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SGLT2 Inhibitors: Emerging "Magic Bullets" beyond Glycemic Control (Volume 2)

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 39605

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Special Issue Editor

Dr. Anastasios Lymperopoulos

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Guest Editor

Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, USA
Interests: cardiovascular G protein-coupled receptors (GPCRs); heart failure; autonomic control of the circulation; adrenal physiology and pharmacology; adrenergic receptors; angiotensin receptors; signal transduction; gene therapy; aldosterone pharmacology; GPCR-Kinases; arrestins; G protein signaling
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Special Issue Information

Dear Colleagues,

This Special Issue follows the publication of the first volume on “SGLT2 Inhibitors: Emerging “Magic Bullets” beyond Glycemic Control”, which presented 13 high-quality papers.

Originally developed for restoring euglycemia in diabetes mellitus, SGLT2 inhibitors (SGLT2is) are increasingly being demonstrated to exert beneficial effects in patients, extending beyond blood glucose regulation. For instance, they reduce cardiovascular disease mortality, ameliorate kidney disease progression, lower blood pressure, and confer weight loss, even in non-diabetics or in people with end-stage chronic kidney disease. Therefore, a lot of information regarding the physiological effects and pharmacological mechanisms of SGLT2is remains to be found, necessitating more research to fully grasp their therapeutic potential.

On these grounds, this Special Issue of the International Journal of Molecular Sciences is focused on studies that explore the biological and pharmacological effects of SGLT2is in human physiology and disease. Investigations with a solid basic/molecular research foundation and/or translational potential are of particular interest, including papers exploring novel molecular and cellular mechanisms underlying the effects of these drugs, as well as pre-clinical investigations testing novel hypotheses that advance the molecular and clinical pharmacology of SGLT2 inhibitors. Original investigations, review articles, and short communications will all be considered. Purely clinical investigations are not suitable, but clinical submissions with at least some component of molecular studies are quite welcome.

Suggested disease areas/topics to be covered include (but are by no means limited to) the following:

cell biology;
signal transduction;
autonomic nervous system;
atherosclerosis/lipid disorders;
cancer;
hypertension;
cognitive dysfunction/neurodegeneration and other central nervous system (CNS) disorders;
heart failure and cardiac arrhythmias;
metabolic syndrome/diabetes mellitus;
stem cell biology/physiology;
inflammatory and/or autoimmune diseases and pain;
cardiovascular endocrinology (e.g., adrenal gland and neuronal control of the circulation);
end-organ damage and sepsis;
respiratory diseases;
kidney disorders;
vascular pathologies;
aging;
obesity/adipose tissue biology;
drug–drug interactions with other drug classes;
adverse effects and toxicology;
pharmacogenetics/pharmacogenomics;
metabolism and pharmacokinetics in humans;
effects in special populations (pediatric, geriatric, pregnancy, etc.);
sex differences in drug action/response;
cellular energetics/mitochondria;

nuclear biology/DNA damage;
oxidative stress.

Dr. Anastasios Lymperopoulos
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

diabetes
glucose reduction
metabolic disorders
heart failure
cardiovascular disease
signal transduction
kidney disease
hypertension
obesity
adverse effects
neurodegeneration
inflammation
adipose tissue
pharmacokinetics
toxicity

Published Papers (13 papers)

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Editorial

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4 pages, 218 KiB

Open AccessEditorial

Editorial for the IJMS Special Issue on Sglt2 Inhibitors (Volume 2)

by Anastasios Lymperopoulos

Int. J. Mol. Sci. 2023, 24(23), 16865; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms242316865 - 28 Nov 2023

Viewed by 523

Abstract

The goal of the second volume of this Special Issue was to build upon the success of the first one and to continue to highlight the ever-expanding list of pharmacological properties of the sodium/glucose co-transporter (SGLT) type 2 (SGLT2) inhibitor (SGLT2i) drug class [...] Read more.

(This article belongs to the Special Issue SGLT2 Inhibitors: Emerging "Magic Bullets" beyond Glycemic Control (Volume 2))

Research

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11 pages, 3253 KiB

Open AccessArticle

Cardioprotective Effects of Sodium Glucose Cotransporter 2 Inhibition in Angiotensin II-Dependent Hypertension Are Mediated by the Local Reduction of Sympathetic Activity and Inflammation

by Giovanna Castoldi, Raffaella Carletti, Silvia Ippolito, Massimiliano Colzani, Sara Pelucchi, Gianpaolo Zerbini, Gianluca Perseghin, Giovanni Zatti and Cira R. T. di Gioia

Int. J. Mol. Sci. 2023, 24(13), 10710; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241310710 - 27 Jun 2023

Cited by 5 | Viewed by 850

Abstract

The cardioprotective effects of sodium glucose cotrasponter 2 (SGLT2) inhibitors seem to be independent from the effects on glycemic control, through little-known mechanisms. In this study, we investigate whether the cardioprotective effects of empagliflozin, a SGLT2 inhibitor, may be associated with myocardial sympathetic activity and inflammatory cell infiltration in an experimental model of angiotensin II-dependent hypertension. Angiotensin II (Ang II), Ang II plus Empagliflozin, physiological saline, or physiological saline plus empagliflozin were administered to Sprague Dawley rats for two weeks. Blood pressure was measured by plethysmographic method. Myocardial hypertrophy and fibrosis were analysed by histomorphometry, and inflammatory cell infiltration and tyrosine hydroxylase expression, implemented as a marker of sympathetic activity, were evaluated by immunohistochemistry. Ang II increased blood pressure, myocardial hypertrophy, fibrosis, inflammatory infiltrates and tyrosine hydroxylase expression, as compared to the control group. Empagliflozin administration prevented the development of myocardial hypertrophy, fibrosis, inflammatory infiltrates and tyrosine hydroxylase overexpression in Ang II-treated rats, without affecting blood glucose and the Ang II-dependent increase in blood pressure. These data demonstrate that the cardioprotective effects of SGLT2 inhibition in Ang II-dependent hypertension may result from the myocardial reduction of sympathetic activity and inflammation and are independent of the modulation of blood pressure and blood glucose levels. Full article

