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Yu B, Cui Y, Lin L, Wu M, Teng J. Morroniside restrains renal glucose reabsorption to regulate glucose metabolism via the PPARδ/SGLT2 signaling pathway. Biochem Biophys Res Commun 2025; 752:151399. [PMID: 39946985 DOI: 10.1016/j.bbrc.2025.151399] [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: 01/24/2025] [Accepted: 01/24/2025] [Indexed: 02/24/2025]
Abstract
Morroniside (Mor) has been documented to has anti-diabetic activity. Nevertheless, the impact of Mor on the glucose metabolism and its underlying mechanism have never been elucidated. Here, we demonstrated that Mor improved the body weight, hyperglycemia, and insulin resistance in rat model of T2DM. Furthermore, Mor restrained renal glucose reabsorption of T2DM rats, accompanied by PPARδ upregulation and SGLT2 downregulation in renal tissues. The protein level of PPARδ was decreased, but SGLT2 was increased in HK-2 cells underwent high glucose stimulation. Mor enhanced PPARδ expression and inhibited SGLT2 expression in HK-2 cells under high glucose condition. PPARδ silencing rescued, but SGLT2 silencing reinforced the inhibitory effect of Mor on glucose uptake of HK-2 cells. In conclusions, Mor restrains renal glucose reabsorption to regulate glucose metabolism by regulating the PPARδ/SGLT2 signaling pathway, manifesting that Mor may be a promising therapeutic medicine for T2DM.
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Affiliation(s)
- Bing Yu
- Department of Nephrology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, 361015, Fujian Province, China; Xiamen Clinical Quality Control Center of Nephrology, Xiamen, 361015, Fujian Province, China
| | - Yukai Cui
- Department of Nephrology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, 361015, Fujian Province, China; Xiamen Clinical Quality Control Center of Nephrology, Xiamen, 361015, Fujian Province, China
| | - Liyu Lin
- Department of Nephrology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, 361015, Fujian Province, China; Xiamen Clinical Quality Control Center of Nephrology, Xiamen, 361015, Fujian Province, China
| | - Meiju Wu
- Department of Nephrology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, 361015, Fujian Province, China; Xiamen Clinical Quality Control Center of Nephrology, Xiamen, 361015, Fujian Province, China
| | - Jie Teng
- Department of Nephrology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, 361015, Fujian Province, China; Xiamen Clinical Quality Control Center of Nephrology, Xiamen, 361015, Fujian Province, China.
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Zheng Y, Sun J. Long-term effect of sodium-glucose cotransporter 2 inhibitors in kidney functions: A systematic review and meta-analysis. Medicine (Baltimore) 2025; 104:e41422. [PMID: 39960956 PMCID: PMC11835073 DOI: 10.1097/md.0000000000041422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 01/15/2025] [Indexed: 02/20/2025] Open
Abstract
BACKGROUND Sodium-glucose cotransporter 2 (SGLT2) inhibitors (such as dapagliflozin, empagliflozin, and canagliflozin) are essential for the treatment of type 2 diabetes because they improve the urine excretion of glucose. Although there are advantages, including weight loss and enhanced heart health, caution is necessary because of possible negative effects, such as higher urine output and euglycemic diabetic ketoacidosis. They may slow chronic kidney disease progression, therefore, renal function must be monitored. This study aims to determine the efficacy of SGLT2 inhibitors in the prevention of renal deterioration in terms of reduction of estimated glomerular filtration rate (eGFR) in patients with compromised renal functions. METHODS This study aimed to document the long-term effects of SGLT2 inhibitors on kidney function. PubMed and Google Scholar were the key sources of scholarly publications, and Boolean operators were used to perform exact searches. Nine articles were considered relevant out of a total of 244, following extensive screening of titles, abstracts, and full texts according to PRISMA recommendations. RESULTS This study included randomized, double-blind, placebo-controlled trials evaluating the long-term effects of SGLT2 inhibitors on renal function across patient demographics and locations. Clinical investigations showed different effects on eGFR across control and study groups, suggesting renal protection. A meta-analysis showed that SGLT2 inhibitors enhanced kidney function more than the controls. CONCLUSION This meta-analysis concluded that SGLT2 inhibitors have the potential to prevent eGFR reduction and improve renal function in patients with compromised renal function and underlying conditions such as chronic kidney disease or type 1 and 2 diabetes. However, this meta-analysis showed beneficial results in the prevention of renal deterioration within several follow-up periods, with an average of 11 to 12 months.
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Affiliation(s)
- Yanqun Zheng
- Department of Nephrology, The First People’s Hospital of Linping District, Hangzhou, China
| | - Jia Sun
- Department of Nephrology, The First People’s Hospital of Linping District, Hangzhou, China
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3
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Dimitriadis K, Pitsiori D, Alexiou P, Pyrpyris N, Sakalidis A, Beneki E, Iliakis P, Tatakis F, Theofilis P, Tsioufis P, Konstantinidis D, Aggeli K, Tsioufis K. Modulating Sympathetic Nervous System With the Use of SGLT2 Inhibitors: Where There Is Smoke, There Is Fire? J Cardiovasc Pharmacol 2025; 85:12-20. [PMID: 39436317 DOI: 10.1097/fjc.0000000000001644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 09/24/2024] [Indexed: 10/23/2024]
Abstract
Heart failure (HF) has become even more prevalent in recent years, because of improved diagnostics and an increase in the risk factors predisposing to its pathology. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) emerged as one of the key pharmacotherapy options for both reduced and preserved ejection fraction, providing cardio- and renoprotection and improving mortality and cardiovascular (CV) outcomes. The pleiotropism of SGLT2i has led to multiple efforts to understand their distinct pathophysiologic interactions with various pathways, including microcirculation, endothelial dysfunction, and inflammation. More recently, the role of SGLT2i on the sympathetic nervous system (SNS) is starting to be recognized, especially because observations of retained or reduced heart rate despite volume contraction have been noted by investigators in the large clinical trials testing the safety and efficacy of these agents. Both preclinical and clinical studies have been performed, with conflicting results. Interestingly, in both settings, although there are indications of SNS modulation by SGLT2i, other studies contradict such findings, without showing, however, worsening of the autonomic homeostasis. Given the importance of neuromodulation in HF, in both pharmacologic and interventional therapies, in this review, we aim to describe the role of SNS in CV disease, focusing on HF, analyze preclinical and clinical data regarding the efficacy of SGLT2i in modulating autonomic dysfunction by examining various markers of SNS activation, and provide the most plausible theoretical backgrounds on the mechanism of benefit of SNS from the inhibition of SGLT2 receptors.
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Affiliation(s)
- Kyriakos Dimitriadis
- First Department of Cardiology, School of Medicine, National and Kapodistrian University of Athens, Hippokration General Hospital, Athens, Greece
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Tang YB, Wang LS, Wu YH, Zhang LX, Hu LY, Wu Q, Zhou ML, Liang ZX. Effect of exercise during pregnancy on offspring development through ameliorating high glucose and hypoxia in gestational diabetes mellitus. World J Diabetes 2024; 15:2203-2219. [PMID: 39582571 PMCID: PMC11580567 DOI: 10.4239/wjd.v15.i11.2203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 09/03/2024] [Accepted: 09/18/2024] [Indexed: 10/16/2024] Open
Abstract
BACKGROUND Gestational diabetes mellitus (GDM) women require prenatal care to minimize short- and long-term complications. The mechanism by which exercise during pregnancy affects organ development and whether glucose transporter (GLUT) 1 plays a role in GDM offspring organ development remains unknown. AIM To determine the effect of exercise during pregnancy on the cardiac, hepatic and renal development of GDM mother's offspring. METHODS Placenta samples were collected from humans and mice. GDM mouse models were created using streptozotocin along with a GDM with exercise group. The hearts, livers and kidneys of 3- and 8-week-old offspring were collected for body composition analysis and staining. The effects of high glucose levels and hypoxia were investigated using HTR8/SVneo. Transwell and wound-healing assays were performed to assess cell migration. Immunofluorescence accompanied with TUNEL and Ki67 staining was used to explore apoptosis and proliferation. RESULTS Exercise during pregnancy downregulated the GLUT1 and hypoxia inducible factor-1α expression in placenta from individuals with GDM. Cobalt chloride-induced hypoxia and high glucose levels also significantly decreased migration and apoptosis of HTR8/SVneo cells. In addition, exercise reduced inflammatory cell infiltration in the liver and decreased the tubular vacuolar area in the kidneys of offspring. CONCLUSION GDM affects the growth and development of organs in offspring. Exercise during pregnancy can reverse adverse effects of GDM on the development of the heart, liver, and kidney in offspring.
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Affiliation(s)
- Yi-Bo Tang
- Department of Obstetrics, Women's Hospital School of Medicine, Zhejiang University, Hangzhou 310006, Zhejiang Province, China
| | - Le-Sha Wang
- Department of Obstetrics, Shaoxing People’s Hospital, Shaoxing 312000, Zhejiang Province, China
| | - Yi-Hui Wu
- Department of Obstetrics, Women's Hospital School of Medicine, Zhejiang University, Hangzhou 310006, Zhejiang Province, China
| | - Li-Xia Zhang
- Department of Obstetrics, Women's Hospital School of Medicine, Zhejiang University, Hangzhou 310006, Zhejiang Province, China
| | - Lu-Yao Hu
- Department of Obstetrics, Women's Hospital School of Medicine, Zhejiang University, Hangzhou 310006, Zhejiang Province, China
| | - Qi Wu
- Department of Obstetrics, Women's Hospital School of Medicine, Zhejiang University, Hangzhou 310006, Zhejiang Province, China
| | - Meng-Lin Zhou
- Department of Obstetrics, Women's Hospital School of Medicine, Zhejiang University, Hangzhou 310006, Zhejiang Province, China
| | - Zhao-Xia Liang
- Department of Obstetrics, Women's Hospital School of Medicine, Zhejiang University, Hangzhou 310006, Zhejiang Province, China
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An S, Ye Z, Che W, Gao Y, Ren J, Li J, Zheng J. Predictive value of stress hyperglycemia ratio on one-year mortality in chronic kidney disease patients admitted to intensive care unit. BMC Nephrol 2024; 25:358. [PMID: 39420295 PMCID: PMC11487764 DOI: 10.1186/s12882-024-03823-4] [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: 12/20/2023] [Accepted: 10/15/2024] [Indexed: 10/19/2024] Open
Abstract
BACKGROUND Stress Hyperglycemia Ratio (SHR) reflects the acute blood glucose variation in critically ill conditions. However, its prognostic value in chronic kidney disease (CKD) remains understudied. This study aimed to investigate the association between SHR and one-year mortality in CKD patients hospitalized in the Intensive Care Unit (ICU). METHODS Patients with diagnosis of CKD in the Medical Information Mart for Intensive Care IV (MIMIC-IV) database were enrolled. Incidence of all-cause mortality within one-year follow-up was used as the primary endpoint. RESULTS 1825 CKD patients were included in the study. A "U-shaped" relationship between SHR and one-year mortality as identified using multivariate restricted cubic spline (RCS) analysis. Then study population were categorized into three groups: Group 1 (SHR < 0.70), Group 2 (0.70 ≤ SHR ≤ 0.95) and Group 3 (SHR > 0.95). Group 2 showed significantly better one-year outcomes compared to the other two groups (p = 0.0031). This survival benefit persisted across subgroup analyses stratified by age, sex, CKD stage, anemia and various clinical conditions. CONCLUSION SHR proved to be a meaningful biomarker for predicting one-year mortality in ICU-admitted CKD patients, with a "U-shaped" correlation. The identification of the optimal SHR range (0.70-0.95) provided clinicians with a valuable tool for detecting high-risk populations.
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Affiliation(s)
- Shuoyan An
- Department of Cardiology, China-Japan Friendship Hospital, No.2 East Yinghua Road, Chaoyang District, Beijing, 100029, China
| | - Zixiang Ye
- Department of Cardiology, Peking University China-Japan Friendship School of Clinical Medicine, Beijing, 100029, China
| | - Wuqiang Che
- Department of Cardiology, China-Japan Friendship Hospital, No.2 East Yinghua Road, Chaoyang District, Beijing, 100029, China
| | - Yanxiang Gao
- Department of Cardiology, China-Japan Friendship Hospital, No.2 East Yinghua Road, Chaoyang District, Beijing, 100029, China
| | - Jingyi Ren
- Department of Cardiology, China-Japan Friendship Hospital, No.2 East Yinghua Road, Chaoyang District, Beijing, 100029, China
| | - Jiahui Li
- Department of Cardiology, China-Japan Friendship Hospital, No.2 East Yinghua Road, Chaoyang District, Beijing, 100029, China.
| | - Jingang Zheng
- Department of Cardiology, China-Japan Friendship Hospital, No.2 East Yinghua Road, Chaoyang District, Beijing, 100029, China.
- Department of Cardiology, Peking University China-Japan Friendship School of Clinical Medicine, Beijing, 100029, China.
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U N, R C T, R KR, Mahalingam G. Glucose transporters and their energy homeostasis function in various organs. VITAMINS AND HORMONES 2024; 128:1-47. [PMID: 40097247 DOI: 10.1016/bs.vh.2024.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/19/2025]
Abstract
Glucose transporters (GLUTs) belong to a membrane-protein family that essentially participates in easing the transportation and absorption of glucose molecules throughout the cellular membranes. From the brain to the eyes, each section delves into the intricate mechanisms of glucose uptake and utilization, shedding light on the unique adaptations and regulatory pathways in different anatomical structures. Beginning with the brain, known for its high energy demands, the chapter explicates the specialized GLUT expression patterns crucial for neuronal function and synaptic transmission. Moving to metabolic powerhouses like the liver, muscles, and adipose tissue, it elucidates the dynamic interplay of GLUT isoforms in energy storage, mobilization, and insulin responsiveness. Furthermore, the chapter navigates through the kidneys, lungs, skin, and reproductive organs, unveiling the diverse roles of GLUTs in renal glucose reabsorption, pulmonary-epithelial transportation, skin barrier associated functions, and gonadal development. It also explores the significance of placental GLUTs in fatal nutrient supply and the implications of cardiac GLUTs in myocardial energy metabolism. Additionally, it examines the intricate regulation of GLUTs at key barriers like the BBB (Blood-Brain Barrier) and placenta, as well as in endocrine glands such as the pancreas, adrenal medulla and thyroid. Moreover, it further elucidates the less-explored territories of GLUT expression in the bones, gastrointestinal tract, and ocular tissues like the retina, unraveling their implications in immune function, bone metabolism, intestinal glucose-sensing, and retinal physiology.
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Affiliation(s)
- Nithya U
- Department of Bio-Medical Sciences, School of Bio, sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Theijeswini R C
- Department of Bio-Medical Sciences, School of Bio, sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Karthick Raja R
- Department of Bio-Medical Sciences, School of Bio, sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - Gayathri Mahalingam
- Department of Bio-Medical Sciences, School of Bio, sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India.
