy and bariatric surgery. Additionally, we highlight the functions of gut microbiota, focusing on specific bacteria, their metabolites, and strategies for modulating gut microbiota to prevent and treat obesity. This review aims to provide insights into the evolving landscape of obesity management and the potential of microbiota-based approaches in addressing this pressing global health challenge.
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Affiliation(s)
- Luyao Zhang
- Department of Gastrocolorectal Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
- Section of Endocrinology, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, United States
| | - Pai Wang
- Department of Gastrocolorectal Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
- Section of Endocrinology, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, United States
| | - Juan Huang
- Section of Endocrinology, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, United States
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, Changsha, Hunan, China
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yanpeng Xing
- Department of Gastrocolorectal Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
- Section of Endocrinology, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, United States
| | - F Susan Wong
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom
| | - Jian Suo
- Department of Gastrocolorectal Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Li Wen
- Section of Endocrinology, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, United States
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30
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Shen J, Ying L, Wu J, Fang Y, Zhou W, Qi C, Gu L, Mou S, Yan Y, Tian M, Ni Z, Che X. Integrative ATAC-seq and RNA-seq analysis associated with diabetic nephropathy and identification of novel targets for treatment by dapagliflozin. Cell Biochem Funct 2024; 42:e3943. [PMID: 38379015 DOI: 10.1002/cbf.3943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Revised: 12/01/2023] [Accepted: 01/12/2024] [Indexed: 02/22/2024]
Abstract
Dapagliflozin (DAPA) are clinically effective in improving diabetic nephropathy (DN). However, whether and how chromatin accessibility changed by DN responds to DAPA treatment is unclear. Therefore, we performed ATAC-seq, RNA-seq, and weighted gene correlation network analysis to identify the chromatin accessibility, the messenger RNA (mRNA) expression, and the correlation between clinical phenotypes and mRNA expression using kidney from three mouse groups: db/m mice (Controls), db/db mice (case group), and those treated with DAPA (treatment group). RNA-Seq and ATAC-seq conjoint analysis revealed many overlapping pathways and networks suggesting that the transcriptional changes of DN and DAPA intervention largely occured dependently on chromatin remodeling. Specifically, the results showed that some key signal transduction pathways, such as immune dysfunction, glucolipid metabolism, oxidative stress and xenobiotic and endobiotic metabolism, were repeatedly enriched in the analysis of the RNA-seq data alone, as well as combined analysis with ATAC-seq data. Furthermore, we identified some candidate genes (UDP glucuronosyltransferase 1 family, Dock2, Tbc1d10c, etc.) and transcriptional regulators (KLF6 and GFI1) that might be associated with DN and DAPA restoration. These reversed genes and regulators confirmed that pathways related to immune response and metabolism pathways were critically involved in DN progression.
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Affiliation(s)
- Jianxiao Shen
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Ren Ji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Liang Ying
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Ren Ji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiajia Wu
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Ren Ji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yan Fang
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Ren Ji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wenyan Zhou
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Ren Ji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chaojun Qi
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Ren Ji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Leyi Gu
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Ren Ji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shan Mou
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Ren Ji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuru Yan
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Ren Ji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ming Tian
- Department of Burn, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhaohui Ni
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Ren Ji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiajing Che
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Ren Ji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Zhang Q, Deng Z, Li T, Chen K, Zeng Z. SGLT2 inhibitor improves the prognosis of patients with coronary heart disease and prevents in-stent restenosis. Front Cardiovasc Med 2024; 10:1280547. [PMID: 38274313 PMCID: PMC10808651 DOI: 10.3389/fcvm.2023.1280547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Accepted: 12/27/2023] [Indexed: 01/27/2024] Open
Abstract
Coronary heart disease is a narrowing or obstruction of the vascular cavity caused by atherosclerosis of the coronary arteries, which leads to myocardial ischemia and hypoxia. At present, percutaneous coronary intervention (PCI) is an effective treatment for coronary atherosclerotic heart disease. Restenosis is the main limiting factor of the long-term success of PCI, and it is also a difficult problem in the field of intervention. Sodium-glucose cotransporter 2 (SGLT2) inhibitor is a new oral glucose-lowering agent used in the treatment of diabetes in recent years. Recent studies have shown that SGLT2 inhibitors can effectively improve the prognosis of patients after PCI and reduce the occurrence of restenosis. This review provides an overview of the clinical studies and mechanisms of SGLT2 inhibitors in the prevention of restenosis, providing a new option for improving the clinical prognosis of patients after PCI.
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Affiliation(s)
| | | | | | | | - Zhihuan Zeng
- Department of Cardiovascular Diseases, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, China
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32
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Gao H, Wang Z, Zhu D, Zhao L, Xiao W. Dioscin: Therapeutic potential for diabetes and complications. Biomed Pharmacother 2024; 170:116051. [PMID: 38154275 DOI: 10.1016/j.biopha.2023.116051] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Revised: 12/13/2023] [Accepted: 12/15/2023] [Indexed: 12/30/2023] Open
Abstract
Diabetes mellitus is a widespread metabolic disorder with increasing incidence worldwide, posing a considerable threat to human health because of its complications. Therefore, cost-effective antidiabetic drugs with minimal side effects are urgently needed. Dioscin, a naturally occurring compound, helps to reduce the complications of diabetes mellitus by regulating glucose and lipid metabolism, protecting islet β cells, improving insulin resistance, and inhibiting oxidative stress and inflammatory response. Plant-derived dioscin reduces the risk of toxicity and side effects associated with chemically synthesized drugs. It is a promising option for treating diabetes mellitus because of its preventive and therapeutic effects, which may be attributed to a variety of underlying mechanisms. However, data compiled by current studies are preliminary. Information about the molecular mechanism of dioscin remains limited, and no high-quality human experiments and clinical trials for testing its safety and efficacy have been conducted. As a resource for research in this area, this review is expected to provide a systematic framework for the application of dioscin in the treatment of diabetes mellitus and its complications.
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Affiliation(s)
- Haoyang Gao
- Shanghai Key Lab of Human Performance (Shanghai University of sport), Shanghai University of Sport, Shanghai 200438, China; The Key Lab of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China
| | - Ze Wang
- Shanghai Key Lab of Human Performance (Shanghai University of sport), Shanghai University of Sport, Shanghai 200438, China; The Key Lab of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China
| | - Danlin Zhu
- Shanghai Key Lab of Human Performance (Shanghai University of sport), Shanghai University of Sport, Shanghai 200438, China; The Key Lab of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China
| | - Linlin Zhao
- Shanghai Key Lab of Human Performance (Shanghai University of sport), Shanghai University of Sport, Shanghai 200438, China; The Key Lab of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China; School of Physical Education, Shanghai Normal University, Shanghai 200234, China.
| | - Weihua Xiao
- Shanghai Key Lab of Human Performance (Shanghai University of sport), Shanghai University of Sport, Shanghai 200438, China; The Key Lab of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China.