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Abiola JO, Oluyemi AA, Idowu OT, Oyinloye OM, Ubah CS, Owolabi OV, Somade OT, Onikanni SA, Ajiboye BO, Osunsanmi FO, Nash O, Omotuyi OI, Oyinloye BE. Potential Role of Phytochemicals as Glucagon-like Peptide 1 Receptor (GLP-1R) Agonists in the Treatment of Diabetes Mellitus. Pharmaceuticals (Basel) 2024; 17:736. [PMID: 38931402 PMCID: PMC11206448 DOI: 10.3390/ph17060736] [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: 04/07/2024] [Revised: 05/28/2024] [Accepted: 06/03/2024] [Indexed: 06/28/2024] Open
Abstract
Currently, there is no known cure for diabetes. Different pharmaceutical therapies have been approved for the management of type 2 diabetes mellitus (T2DM), some are in clinical trials and they have been classified according to their route or mechanism of action. Insulin types, sulfonylureas, biguanides, alpha-glucosidase inhibitors, thiazolidinediones, meglitinides, sodium-glucose cotransporter type 2 inhibitors, and incretin-dependent therapies (glucagon-like peptide-1 receptor agonists: GLP-1R, and dipeptidyl peptidase 4 inhibitors: DPP-4). Although some of the currently available drugs are effective in the management of T2DM, the side effects resulting from prolonged use of these drugs remain a serious challenge. GLP-1R agonists are currently the preferred medications to include when oral metformin alone is insufficient to manage T2DM. Medicinal plants now play prominent roles in the management of various diseases globally because they are readily available and affordable as well as having limited and transient side effects. Recently, studies have reported the ability of phytochemicals to activate glucagon-like peptide-1 receptor (GLP-1R), acting as an agonist just like the GLP-1R agonist with beneficial effects in the management of T2DM. Consequently, we propose that careful exploration of phytochemicals for the development of novel therapeutic candidates as GLP-1R agonists will be a welcome breakthrough in the management of T2DM and the co-morbidities associated with T2DM.
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Affiliation(s)
- Julianah Ore Abiola
- Phytomedicine, Biochemical Toxicology and Biotechnology Research Laboratories, Department of Biochemistry, College of Sciences, Afe Babalola University, Ado-Ekiti 360001, Nigeria; (J.O.A.)
- Center for Genomics Research and Innovation, National Biotechnology Development Agency, Abuja 09004, Nigeria
- Institute of Drug Research and Development, S.E. Bogoro Center, Afe Babalola University, Ado-Ekiti 360001, Nigeria
| | - Ayoola Abidemi Oluyemi
- Institute of Drug Research and Development, S.E. Bogoro Center, Afe Babalola University, Ado-Ekiti 360001, Nigeria
| | - Olajumoke Tolulope Idowu
- Industrial Chemistry Unit, Department of Chemical Sciences, College of Sciences, Afe Babalola University, Ado-Ekiti 360001, Nigeria
| | - Oluwatoyin Mary Oyinloye
- Department of Mathematics, Science and Technology Education, Faculty of Education, University of Zululand, Kwadlangezwa 3886, South Africa
| | - Chukwudi Sunday Ubah
- Department of Epidemiology and Biostatistics, College of Public Health, Temple University, Philadelphia, PA 19121, USA
| | - Olutunmise Victoria Owolabi
- Medical Biochemistry Unit, College of Medicine and Health Sciences, Afe Babalola University, Ado-Ekiti 360001, Nigeria
| | - Oluwatobi T. Somade
- Phytomedicine, Biochemical Toxicology and Biotechnology Research Laboratories, Department of Biochemistry, College of Sciences, Afe Babalola University, Ado-Ekiti 360001, Nigeria; (J.O.A.)
- Department of Biochemistry, College of Biosciences, Federal University of Agriculture, Abeokuta 111101, Nigeria
| | - Sunday Amos Onikanni
- Phytomedicine, Biochemical Toxicology and Biotechnology Research Laboratories, Department of Biochemistry, College of Sciences, Afe Babalola University, Ado-Ekiti 360001, Nigeria; (J.O.A.)
- College of Medicine, Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan
| | - Basiru Olaitan Ajiboye
- Institute of Drug Research and Development, S.E. Bogoro Center, Afe Babalola University, Ado-Ekiti 360001, Nigeria
- Phytomedicine and Molecular Toxicology Research Laboratory, Department of Biochemistry, Federal University Oye-Ekiti, Oye-Ekiti 371104, Nigeria
| | - Foluso Oluwagbemiga Osunsanmi
- Biotechnology and Structural Biology (BSB) Group, Department of Biochemistry and Microbiology, University of Zululand, Kwadlangezwa 3886, South Africa
| | - Oyekanmi Nash
- Center for Genomics Research and Innovation, National Biotechnology Development Agency, Abuja 09004, Nigeria
| | - Olaposi Idowu Omotuyi
- Institute of Drug Research and Development, S.E. Bogoro Center, Afe Babalola University, Ado-Ekiti 360001, Nigeria
- Department of Pharmacology and Toxicology, College of Pharmacy, Afe Babalola University, Ado-Ekiti 360001, Nigeria
| | - Babatunji Emmanuel Oyinloye
- Phytomedicine, Biochemical Toxicology and Biotechnology Research Laboratories, Department of Biochemistry, College of Sciences, Afe Babalola University, Ado-Ekiti 360001, Nigeria; (J.O.A.)
- Institute of Drug Research and Development, S.E. Bogoro Center, Afe Babalola University, Ado-Ekiti 360001, Nigeria
- Biotechnology and Structural Biology (BSB) Group, Department of Biochemistry and Microbiology, University of Zululand, Kwadlangezwa 3886, South Africa
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Rahmouni K. Neural Circuits Underlying Reciprocal Cardiometabolic Crosstalk: 2023 Arthur C. Corcoran Memorial Lecture. Hypertension 2024; 81:1233-1243. [PMID: 38533662 PMCID: PMC11096079 DOI: 10.1161/hypertensionaha.124.22066] [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] [Indexed: 03/28/2024]
Abstract
The interplay of various body systems, encompassing those that govern cardiovascular and metabolic functions, has evolved alongside the development of multicellular organisms. This evolutionary process is essential for the coordination and maintenance of homeostasis and overall health by facilitating the adaptation of the organism to internal and external cues. Disruption of these complex interactions contributes to the development and progression of pathologies that involve multiple organs. Obesity-associated cardiovascular risks, such as hypertension, highlight the significant influence that metabolic processes exert on the cardiovascular system. This cardiometabolic communication is reciprocal, as indicated by substantial evidence pointing to the ability of the cardiovascular system to affect metabolic processes, with pathophysiological implications in disease conditions. In this review, I outline the bidirectional nature of the cardiometabolic interaction, with special emphasis on the impact that metabolic organs have on the cardiovascular system. I also discuss the contribution of the neural circuits and autonomic nervous system in mediating the crosstalk between cardiovascular and metabolic functions in health and disease, along with the molecular mechanisms involved.
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Affiliation(s)
- Kamal Rahmouni
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa
- Veterans Affairs Health Care System, Iowa City, Iowa
- Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa
- Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa
- Obesity Research and Education Initiative, University of Iowa Carver College of Medicine, Iowa City, Iowa
- Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, Iowa
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Starr JA, Pinner NA. The Impact of SGLT2 Inhibitors on Cardiovascular Outcomes in Patients With Heart Failure With Preserved Ejection Fraction. Ann Pharmacother 2024; 58:506-513. [PMID: 37542422 DOI: 10.1177/10600280231189508] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/07/2023] Open
Abstract
OBJECTIVE To evaluate the role of sodium-glucose cotransporter-2 (SGLT2) inhibitors in patients with heart failure with preserved ejection fraction (HFpEF). DATA SOURCES A literature search of PubMed, the Cochrane Library, and Google Scholar databases (January 2015 to June 20, 2023) was performed with keywords: sodium-glucose co-transporter 2 inhibitors OR SGLT2 inhibitors OR bexagliflozin OR canagliflozin OR dapagliflozin OR empagliflozin OR ertugliflozin OR sotagliflozin AND heart failure OR heart failure with preserved ejection fraction, and terms related to CV outcomes including cardiovascular death, hospitalization, hospitalization for heart failure, mortality, death, and major adverse cardiovascular event (MACE). STUDY SELECTION AND DATA EXTRACTION The reference list from retrieved articles as well as relevant review articles was considered. Pivotal randomized controlled trials and meta-analyses with a primary or secondary end point of CV death or heart failure hospitalization were included. Studies conducted solely in a diabetic patient population were excluded. DATA SYNTHESIS Dapagliflozin and empagliflozin, in a broad population of heart failure patients including, HFrEF, HFmrEF, HFpEF, and without diabetes, have shown consistent improvement in the combined outcome of CV death and hospitalization for heart failure (HR 0.80, 95% CI 0.73-0.87) and in the reduction of heart failure hospitalizations (HR 0.74, 95% CI 0.67-0.83). In patients with HFpEF, cardiovascular mortality was not demonstrated (HR 0.88, 95% CI 0.77-1.00). Rates of adverse events were low. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE Patients with HFpEF and NYHA class II-III with frequent symptoms or hospitalizations for heart failure derive the most benefit from SGLT2 inhibitors with an overall goal of a reduction in heart failure hospitalizations. CONCLUSIONS The treatment of HFpEF has made progress, but there is still work to be done. Now, SGLT2 inhibitor therapy can be used to further help with symptom control and reduce overall hospitalizations for heart failure.
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Affiliation(s)
- Jessica A Starr
- Department of Pharmacy Practice, Harrison School of Pharmacy, Auburn University, Birmingham, AL, USA
| | - Nathan A Pinner
- Department of Pharmacy Practice, Harrison School of Pharmacy, Auburn University, Birmingham, AL, USA
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10
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Balestrieri G, Limonta R, Ponti E, Merlo A, Sciatti E, D'Isa S, Gori M, Casu G, Giannattasio C, Senni M, D'Elia E. The Therapy and Management of Heart Failure with Preserved Ejection Fraction: New Insights on Treatment. Card Fail Rev 2024; 10:e05. [PMID: 38708376 PMCID: PMC11066852 DOI: 10.15420/cfr.2023.13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Accepted: 10/28/2023] [Indexed: 05/07/2024] Open
Abstract
Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome characterised by the presence of diastolic dysfunction and elevated left ventricular filling pressure, in the setting of a left ventricular ejection fraction of at least 50%. Despite the epidemiological prevalence of HFpEF, a prompt diagnosis is challenging and many uncertainties exist. HFpEF is characterised by different phenotypes driven by various cardiac and non-cardiac comorbidities. This is probably the reason why several HFpEF clinical trials in the past did not reach strong outcomes to recommend a single therapy for this syndrome; however, this paradigm has recently changed, and the unmet clinical need for HFpEF treatment found a proper response as a result of a new class of drug, the sodium-glucose cotransporter 2 inhibitors, which beneficially act through the whole spectrum of left ventricular ejection fraction. The aim of this review was to focus on the therapeutic target of HFpEF, the role of new drugs and the potential role of new devices to manage the syndrome.
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Affiliation(s)
| | - Raul Limonta
- School of Medicine and Surgery, Milano Bicocca UniversityMilan, Italy
| | - Enrico Ponti
- Department of Medical, Surgical and Experimental Sciences, University of SassariSassari, Italy
| | - Anna Merlo
- School of Medicine and Surgery, Milano Bicocca UniversityMilan, Italy
| | - Edoardo Sciatti
- Cardiovascular Department, ASST Papa Giovanni XXIIIBergamo, Italy
| | - Salvatore D'Isa
- Cardiovascular Department, ASST Papa Giovanni XXIIIBergamo, Italy
| | - Mauro Gori
- Cardiovascular Department, ASST Papa Giovanni XXIIIBergamo, Italy
| | - Gavino Casu
- Department of Medical, Surgical and Experimental Sciences, University of SassariSassari, Italy
| | | | - Michele Senni
- Cardiovascular Department, ASST Papa Giovanni XXIIIBergamo, Italy
- Department of Medicine and Surgery, University of Milano BicoccaMilan, Italy
| | - Emilia D'Elia
- Cardiovascular Department, ASST Papa Giovanni XXIIIBergamo, Italy
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11
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Żołnierkiewicz O, Rogacka D. Hyperglycemia - A culprit of podocyte pathology in the context of glycogen metabolism. Arch Biochem Biophys 2024; 753:109927. [PMID: 38350532 DOI: 10.1016/j.abb.2024.109927] [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: 10/26/2023] [Revised: 01/31/2024] [Accepted: 02/10/2024] [Indexed: 02/15/2024]
Abstract
Prolonged disruption in the balance of glucose can result in metabolic disorders. The kidneys play a significant role in regulating blood glucose levels. However, when exposed to chronic hyperglycemia, the kidneys' ability to handle glucose metabolism may be impaired, leading to an accumulation of glycogen. Earlier studies have shown that there can be a significant increase in glucose storage in the form of glycogen in the kidneys in diabetes. Podocytes play a crucial role in maintaining the integrity of filtration barrier. In diabetes, exposure to elevated glucose levels can lead to significant metabolic and structural changes in podocytes, contributing to kidney damage and the development of diabetic kidney disease. The accumulation of glycogen in podocytes is not a well-established phenomenon. However, a recent study has demonstrated the presence of glycogen granules in podocytes. This review delves into the intricate connections between hyperglycemia and glycogen metabolism within the context of the kidney, with special emphasis on podocytes. The aberrant storage of glycogen has the potential to detrimentally impact podocyte functionality and perturb their structural integrity. This review provides a comprehensive analysis of the alterations in cellular signaling pathways that may potentially lead to glycogen overproduction in podocytes.
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Affiliation(s)
- Olga Żołnierkiewicz
- Mossakowski Medical Research Institute, Polish Academy of Sciences, Laboratory of Molecular and Cellular Nephrology, Wita Stwosza 63, 80-308, Gdansk, Poland
| | - Dorota Rogacka
- Mossakowski Medical Research Institute, Polish Academy of Sciences, Laboratory of Molecular and Cellular Nephrology, Wita Stwosza 63, 80-308, Gdansk, Poland; University of Gdansk, Faculty of Chemistry, Department of Molecular Biotechnology, Wita Stwosza 63, 80-308, Gdansk, Poland.