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33
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Dimitriadis K, Adamopoulou E, Pyrpyris N, Sakalidis A, Leontsinis I, Manta E, Mantzouranis E, Beneki E, Soulaidopoulos S, Konstantinidis D, Fragkoulis C, Aggeli K, Tsioufis K. The effect of SGLT2 inhibitors on the endothelium and the microcirculation: from bench to bedside and beyond. EUROPEAN HEART JOURNAL. CARDIOVASCULAR PHARMACOTHERAPY 2023; 9:741-757. [PMID: 37500266 DOI: 10.1093/ehjcvp/pvad053] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 06/22/2023] [Accepted: 07/26/2023] [Indexed: 07/29/2023]
Abstract
AIMS The beneficial cardiovascular effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors irrespective of the presence of diabetes mellitus are nowadays well established and they already constitute a significant pillar for the management of heart failure, irrespective of the ejection fraction. The exact underlying mechanisms accountable for these effects, however, remain largely unknown. The direct effect on endothelial function and microcirculation is one of the most well studied. The broad range of studies presented in this review aims to link all available data from the bench to bedside and highlight the existing gaps as well as the future directions in the investigations concerning the effects of SGLT2 inhibitors on the endothelium and the microcirculation. METHODS AND RESULTS An extensive search has been conducted using the MEDLINE/PubMed database in order to identify the relevant studies. Preclinical data suggest that SGLT2 inhibitors directly affect endothelial function independently of glucose and specifically via several interplaying molecular pathways, resulting in improved vasodilation, increased NO production, enhanced mitochondrial homeostasis, endothelial cell viability, and angiogenesis as well as attenuation of oxidative stress and inflammation. Clinical data systematically confirm this beneficial effect on the endothelium, whereas the evidence concerning the effect on the microcirculation is conflicting. CONCLUSION Preclinical and clinical studies indicate that SGLT2 inhibitors attenuate endothelial and microvascular dysfunction via a combination of mechanisms, which play a role in their beneficial cardiovascular effect.
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Affiliation(s)
- Kyriakos Dimitriadis
- First Department of Cardiology, School of Medicine, National and Kapodistrian University of Athens, Hippokration General Hospital, 115 27, Athens, Greece
| | - Eleni Adamopoulou
- First Department of Cardiology, School of Medicine, National and Kapodistrian University of Athens, Hippokration General Hospital, 115 27, Athens, Greece
| | - Nikolaos Pyrpyris
- First Department of Cardiology, School of Medicine, National and Kapodistrian University of Athens, Hippokration General Hospital, 115 27, Athens, Greece
| | - Athanasios Sakalidis
- First Department of Cardiology, School of Medicine, National and Kapodistrian University of Athens, Hippokration General Hospital, 115 27, Athens, Greece
| | - Ioannis Leontsinis
- First Department of Cardiology, School of Medicine, National and Kapodistrian University of Athens, Hippokration General Hospital, 115 27, Athens, Greece
| | - Eleni Manta
- First Department of Cardiology, School of Medicine, National and Kapodistrian University of Athens, Hippokration General Hospital, 115 27, Athens, Greece
| | - Emmanouil Mantzouranis
- First Department of Cardiology, School of Medicine, National and Kapodistrian University of Athens, Hippokration General Hospital, 115 27, Athens, Greece
| | - Eirini Beneki
- First Department of Cardiology, School of Medicine, National and Kapodistrian University of Athens, Hippokration General Hospital, 115 27, Athens, Greece
| | - Stergios Soulaidopoulos
- First Department of Cardiology, School of Medicine, National and Kapodistrian University of Athens, Hippokration General Hospital, 115 27, Athens, Greece
| | - Dimitrios Konstantinidis
- First Department of Cardiology, School of Medicine, National and Kapodistrian University of Athens, Hippokration General Hospital, 115 27, Athens, Greece
| | - Christos Fragkoulis
- First Department of Cardiology, School of Medicine, National and Kapodistrian University of Athens, Hippokration General Hospital, 115 27, Athens, Greece
| | - Konstantina Aggeli
- First Department of Cardiology, School of Medicine, National and Kapodistrian University of Athens, Hippokration General Hospital, 115 27, Athens, Greece
| | - Konstantinos Tsioufis
- First Department of Cardiology, School of Medicine, National and Kapodistrian University of Athens, Hippokration General Hospital, 115 27, Athens, Greece
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Wang W, Li Y, Zhang Y, Ye T, Wang K, Li S, Zhang Y. SIRT1 mediates the inhibitory effect of Dapagliflozin on EndMT by inhibiting the acetylation of endothelium Notch1. Cardiovasc Diabetol 2023; 22:331. [PMID: 38017499 PMCID: PMC10685714 DOI: 10.1186/s12933-023-02040-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 10/20/2023] [Indexed: 11/30/2023] Open
Abstract
BACKGROUND Endothelial-mesenchymal transition (EndMT) plays a crucial role in promoting myocardial fibrosis and exacerbating cardiac dysfunction. Dapagliflozin (DAPA) is a sodium-glucose-linked transporter 2 (SGLT-2) inhibitor that has been shown to improve cardiac function in non-diabetic patients with heart failure (HF). However, the precise mechanisms by which DAPA exerts its beneficial effects are yet to be fully elucidated. METHODS Isoproterenol (ISO) was used to generate a HF model in mice. For in vitro experiments, we used TGF-β1-stimulated human umbilical vein endothelial cells (HUVECs) and mouse aortic endothelial cells (MAECs). RESULTS Both our in vivo and in vitro results showed that EndMT occurred with decreased SIRT1 (NAD+-dependent deacetylase) protein expression, which could be reversed by DAPA therapy. We found that the protective effect of DAPA was significantly impaired upon SIRT1 inhibition. Mechanistically, we observed that SIRT1 phosphorylation, a required modification for its ubiquitination and degradation, was reduced by DAPA treatment, which induces the nucleus translocation of SIRT1 and promotes its binding to the active intracellular domain of Notch1 (NICD). This interaction led to the deacetylation and degradation of NICD, and the subsequent inactivation of the Notch1 signaling pathway which contributes to ameliorating EndMT. CONCLUSIONS Our study revealed that DAPA can attenuate EndMT induced by ISO in non-diabetic HF mice. This beneficial effect is achieved through SIRT1-mediated deacetylation and degradation of NICD. Our findings provide greater insight into the underlying mechanisms of the therapeutic effects of DAPA in non-diabetic HF.
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Affiliation(s)
- Weijie Wang
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin, 150086, China
- Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical University, Harbin, China
| | - Yilan Li
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin, 150086, China
- Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical University, Harbin, China
| | - Yanxiu Zhang
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin, 150086, China
- Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical University, Harbin, China
| | - Tao Ye
- Department of Organic Chemistry, College of Pharmacy, Harbin Medical University, Harbin, China
| | - Kui Wang
- Department of Organic Chemistry, College of Pharmacy, Harbin Medical University, Harbin, China
| | - Shuijie Li
- Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University, Harbin, 150081, China.
- State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Harbin, China.
| | - Yao Zhang
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin, 150086, China.
- Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical University, Harbin, China.
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Caldarelli M, Franza L, Rio P, Gasbarrini A, Gambassi G, Cianci R. Gut-Kidney-Heart: A Novel Trilogy. Biomedicines 2023; 11:3063. [PMID: 38002063 PMCID: PMC10669427 DOI: 10.3390/biomedicines11113063] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 11/12/2023] [Accepted: 11/13/2023] [Indexed: 11/26/2023] Open
Abstract
The microbiota represents a key factor in determining health and disease. Its role in inflammation and immunological disorders is well known, but it is also involved in several complex conditions, ranging from neurological to psychiatric, from gastrointestinal to cardiovascular diseases. It has recently been hypothesized that the gut microbiota may act as an intermediary in the close interaction between kidneys and the cardiovascular system, leading to the conceptualization of the "gut-kidney-heart" axis. In this narrative review, we will discuss the impact of the gut microbiota on each system while also reviewing the available data regarding the axis itself. We will also describe the role of gut metabolites in this complex interplay, as well as potential therapeutical perspectives.
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Affiliation(s)
- Mario Caldarelli
- Department of Translational Medicine and Surgery, Fondazione Policlinico Universitario A. Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (M.C.); (P.R.); (A.G.); (G.G.)
| | - Laura Franza
- Emergency Medicine Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy;
| | - Pierluigi Rio
- Department of Translational Medicine and Surgery, Fondazione Policlinico Universitario A. Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (M.C.); (P.R.); (A.G.); (G.G.)
| | - Antonio Gasbarrini
- Department of Translational Medicine and Surgery, Fondazione Policlinico Universitario A. Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (M.C.); (P.R.); (A.G.); (G.G.)
| | - Giovanni Gambassi
- Department of Translational Medicine and Surgery, Fondazione Policlinico Universitario A. Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (M.C.); (P.R.); (A.G.); (G.G.)
| | - Rossella Cianci
- Department of Translational Medicine and Surgery, Fondazione Policlinico Universitario A. Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (M.C.); (P.R.); (A.G.); (G.G.)
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Zhang Y, He Y, Liu S, Deng L, Zuo Y, Huang K, Liao B, Li G, Feng J. SGLT2 Inhibitors in Aging-Related Cardiovascular Disease: A Review of Potential Mechanisms. Am J Cardiovasc Drugs 2023; 23:641-662. [PMID: 37620652 DOI: 10.1007/s40256-023-00602-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/31/2023] [Indexed: 08/26/2023]
Abstract
Population aging combined with higher susceptibility to cardiovascular diseases in older adults is increasing the incidence of conditions such as atherosclerosis, myocardial infarction, heart failure, myocardial hypertrophy, myocardial fibrosis, arrhythmia, and hypertension. sodium-glucose cotransporter 2 inhibitors (SGLT2i) were originally developed as a novel oral drug for patients with type 2 diabetes mellitus. Unexpectedly, recent studies have shown that, beyond their effect on hyperglycemia, SGLT2i also have a variety of beneficial effects on cardiovascular disease. Experimental models of cardiovascular disease have shown that SGLT2i ameliorate the process of aging-related cardiovascular disease by inhibiting inflammation, reducing oxidative stress, and reversing endothelial dysfunction. In this review, we discuss the role of SGLT2i in aging-related cardiovascular disease and propose the use of SGLT2i to prevent and treat these conditions in older adults.
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Affiliation(s)
- Yali Zhang
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Yufeng He
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Siqi Liu
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Li Deng
- Department of Rheumatology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Yumei Zuo
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Keming Huang
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Bin Liao
- Department of Cardiac Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Guang Li
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China.
| | - Jian Feng
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China.
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Crudele L, Gadaleta RM, Cariello M, Moschetta A. Gut microbiota in the pathogenesis and therapeutic approaches of diabetes. EBioMedicine 2023; 97:104821. [PMID: 37804567 PMCID: PMC10570704 DOI: 10.1016/j.ebiom.2023.104821] [Citation(s) in RCA: 79] [Impact Index Per Article: 39.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 09/11/2023] [Accepted: 09/21/2023] [Indexed: 10/09/2023] Open
Abstract
The gut-liver axis plays a prominent role in the pathogenesis and therapy of metabolic diseases such as diabetes. The intestinal specific origin of several hormones that guide both inter- and post-prandial metabolism of carbohydrates and lipids, drives the attention of scientists and clinicians on the gut as a major site to intervene with novel diagnostic or prognostic markers. The role of intestinal ecology in the metabolic syndrome was postulated when gut microbiota was directly connected with inflammation, hyperinsulinemia, and diabetes. There have been several discoveries with the role of gut microbiota and gut-liver axis in diabetes. Also, there are several trials ongoing on the therapeutic efficacy of probiotic administration in diabetes and its complications. Here we point to the metabolic action of microbiota and discuss the actual state of the art on gut microbiota as a novel prognostic biomarker with a putative therapeutic role in diabetes.
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Affiliation(s)
- Lucilla Crudele
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro", Piazza Giulio Cesare 11, 70124, Bari, Italy
| | - Raffaella Maria Gadaleta
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro", Piazza Giulio Cesare 11, 70124, Bari, Italy
| | - Marica Cariello
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro", Piazza Giulio Cesare 11, 70124, Bari, Italy
| | - Antonio Moschetta
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro", Piazza Giulio Cesare 11, 70124, Bari, Italy; INBB National Institute for Biostructure and Biosystems, Viale delle Medaglie d'Oro 305, 00136, Rome, Italy.
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Khaznadar F, Petrovic A, Khaznadar O, Roguljic H, Bojanic K, Kuna Roguljic L, Siber S, Smolic R, Bilic-Curcic I, Wu GY, Smolic M. Biomarkers for Assessing Non-Alcoholic Fatty Liver Disease in Patients with Type 2 Diabetes Mellitus on Sodium-Glucose Cotransporter 2 Inhibitor Therapy. J Clin Med 2023; 12:6561. [PMID: 37892698 PMCID: PMC10607797 DOI: 10.3390/jcm12206561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 10/11/2023] [Accepted: 10/13/2023] [Indexed: 10/29/2023] Open
Abstract
In the current modern era of unhealthy lifestyles, non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease and has become a serious global health problem. To date, there is no approved pharmacotherapy for the treatment of NAFLD, and necessary lifestyle changes such as weight loss, diet, and exercise are usually not sufficient to manage this disease. Patients with type 2 diabetes mellitus (T2DM) have a significantly higher risk of developing NAFLD and vice versa. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are antidiabetic agents that have recently been approved for two other indications: chronic kidney disease and heart failure in diabetics and non-diabetics. They are also emerging as promising new agents for NAFLD treatment, as they have shown beneficial effects on hepatic inflammation, steatosis, and fibrosis. Studies in animals have reported favorable effects of SGLT2 inhibitors, and studies in patients also found positive effects on body mass index (BMI), insulin resistance, glucose levels, liver enzymes, apoptosis, and transcription factors. There are some theories regarding how SGLT2 inhibitors affect the liver, but the exact mechanism is not yet fully understood. Therefore, biomarkers to evaluate underlying mechanisms of action of SGLT2 inhibitors on the liver have now been scrutinized to assess their potential as a future in-label therapy for NAFLD. In addition, finding suitable non-invasive biomarkers could be helpful in clinical practice for the early detection of NAFLD in patients. This is crucial for a positive disease outcome. The aim of this review is to provide an overview of the most recent findings on the effects of SGLT2 inhibitors on NAFLD biomarkers and the potential of SGLT2 inhibitors to successfully treat NAFLD.