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12
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Zeng XC, Tian Y, Liang XM, Wu XB, Yao CM, Chen XM. SGLT2i relieve proteinuria in diabetic nephropathy patients potentially by inhibiting renal oxidative stress rather than through AGEs pathway. Diabetol Metab Syndr 2024; 16:46. [PMID: 38365853 PMCID: PMC10870536 DOI: 10.1186/s13098-024-01280-5] [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: 10/07/2023] [Accepted: 01/31/2024] [Indexed: 02/18/2024] Open
Abstract
AIMS To estimate the effects of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) on proteinuria and oxidative stress expression in type 2 diabetes patients. MATERIALS AND METHODS 68 patients with type 2 diabetes mellitus (T2DM) were divided into three groups according urinary albumin-to-creatinine ratio (UACR), including T2DM with non-albuminuria group (UACR < 30 mg/g), T2DM with microalbuminuria group (30 ≤ UACR ≤ 300 mg/g), T2DM with macroalbuminuria group (UACR>300 mg/g). They all received SGLT2 inhibitors (SGLT2i) treatment for 12 weeks. The expression of advanced glycation end products (AGEs) in plasma and 8-hydroxy-2-deoxyguanosine (8-OHdG) in urine were measured as indications of oxidative stress. The 24-hour urine samples were collected to measure the concentration of proteinuria and 8-OHdG before and after 12 weeks SGLT2i treatment. Plasma renin activity (PRA), angiotensin II (Ang II) and Aldosterone (ALD) were measured to evaluate renin angiotensin aldosterone system (RASS) levels. RESULTS After 12 weeks SGLT2 inhibitors treatment, the median values of 24-hour proteinuria decreased in macroalbuminuria compared to baseline (970 vs. 821 mg/d, P = 0.006). The median values of AGEs and 8-OHdG decreased in microalbuminuria and macroalbuminuria groups when compared to baseline, AGEs (777 vs. 136 ug/ml, P = 0.003) and (755 vs. 210 ug/ml, P = 0.001), 8-OHdG (8.00 vs. 1.88 ng/ml, P = 0.001) and (11.18 vs. 1.90 ng/ml, P < 0.001), respectively. Partial correlations showed that 8-OHdG were relevant to the baseline 24-h proteinuria (r = 0.389, p = 0.001), the reduction of OHdG (Δ8-OHdG) were positively correlated with the decrease of 24-h proteinuria (Δ24-h proteinuria) after 12 weeks of SGLT2i treatment (r = 0.283, P = 0.031). There was no significant correlation between 24-h proteinuria and AGEs in baseline (r = -0.059, p = 0.640) as well as between ΔAGEs and Δ24-h proteinuria (r = 0.022, p = 0.872) after12 weeks of SGLT2i treatment in T2DM patients. CONCLUSIONS SGLT2i may reduce proteinuria in diabetic nephropathy patients, potentially by inhibiting renal oxidative stress, but not through the AGEs pathway and does not induce RAAS activation. TRIAL REGISTRATION This clinical trial was registered on 15/10/2019, in ClinicalTrials.gov, and the registry number is NCT04127084.
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Affiliation(s)
- Xiao-Chun Zeng
- Department of Endocrinology and Metabolism, School of Medicine, Zhongshan Hospital of Xiamen University, Xiamen University, 201-209 Hubin South Road, 361004, Xiamen, P.R. China
- The School of Clinical Medicine, Fujian Medical University, 350004, Fuzhou, P.R. China
| | - Yuan Tian
- Department of Endocrinology and Metabolism, School of Medicine, Zhongshan Hospital of Xiamen University, Xiamen University, 201-209 Hubin South Road, 361004, Xiamen, P.R. China
| | - Xian-Ming Liang
- Center of Clinical Laboratory, School of Medicine, Zhongshan Hospital of Xiamen University, Xiamen University, 201-209 Hubin South Road, 361004, Xiamen, P. R. China
| | - Xiao-Bin Wu
- Department of Endocrinology and Metabolism, School of Medicine, Zhongshan Hospital of Xiamen University, Xiamen University, 201-209 Hubin South Road, 361004, Xiamen, P.R. China
| | - Chun-Meng Yao
- Department of Nephrology, School of Medicine, Zhongshan Hospital of Xiamen University, Xiamen University, 201-209 Hubin South Road, 361004, Xiamen, P. R. China
| | - Xiao-Min Chen
- Department of Endocrinology and Metabolism, School of Medicine, Zhongshan Hospital of Xiamen University, Xiamen University, 201-209 Hubin South Road, 361004, Xiamen, P.R. China.
- The School of Clinical Medicine, Fujian Medical University, 350004, Fuzhou, P.R. China.
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Klip A, De Bock K, Bilan PJ, Richter EA. Transcellular Barriers to Glucose Delivery in the Body. Annu Rev Physiol 2024; 86:149-173. [PMID: 38345907 DOI: 10.1146/annurev-physiol-042022-031657] [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] [Indexed: 02/15/2024]
Abstract
Glucose is the universal fuel of most mammalian cells, and it is largely replenished through dietary intake. Glucose availability to tissues is paramount for the maintenance of homeostatic energetics and, hence, supply should match demand by the consuming organs. In its journey through the body, glucose encounters cellular barriers for transit at the levels of the absorbing intestinal epithelial wall, the renal epithelium mediating glucose reabsorption, and the tight capillary endothelia (especially in the brain). Glucose transiting through these cellular barriers must escape degradation to ensure optimal glucose delivery to the bloodstream or tissues. The liver, which stores glycogen and generates glucose de novo, must similarly be able to release it intact to the circulation. We present the most up-to-date knowledge on glucose handling by the gut, liver, brain endothelium, and kidney, and discuss underlying molecular mechanisms and open questions. Diseases associated with defects in glucose delivery and homeostasis are also briefly addressed. We propose that the universal problem of sparing glucose from catabolism in favor of translocation across the barriers posed by epithelia and endothelia is resolved through common mechanisms involving glucose transfer to the endoplasmic reticulum, from where glucose exits the cells via unconventional cellular mechanisms.
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Affiliation(s)
- Amira Klip
- Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada;
| | - Katrien De Bock
- Laboratory of Exercise and Health, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH), Zürich, Switzerland
| | - Philip J Bilan
- Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada;
| | - Erik A Richter
- The August Krogh Section for Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
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Liu J, Chang X, Ding X, He X, Wang J, Wang G. Effect of dapagliflozin on proteomics and metabolomics of serum from patients with type 2 diabetes. Diabetol Metab Syndr 2023; 15:251. [PMID: 38044448 PMCID: PMC10694884 DOI: 10.1186/s13098-023-01229-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 11/24/2023] [Indexed: 12/05/2023] Open
Abstract
BACKGROUND Sodium-glucose co-transporter 2 (SGLT2) inhibitors reduced the risk of cardiovascular and renal outcomes in patients with type 2 diabetes (T2D), but the underlying mechanism has not been well elucidated. The circulating levels of proteins and metabolites reflect the overall state of the human body. This study aimed to evaluate the effect of dapagliflozin on the proteome and metabolome in patients with newly diagnosed T2D. METHODS A total of 57 newly diagnosed T2D patients were enrolled, and received 12 weeks of dapagliflozin treatment (10 mg/d, AstraZeneca). Serum proteome and metabolome were investigated at the baseline and after dapagliflozin treatment. RESULTS Dapagliflozin significantly decreased HbA1c, BMI, and HOMA-IR in T2D patients (all p < 0.01). Multivariate models indicated clear separations of proteomics and metabolomics data between the baseline and after dapagliflozin treatment. A total of 38 differentially abundant proteins including 23 increased and 15 decreased proteins, and 35 differentially abundant metabolites including 17 increased and 18 decreased metabolites, were identified. In addition to influencing glucose metabolism (glycolysis/gluconeogenesis and pentose phosphate pathway), dapagliflozin significantly increased sex hormone-binding globulin, transferrin receptor protein 1, disintegrin, and metalloprotease-like decysin-1 and apolipoprotein A-IV levels, and decreased complement C3, fibronectin, afamin, attractin, xanthine, and uric acid levels. CONCLUSIONS The circulating proteome and metabolome in newly diagnosed T2D patients were significantly changed after dapagliflozin treatment. These changes in proteins and metabolites might be associated with the beneficial effect of dapagliflozin on cardiovascular and renal outcomes.
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Affiliation(s)
- Jia Liu
- Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, NO. 8, Gongti South Road, Chaoyang District, 100020, Beijing, China
| | - Xiaona Chang
- Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, NO. 8, Gongti South Road, Chaoyang District, 100020, Beijing, China
| | - Xiaoyu Ding
- Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, NO. 8, Gongti South Road, Chaoyang District, 100020, Beijing, China
| | - Xueqing He
- Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, NO. 8, Gongti South Road, Chaoyang District, 100020, Beijing, China
| | - Jiaxuan Wang
- Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, NO. 8, Gongti South Road, Chaoyang District, 100020, Beijing, China
| | - Guang Wang
- Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, NO. 8, Gongti South Road, Chaoyang District, 100020, Beijing, China.
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15
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Rao H, Cheng W, Yu J, An X, Deng H, Zhang Z, Wu F, Ji F, Li S. [Preliminary Investigation of the Molecular Mechanism of Empagliflozin Suppressing Gastric Cancer Through Mammalian Target of Rapamycin]. SICHUAN DA XUE XUE BAO. YI XUE BAN = JOURNAL OF SICHUAN UNIVERSITY. MEDICAL SCIENCE EDITION 2023; 54:1146-1153. [PMID: 38162062 PMCID: PMC10752783 DOI: 10.12182/20231160204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Indexed: 01/03/2024]
Abstract
Objective To predict the intervention targets of empagliflozin (EMPA), a specific inhibitor of sodium-glucose cotransporter 2 (SGLT2), in gastric adenocarcinoma through comprehensive network pharmacology, and to validate the effects and the molecular mechanisms of EMPA through cellular and molecular biology experiments. Methods Bioinformatics analysis of gastric adenocarcinoma was conducted to assess the correlation between gastric adenocarcinoma prognosis and SGLT2 expression. Network pharmacology was utilized to identify shared targets of EMPA and gastric adenocarcinoma. AGS cells, a human gastric adenocarcinoma cells line, were incubated with EMPA at different concentrations for 24 h and, then, cell proliferation was assessed using the CCK8 assay. After AGS cells were incubated with EMPA at the doses of 0, 3, and 6 mmol/L, real-time cell analysis (RTCA) and 5-ethynyl-2-deoxyuridine (EdU) incorporation were used to evaluate EMPA's inhibitory effects on the proliferation of the AGS cells. In addition, wound healing and Transwell assays were performed to assess the inhibitory effect of EMPA on the migration and invasion of the APC cells and Western blot analysis was conducted to examine the expression of mammalian target of rapamycin (mTOR) and phosphorylated mTOR (p-mTOR). BALB/c (nu/nu) nude mice were implanted with 5×106 AGS cells in the axilla. The mice were divided into three groups, a control group, a low-dose group, and a high-dose group, each consisting of 7 mice. After one week, the control group received daily intraperitoneal injections of normal saline, while the low-dose group and high-dose group received daily intraperitoneal injections of EMPA at the doses of 3 mg/kg and 5 mg/kg, respectively. The tumor volume was measured one week after the drug intervention started. Results Gastric adenocarcinoma patients with low expression of SGLT2 exhibited longer survival time and higher survival rate than those with high expression of SGLT2 did. A total of 104 EMPA-related potential targets and 2028 targets associated with gastric adenocarcinoma were identified. Among these, 45 targets associated with gastric adenocarcinoma overlapped with potential targets of EMPA. Further analysis revealed 10 relevant pathways and 4 core genes. The core genes were cyclin-dependent kinase 4 (CDK4), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), mTOR, and cyclin E1 (CCNE1). CCK-8 assay revealed that EMPA at concentrations ranging from 0.39 to 50 mmol/L effectively inhibited the proliferation of AGS cells. RTCA results indicated a downward shift in the cell growth curve. In comparison to the findings for the control group, EdU assay demonstrated that EMPA at the concentrations of 3 mmol/L and 6 mmol/L significantly inhibited AGS cell proliferation (P<0.05). Results from wound healing and Transwell assays indicated a decrease in the levels of cell migration and invasion (P<0.05) and, notably, there was a significant difference between the high and low-dose EMPA groups (P<0.05). Western blot showed no statistically significant difference in the expression of total mTOR protein between the groups. However, the expression of p-mTOR in the 3 mmol/L and 6 mmol/L EMPA groups decreased compared to that of the control group (P<0.05), with the 6 mmol/L EMPA group exhibiting a more pronounced reduction (P<0.05). Nude mice xenograft tumor experiment demonstrated that, compared to that of the control group, the tumor volumes in the EMPA-treatment groups were significantly reduced (P<0.05), with the high-dose group showing a more pronounced reduction (P<0.05). Conclusion EMPA inhibits the abnormal proliferation and migration of gastric adenocarcinoma cells, potentially through the modulation of mTOR protein activation. This study provides new potential medication and intervention targets for gastric adenocarcinoma treatment.
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Affiliation(s)
- Huiling Rao
- （ 442000） Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan 442000, China
- （ 400038） Department of Medical Engineering, The First Affiliated Hospital of Army Medical University, Chongqing 400038, China
| | - Wang Cheng
- （ 442000） Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan 442000, China
| | - Juan Yu
- （ 442000） Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan 442000, China
| | - Xiaotong An
- （ 442000） Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan 442000, China
| | - Haojun Deng
- （ 442000） Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan 442000, China
| | - Zhaoyang Zhang
- （ 442000） Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan 442000, China
| | - Fuyun Wu
- （ 442000） Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan 442000, China
| | - Fuyun Ji
- （ 442000） Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan 442000, China
| | - Shan Li
- （ 442000） Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan 442000, China
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16
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Manolis AA, Manolis TA, Manolis AS. Neurohumoral Activation in Heart Failure. Int J Mol Sci 2023; 24:15472. [PMID: 37895150 PMCID: PMC10607846 DOI: 10.3390/ijms242015472] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 10/16/2023] [Accepted: 10/21/2023] [Indexed: 10/29/2023] Open
Abstract
In patients with heart failure (HF), the neuroendocrine systems of the sympathetic nervous system (SNS), the renin-angiotensin-aldosterone system (RAAS) and the arginine vasopressin (AVP) system, are activated to various degrees producing often-observed tachycardia and concomitant increased systemic vascular resistance. Furthermore, sustained neurohormonal activation plays a key role in the progression of HF and may be responsible for the pathogenetic mechanisms leading to the perpetuation of the pathophysiology and worsening of the HF signs and symptoms. There are biomarkers of activation of these neurohormonal pathways, such as the natriuretic peptides, catecholamine levels and neprilysin and various newer ones, which may be employed to better understand the mechanisms of HF drugs and also aid in defining the subgroups of patients who might benefit from specific therapies, irrespective of the degree of left ventricular dysfunction. These therapies are directed against these neurohumoral systems (neurohumoral antagonists) and classically comprise beta blockers, angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers and vaptans. Recently, the RAAS blockade has been refined by the introduction of the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan, which combines the RAAS inhibition and neprilysin blocking, enhancing the actions of natriuretic peptides. All these issues relating to the neurohumoral activation in HF are herein reviewed, and the underlying mechanisms are pictorially illustrated.
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Affiliation(s)
- Antonis A. Manolis
- First Department of Cardiology, Evagelismos Hospital, 106 76 Athens, Greece;
| | - Theodora A. Manolis
- Department of Psychiatry, Aiginiteio University Hospital, 115 28 Athens, Greece;
| | - Antonis S. Manolis
- First Department of Cardiology, Ippokrateio University Hospital, 115 27 Athens, Greece
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Wen CY, Hsiao JH, Tzeng YDT, Chang R, Tsang YL, Kuo CH, Li CJ. Single-cell landscape and spatial transcriptomic analysis reveals macrophage infiltration and glycolytic metabolism in kidney renal clear cell carcinoma. Aging (Albany NY) 2023; 15:11298-11312. [PMID: 37847178 PMCID: PMC10637799 DOI: 10.18632/aging.205128] [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: 06/30/2023] [Accepted: 10/02/2023] [Indexed: 10/18/2023]
Abstract
The present study investigates the clinical relevance of glycolytic factors, specifically PGAM1, in the tumor microenvironment of kidney renal clear cell carcinoma (KIRC). Despite the established role of glycolytic metabolism in cancer pathophysiology, the prognostic implications and key targets in KIRC remain elusive. We analyzed GEO and TCGA datasets to identify DEGs in KIRC and studied their relationship with immune gene expression, survival, tumor stage, gene mutations, and infiltrating immune cells. We explored Pgam1 gene expression in different kidney regions using spatial transcriptomics after mouse kidney injury analysis. Single-cell RNA-sequencing was used to assess the association of PGAM1 with immune cells. Findings were validated with tumor specimens from 60 KIRC patients, correlating PGAM1 expression with clinicopathological features and prognosis using bioinformatics and immunohistochemistry. We demonstrated the expression of central gene regulators in renal cancer in relation to genetic variants, deletions, and tumor microenvironment. Mutations in these hub genes were positively associated with distinct immune cells in six different immune datasets and played a crucial role in immune cell infiltration in KIRC. Single-cell RNA-sequencing revealed that elevated PGAM1 was associated with immune cell infiltration, specifically macrophages. Furthermore, pharmacogenomic analysis of renal cancer cell lines indicated that inactivation of PGAM1 was associated with increased sensitivity to specific small-molecule drugs. Altered PGAM1 in KIRC is associated with disease progression and immune microenvironment. It has diagnostic and prognostic implications, indicating its potential in precision medicine and drug screening.
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Affiliation(s)
- Chen-Yueh Wen
- Division of Urology, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan
| | - Jui-Hu Hsiao
- Department of Surgery, Kaohsiung Municipal Minsheng Hospital, Kaohsiung 802, Taiwan
| | - Yen-Dun Tony Tzeng
- Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan
| | - Renin Chang
- Department of Emergency Medicine, Kaohsiung Veterans General Hospital, Kaohsiung 802, Taiwan
| | - Yi-Ling Tsang
- Institute of Physiological Chemistry and Pathobiochemistry and Cells in Motion Interfaculty Centre (CiMIC), University of Münster, Münster 48149, Germany
| | - Chen-Hsin Kuo
- Genomics Research Center, Academia Sinica, Taipei 115, Taiwan
| | - Chia-Jung Li
- Department of Obstetrics and Gynecology, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan
- Institute of BioPharmaceutical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan
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Daza-Arnedo R, Rico-Fontalvo J, Aroca-Martínez G, Rodríguez-Yanez T, Martínez-Ávila MC, Almanza-Hurtado A, Cardona-Blanco M, Henao-Velásquez C, Fernández-Franco J, Unigarro-Palacios M, Osorio-Restrepo C, Uparella-Gulfo I. Insulin and the kidneys: a contemporary view on the molecular basis. FRONTIERS IN NEPHROLOGY 2023; 3:1133352. [PMID: 37675359 PMCID: PMC10479562 DOI: 10.3389/fneph.2023.1133352] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 07/07/2023] [Indexed: 09/08/2023]
Abstract
Insulin is a hormone that is composed of 51 amino acids and structurally organized as a hexamer comprising three heterodimers. Insulin is the central hormone involved in the control of glucose and lipid metabolism, aiding in processes such as body homeostasis and cell growth. Insulin is synthesized as a large preprohormone and has a leader sequence or signal peptide that appears to be responsible for transport to the endoplasmic reticulum membranes. The interaction of insulin with the kidneys is a dynamic and multicenter process, as it acts in multiple sites throughout the nephron. Insulin acts on a range of tissues, from the glomerulus to the renal tubule, by modulating different functions such as glomerular filtration, gluconeogenesis, natriuresis, glucose uptake, regulation of ion transport, and the prevention of apoptosis. On the other hand, there is sufficient evidence showing the insulin receptor's involvement in renal functions and its responsibility for the regulation of glucose homeostasis, which enables us to understand its contribution to the insulin resistance phenomenon and its association with the progression of diabetic kidney disease.
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Affiliation(s)
- Rodrigo Daza-Arnedo
- Department of Nephrology, Colombian Association of Nephrology, Cartagena, Colombia
| | - Jorge Rico-Fontalvo
- Department of Nephrology, Colombian Association of Nephrology, Cartagena, Colombia
- Faculty of Medicine, Universidad Simón Bolívar, Barranquilla, Colombia
| | - Gustavo Aroca-Martínez
- Department of Nephrology, Colombian Association of Nephrology, Cartagena, Colombia
- Faculty of Medicine, Universidad Simón Bolívar, Barranquilla, Colombia
| | | | | | | | - María Cardona-Blanco
- Department of Nephrology, Colombian Association of Nephrology, Cartagena, Colombia
| | | | - Jorge Fernández-Franco
- Department of Internal Medicine, Endocrinology Fellowship, Fundación Universitaria de Ciencias de la Salud—Hospital San José, Bogotá, Colombia
| | - Mario Unigarro-Palacios
- Department of Internal Medicine, Endocrinology Fellowship, Fundación Universitaria de Ciencias de la Salud—Hospital San José, Bogotá, Colombia
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Nyrén R, Scherman H, Axelsson J, Chang CL, Olivecrona G, Ericsson M. Visualizing increased uptake of [18F]FDG and [18F]FTHA in kidneys from obese high-fat diet fed C57BL/6J mice using PET/CT ex vivo. PLoS One 2023; 18:e0281705. [PMID: 36787333 PMCID: PMC9928095 DOI: 10.1371/journal.pone.0281705] [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: 06/22/2022] [Accepted: 01/31/2023] [Indexed: 02/15/2023] Open
Abstract
It is known that high-fat diet (HFD) and/or diabetes may influence substrate preferences and energy demands in the heart preceding diabetic cardiomyopathy. They may also induce structural glomerular changes causing diabetic nephropathy. PET/CT has been utilized to examine uptake of energy substrates, and to study metabolic changes or shifts before onset of metabolic disorders. However, conventional PET/CT scanning of organs with relatively low uptake, such as the kidney, in small animals in vivo may render technical difficulties. To address this issue, we developed a PET/CT ex vivo protocol with radiolabeled glucose and fatty acid analouges, [18F]FDG and [18F]FTHA,to study substrate uptake in mouse kidneys. We also aimed to detect a possible energy substrate shift before onset of diabetic nephropathy. The ex vivo protocol reduced interfering background as well as interindividual variances. We found increased uptake of [18F]FDG and [18F]FTHA in kidneys after HFD, compared to kidneys from young mice on standard chow. Levels of kidney triglycerides also increased on HFD. Lipoprotein lipase (LPL) activity, the enzyme responsible for release of fatty acids from circulating lipoproteins, is normally increased in postprandial mice kidneys. After long-term HFD, we found that LPL activity was suppressed, and could therefore not explain the increased levels of stored triglycerides. Suppressed LPL activity was associated with increased expression of angiopoietin-like protein4, an inhibitor of LPL. HFD did not alter the transcriptional control of some common glucose and fatty acid transporters that may mediate uptake of [18F]FDG and [18F]FTHA. Performing PET/CT ex vivo reduced interfering background and interindividual variances. Obesity and insulin resistance induced by HFD increased the uptake of [18F]FDG and [18F]FTHA and triglyceride accumulation in mouse kidneys. Increased levels of [18F]FDG and [18F]FTHA in obese insulin resistant mice could be used clinically as an indicator of poor metabolic control, and a complementary test for incipient diabetic nephropathy.
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Affiliation(s)
- Rakel Nyrén
- Department of Medical Biosciences/Physiological Chemistry, Umeå University, Umeå, Sweden
- Department of Medical Biosciences/Pathology, Umeå University, Umeå, Sweden
| | - Henrik Scherman
- Department of Radiation Sciences, Umeå University, Umeå, Sweden
| | - Jan Axelsson
- Department of Radiation Sciences, Umeå University, Umeå, Sweden
| | - Chuchun L. Chang
- Institute of Human Nutrition, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York, United States of America
| | - Gunilla Olivecrona
- Department of Medical Biosciences/Physiological Chemistry, Umeå University, Umeå, Sweden
| | - Madelene Ericsson
- Department of Medical Biosciences/Physiological Chemistry, Umeå University, Umeå, Sweden
- Umeå Centre for Molecular Medicine, Umeå University, Umeå, Sweden
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20
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Palazzuoli A, Correale M, Iacoviello M, Gronda E. Does the Measurement of Ejection Fraction Still Make Sense in the HFpEF Framework? What Recent Trials Suggest. J Clin Med 2023; 12:693. [PMID: 36675622 PMCID: PMC9867046 DOI: 10.3390/jcm12020693] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 01/06/2023] [Accepted: 01/11/2023] [Indexed: 01/17/2023] Open
Abstract
Left ventricular ejection fraction (LVEF) is universally accepted as a cardiac systolic function index and it provides intuitive interpretation of cardiac performance. Over the last two decades, it has erroneously become the leading feature used by clinicians to characterize the left ventricular function in heart failure (HF). Notably, LVEF sets the basis for structural and functional HF phenotype classification in current guidelines. However, its diagnostic and prognostic role in patients with preserved or mildly reduced contractile function is less clear. This is related to several concerns due to intrinsic technical, methodological and hemodynamic limitations entailed in LVEF measurement that do not describe the chamber's real contractile performance as expressed by pressure volume loop relationship. In patients with HF and preserved ejection fraction (HFpEF), it does not reflect the effective systolic function because it is prone to preload and afterload variability and it does not account for both longitudinal and torsional contraction. Moreover, a repetitive measurement could be assessed over time to better identify HF progression related to natural evolution of disease and to the treatment response. Current gaps may partially explain the causes of negative or neutral effects of traditional medical agents observed in HFpEF. Nevertheless, recent pooled analysis has evidenced the positive effects of new therapies across the LVEF range, suggesting a potential role irrespective of functional status. Additionally, a more detailed analysis of randomized trials suggests that patients with higher LVEF show a risk reduction strictly related to overall cardiovascular (CV) events; on the other hand, patients experiencing lower LVEF values have a decrease in HF-related events. The current paper reports the main limitations and shortcomings in LVEF assessment, with specific focus on patients affected by HFpEF, and it suggests alternative measurements better reflecting the real hemodynamic status. Future investigations may elucidate whether the development of non-invasive stroke volume and longitudinal function measurements could be extensively applied in clinical trials for better phenotyping and screening of HFpEF patients.
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Affiliation(s)
- Alberto Palazzuoli
- Cardiovascular Diseases Unit Cardio Thoracic and Vascular Department, S. Maria alle Scotte Hospital University of Siena, 53100 Siena, Italy
| | - Michele Correale
- Cardiology Unit, Policlinico Riuniti University Hospital, 71122 Foggia, Italy
| | - Massimo Iacoviello
- Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
| | - Edoardo Gronda
- Medicine and Medicine Sub-Specialties Department, Cardio Renal Program, UOC Nephrology, Dialysis and Adult Renal Transplant Program, IRCCS Ca’ Granda Foundation, Ospedale Maggiore Policlinico, 20122 Milano, Italy
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21
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Hwang JA, Shin J, Cho E, Ahn SY, Ko GJ, Kwon YJ, Kim JE. Risk factors associated with the discordance in kidney function decline rate in identical twins. PLoS One 2023; 18:e0284154. [PMID: 37053150 PMCID: PMC10101412 DOI: 10.1371/journal.pone.0284154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 03/26/2023] [Indexed: 04/14/2023] Open
Abstract
BACKGROUND The rate of kidney function decline is different for each individual regardless of any difference in the medical histories. This study set out to identify the risk factors for high discordance in kidney function decline in an identical twin cohort. METHODS This study included 333 identical twins from the Korean Genome and Epidemiology Study who were categorized into two groups according to the estimated glomerular filtration rate (eGFR) decline: the slow and rapid progressor groups. The mean differences of variables were compared between the two groups. We calculated the difference in the annual eGFR change between twins and analyzed the risk factors associated with high discordance in twins who had > 5 mL/min/1.73 m2 /yr of the intra-twin difference in the annual eGFR decline. Identical twins with diabetes and baseline eGFR < 60 mL/min/1.73 m2 were excluded. RESULTS The high discordance twins showed significant differences in body mass index; waist-to-hip ratio; total body fat percentage; and levels of blood hemoglobin, serum fasting glucose, albumin, triglyceride, and uric acid; however, there were no differences in low discordance twins. Multivariable logistic regression showed that blood hemoglobin level is the only significant factor associated with high discordance of eGFR decline in twins. CONCLUSIONS Blood hemoglobin level may play a role in the individual differences in kidney function decline.
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Affiliation(s)
- Jeong Ah Hwang
- Department of Internal Medicine, Korea University Guro Hospital, Seoul, Republic of Korea
| | - Jaeun Shin
- Department of Internal Medicine, Korea University Guro Hospital, Seoul, Republic of Korea
| | - Eunjung Cho
- Department of Internal Medicine, Korea University Guro Hospital, Seoul, Republic of Korea
| | - Shin Young Ahn
- Department of Internal Medicine, Korea University Guro Hospital, Seoul, Republic of Korea
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Gang-Jee Ko
- Department of Internal Medicine, Korea University Guro Hospital, Seoul, Republic of Korea
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Young Joo Kwon
- Department of Internal Medicine, Korea University Guro Hospital, Seoul, Republic of Korea
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Ji Eun Kim
- Department of Internal Medicine, Korea University Guro Hospital, Seoul, Republic of Korea
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
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22
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Tsukamoto S, Morita R, Yamada T, Urate S, Azushima K, Uneda K, Kobayashi R, Kanaoka T, Wakui H, Tamura K. Cardiovascular and kidney outcomes of combination therapy with sodium-glucose cotransporter-2 inhibitors and mineralocorticoid receptor antagonists in patients with type 2 diabetes and chronic kidney disease: A systematic review and network meta-analysis. Diabetes Res Clin Pract 2022; 194:110161. [PMID: 36403681 DOI: 10.1016/j.diabres.2022.110161] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 10/25/2022] [Accepted: 11/14/2022] [Indexed: 11/18/2022]
Abstract
AIMS Both sodium-glucose cotransporter-2 (SGLT-2) inhibitors and mineralocorticoid receptor antagonists (MRAs) have been shown to reduce cardiovascular (CV) event in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). However, little evidence pertains to the benefits of their combined use. METHODS We systematically searched the PubMed, MEDLINE, EMBASE, and Cochrane Library databases through July 2022. We selected randomized controlled trials comparing SGLT-2 inhibitors, MRAs, or SGLT-2 inhibitor + MRA combination therapy, with placebo in patients with T2D and CKD. We performed a network meta-analysis to indirectly compare the treatments. The primary outcome was a composite of CV events. RESULTS Eight studies were selected with 36,186 patients. The primary outcome was significantly improved in the combination therapy group compared with the other groups (RR [95% CI]; vs SGLT-2 inhibitors, 0.76 [0.60; 0.96]; vs MRAs, 0.66 [0.53; 0.82]; vs placebo, 0.58 [0.47; 0.73]). Additionally, the combination therapy was associated with a considerable reduction in the risk of hyperkalemia (RR vs MRA, 0.43 [0.23; 0.79]). CONCLUSION Combination of SGLT-2 inhibitors and MRAs potentially reduced CV events compared with SGLT-2 inhibitors or MRAs alone. This combination may be a candidate treatment strategy for patients with T2D and CKD.