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Affiliation(s)
- Farah Khaznadar
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; (F.K.); (A.P.); (H.R.); (K.B.); (L.K.R.); (S.S.); (R.S.)
- Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia;
| | - Ana Petrovic
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; (F.K.); (A.P.); (H.R.); (K.B.); (L.K.R.); (S.S.); (R.S.)
| | - Omar Khaznadar
- Department of Radiology, “Dr. Juraj Njavro” National Memorial Hospital Vukovar, 32000 Vukovar, Croatia;
| | - Hrvoje Roguljic
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; (F.K.); (A.P.); (H.R.); (K.B.); (L.K.R.); (S.S.); (R.S.)
- Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia;
- Clinical Hospital Center, 31000 Osijek, Croatia
| | - Kristina Bojanic
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; (F.K.); (A.P.); (H.R.); (K.B.); (L.K.R.); (S.S.); (R.S.)
- Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia;
- Health Center Osijek-Baranja County, 31000 Osijek, Croatia
| | - Lucija Kuna Roguljic
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; (F.K.); (A.P.); (H.R.); (K.B.); (L.K.R.); (S.S.); (R.S.)
| | - Stjepan Siber
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; (F.K.); (A.P.); (H.R.); (K.B.); (L.K.R.); (S.S.); (R.S.)
| | - Robert Smolic
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; (F.K.); (A.P.); (H.R.); (K.B.); (L.K.R.); (S.S.); (R.S.)
| | - Ines Bilic-Curcic
- Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia;
- Clinical Hospital Center, 31000 Osijek, Croatia
| | - George Y. Wu
- Department of Medicine, Division of Gastrenterology/Hepatology, University of Connecticut Health Center, Farmington, CT 06030, USA;
| | - Martina Smolic
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia; (F.K.); (A.P.); (H.R.); (K.B.); (L.K.R.); (S.S.); (R.S.)
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Cinakova A, Krenek P, Klimas J, Kralova E. Adding SGLT2 Cotransporter Inhibitor to PPARγ Activator Does Not Provide an Additive Effect in the Management of Diabetes-Induced Vascular Dysfunction. Pharmacology 2023; 108:565-575. [PMID: 37844554 DOI: 10.1159/000533592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 08/10/2023] [Indexed: 10/18/2023]
Abstract
INTRODUCTION Endothelial dysfunction (ED) plays a key role in the pathogenesis of diabetic vascular complications. In monotherapy, dapagliflozin (Dapa) as well as pioglitazone (Pio) prevent the progression of target organ damage in both type 1 (T1DM) and type 2 diabetes. We investigated whether the simultaneous PPAR-γ activation and SGLT2 cotransporter inhibition significantly alleviate ED-related pathological processes and thus normalize vascular response in experimental T1DM. METHODS Experimental diabetes was induced by streptozotocin (STZ; 55 mg/kg, i.p.) in Wistar rats. Dapa (10 mg/kg), Pio (12 mg/kg), or their combination were administrated to the STZ rats orally. Six weeks after STZ administration, the aorta was excised for functional studies and real-time qPCR analysis. RESULTS In the aorta of diabetic rats, impaired endothelium-dependent and independent relaxation were accompanied by the imbalance between vasoactive factors (eNos, Et1) and overexpression of inflammation (Tnfα, Il1b, Il6, Icam, Vcam) and oxidative stress (Cybb) markers. Pio monotherapy normalized response to vasoactive substances and restored balance between Et1-eNos expression, while Dapa treatment was ineffective. Nevertheless, Dapa and Pio monotherapy significantly reverted inflammation and oxidative stress markers to normal values. The combination treatment exhibited an additive effect in modulating Il6 expression, reaching the effect of Pio monotherapy in other measured parameters. CONCLUSION Particularly, Pio exerts a vasoprotective character when used in monotherapy. When combined with Dapa, it does not exhibit an expected additive effect within modulating vasoreactivity or oxidative stress, though having a significant influence on IL6 downregulation.
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Affiliation(s)
- Aneta Cinakova
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovakia
| | - Peter Krenek
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovakia
| | - Jan Klimas
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovakia
| | - Eva Kralova
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovakia
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Chandrasekar B, Mummidi S, DeMarco VG, Higashi Y. Empagliflozin Reverses Oxidized LDL-Induced RECK Suppression, Cardiotrophin-1 Expression, MMP Activation, and Human Aortic Smooth Muscle Cell Proliferation and Migration. Mediators Inflamm 2023; 2023:6112301. [PMID: 37830075 PMCID: PMC10567511 DOI: 10.1155/2023/6112301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 09/04/2023] [Accepted: 09/07/2023] [Indexed: 10/14/2023] Open
Abstract
Persistent oxidative stress and inflammation contribute causally to smooth muscle cell (SMC) proliferation and migration, the characteristic features of vascular proliferative diseases. Oxidatively modified low-density lipoproteins (OxLDL) elevate oxidative stress levels, inflammatory responses, and matrix metallopeptidase (MMP) activation, resulting ultimately in SMC migration, proliferation, and phenotype change. Reversion-inducing cysteine-rich protein with Kazal motifs (RECK) is a membrane-anchored MMP inhibitor. Empagliflozin is an SGLT2 inhibitor and exerts pleiotropic cardiovascular protective effects, including antioxidant and anti-inflammatory effects. Here, we investigated (i) whether OxLDL regulates RECK expression, (ii) whether ectopic expression of RECK reverses OxLDL-induced SMC migration and proliferation, and (iii) whether pretreatment with empagliflozin reverses OxLDL-induced RECK suppression, MMP activation, and SMC migration, proliferation, and differentiation. Indeed, results show that OxLDL at pathophysiological concentration promotes SMC migration and proliferation via NF-κB/miR-30b-dependent RECK suppression. Moreover, OxLDL changed the SMC phenotype to a more pro-inflammatory type, and this effect is blunted by RECK overexpression. Further, treatment with empagliflozin reversed OxLDL-induced miR-30b induction, RECK suppression, MMP activation, SMC migration, proliferation, and proinflammatory phenotype changes. OxLDL-induced cardiotrophin (CT)-1 expression and CT-1 stimulated SMC proliferation and migration in part via leukemia inhibitory factor receptor (LIFR) and glycoprotein 130 (gp130). Ectopic expression of RECK inhibited these effects by physically associating with LIFR and gp130, as evidenced by immunoprecipitation/immunoblotting and double immunofluorescence. Importantly, empagliflozin inhibited CT-1-induced mitogenic and migratory effects. Together, these results suggest the therapeutic potential of sustaining RECK expression or empagliflozin in vascular diseases characterized by SMC proliferation and migration.