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Affiliation(s)
- Shunichiro Tsukamoto
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Ryutaro Morita
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Takayuki Yamada
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan; Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
| | - Shingo Urate
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Kengo Azushima
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Kazushi Uneda
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan; Department of Kampo Medicine, Aizu Medical Center, Fukushima Medical University, Aizuwakamatsu, Japan
| | - Ryu Kobayashi
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Tomohiko Kanaoka
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Hiromichi Wakui
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
| | - Kouichi Tamura
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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23
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Alicic RZ, Neumiller JJ, Galindo RJ, Tuttle KR. Use of Glucose-Lowering Agents in Diabetes and CKD. Kidney Int Rep 2022; 7:2589-2607. [PMID: 36506243 PMCID: PMC9727535 DOI: 10.1016/j.ekir.2022.09.018] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 08/31/2022] [Accepted: 09/19/2022] [Indexed: 12/15/2022] Open
Abstract
Diabetes is the most common cause of kidney failure worldwide. Patients with diabetes and chronic kidney disease (CKD) are also at markedly higher risk of cardiovascular disease, particularly heart failure (HF), and death. Through the processes of gluconeogenesis and glucose reabsorption, the kidney plays a central role in glucose homeostasis. Insulin resistance is an early alteration observed in CKD, worsened by the frequent presence of hypertension, obesity, and ongoing chronic inflammation, and oxidative stress. Management of diabetes in moderate to severe CKD warrants special consideration because of changes in glucose and insulin homeostasis and altered metabolism of glucose-lowering therapies. Kidney failure and initiation of kidney replacement therapy by dialysis adds to management complexity by further limiting therapeutic options, and predisposing individuals to hypoglycemia and hyperglycemia. Glycemic goals should be individualized, considering CKD severity, presence of macrovascular and microvascular complications, and life expectancy. A general hemoglobin A1c (HbA1c) goal of approximately 7% may be appropriate in earlier stages of CKD, with more relaxed targets often appropriate in later stages. Use of sodium glucose cotransporter2 (SGLT2) inhibitors and glucagon like peptide-1 receptor agonists (GLP-1RAs) meaningfully improves kidney and heart outcomes for patients with diabetes and CKD, irrespective of HbA1c targets, and are now part of guideline-directed medical therapy in this high-risk population. Delivery of optimal care for patients with diabetes and CKD will require collaboration across health care specialties and disciplines.
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Affiliation(s)
- Radica Z. Alicic
- Providence Medical Research Center, Providence Health Care, Spokane, Washington, USA
- Department of Medicine, University of Washington School of Medicine, Spokane and Seattle, Washington, USA
- Correspondence: Radica Z. Alicic, Providence Medical Research Center, 105 West 8th Avenue, Suite 250E, Spokane, Washington 99204, USA.
| | - Joshua J. Neumiller
- Providence Medical Research Center, Providence Health Care, Spokane, Washington, USA
- Department of Pharmacotherapy, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, Washington, USA
| | - Rodolfo J. Galindo
- Department of Medicine, Division of Endocrinology, Emory University School of Medicine
| | - Katherine R. Tuttle
- Providence Medical Research Center, Providence Health Care, Spokane, Washington, USA
- Department of Medicine, University of Washington School of Medicine, Spokane and Seattle, Washington, USA
- Nephrology Division, Kidney Research Institute and Institute of Translational Health Sciences, University of Washington, Spokane and Seattle, Washington, USA
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24
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Wilson PC, Muto Y, Wu H, Karihaloo A, Waikar SS, Humphreys BD. Multimodal single cell sequencing implicates chromatin accessibility and genetic background in diabetic kidney disease progression. Nat Commun 2022; 13:5253. [PMID: 36068241 PMCID: PMC9448792 DOI: 10.1038/s41467-022-32972-z] [Citation(s) in RCA: 76] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 08/25/2022] [Indexed: 11/09/2022] Open
Abstract
The proximal tubule is a key regulator of kidney function and glucose metabolism. Diabetic kidney disease leads to proximal tubule injury and changes in chromatin accessibility that modify the activity of transcription factors involved in glucose metabolism and inflammation. Here we use single nucleus RNA and ATAC sequencing to show that diabetic kidney disease leads to reduced accessibility of glucocorticoid receptor binding sites and an injury-associated expression signature in the proximal tubule. We hypothesize that chromatin accessibility is regulated by genetic background and closely-intertwined with metabolic memory, which pre-programs the proximal tubule to respond differently to external stimuli. Glucocorticoid excess has long been known to increase risk for type 2 diabetes, which raises the possibility that glucocorticoid receptor inhibition may mitigate the adverse metabolic effects of diabetic kidney disease.
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Affiliation(s)
- Parker C Wilson
- Division of Anatomic and Molecular Pathology, Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, USA
| | - Yoshiharu Muto
- Division of Nephrology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA
| | - Haojia Wu
- Division of Nephrology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA
| | - Anil Karihaloo
- Novo Nordisk Research Center Seattle Inc, Seattle, WA, USA
| | - Sushrut S Waikar
- Section of Nephrology, Department of Medicine, Boston University School of Medicine, Boston Medical Center, Boston, MA, USA
| | - Benjamin D Humphreys
- Division of Nephrology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA.
- Department of Developmental Biology, Washington University in St. Louis, St. Louis, MO, USA.
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25
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Gorica E, Mohammed SA, Ambrosini S, Calderone V, Costantino S, Paneni F. Epi-Drugs in Heart Failure. Front Cardiovasc Med 2022; 9:923014. [PMID: 35911511 PMCID: PMC9326055 DOI: 10.3389/fcvm.2022.923014] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 06/17/2022] [Indexed: 11/13/2022] Open
Abstract
Unveiling the secrets of genome's flexibility does not only foster new research in the field, but also gives rise to the exploration and development of novel epigenetic-based therapies as an approach to alleviate disease phenotypes. A better understanding of chromatin biology (DNA/histone complexes) and non-coding RNAs (ncRNAs) has enabled the development of epigenetic drugs able to modulate transcriptional programs implicated in cardiovascular diseases. This particularly applies to heart failure, where epigenetic networks have shown to underpin several pathological features, such as left ventricular hypertrophy, fibrosis, cardiomyocyte apoptosis and microvascular dysfunction. Targeting epigenetic signals might represent a promising approach, especially in patients with heart failure with preserved ejection fraction (HFpEF), where prognosis remains poor and breakthrough therapies have yet to be approved. In this setting, epigenetics can be employed for the development of customized therapeutic approaches thus paving the way for personalized medicine. Even though the beneficial effects of epi-drugs are gaining attention, the number of epigenetic compounds used in the clinical practice remains low suggesting that more selective epi-drugs are needed. From DNA-methylation changes to non-coding RNAs, we can establish brand-new regulations for drug targets with the aim of restoring healthy epigenomes and transcriptional programs in the failing heart. In the present review, we bring the timeline of epi-drug discovery and development, thus highlighting the emerging role of epigenetic therapies in heart failure.
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Affiliation(s)
- Era Gorica
- Center for Molecular Cardiology, University of Zürich, Schlieren, Switzerland
- Department of Pharmacy, University of Pisa, Pisa, Italy
| | - Shafeeq A. Mohammed
- Center for Molecular Cardiology, University of Zürich, Schlieren, Switzerland
| | - Samuele Ambrosini
- Center for Molecular Cardiology, University of Zürich, Schlieren, Switzerland
| | | | - Sarah Costantino
- Center for Molecular Cardiology, University of Zürich, Schlieren, Switzerland
- Department of Cardiology, University Heart Center, Zurich, Switzerland
| | - Francesco Paneni
- Center for Molecular Cardiology, University of Zürich, Schlieren, Switzerland
- Department of Cardiology, University Heart Center, Zurich, Switzerland
- Department of Research and Education, University Hospital Zurich, Zurich, Switzerland
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26
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Alcidi G, Goffredo G, Correale M, Brunetti ND, Iacoviello M. Brain Natriuretic Peptide Biomarkers in Current Clinical and Therapeutic Scenarios of Heart Failure. J Clin Med 2022; 11:3192. [PMID: 35683578 PMCID: PMC9181765 DOI: 10.3390/jcm11113192] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Revised: 05/23/2022] [Accepted: 06/01/2022] [Indexed: 01/25/2023] Open
Abstract
Brain natriuretic peptide (BNP) and its inactive N-terminal fragment, NT-proBNP, are serum biomarkers with key roles in the management of heart failure (HF). An increase in the serum levels of these peptides is closely associated with the pathophysiological mechanisms underlying HF such as the presence of structural and functional cardiac abnormalities, myocardial stretch associated with a high filling pressure and neuro-hormonal activation. As BNP and NT-proBNP measurements are possible, several studies have investigated their clinical utility in the diagnosis, prognostic stratification, monitoring and guiding therapy of patients with HF. BNP and NT-proBNP have also been used as criteria for enrollment in randomized trials evaluating the efficacy of new therapeutic strategies for HF. Nevertheless, the use of natriuretic peptides is still limited in clinical practice due to the controversial aspect of their use in different clinical settings. The purpose of this review is to discuss the main issues associated with using BNP and NT-proBNP serum levels in the management of patients with HF under current clinical and therapeutic scenarios.
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Affiliation(s)
- Gianmarco Alcidi
- Department of Medical and Surgical Sciences, University of Foggia, Viale Luigi Pinto 1, 71122 Foggia, Italy; (G.A.); (M.C.); (N.D.B.)
- Cardiology Unit, Polyclinic University Hospital Riuniti of Foggia, Viale Luigi Pinto 1, 71122 Foggia, Italy
| | - Giovanni Goffredo
- Department of Medical and Surgical Sciences, University of Foggia, Viale Luigi Pinto 1, 71122 Foggia, Italy; (G.A.); (M.C.); (N.D.B.)
- Cardiology Unit, Polyclinic University Hospital Riuniti of Foggia, Viale Luigi Pinto 1, 71122 Foggia, Italy
| | - Michele Correale
- Department of Medical and Surgical Sciences, University of Foggia, Viale Luigi Pinto 1, 71122 Foggia, Italy; (G.A.); (M.C.); (N.D.B.)
- Cardiology Unit, Polyclinic University Hospital Riuniti of Foggia, Viale Luigi Pinto 1, 71122 Foggia, Italy
| | - Natale Daniele Brunetti
- Department of Medical and Surgical Sciences, University of Foggia, Viale Luigi Pinto 1, 71122 Foggia, Italy; (G.A.); (M.C.); (N.D.B.)
- Cardiology Unit, Polyclinic University Hospital Riuniti of Foggia, Viale Luigi Pinto 1, 71122 Foggia, Italy
| | - Massimo Iacoviello
- Department of Medical and Surgical Sciences, University of Foggia, Viale Luigi Pinto 1, 71122 Foggia, Italy; (G.A.); (M.C.); (N.D.B.)
- Cardiology Unit, Polyclinic University Hospital Riuniti of Foggia, Viale Luigi Pinto 1, 71122 Foggia, Italy
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27
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Wu K, Fei L, Wang X, Lei Y, Liu Y, Xu W, Chen J, Zhu E, Zhong M, Huang M, Jiang X, Yin F, Yan Z, Zhao X, Tang C, Patzak A, Liu X, Zheng Z. ZIP14 is involved in iron deposition and triggers ferroptosis in diabetic nephropathy. Metallomics 2022; 14:6596292. [PMID: 35641158 DOI: 10.1093/mtomcs/mfac034] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Accepted: 05/25/2022] [Indexed: 11/12/2022]
Abstract
Ferroptosis is caused by lipid peroxidation and iron accumulation and can cause cell death. Abnormally expressed iron transporters are involved in ferroptosis in a variety of diseases. ZRT/IRT-like protein 14 (ZIP14) is a transport protein that can mediate cellular uptake of iron, zinc and manganese. Herein, we have tested the hypothesis that the divalent metal transporter ZIP14 is involved in the initiation of ferroptosis in diabetic nephropathy (DN). DN was induced in eight-week old male rats by streptozotocin (STZ) before analysis of the degree of renal tubular injury. In addition, an in vitro model of DN in HK2 cells was used. We showed that ZIP14 was upregulated and Fe2+ levels increased both in vivo and in vitro. Expression of glutathione peroxidase 4 (GPX4) and the level of glutathione (GSH) were reduced, whereas that of malondialdehyde (MDA) increased. Ferrostatin-1(Fer-1) treatment reduced the expression of ZIP14 and the levels of Fe2+ and MDA, which is consistent with ferroptosis. Fer-1 improved kidney function in DN rats. This was characterized by urine levels of protein-to-creatinine ratio, α 1-microglobulin and N-acetyl-β-D-glucosaminidase. Our study demonstrates a novel role for ZIP14 in diabetic kidney injury mediated by ferroptosis, and suggests a potential new therapeutic approach for the treatment of diabetic nephropathy.