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Affiliation(s)
- Bysani Chandrasekar
- Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO, USA
- Medicine, University of Missouri School of Medicine, Columbia, MO, USA
- Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, USA
- Dalton Cardiovascular Center, University of Missouri, Columbia, MO, USA
| | - Srinivas Mummidi
- Life Sciences, Texas A&M University-San Antonio, San Antonio, TX, USA
| | - Vincent G. DeMarco
- Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO, USA
- Medicine, University of Missouri School of Medicine, Columbia, MO, USA
- Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, USA
| | - Yusuke Higashi
- Medicine/Cardiology, Tulane University School of Medicine, New Orleans, LA, USA
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Al Thani NA, Hasan M, Yalcin HC. Use of Animal Models for Investigating Cardioprotective Roles of SGLT2 Inhibitors. J Cardiovasc Transl Res 2023; 16:975-986. [PMID: 37052784 PMCID: PMC10615955 DOI: 10.1007/s12265-023-10379-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Accepted: 03/14/2023] [Indexed: 04/14/2023]
Abstract
Sodium-glucose co-transporter 2 (SGLT2) inhibitors represent one type of new-generation type 2 diabetes (T2DM) drug treatment. The mechanism of action of an SGLT2 inhibitor (SGLT2i) in treating T2DM depends on lowering blood glucose levels effectively via increasing the glomerular excretion of glucose. A good number of randomized clinical trials revealed that SGLT2is significantly prevented heart failure (HF) and cardiovascular death in T2DM patients. Despite ongoing clinical trials in HF patients without T2DM, there have been a limited number of translational studies on the cardioprotective properties of SGLT2is. As the cellular mechanism behind the cardiac benefits of SGLT2is is still to be elucidated, animal models are used to better understand the pathways behind the cardioprotective mechanism of SGLT2i. In this review, we summarize the animal models constructed to study the cardioprotective mechanisms of SGLT2is to help deliver a more comprehensive understanding of the in vivo work that has been done in this field and to help select the most optimal animal model to use when studying the different cardioprotective effects of SGLT2is.
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Affiliation(s)
- Najlaa A Al Thani
- Research and Development Department, Barzan Holdings, P. O. Box 7178, Doha, Qatar
| | - Maram Hasan
- Biomedical Research Center, Qatar University, P. O. Box 2713, Doha, Qatar
| | - Huseyin C Yalcin
- Biomedical Research Center, Qatar University, P. O. Box 2713, Doha, Qatar.
- Department of Biomedical Science, College of Health Sciences, QU Health, Qatar University, P. O. Box 2713, Doha, Qatar.
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Yang H, Lan W, Liu W, Chen T, Tang Y. Dapagliflozin promotes angiogenesis in hindlimb ischemia mice by inducing M2 macrophage polarization. Front Pharmacol 2023; 14:1255904. [PMID: 37808194 PMCID: PMC10558177 DOI: 10.3389/fphar.2023.1255904] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 09/12/2023] [Indexed: 10/10/2023] Open
Abstract
Critical limb ischemia (CLI) is associated with a higher risk of limb amputation and cardiovascular death. Dapagliflozin has shown great potential in the treatment of cardiovascular disease. However, the effects of dapagliflozin on CLI and the underlying mechanisms have not been fully elucidated. We evaluated the effect of dapagliflozin on recovery from limb ischemia using a mouse model of hindlimb ischemia. The flow of perfusion was evaluated using a laser Doppler system. Tissue response was assessed by analyzing capillary density, arterial density, and the degree of fibrosis in the gastrocnemius muscle. Immunofluorescence and Western blot were used to detect the expression of macrophage polarization markers and inflammatory factors. Our findings demonstrate the significant impact of dapagliflozin on the acceleration of blood flow recovery in a hindlimb ischemia mouse model, concomitant with a notable reduction in limb necrosis. Histological analysis revealed that dapagliflozin administration augmented the expression of key angiogenic markers, specifically CD31 and α-SMA, while concurrently mitigating muscle fibrosis. Furthermore, our investigation unveiled dapagliflozin's ability to induce a phenotypic shift of macrophages from M1 to M2, thereby diminishing the expression of inflammatory factors, including IL-1β, IL-6, and TNF-α. These effects were partially mediated through modulation of the NF-κB signaling pathway. Lastly, we observed that endothelial cell proliferation, migration, and tube-forming function are enhanced in vitro by utilizing a macrophage-conditioned medium derived from dapagliflozin treatment. Taken together, our study provides evidence that dapagliflozin holds potential as an efficacious therapeutic intervention in managing CLI by stimulating angiogenesis, thereby offering a novel option for clinical CLI treatment.
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Affiliation(s)
- Heng Yang
- Department of Cardiovascular Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- The Second Clinical Medical College of Nanchang University, Nanchang, China
| | - Wanqi Lan
- Department of Cardiovascular Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- The Second Clinical Medical College of Nanchang University, Nanchang, China
| | - Wu Liu
- Department of Cardiovascular Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- The Second Clinical Medical College of Nanchang University, Nanchang, China
| | - Tingtao Chen
- The Institute of Translational Medicine, Nanchang University, Nanchang, China
| | - Yanhua Tang
- Department of Cardiovascular Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
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Matthews J, Herat L, Schlaich MP, Matthews V. The Impact of SGLT2 Inhibitors in the Heart and Kidneys Regardless of Diabetes Status. Int J Mol Sci 2023; 24:14243. [PMID: 37762542 PMCID: PMC10532235 DOI: 10.3390/ijms241814243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 09/12/2023] [Accepted: 09/15/2023] [Indexed: 09/29/2023] Open
Abstract
Chronic Kidney Disease (CKD) and Cardiovascular Disease (CVD) are two devastating diseases that may occur in nondiabetics or individuals with diabetes and, when combined, it is referred to as cardiorenal disease. The impact of cardiorenal disease on society, the economy and the healthcare system is enormous. Although there are numerous therapies for cardiorenal disease, one therapy showing a great deal of promise is sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors. The SGLT family member, SGLT2, is often implicated in the pathogenesis of a range of diseases, and the dysregulation of the activity of SGLT2 markedly effects the transport of glucose and sodium across the luminal membrane of renal cells. Inhibitors of SGLT2 were developed based on the antidiabetic action initiated by inhibiting renal glucose reabsorption, thereby increasing glucosuria. Of great medical significance, large-scale clinical trials utilizing a range of SGLT2 inhibitors have demonstrated both metabolic and biochemical benefits via numerous novel mechanisms, such as sympathoinhibition, which will be discussed in this review. In summary, SGLT2 inhibitors clearly exert cardio-renal protection in people with and without diabetes in both preclinical and clinical settings. This exciting class of inhibitors improve hyperglycemia, high blood pressure, hyperlipidemia and diabetic retinopathy via multiple mechanisms, of which many are yet to be elucidated.
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Affiliation(s)
- Jennifer Matthews
- Royal Perth Hospital Unit, Dobney Hypertension Centre, School of Biomedical Sciences, University of Western Australia, Crawley, WA 6009, Australia; (J.M.); (L.H.)
| | - Lakshini Herat
- Royal Perth Hospital Unit, Dobney Hypertension Centre, School of Biomedical Sciences, University of Western Australia, Crawley, WA 6009, Australia; (J.M.); (L.H.)
| | - Markus P. Schlaich
- Royal Perth Hospital Unit, Dobney Hypertension Centre, School of Medicine, University of Western Australia, Crawley, WA 6009, Australia;
- Department of Cardiology and Department of Nephrology, Royal Perth Hospital, Perth, WA 6000, Australia
| | - Vance Matthews
- Royal Perth Hospital Unit, Dobney Hypertension Centre, School of Biomedical Sciences, University of Western Australia, Crawley, WA 6009, Australia; (J.M.); (L.H.)
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Kusunoki M, Hisano F, Matsuda SI, Kusunoki A, Wakazono N, Tsutsumi K, Miyata T. Effects of SGLT2 inhibitors on the intestinal bacterial flora in Japanese patients with type 2 diabetes mellitus. Drug Res (Stuttg) 2023; 73:412-416. [PMID: 37236230 DOI: 10.1055/a-2037-5250] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
Selective inhibitors of sodium glucose co-transporter-2 (SGLT2) suppress renal glucose reabsorption and promote urinary glucose excretion, thereby lowering blood glucose. SGLT2 inhibitors have been reported to reduce body weight. However, the mechanism underlying the reduction in the body weight induced by SGLT2 inhibitor treatment remains to be elucidated. In this study, we investigated the effects of SGLT2 inhibitors on the intestinal bacterial flora. A total of 36 Japanese patients with type 2 diabetes mellitus received a SGLT2 inhibitor (luseogliflozin or dapagliflozin) for 3 months, and the prevalences of balance-regulating bacteria and balance-disturbing bacteria in the feces of the patients before and after SGLT2 inhibitor treatment were determined. SGLT2 inhibitor treatment was associated with a significant increase of the overall prevalence of the 12 types of balance-regulating bacteria. In addition, significant increases in the prevalences of the short-chain fatty acid (SCFAs)-producing bacteria among the balance-regulating bacteria were also observed. Individual analyses of the balance-regulating bacteria revealed that the SGLT2 inhibitor treatment was associated with a significant increase in the prevalence of Ruminococci, which are balance-regulating bacteria classified as SCFAs-producing bacteria. However, SGLT2 inhibitor had no effect on the balance-disturbing bacteria. These results suggested that SGLT2 inhibitor treatment was associated with an overall increase in the prevalence of balance-regulating bacteria. Among the balance-regulating bacteria, the prevalences of SCFAs-producing bacteria increased. SCFAs have been reported to prevent obesity. The results of the present study suggest that SGLT2 inhibitors might induce body weight reduction via their actions on the intestinal bacterial flora.
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Affiliation(s)
- Masataka Kusunoki
- Department of Diabetes, Motor Function and Metabolism, Research Center of Health, Physical Fitness and Sports, Nagoya University, Nagoya City, Aichi, Japan
| | - Fumiya Hisano
- Graduate School of Medicine, Department of Integrated Health Sciences, Nagoya University, Nagoya City, Aichi, Japan
| | - Shin-Ichi Matsuda
- Department of Data Science, Faculty of Science and Technology, Nanzan University, Nagoya City, Aichi, Japan
| | | | - Naomi Wakazono
- Department of Diabetes, Motor Function and Metabolism, Research Center of Health, Physical Fitness and Sports, Nagoya University, Nagoya City, Aichi, Japan
| | | | - Tetsuro Miyata
- Office of Medical Education, School of Medicine, International University of Health and Welfare, Narita City, Chiba, Japan
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Zhou Y, Tai S, Zhang N, Fu L, Wang Y. Dapagliflozin prevents oxidative stress-induced endothelial dysfunction via sirtuin 1 activation. Biomed Pharmacother 2023; 165:115213. [PMID: 37517289 DOI: 10.1016/j.biopha.2023.115213] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 07/16/2023] [Accepted: 07/21/2023] [Indexed: 08/01/2023] Open
Abstract
Recent studies have demonstrated that dapagliflozin, a sodium-glucose cotransporter type 2 (SGLT2) inhibitor, prevents endothelial dysfunction; however, direct effects of dapagliflozin on the endothelium under oxidative stress and the underlying mechanism of action are not completely understood. This study aimed to define the role and related mechanisms of dapagliflozin in hydrogen peroxide (H2O2)-induced endothelial dysfunction. The endothelium-dependent vasorelaxation effect of dapagliflozin was assessed in an organ bath study. Endothelial dysfunction was assessed using protein expression level and phosphorylation of endothelial nitric oxide synthase (eNOS), nitric oxide (NO), reactive oxygen species (ROS), senescence-associated beta-galactosidase (SA-β-gal) activity, and senescence marker proteins (p21, p53). Co-immunoprecipitation and protein acetylation were performed to detect protein interactions. Dapagliflozin exerted a direct vasorelaxant effect in the aortic rings of C57BL/6 J mice. Furthermore, there was a significant improvement in endothelium-dependent vasorelaxation in dapagliflozin-treated diabetic mice compared to vehicle controls. Moreover, intracellular ROS levels and ONOO- levels, increased by H2O2, were reduced by dapagliflozin. Importantly, dapagliflozin inhibited H2O2-induced senescence in the human umbilical vein endothelial cells (HUVECs), as indicated by reduced SA-β-gal, p21, and p53. Mechanistically, dapagliflozin reversed the H2O2-mediated inhibition of eNOS serine phosphorylation and sirtuin 1 (SIRT1) expression in endothelial cells. In particular, SIRT1-mediated eNOS deacetylation is reportedly involved in dapagliflozin-enhanced eNOS activity. These findings indicate that dapagliflozin ameliorates endothelial dysfunction by restoring eNOS activity, restoring NO bioavailability, and reducing ROS generation via SIRT1 activation in oxidative stress-stimulated endothelial cells.
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Affiliation(s)
- Ying Zhou
- Department of Blood Transfusion, The Second Xiangya Hospital of Central South University, Changsha 410011, China; Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, Changsha 410011, China
| | - Shi Tai
- Department of Cardiovascular Medicine, The Second Xiangya Hospital of Central South University, Changsha 410011, China
| | - Ningjie Zhang
- Department of Blood Transfusion, The Second Xiangya Hospital of Central South University, Changsha 410011, China
| | - Liyao Fu
- Department of Blood Transfusion, The Second Xiangya Hospital of Central South University, Changsha 410011, China; Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha 410000, China.
| | - Yongjun Wang
- Department of Blood Transfusion, The Second Xiangya Hospital of Central South University, Changsha 410011, China.