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Affiliation(s)
- Keping Wu
- Department of Nephrology, Kidney and Urology Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China.,Department of Nephrology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Lingyan Fei
- Department of Nephrology, Kidney and Urology Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China.,Institute of Translation Physiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin.,Department of Nephrology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xiaohua Wang
- Department of Nephrology, Kidney and Urology Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Yan Lei
- Department of Nephrology, Kidney and Urology Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Yu Liu
- Department of Nephrology, Kidney and Urology Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Wenqian Xu
- Department of Nephrology, Kidney and Urology Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Jiasi Chen
- Department of Nephrology, Kidney and Urology Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Enyi Zhu
- Department of Nephrology, Kidney and Urology Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Ming Zhong
- Department of Nephrology, Kidney and Urology Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Mingcheng Huang
- Department of Nephrology, Kidney and Urology Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Xi Jiang
- Department of Clinical Laboratory, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Fei Yin
- Department of Thoracic Surgery, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Zhijun Yan
- Department of Anesthesia, The First Affiliated Hospital of Nanhua University, Hunan, China
| | - Xinying Zhao
- Department of Hematology, Guangzhou Women and Children's Medical center, Guangzhou Medical University, Guangzhou, China
| | - Chun Tang
- Department of Nephrology, Kidney and Urology Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Andreas Patzak
- Institute of Translation Physiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin
| | - Xiaoping Liu
- Department of Hematology, Guangzhou Women and Children's Medical center, Guangzhou Medical University, Guangzhou, China
| | - Zhihua Zheng
- Department of Nephrology, Kidney and Urology Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
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28
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Cui Y, Fang J, Guo H, Cui H, Deng J, Yu S, Gou L, Wang F, Ma X, Ren Z, Xie Y, Geng Y, Wang Y, Zuo Z. Notch3-Mediated mTOR Signaling Pathway Is Involved in High Glucose-Induced Autophagy in Bovine Kidney Epithelial Cells. Molecules 2022; 27:molecules27103121. [PMID: 35630598 PMCID: PMC9143202 DOI: 10.3390/molecules27103121] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 05/04/2022] [Accepted: 05/09/2022] [Indexed: 02/04/2023] Open
Abstract
It is reported that Notch3 and mTOR signaling pathways are involved in autophagy, and both can be activated by high glucose (HG). However, the relationship between Notch3 and mTOR and how Notch3 affects mTOR to regulate HG-induced autophagy in bovine kidney epithelial cells is still unclear. The purpose of this study is to explore how Notch3 affects mTOR to modulate HG-induced autophagy in bovine kidney cells. Our results showed that HG treatment significantly decreased the cell viability of MDBK cells in a dose-dependent manner. HG treatment significantly increased the expression of LC3-II/I ratio and Beclin1 protein and significantly decreased the expression of p62 protein. Consistently, LC3 fluorescence signal formation was detected by immunofluorescence in both dose and time-dependent manners. In addition, HG treatment significantly increased the expression of Notch3 protein and decreased the expression of the p-mTOR protein in both dose and time-dependent manners. Inhibition of Notch3 upregulated the expression of p-mTOR and p62 protein, and downregulated the expression of LC3-II/I ratio and Beclin1 protein. Besides, the function of Notch3 was investigated. In this study, inhibition of Notch3 activity significantly increased the viability of HG-stimulated MDBK cells. In summary, our results revealed that the Notch3-mediated mTOR signaling pathway was involved in HG-induced autophagy in MDBK cells.
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Affiliation(s)
- Yaocheng Cui
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (Y.C.); (J.F.); (H.G.); (H.C.); (J.D.); (S.Y.); (L.G.); (X.M.); (Z.R.); (Y.X.); (Y.G.); (Y.W.)
| | - Jing Fang
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (Y.C.); (J.F.); (H.G.); (H.C.); (J.D.); (S.Y.); (L.G.); (X.M.); (Z.R.); (Y.X.); (Y.G.); (Y.W.)
| | - Hongrui Guo
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (Y.C.); (J.F.); (H.G.); (H.C.); (J.D.); (S.Y.); (L.G.); (X.M.); (Z.R.); (Y.X.); (Y.G.); (Y.W.)
| | - Hengmin Cui
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (Y.C.); (J.F.); (H.G.); (H.C.); (J.D.); (S.Y.); (L.G.); (X.M.); (Z.R.); (Y.X.); (Y.G.); (Y.W.)
| | - Junliang Deng
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (Y.C.); (J.F.); (H.G.); (H.C.); (J.D.); (S.Y.); (L.G.); (X.M.); (Z.R.); (Y.X.); (Y.G.); (Y.W.)
| | - Shumin Yu
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (Y.C.); (J.F.); (H.G.); (H.C.); (J.D.); (S.Y.); (L.G.); (X.M.); (Z.R.); (Y.X.); (Y.G.); (Y.W.)
| | - Liping Gou
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (Y.C.); (J.F.); (H.G.); (H.C.); (J.D.); (S.Y.); (L.G.); (X.M.); (Z.R.); (Y.X.); (Y.G.); (Y.W.)
| | - Fengyuan Wang
- College of Animal & Veterinary Sciences, Southwest Minzu University, Chengdu 610041, China;
| | - Xiaoping Ma
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (Y.C.); (J.F.); (H.G.); (H.C.); (J.D.); (S.Y.); (L.G.); (X.M.); (Z.R.); (Y.X.); (Y.G.); (Y.W.)
| | - Zhihua Ren
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (Y.C.); (J.F.); (H.G.); (H.C.); (J.D.); (S.Y.); (L.G.); (X.M.); (Z.R.); (Y.X.); (Y.G.); (Y.W.)
| | - Yue Xie
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (Y.C.); (J.F.); (H.G.); (H.C.); (J.D.); (S.Y.); (L.G.); (X.M.); (Z.R.); (Y.X.); (Y.G.); (Y.W.)
| | - Yi Geng
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (Y.C.); (J.F.); (H.G.); (H.C.); (J.D.); (S.Y.); (L.G.); (X.M.); (Z.R.); (Y.X.); (Y.G.); (Y.W.)
| | - Ya Wang
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (Y.C.); (J.F.); (H.G.); (H.C.); (J.D.); (S.Y.); (L.G.); (X.M.); (Z.R.); (Y.X.); (Y.G.); (Y.W.)
| | - Zhicai Zuo
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China; (Y.C.); (J.F.); (H.G.); (H.C.); (J.D.); (S.Y.); (L.G.); (X.M.); (Z.R.); (Y.X.); (Y.G.); (Y.W.)
- Correspondence: ; Tel.: +86-180-3064-8320
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Gronda E, Lopaschuk GD, Arduini A, Santoro A, Benincasa G, Palazzuoli A, Gabrielli D, Napoli C. Mechanisms of action of SGLT2 inhibitors and their beneficial effects on the cardiorenal axis. Can J Physiol Pharmacol 2022; 100:93-106. [PMID: 35112597 DOI: 10.1139/cjpp-2021-0399] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Large clinical studies conducted with sodium-glucose co-transporter 2 inhibitors (SGLT2i) in patients with type 2 diabetes and heart failure with reduced ejection fraction have demonstrated their ability to achieve both cardiac and kidney benefits. Although there is huge evidence on SGLT2i-mediated clinical benefits both in diabetic and non-diabetic patients, the pathophysiological mechanisms underlying their efficacy are still poorly understood. Some favorable mechanisms are likely due to the prompt glycosuric action which is associated with natriuretic effects leading to hemodynamic benefits as well as a reduction in glomerular hyperfiltration and renin-angiotensin-aldosterone system activation. In addition to the renal mechanisms, SGLT2i may play a relevant role in cardiorenal axis protection by improving the cardiomyocyte metabolism, by exerting anti-fibrotic and anti-inflammatory actions, and by increasing cardioprotective adipokine expression. New studies will be needed to better understand the specific molecular mechanisms that mediate the SGLT2i favorable effects in patients suffering diabetes. Our aim is to first discuss about the molecular mechanisms underlying the cardiovascular benefits of SGLT2i in each of the main organs involved in the cardiorenal axis. Furthermore, we update on the most recent clinical trials evaluating the beneficial effects of SGLT2i in treatment of both diabetic and non-diabetic patients suffering heart failure.
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Affiliation(s)
- Edoardo Gronda
- Dipartimento di Medicina e Specialità Mediche, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico di Milano UOC di Nefrologia, Dialisi e Trapianto Renale dell'adulto, Milan, Italy
| | - Gary D Lopaschuk
- Cardiovascular Research Centre, University of Alberta, 423 Heritage Medical Research Centre, Edmonton, AB T6G 2S2, Canada
| | - Arduino Arduini
- Department of Research and Development, CoreQuest Sagl, Tecnopolo, 6934 Bioggio, Switzerland
| | - Antonio Santoro
- Nephrology Unit, S. Orsola-Malpighi Hospital, University of Bologna, Italy
| | - Giuditta Benincasa
- Clinical Department of Internal Medicine and Specialistic Units, Azienda Ospedaliera Universitaria and Department of Advanced Medical and Surgical Sciences (DAMSS), University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Alberto Palazzuoli
- Cardiovascular Diseases Unit, Department of Medical Sciences, Le Scotte Hospital University of Siena, Italy
| | - Domenico Gabrielli
- Division of Cardiology, San Camillo Hospital, Rome, Italy and Associazione Nazionale Medici Cardiologi Ospedalieri (ANMCO)
| | - Claudio Napoli
- Clinical Department of Internal Medicine and Specialistic Units, Azienda Ospedaliera Universitaria and Department of Advanced Medical and Surgical Sciences (DAMSS), University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
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30
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Marfella R, D'Onofrio N, Trotta MC, Sardu C, Scisciola L, Amarelli C, Balestrieri ML, Grimaldi V, Mansueto G, Esposito S, D'Amico M, Golino P, Signoriello G, De Feo M, Maiello C, Napoli C, Paolisso G. Sodium/glucose cotransporter 2 (SGLT2) inhibitors improve cardiac function by reducing JunD expression in human diabetic hearts. Metabolism 2022; 127:154936. [PMID: 34801581 DOI: 10.1016/j.metabol.2021.154936] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 11/08/2021] [Accepted: 11/09/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND The pathogenesis of experimental diabetic cardiomyopathy may involve the activator protein 1 (AP-1) member, JunD. Using non-diabetic heart transplant (HTX) in recipients with diabetes, we examined the effects of the diabetic milieu (hyperglycemia and insulin resistance) on cardiac JunD expression over 12 months. Because sodium/glucose cotransporter-2 inhibitors (SGLT2i) significantly reverse high glucose-induced AP-1 binding in the proximal tubular cell, we investigated JunD expression in a subgroup of type 2 diabetic recipients receiving SGLT2i treatment. METHODS We evaluated 77 first HTX recipients (40 and 37 patients with and without diabetes, respectively). Among the recipients with diabetes, 17 (45.9%) were receiving SGLT2i treatment. HTX recipients underwent standard clinical evaluation (metabolic status, echocardiography, coronary computed tomography angiography, and endomyocardial biopsy). In the biopsy samples, we evaluated JunD, insulin receptor substrates 1 and 2 (IRS1 and IRS2), peroxisome proliferator-activated receptor-γ (PPAR-γ), and ceramide levels using real-time polymerase chain reaction and immunofluorescence. The biopsy evaluations in this study were performed at 1-4 weeks (basal), 5-12 weeks (intermediate), and up to 48 weeks (final, end of 12-month follow-up) after HTX. RESULTS There was a significant early and progressive increase in the cardiac expression of JunD/PPAR-γ and ceramide levels, along with a significant decrease in IRS1 and IRS2 in recipients with diabetes but not in those without diabetes. These molecular changes were blunted in patients with diabetes receiving SGLT2i treatment. CONCLUSION Early pathogenesis in human diabetic cardiomyopathy is associated with JunD/PPAR-γ overexpression and lipid accumulation following HTX in recipients with diabetes. Remarkably, this phenomenon was reduced by concomitant therapy with SGLT2i, which acted directly on diabetic hearts.
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Affiliation(s)
- Raffaele Marfella
- Department of Advanced Medical and Surgical Sciences, Università degli Studi della Campania "Luigi Vanvitelli", 80138 Naples, Italy; Mediterranea Cardiocentro, Naples, Italy.
| | - Nunzia D'Onofrio
- Department of Precision Medicine, the University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Maria Consiglia Trotta
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Celestino Sardu
- Department of Advanced Medical and Surgical Sciences, Università degli Studi della Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Lucia Scisciola
- Department of Advanced Medical and Surgical Sciences, Università degli Studi della Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Cristiano Amarelli
- Unit of Cardiac Surgery and Transplants, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy
| | - Maria Luisa Balestrieri
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Vincenzo Grimaldi
- Department of Advanced Medical and Surgical Sciences, Università degli Studi della Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Gelsomina Mansueto
- Department of Advanced Medical and Surgical Sciences, Università degli Studi della Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | | | - Michele D'Amico
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Paolo Golino
- Cardiology Division, University "L. Vanvitelli" - Monaldi Hospital, 80131 Naples, Italy
| | - Giuseppe Signoriello
- Statistical Unit, Department of Mental Health and Public Medicine, University of Campania, Naples, Italy
| | - Marisa De Feo
- Department of Cardio-Thoracic Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Ciro Maiello
- Unit of Cardiac Surgery and Transplants, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy
| | - Claudio Napoli
- Department of Advanced Medical and Surgical Sciences, Università degli Studi della Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Giuseppe Paolisso
- Department of Advanced Medical and Surgical Sciences, Università degli Studi della Campania "Luigi Vanvitelli", 80138 Naples, Italy; Mediterranea Cardiocentro, Naples, Italy
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Lisco G, Giagulli VA, Iovino M, Zupo R, Guastamacchia E, De Pergola G, Iacoviello M, Triggiani V. Endocrine system dysfunction and chronic heart failure: a clinical perspective. Endocrine 2022; 75:360-376. [PMID: 34713389 PMCID: PMC8553109 DOI: 10.1007/s12020-021-02912-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Accepted: 10/13/2021] [Indexed: 11/01/2022]
Abstract
Chronic heart failure (CHF) leads to an excess of urgent ambulatory visits, recurrent hospital admissions, morbidity, and mortality regardless of medical and non-medical management of the disease. This excess of risk may be attributable, at least in part, to comorbid conditions influencing the development and progression of CHF. In this perspective, the authors examined and described the most common endocrine disorders observed in patients with CHF, particularly in individuals with reduced ejection fraction, aiming to qualify the risks, quantify the epidemiological burden and discuss about the potential role of endocrine treatment. Thyroid dysfunction is commonly observed in patients with CHF, and sometimes it could be the consequence of certain medications (e.g., amiodarone). Male and female hypogonadism may also coexist in this clinical context, contributing to deteriorating the prognosis of these patients. Furthermore, growth hormone deficiency may affect the development of adult myocardium and predispose to CHF. Limited recommendation suggests to screen endocrine disorders in CHF patients, but it could be interesting to evaluate possible endocrine dysfunction in this setting, especially when a high suspicion coexists. Data referring to long-term safety and effectiveness of endocrine treatments in patients with CHF are limited, and their impact on several "hard" endpoints (such as hospital admission, all-cause, and cardiovascular mortality) are still poorly understood.
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Affiliation(s)
- Giuseppe Lisco
- Interdisciplinary Department of Medicine, Section of Internal Medicine, Geriatrics, Endocrinology and Rare Diseases, University of Bari "Aldo Moro", School of Medicine, Policlinico, Piazza Giulio Cesare 11, 70124, Bari, Italy
| | - Vito Angelo Giagulli
- Interdisciplinary Department of Medicine, Section of Internal Medicine, Geriatrics, Endocrinology and Rare Diseases, University of Bari "Aldo Moro", School of Medicine, Policlinico, Piazza Giulio Cesare 11, 70124, Bari, Italy
| | - Michele Iovino
- Interdisciplinary Department of Medicine, Section of Internal Medicine, Geriatrics, Endocrinology and Rare Diseases, University of Bari "Aldo Moro", School of Medicine, Policlinico, Piazza Giulio Cesare 11, 70124, Bari, Italy
| | - Roberta Zupo
- National Institute of Gastroenterology, Saverio de Bellis, Research Hospital, Castellana Grotte, Bari, Italy
| | - Edoardo Guastamacchia
- Interdisciplinary Department of Medicine, Section of Internal Medicine, Geriatrics, Endocrinology and Rare Diseases, University of Bari "Aldo Moro", School of Medicine, Policlinico, Piazza Giulio Cesare 11, 70124, Bari, Italy
| | - Giovanni De Pergola
- National Institute of Gastroenterology, Saverio de Bellis, Research Hospital, Castellana Grotte, Bari, Italy
- Clinical Nutrition Unit, Medical Oncology, Department of Internal Medicine and Clinical Oncology, University of Bari, School of Medicine, Policlinico, Piazza Giulio Cesare 11, 70124, Bari, Italy
| | - Massimo Iacoviello
- Department of Medical and Surgical Sciences, Cardiology Department, University of Foggia, Foggia, Italy
| | - Vincenzo Triggiani
- Interdisciplinary Department of Medicine, Section of Internal Medicine, Geriatrics, Endocrinology and Rare Diseases, University of Bari "Aldo Moro", School of Medicine, Policlinico, Piazza Giulio Cesare 11, 70124, Bari, Italy.
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Benedetti R, Benincasa G, Glass K, Chianese U, Vietri MT, Congi R, Altucci L, Napoli C. Effects of novel SGLT2 inhibitors on cancer incidence in hyperglycemic patients: a meta-analysis of randomized clinical trials. Pharmacol Res 2021; 175:106039. [PMID: 34929299 DOI: 10.1016/j.phrs.2021.106039] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Revised: 12/10/2021] [Accepted: 12/15/2021] [Indexed: 02/06/2023]
Abstract
Epidemiological evidence shows that diabetic patients have an increased cancer risk and a higher mortality rate. Glucose could play a central role in metabolism and growth of many tumor types, and this possible mechanism is supported by the high rate of glucose demand and uptake in cancer. Thus, growing evidence suggests that hyperglycemia contributes to cancer progression but also to its onset. Many mechanisms underlying this association have been hypothesized, such as insulin resistance, hyperinsulinemia, and increased inflammatory processes. Inflammation is a common pathophysiological feature in both diabetic and oncological patients, and inflammation linked to high glucose levels sensitizes microenvironment to tumorigenesis, promoting the development of malignant lesions by altering and sustaining a pathological condition in tissues. Glycemic control is the first goal of antidiabetic therapy, and glucose level reduction has also been associated with favorable outcomes in cancer. Here, we describe key events in carcinogenesis focusing on hyperglycemia as supporter in tumor progression and in particular, related to the role of a specific hypoglycemic drug class, sodium-glucose linked transporters (SGLTs). We also discuss the use of SGLT2 inhibitors as a novel potential cancer therapy. Our meta-analysis showed that SGLT-2 inhibitors were significantly associated with an overall reduced risk of cancer as compared to placebo (RR = 0.35, CI 0.33-0.37, P = 0. 00) with a particular effectiveness for dapaglifozin and ertuglifozin (RR = 0. 06, CI 0. 06-0. 07 and RR = 0. 22, CI 0. 18-0. 26, respectively). Network Medicine approaches may advance the possible repurposing of these drugs in patients with concomitant diabetes and cancer.
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Affiliation(s)
- Rosaria Benedetti
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Via L. De Crecchio 7, 80138 Naples, Italy
| | - Giuditta Benincasa
- Department of Advanced Medical and Surgical Sciences (DAMSS), University of Campania "Luigi Vanvitelli", Pz. Miraglia 2, 80138 Naples, Italy.
| | - Kimberly Glass
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Ugo Chianese
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Via L. De Crecchio 7, 80138 Naples, Italy
| | - Maria Teresa Vietri
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Via L. De Crecchio 7, 80138 Naples, Italy
| | - Raffaella Congi
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Via L. De Crecchio 7, 80138 Naples, Italy
| | - Lucia Altucci
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Via L. De Crecchio 7, 80138 Naples, Italy; Biogem Institute of Molecular and Genetic Biology, 83031 Ariano Irpino, Italy.
| | - Claudio Napoli
- Department of Advanced Medical and Surgical Sciences (DAMSS), University of Campania "Luigi Vanvitelli", Pz. Miraglia 2, 80138 Naples, Italy; Clinical Department of Internal Medicine and Specialistics, Division of Clinical Immunology, Transfusion Medicine and Transplant Immunology, AOU University of Campania "Luigi Vanvitelli", Via L. De Crecchio 7, 80138 Naples, Italy.
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Sędzikowska A, Szablewski L. Human Glucose Transporters in Renal Glucose Homeostasis. Int J Mol Sci 2021; 22:13522. [PMID: 34948317 PMCID: PMC8708129 DOI: 10.3390/ijms222413522] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 12/13/2021] [Accepted: 12/14/2021] [Indexed: 12/26/2022] Open
Abstract
The kidney plays an important role in glucose homeostasis by releasing glucose into the blood stream to prevent hypoglycemia. It is also responsible for the filtration and subsequent reabsorption or excretion of glucose. As glucose is hydrophilic and soluble in water, it is unable to pass through the lipid bilayer on its own; therefore, transport takes place using carrier proteins localized to the plasma membrane. Both sodium-independent glucose transporters (GLUT proteins) and sodium-dependent glucose transporters (SGLT proteins) are expressed in kidney tissue, and mutations of the genes coding for these glucose transporters lead to renal disorders and diseases, including renal cancers. In addition, several diseases may disturb the expression and/or function of renal glucose transporters. The aim of this review is to describe the role of the kidney in glucose homeostasis and the contribution of glucose transporters in renal physiology and renal diseases.
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Affiliation(s)
| | - Leszek Szablewski
- Chair and Department of General Biology and Parasitology, Medical University of Warsaw, Chalubinskiego 5, 02-004 Warsaw, Poland;
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34
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Napoli C, Gabrielli D, Gronda E. Tandem positive action of SGLT2 inhibitors and ARNI in patients with heart failure. Acta Diabetol 2021; 58:1579-1580. [PMID: 34216234 DOI: 10.1007/s00592-021-01757-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 06/03/2021] [Indexed: 10/20/2022]
Affiliation(s)
- Claudio Napoli
- University Department of Advanced Medical and Surgical Sciences (DAMSS) and Clinical Department of Internal Medicine and Specialistic Units, Azienda Ospedaliera Universitaria, University of Campania "Luigi Vanvitelli", 80138, Naples, Italy.
| | - Domenico Gabrielli
- Division of Cardiology, Azienda Ospedaliera San Camillo Forlanini, Roma, Italy
- Associazione Nazionale Medici Cardiologi Ospedalieri (ANMCO), Florence, Italy
| | - Edoardo Gronda
- Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico Di Milano UOC Di Nefrologia, Dialisi e Trapianto Renale Dell'adulto, Dipartimento Di Medicina E Specialità Mediche, Milan, Italy
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Iacoviello M, Palazzuoli A, Gronda E. Recent advances in pharmacological treatment of heart failure. Eur J Clin Invest 2021; 51:e13624. [PMID: 34043809 PMCID: PMC8596398 DOI: 10.1111/eci.13624] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 05/23/2021] [Accepted: 05/24/2021] [Indexed: 12/20/2022]
Abstract
BACKGROUND Over the last years, several trials offered new evidence on heart failure (HF) treatment. DESIGN AND RESULTS For HF with reduced left ventricular ejection fraction, type 2 sodium-glucose cotransporter inhibitors, aside from sacubitril-valsartan, demonstrated extraordinary efficacy in ameliorating patients' prognosis. Some new molecules (eg vericiguat, omecamtiv mecarbil and ferric carboxymaltose) correct iron deficiency and have shown to be capable of furthering reducing the burden of HF hospitalisation. Finally, there is new evidence on the possible therapeutic approaches of HF patients with mid-range or preserved left ventricular ejection fraction. CONCLUSIONS This review aimed to revise the main novelties in the field of HF therapy and focus on how the daily clinical approach to patient treatment is changing.
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Affiliation(s)
- Massimo Iacoviello
- Cardiology UnitDepartment of Medical and Surgical ScienceUniversity of FoggiaFoggiaItaly
| | - Alberto Palazzuoli
- Cardiovascular Diseases UnitDepartment of Internal MedicineS. Maria alle Scotte HospitalUniversity of SienaSienaItaly
| | - Edoardo Gronda
- Dialisi e Trapianto Renale dell’adulto Dipartimento Di Medicina e Specialità MedicheFondazione IRCCS Ca’ Granda ‐ Ospedale Maggiore Policlinico di Milano UOC di NefrologiaMilanItaly
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36
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Sharma I, Liao Y, Zheng X, Kanwar YS. New Pandemic: Obesity and Associated Nephropathy. Front Med (Lausanne) 2021; 8:673556. [PMID: 34268323 PMCID: PMC8275856 DOI: 10.3389/fmed.2021.673556] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 05/28/2021] [Indexed: 12/12/2022] Open
Abstract
Incidence of obesity related renal disorders have increased 10-folds in recent years. One of the consequences of obesity is an increased glomerular filtration rate (GFR) that leads to the enlargement of the renal glomerulus, i.e., glomerulomegaly. This heightened hyper-filtration in the setting of type 2 diabetes irreparably damages the kidney and leads to progression of end stage renal disease (ESRD). The patients suffering from type 2 diabetes have progressive proteinuria, and eventually one third of them develop chronic kidney disease (CKD) and ESRD. For ameliorating the progression of CKD, inhibitors of renin angiotensin aldosterone system (RAAS) seemed to be effective, but on a short-term basis only. Long term and stable treatment strategies like weight loss via restricted or hypo-caloric diet or bariatric surgery have yielded better promising results in terms of amelioration of proteinuria and maintenance of normal GFR. Body mass index (BMI) is considered as a traditional marker for the onset of obesity, but apparently, it is not a reliable indicator, and thus there is a need for more precise evaluation of regional fat distribution and amount of muscle mass. With respect to the pathogenesis, recent investigations have suggested perturbation in fatty acid and cholesterol metabolism as the critical mediators in ectopic renal lipid accumulation associated with inflammation, increased generation of ROS, RAAS activation and consequential tubulo-interstitial injury. This review summarizes the renewed approaches for the obesity assessment and evaluation of the pathogenesis of CKD, altered renal hemodynamics and potential therapeutic targets.
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Affiliation(s)
- Isha Sharma
- Departments of Pathology and Medicine, Northwestern University, Chicago, IL, United States
| | - Yingjun Liao
- Departments of Pathology and Medicine, Northwestern University, Chicago, IL, United States.,Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, China
| | - Xiaoping Zheng
- Departments of Pathology and Medicine, Northwestern University, Chicago, IL, United States.,Department of Urology, Third Xiangya Hospital, Central South University, Changsha, China
| | - Yashpal S Kanwar
- Departments of Pathology and Medicine, Northwestern University, Chicago, IL, United States
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Napoli C, Bontempo P, Palmieri V, Coscioni E, Maiello C, Donatelli F, Benincasa G. Epigenetic Therapies for Heart Failure: Current Insights and Future Potential. Vasc Health Risk Manag 2021; 17:247-254. [PMID: 34079271 PMCID: PMC8164213 DOI: 10.2147/vhrm.s287082] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 04/29/2021] [Indexed: 12/20/2022] Open
Abstract
Despite the current reductionist approach providing an optimal indication for diagnosis and treatment of patients with heart failure with reduced ejection fraction (HFrEF), there are no standard pharmacological therapies for heart failure with preserved ejection fraction (HFpEF). Although in its infancy in cardiovascular diseases, the epigenetic-based therapy ("epidrugs") is capturing the interest of physician community. In fact, an increasing number of controlled clinical trials is evaluating the putative beneficial effects of: 1) direct epigenetic-oriented drugs, eg, apabetalone, and 2) repurposed drugs with a possible indirect epigenetic interference, eg, metformin, statins, sodium glucose transporter inhibitors 2 (SGLT2i), and omega 3 polyunsaturated fatty acids (PUFAs) in both HFrEF and HFpEF, separately. Apabetalone is the first and unique direct epidrug tested in cardiovascular patients to date, and the BETonMACE trial has reported a reduction in first HF hospitalization (any EF value) and cardiovascular death in patients with type 2 diabetes and recent acute coronary syndrome, suggesting a possible role in secondary prevention. Patients with HFpEF seem to benefit from supplementation to the standard therapy with statins, metformin, and SGLT2i owing to their ability in reducing mortality. In contrast, the vasodilator hydralazine, with or without isosorbide dinitrate, did not provide beneficial effects. In HFrEF, metformin and SGLT2i could reduce the risk of incident HF and mortality in affected patients whereas clinical trials based on statins provided mixed results. Furthermore, PUFAs diet supplementation was significantly associated with reduced cardiovascular risk in both HFpEF and HFrEF. Future large trials will reveal whether direct and indirect epitherapy will remain a work in progress or become a useful way to customize the therapy in the real-world management of HFpEF and HFrEF. Our goal is to discuss the recent advancement in the epitherapy as a possible way to improve personalized therapy of HF.