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Tai S, Zhou Y, Fu L, Ding H, Zhou Y, Yin Z, Yang R, Liu Z, Zhou S. Dapagliflozin impedes endothelial cell senescence by activating the SIRT1 signaling pathway in type 2 diabetes. Heliyon 2023; 9:e19152. [PMID: 37664712 PMCID: PMC10469571 DOI: 10.1016/j.heliyon.2023.e19152] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Revised: 07/27/2023] [Accepted: 08/14/2023] [Indexed: 09/05/2023] Open
Abstract
Background Sodium-glucose cotransporter 2 inhibitors (SGLT2i) clinically reduce atherosclerosis and lower blood pressure. However, their impact on endothelial dysfunction in type 2 diabetes (T2D) remains unclear. In this study, we investigated the protective effect and underlying mechanism of the SGLT2 inhibitor dapagliflozin in diabetes. Methods Vascular reactivity was measured to assess the vasoprotective effect of dapagliflozin in a mouse model of high glucose (HG)-induced T2D. Pulse wave velocity was measured to quantify arterial stiffness. Protein expression was assessed by western blotting and immunofluorescence, oxidative stress was evaluated using dihydroethidium, nitric oxide was evaluated using the Griess reaction, and cellular senescence was assessed based on senescence-associated beta-galactosidase (SA-β-gal) activity and the expression of senescence markers. Furthermore, the endothelial nitric oxide synthase (eNOS) acetylation status was determined and eNOS interactions with SIRT1 were evaluated by coimmunoprecipitation assays. Results Dapagliflozin protected against impaired endothelium-dependent vasorelaxation and improved arterial stiffness in the mouse model of T2D; mouse aortas had significantly reduced levels of senescence activity and senescence-associated inflammatory factors. HG-induced increases in senescence activity, protein marker levels, and oxidative stress in vitro were all ameliorated by dapagliflozin. The decreases in eNOS phosphorylation and nitric oxide (NO) production in senescent endothelial cells were restored by dapagliflozin. SIRT1 expression was reduced in HG-induced senescent endothelial cells, and dapagliflozin restored SIRT1 expression. SIRT1 inhibition diminished the antisenescence effects of dapagliflozin. Coimmunoprecipitation showed that SIRT1 was physically associated with eNOS, suggesting that the effects of dapagliflozin are dependent on SIRT1 activation. Conclusion These findings indicate that dapagliflozin protects against endothelial cell senescence by regulating SIRT1 signaling in diabetic mice.
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Affiliation(s)
- Shi Tai
- Department of Cardiology, The Second Xiangya Hospital of Central South University, Changsha, 410011, China
| | - Ying Zhou
- Department of Blood Transfusion, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Liyao Fu
- Department of Blood Transfusion, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Huiqing Ding
- Department of Cardiology, The Second Xiangya Hospital of Central South University, Changsha, 410011, China
| | - Yuying Zhou
- Department of Cardiology, Xiangtan Central Hospital, Xiangtan, 411100, China
| | - Zhiyi Yin
- Department of Blood Transfusion, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Rukai Yang
- Department of Cardiology, The Second Xiangya Hospital of Central South University, Changsha, 410011, China
| | - Zhenjiang Liu
- Department of Cardiology, The Second Xiangya Hospital of Central South University, Changsha, 410011, China
| | - Shenghua Zhou
- Department of Cardiology, The Second Xiangya Hospital of Central South University, Changsha, 410011, China
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Bao N, Liu X, Zhong X, Jia S, Hua N, Zhang L, Mo G. Dapagliflozin-affected endothelial dysfunction and altered gut microbiota in mice with heart failure. PeerJ 2023; 11:e15589. [PMID: 37520255 PMCID: PMC10386824 DOI: 10.7717/peerj.15589] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 05/26/2023] [Indexed: 08/01/2023] Open
Abstract
Aim To investigate the potential microbiome profile of a mouse model with heart failure (HF) during dapagliflozin treatment. Method An HF model was constructed in 8-week-old male mice, and cardiac tissues were analyzed using histological staining. Hemodynamic indexes were measured, and fecal samples were collected for 16S rDNA sequencing. Chao1, Shannon, and Simpson were used for α-diversity analysis. b-Diversity analysis was conducted using principal coordinate analysis (PCoA) and non-metric multidimensional scaling (NMDS) based on the Bray-Curtis distance. Linear discriminant analysis coupled with effect size measurements (LEfSe) was used to identify signature gut microbiota, and phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) was used to predict the function of altered gut microbiota. Result Dapagliflozin treatment reduced inflammation, infarction area, and cardiac fibrosis in HF mice. It also increased endothelial-dependent dilation and inflammation in mice with HF. Dapagliflozin decreased the ratio of Firmicutes/Bacteroidetes, which was increased in HF mice. There was no significant statistical difference in α-diversity among the control, HF, and HF+dapagliflozin groups. Desulfovibrio, AF12, and Paraprevotella were enriched in HF+dapagliflozin, while Rikenella and Mucispirillum were enriched in HF based on LEfSe. KEGG analysis revealed that altered gut microbiota was associated with fermentation, amino acid biosynthesis, nucleoside and nucleotide biosynthesis/degradation, fatty acid and lipid biosynthesis, carbohydrate biosynthesis/degradation, and cofactor/prosthetic group/electron carrier/vitamin biosynthesis. Conclusion Understanding the microbiome profile helps elucidate the mechanism of dapagliflozin for HF. The signature genera identified in this study could be used as a convenient method to distinguish between HF patients and healthy individuals.
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Affiliation(s)
- Nandi Bao
- Chinese PLA General Hospital, Beijing, China
| | - Xiaoli Liu
- First Medical Center of Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
| | | | | | - Ning Hua
- Chinese PLA General Hospital, Beijing, China
| | - Li Zhang
- Chinese PLA General Hospital, Beijing, China
| | - Guoxin Mo
- The Eighth Medical Center of PLA General Hospital, Beijing, China
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Aziz F, Tripolt NJ, Pferschy PN, Kolesnik E, Mangge H, Curcic P, Hermann M, Meinitzer A, von Lewinski D, Sourij H. Alterations in trimethylamine-N-oxide in response to Empagliflozin therapy: a secondary analysis of the EMMY trial. Cardiovasc Diabetol 2023; 22:184. [PMID: 37475009 PMCID: PMC10357596 DOI: 10.1186/s12933-023-01920-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 07/11/2023] [Indexed: 07/22/2023] Open
Abstract
INTRODUCTION The relationship between sodium glucose co-transporter 2 inhibitors (SGLT2i) and trimethylamine N-oxide (TMAO) following acute myocardial infarction (AMI) is not yet explored. METHODS In this secondary analysis of the EMMY trial (ClinicalTrials.gov registration: NCT03087773), changes in serum TMAO levels were investigated in response to 26-week Empagliflozin treatment following an AMI compared to the standard post-MI treatment. Additionally, the association of TMAO changes with clinical risk factors and cardiorenal biomarkers was assessed. RESULTS The mean age of patients (N = 367) was 57 ± 9 years, 82% were males, and 14% had type 2 diabetes. In the Empagliflozin group, the median TMAO value was 2.62 µmol/L (IQR: 1.81) at baseline, 3.74 µmol/L (2.81) at 6 weeks, and 4.20 µmol/L (3.14) at 26 weeks. In the placebo group, the median TMAO value was 2.90 µmol/L (2.17) at baseline, 3.23 µmol/L (1.90) at 6 weeks, and 3.35 µmol/L (2.50) at 26 weeks. The serum TMAO levels increased significantly from baseline to week 6 (coefficient: 0.233; 95% confidence interval 0.149-0.317, p < 0.001) and week 26 (0.320, 0.236-0.405, p < 0.001). The average increase in TMAO levels over time (pinteraction = 0.007) was significantly higher in the Empagliflozin compared to the Placebo group. Age was positively associated with TMAO, whereas eGFR and LVEF were negatively associated with TMAO. CONCLUSIONS Our results are contrary to existing experimental studies that showed the positive impact of SGLT2i on TMAO precursors and cardiovascular events. Therefore, we recommend further research investigating the impact of SGLT2i therapy on acute and long-term changes in TMAO in cardiovascular cohorts.
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Affiliation(s)
- Faisal Aziz
- Interdisciplinary Metabolic Medicine Trials Unit, Graz, Austria
- Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria
| | - Norbert J Tripolt
- Interdisciplinary Metabolic Medicine Trials Unit, Graz, Austria
- Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria
| | - Peter N Pferschy
- Interdisciplinary Metabolic Medicine Trials Unit, Graz, Austria
- Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria
| | - Ewald Kolesnik
- Division of Cardiology, Medical University of Graz, Graz, Austria
| | - Harald Mangge
- Clinical Institute for Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
| | - Pero Curcic
- Clinical Institute for Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
| | - Markus Hermann
- Clinical Institute for Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
| | - Andreas Meinitzer
- Clinical Institute for Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
| | | | - Harald Sourij
- Interdisciplinary Metabolic Medicine Trials Unit, Graz, Austria.
- Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria.
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Tian E, Wang F, Zhao L, Sun Y, Yang J. The pathogenic role of intestinal flora metabolites in diabetic nephropathy. Front Physiol 2023; 14:1231621. [PMID: 37469558 PMCID: PMC10352811 DOI: 10.3389/fphys.2023.1231621] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 06/26/2023] [Indexed: 07/21/2023] Open
Abstract
With the increasing incidence of diabetes, diabetic kidney disease has become a major cause of chronic kidney disease. The role of the gut microbiota in diabetes and its related complications have been extensively investigated; the modulatory effect of the gut microbiota on the host depends on several gut microbial metabolites, particularly short-chain fatty acids, secondary bile acids, and trimethylamine N-oxide. In this review, we focused on the evidence related to the pathogenic role of each of the gut microbial metabolites in diabetic nephropathy. The main novel therapies targeting the gut microbiota include probiotics, dietary prebiotics, synbiotic supplements, and faecal microbiota transplants, although there is no standard treatment principle. Further research is therefore needed to elucidate the link between gut microbes and diabetic nephropathy, and more therapeutic targets should be explored to treat diabetic nephropathy with dysbiosis of the gut microbes.
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Affiliation(s)
- En Tian
- The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Feng Wang
- Beibei Traditional Chinese Medicine Hospital, Chongqing, China
| | - Lei Zhao
- The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yan Sun
- The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jurong Yang
- The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Ecton KE, Graham EL, Risk BD, Brown GD, Stark GC, Wei Y, Trikha SRJ, Weir TL, Gentile CL. Toll-like receptor 4 deletion partially protects mice from high fat diet-induced arterial stiffness despite perturbation to the gut microbiota. FRONTIERS IN MICROBIOMES 2023; 2:1095997. [PMID: 39323483 PMCID: PMC11423633 DOI: 10.3389/frmbi.2023.1095997] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 09/27/2024]
Abstract
The present study aimed to determine the effects of toll-like receptor 4 (TLR4) deletion on high fat diet-induced aortic stiffness and gut microbiota alterations. We hypothesized that a high fat diet would result in perturbation of the gut microbiota in both control and TLR4 knockout mice (TLR4-/-), but that the absence of TLR4 signaling would protect mice from downstream vascular consequences of the high fat diet. Male control mice (CON, n=12) and TLR4-/- mice (KO, n=12) were fed either a standard low-fat diet (SD) or a high fat diet (HFD) (60% kcals from fat) for 6 months, after which time measurements of aortic stiffness (via pulse wave velocity [aPWV]) and gut microbiota composition (16S rRNA sequencing) were determined. Compared to the SD, HFD reduced microbial variability, promoted perturbation of the gut microbiota, and increased intestinal permeability in both CON and KO mice, with no effect of genotype. This increased intestinal permeability in HFD mice was accompanied by increases in plasma lipopolysaccharide binding protein (LBP) levels, an indicator of circulating endotoxin (p<0.05 for all comparisons between HFD and SD groups). aPWV was increased in CON+HFD mice (CON+HFD vs CON+SD: 525.4 ± 16.5 cm/sec vs. 455.2 ± 16.5 cm/sec; p<0.05), whereas KO+HFD mice displayed partial protection from HFD-induced arterial stiffening (KO+HFD vs. CON+SD: 488.2 ± 16.6 cm/sec vs. 455.2 ± 16.5 cm/sec; p=0.8) (KO+HFD vs. CON+HFD: 488.2 ± 16.6 cm/sec vs. 525.4 ± 16.5 cm/sec; p=0.1). In summary, TLR4 KO mice are not protected from deleterious alterations in gut microbial composition or intestinal permeability following a HFD, but are partially protected from the downstream arterial stiffening, suggesting that TLR4 signaling is not required for HFD-mediated intestinal disturbances, but is an important determinant of downstream vascular consequences.
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Affiliation(s)
- Kayl E Ecton
- Cell and Molecular Biology Graduate Program, Colorado State University, Fort Collins, CO, United States
- Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO, United States
| | - Elliot L Graham
- Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, CO, United States
| | - Briana D Risk
- Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, CO, United States
| | - Gabriele D Brown
- Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, CO, United States
| | - Grace C Stark
- Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, CO, United States
| | - Yuren Wei
- Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, CO, United States
| | - S Raj J Trikha
- Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, CO, United States
- University of Colorado School of Medicine at Colorado State Univeristy, Fort Collins, CO, United States
| | - Tiffany L Weir
- Cell and Molecular Biology Graduate Program, Colorado State University, Fort Collins, CO, United States
- Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, CO, United States
| | - Christopher L Gentile
- Cell and Molecular Biology Graduate Program, Colorado State University, Fort Collins, CO, United States
- Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, CO, United States
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