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Affiliation(s)
- Claudio Napoli
- Department of Advanced Medical and Surgical Sciences (DAMSS), University of Campania "Luigi Vanvitelli", Naples, 80138, Italy
| | - Paola Bontempo
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, 80138, Italy
| | - Vittorio Palmieri
- Department of Cardiac Surgery and Transplantation, Heart Transplantation Unit in Adults of the 'Ospedali dei Colli Monaldi-Cotugno-CTO', Naples, Italy
| | - Enrico Coscioni
- Department of Cardiac Surgery, Azienda Ospedaliera Universitaria San Giovanni di Dio e Ruggi d'Aragona, Salerno, Italy
| | - Ciro Maiello
- Department of Cardiovascular Surgery and Transplants, Monaldi Hospital, Azienda dei Colli, Naples, Italy
| | - Francesco Donatelli
- Chair of Cardiac Surgery, Department of Cardiothoracic Center, Istituto Clinico Sant'Ambrogio, University of Milan, Milan, Italy
| | - Giuditta Benincasa
- Department of Advanced Medical and Surgical Sciences (DAMSS), University of Campania "Luigi Vanvitelli", Naples, 80138, Italy
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Li HL, Lip GYH, Feng Q, Fei Y, Tse YK, Wu MZ, Ren QW, Tse HF, Cheung BMY, Yiu KH. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and cardiac arrhythmias: a systematic review and meta-analysis. Cardiovasc Diabetol 2021; 20:100. [PMID: 33962654 PMCID: PMC8106208 DOI: 10.1186/s12933-021-01293-8] [Citation(s) in RCA: 113] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 04/27/2021] [Indexed: 02/06/2023] Open
Abstract
Background Cardiac arrhythmias are associated with poorer outcomes in patients with heart failure (HF), diabetes mellitus (DM), and chronic kidney disease (CKD). Previous studies have shown inconsistent conclusions regarding the association between sodium-glucose cotransporter 2 inhibitors (SGLT2i) and the risk of developing arrhythmias. This study aims to investigate the association of SGLT2i treatment with arrhythmia outcomes in clinical trials of patients with HF, DM, or CKD. Methods MEDLINE, EMBASE, and ClinicalTrials.gov were searched from inception up to 27 August 2020. Randomized controlled trials that randomized patients with DM, CKD, or HF to SGLT2i or placebo were included. The outcomes of interest include atrial fibrillation (AF), embolic stroke, atrial flutter (AFL), AF/AFL, ventricular tachycardia (VT), and cardiac arrest. Relative risks (RRs) and 95% confidence intervals (CI) were pooled using a random-effects model. Results Out of 4,532 citations, 22 trials with altogether 52,115 patients were included (mean age 63.2 years; 33,747 [64.8%] of participants were men). SGLT2i were associated with a lower risk of AF (RR 0.82, 95% CI 0.70–0.96), embolic stroke (RR 0.32, 95% CI 0.12–0.85), AF/AFL (RR 0.82, 95% CI 0.71–0.95), and VT (RR 0.73, 95% CI 0.53–0.99), while the risk reductions in AFL (RR 0.83, 95% CI 0.58–1.17) and cardiac arrest (RR 0.83, 95% CI 0.61–1.14) did not reach statistical significance. The associations appeared to be consistent across different baseline conditions (DM vs CKD vs HF; atherosclerotic cardiovascular disease [ASCVD] vs no ASCVD) and the SGLT2i used. Conclusions SGLT2i reduced the risk of cardiac arrhythmias. Our study provides further evidence for recommending the use of SGLT2i in patients with DM, CKD, and HF. Further research is needed to fully elucidate the mechanism by which SGLT2i protect against arrhythmias. Supplementary Information The online version contains supplementary material available at 10.1186/s12933-021-01293-8.
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Affiliation(s)
- Hang-Long Li
- Division of Cardiology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Room 1929B/K1931, Block K, Hong Kong, China.,Division of Cardiology, Department of Medicine, The University of Hong Kong Shenzhen Hospital, Shenzhen, China
| | - Gregory Y H Lip
- Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool, UK.,Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Qi Feng
- Jockey Club School of Public Health and Primary Care, The Chinese University of Hong Kong, Hong Kong, China
| | - Yue Fei
- Division of Clinical Pharmacology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
| | - Yi-Kei Tse
- Division of Cardiology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Room 1929B/K1931, Block K, Hong Kong, China
| | - Mei-Zhen Wu
- Division of Cardiology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Room 1929B/K1931, Block K, Hong Kong, China.,Division of Cardiology, Department of Medicine, The University of Hong Kong Shenzhen Hospital, Shenzhen, China
| | - Qing-Wen Ren
- Division of Cardiology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Room 1929B/K1931, Block K, Hong Kong, China.,Division of Cardiology, Department of Medicine, The University of Hong Kong Shenzhen Hospital, Shenzhen, China
| | - Hung-Fat Tse
- Division of Cardiology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Room 1929B/K1931, Block K, Hong Kong, China.,Division of Cardiology, Department of Medicine, The University of Hong Kong Shenzhen Hospital, Shenzhen, China
| | - Bernard-M Y Cheung
- Division of Clinical Pharmacology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
| | - Kai-Hang Yiu
- Division of Cardiology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Room 1929B/K1931, Block K, Hong Kong, China. .,Division of Cardiology, Department of Medicine, The University of Hong Kong Shenzhen Hospital, Shenzhen, China.
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Starr JA, Pinner NA, Lisenby KM, Osmonson A. Impact of SGLT2 inhibitors on cardiovascular outcomes in patients with heart failure with reduced ejection fraction. Pharmacotherapy 2021; 41:526-536. [PMID: 33866578 DOI: 10.1002/phar.2527] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 03/22/2021] [Accepted: 03/26/2021] [Indexed: 01/01/2023]
Abstract
Heart failure (HF) impacts more than 6 million Americans with an annual mortality rate approaching 22%. Along with optimizing guideline-directed management and therapy (GDMT), the development of treatment options to improve mortality and morbidity in patients with HF with reduced ejection fraction (HFrEF) is paramount. Cardiovascular outcome trials in patients with type 2 diabetes have shown that sodium-glucose cotransporter-2 (SGLT2) inhibitors improve both cardiovascular (CV) and renal outcomes and have consistently reduced hospitalizations for HF in patients with and without a previous history of HF. A precise mechanism by which SGLT2 inhibitors provide benefits for patients with HFrEF has not been identified, and it is probable that multiple pathways may best explain the outcomes seen in recent clinical trials. The mounting evidence that SGLT2 inhibitors reduce HF-related hospitalizations in patients with type 2 diabetes led to the publication of two pivotal trials, the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial and the Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure (EMPEROR-Reduced) trial. Data from these publications demonstrate significant benefit of dapagliflozin and empagliflozin on a variety of CV and HF quality of life end points in patients with HFrEF independent of the presence of type 2 diabetes. Now, widespread application of the clinical findings from the DAPA-HF and EMPEROR-Reduced trials must follow with SGLT2 inhibitors incorporated into GDMT for HFrEF regardless of the presence or absence of diabetes. In this review, we examine key literature surrounding the CV outcome data for SGLT2 inhibitors with a specific focus on patients with HFrEF.
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Affiliation(s)
- Jessica A Starr
- Auburn University Harrison School of Pharmacy, Birmingham, Alabama, USA
| | - Nathan A Pinner
- Auburn University Harrison School of Pharmacy, Birmingham, Alabama, USA
| | - Katelin M Lisenby
- Auburn University Harrison School of Pharmacy, Tuscaloosa, Alabama, USA
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Martín E, López-Aguilera J, González-Manzanares R, Anguita M, Gutiérrez G, Luque A, Paredes N, Oneto J, Perea J, Castillo JC. Impact of Canagliflozin in Patients with Type 2 Diabetes after Hospitalization for Acute Heart Failure: A Cohort Study. J Clin Med 2021; 10:jcm10030505. [PMID: 33535424 PMCID: PMC7867051 DOI: 10.3390/jcm10030505] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 01/22/2021] [Accepted: 01/25/2021] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Heart failure (HF) is one of the mayor contributors to cardiovascular morbidity and mortality in patients with diabetes. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have demonstrated to reduce the risk of hospitalization for HF in patients with type 2 diabetes mellitus (T2D). We aimed to assess the risk for re-hospitalization in a cohort of patients hospitalized for HF according to whether or not they received canagliflozin at discharge, as well as changes in N-terminal pro-B-type natriuretic peptide (NT-ProBNP) concentration during follow-up. METHODS We conducted a retrospective longitudinal study at a tertiary centre including 102 consecutive T2D patients discharged for acute HF without contraindication for SGLT2 inhibitors. We compared adverse clinical events (HF rehospitalization and cardiovascular death) and NT-ProBNP changes according to canagliflozin prescription at discharge. RESULTS Among the 102 patients included, 45 patients (44.1%) were prescribed canagliflozin and the remaining 57 (55.9%) were not prescribed any SGLT2 inhibitors (control group). After a median follow-up of 22 months, 45 patients (44.1%) were hospitalized for HF. Most of the rehospitalizations occurred during the first year (37.3%). HF readmission at first year occurred in 10 patients (22.2%) in the canagliflozin group and 29 patients (49.1%) in the control group (hazard ratio (HR): 0.45; 95% confidence interval (CI): 0.21-0.96; p < 0.039). A composite outcome of hospitalization for HF or death from cardiovascular causes was lower in the canagliflozin group (37.8%) than in the control group (70.2%) (HR: 0.51; 95% CI: 0.27-0.95; p < 0.035). Analysis of NT-ProBNP concentration showed an interaction between canagliflozin therapy and follow-up time (p = 0.002). CONCLUSIONS Canagliflozin therapy at discharge was associated with a lower risk of readmission for HF and a reduction in NT-ProBNP concentration in patients with diabetes after hospitalization for HF.
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Affiliation(s)
- Ernesto Martín
- Department of Cardiology, Hospital Universitario Reina Sofía, 14004 Córdoba, Spain; (J.L.-A.); (R.G.-M.); (M.A.); (G.G.); (A.L.); (N.P.); (J.O.); (J.P.); (J.C.C.)
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Universidad de Córdoba, 14004 Córdoba, Spain
- Correspondence: ; Tel./Fax: +34-659-93-56-15
| | - José López-Aguilera
- Department of Cardiology, Hospital Universitario Reina Sofía, 14004 Córdoba, Spain; (J.L.-A.); (R.G.-M.); (M.A.); (G.G.); (A.L.); (N.P.); (J.O.); (J.P.); (J.C.C.)
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Universidad de Córdoba, 14004 Córdoba, Spain
| | - Rafael González-Manzanares
- Department of Cardiology, Hospital Universitario Reina Sofía, 14004 Córdoba, Spain; (J.L.-A.); (R.G.-M.); (M.A.); (G.G.); (A.L.); (N.P.); (J.O.); (J.P.); (J.C.C.)
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Universidad de Córdoba, 14004 Córdoba, Spain
| | - Manuel Anguita
- Department of Cardiology, Hospital Universitario Reina Sofía, 14004 Córdoba, Spain; (J.L.-A.); (R.G.-M.); (M.A.); (G.G.); (A.L.); (N.P.); (J.O.); (J.P.); (J.C.C.)
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Universidad de Córdoba, 14004 Córdoba, Spain
| | - Guillermo Gutiérrez
- Department of Cardiology, Hospital Universitario Reina Sofía, 14004 Córdoba, Spain; (J.L.-A.); (R.G.-M.); (M.A.); (G.G.); (A.L.); (N.P.); (J.O.); (J.P.); (J.C.C.)
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Universidad de Córdoba, 14004 Córdoba, Spain
| | - Aurora Luque
- Department of Cardiology, Hospital Universitario Reina Sofía, 14004 Córdoba, Spain; (J.L.-A.); (R.G.-M.); (M.A.); (G.G.); (A.L.); (N.P.); (J.O.); (J.P.); (J.C.C.)
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Universidad de Córdoba, 14004 Córdoba, Spain
| | - Nick Paredes
- Department of Cardiology, Hospital Universitario Reina Sofía, 14004 Córdoba, Spain; (J.L.-A.); (R.G.-M.); (M.A.); (G.G.); (A.L.); (N.P.); (J.O.); (J.P.); (J.C.C.)
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Universidad de Córdoba, 14004 Córdoba, Spain
| | - Jesús Oneto
- Department of Cardiology, Hospital Universitario Reina Sofía, 14004 Córdoba, Spain; (J.L.-A.); (R.G.-M.); (M.A.); (G.G.); (A.L.); (N.P.); (J.O.); (J.P.); (J.C.C.)
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Universidad de Córdoba, 14004 Córdoba, Spain
| | - Jorge Perea
- Department of Cardiology, Hospital Universitario Reina Sofía, 14004 Córdoba, Spain; (J.L.-A.); (R.G.-M.); (M.A.); (G.G.); (A.L.); (N.P.); (J.O.); (J.P.); (J.C.C.)
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Universidad de Córdoba, 14004 Córdoba, Spain
| | - Juan Carlos Castillo
- Department of Cardiology, Hospital Universitario Reina Sofía, 14004 Córdoba, Spain; (J.L.-A.); (R.G.-M.); (M.A.); (G.G.); (A.L.); (N.P.); (J.O.); (J.P.); (J.C.C.)
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Universidad de Córdoba, 14004 Córdoba, Spain
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Gronda E, Jessup M, Iacoviello M, Palazzuoli A, Napoli C. Glucose Metabolism in the Kidney: Neurohormonal Activation and Heart Failure Development. J Am Heart Assoc 2020; 9:e018889. [PMID: 33190567 PMCID: PMC7763788 DOI: 10.1161/jaha.120.018889] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
The liver is not the exclusive site of glucose production in humans in the postabsorptive state. Robust data support that the kidney is capable of gluconeogenesis and studies have demonstrated that renal glucose production can increase systemic glucose production. The kidney has a role in maintaining glucose body balance, not only as an organ for gluconeogenesis but by using glucose as a metabolic substrate. The kidneys reabsorb filtered glucose through the sodium-glucose cotransporters sodium-glucose cotransporter (SGLT) 1 and SGLT2, which are localized on the brush border membrane of the early proximal tubule with immune detection of their expression in the tubularized Bowman capsule. In patients with diabetes mellitus, the renal maximum glucose reabsorptive capacity, and the threshold for glucose passage into the urine, are higher and contribute to the hyperglycemic state. The administration of SGLT2 inhibitors to patients with diabetes mellitus enhances sodium and glucose excretion, leading to a reduction of the glycosuria threshold and tubular maximal transport of glucose. The net effects of SGLT2 inhibition are to drive a reduction in plasma glucose levels, improving insulin secretion and sensitivity. The benefit of SGLT2 inhibitors goes beyond glycemic control, since inhibition of renal glucose reabsorption affects blood pressure and improves the hemodynamic profile and the tubule glomerular feedback. This action acts to rebalance the dense macula response by restoring adenosine production and restraining renin-angiotensin-aldosterone activation. By improving renal and cardiovascular function, we explain the impressive reduction in adverse outcomes associated with heart failure supporting the current clinical perspective.
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Affiliation(s)
- Edoardo Gronda
- Programma CardiorenaleU.O.C. NefrologiaDialisi e Trapianto Renale dell’AdultoDipartimento di Medicina e Specialità MedicheFondazione IRCCS Ca’ GrandaOspedale Maggiore PoliclinicoMilanItaly
| | | | - Massimo Iacoviello
- SC CardiologiaDipartimento delle Scienze Mediche e ChirurgicheAOU Policlinico Riuniti di FoggiaUniversità degli Studi di FoggiaFoggiaItaly
| | - Alberto Palazzuoli
- Divisione di Malattie CardiovascolariDipartimento di Medicina InternaUniversità di SienaItaly
| | - Claudio Napoli
- Clinical Department of Internal Medicine and SpecialisticsDepartment of Advanced Medical and Surgical SciencesUniversità della Campania "Luigi Vanvitelli"NaplesItaly
- IRCCS SDNNaplesItaly
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