(This article belongs to the Special Issue SGLT2 Inhibitors: Emerging "Magic Bullets" beyond Glycemic Control (Volume 2))

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15 pages, 4592 KiB

Open AccessArticle

Empagliflozin Attenuates Vascular Calcification in Mice with Chronic Kidney Disease by Regulating the NFR2/HO-1 Anti-Inflammatory Pathway through AMPK Activation

by Chia-Wen Lu, Chung-Jen Lee, Yi-Jen Hsieh and Bang-Gee Hsu

Int. J. Mol. Sci. 2023, 24(12), 10016; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241210016 - 12 Jun 2023

Cited by 5 | Viewed by 1841

Abstract

Vascular calcification (VC) is associated with increased cardiovascular risks in patients with chronic kidney disease (CKD). Sodium-glucose cotransporter 2 inhibitors, such as empagliflozin, can improve cardiovascular and renal outcomes. We assessed the expression of Runt-related transcription factor 2 (Runx2), interleukin (IL)-1β, IL-6, AMP-activated protein kinase (AMPK), nuclear factor erythroid-2-related factor (Nrf2), and heme oxygenase 1 (HO-1) in inorganic phosphate-induced VC in mouse vascular smooth muscle cells (VSMCs) to investigate the mechanisms underlying empagliflozin’s therapeutic effects. We evaluated biochemical parameters, mean artery pressure (MAP), pulse wave velocity (PWV), transcutaneous glomerular filtration rate (GFR), and histology in an in vivo mouse model with VC induced by an oral high-phosphorus diet following a 5/6 nephrectomy in ApoE^−/− mice. Compared to the control group, empagliflozin-treated mice showed significant reductions in blood glucose, MAP, PWV, and calcification, as well as increased calcium and GFR levels. Empagliflozin inhibited osteogenic trans-differentiation by decreasing inflammatory cytokine expression and increasing AMPK, Nrf2, and HO-1 levels. Empagliflozin mitigates high phosphate-induced calcification in mouse VSMCs through the Nrf2/HO-1 anti-inflammatory pathway by activating AMPK. Animal experiments suggested that empagliflozin reduces VC in CKD ApoE^−/− mice on a high-phosphate diet. Full article

(This article belongs to the Special Issue SGLT2 Inhibitors: Emerging "Magic Bullets" beyond Glycemic Control (Volume 2))

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11 pages, 1182 KiB

Open AccessArticle

Canagliflozin Inhibits Human Endothelial Cell Inflammation through the Induction of Heme Oxygenase-1

by Kelly J. Peyton, Ghazaleh Behnammanesh, Giovanna L. Durante and William Durante

Int. J. Mol. Sci. 2022, 23(15), 8777; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23158777 - 07 Aug 2022

Cited by 6 | Viewed by 1523

Abstract

Sodium-glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in patients with type 2 diabetes mellitus (T2DM). Studies have also shown that canagliflozin directly acts on endothelial cells (ECs). Since heme oxygenase-1 (HO-1) is an established modulator of EC function, we investigated if canagliflozin regulates the endothelial expression of HO-1, and if this enzyme influences the biological actions of canagliflozin in these cells. Treatment of human ECs with canagliflozin stimulated a concentration- and time-dependent increase in HO-1 that was associated with a significant increase in HO activity. Canagliflozin also evoked a concentration-dependent blockade of EC proliferation, DNA synthesis, and migration that was unaffected by inhibition of HO-1 activity and/or expression. Exposure of ECs to a diabetic environment increased the adhesion of monocytes to ECs, and this was attenuated by canagliflozin. Knockdown of HO-1 reduced the anti-inflammatory effect of canagliflozin which was restored by bilirubin but not carbon monoxide. In conclusion, this study identified canagliflozin as a novel inducer of HO-1 in human ECs. It also found that HO-1-derived bilirubin contributed to the anti-inflammatory action of canagliflozin, but not the anti-proliferative and antimigratory effects of the drug. The ability of canagliflozin to regulate HO-1 expression and EC function may contribute to the clinical profile of the drug. Full article

(This article belongs to the Special Issue SGLT2 Inhibitors: Emerging "Magic Bullets" beyond Glycemic Control (Volume 2))

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17 pages, 1895 KiB

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Differential In Vitro Effects of SGLT2 Inhibitors on Mitochondrial Oxidative Phosphorylation, Glucose Uptake and Cell Metabolism

by Elmar Zügner, Hsiu-Chiung Yang, Petra Kotzbeck, Beate Boulgaropoulos, Harald Sourij, Sepideh Hagvall, Charles S. Elmore, Russell Esterline, Sven Moosmang, Jan Oscarsson, Thomas R. Pieber, Xiao-Rong Peng and Christoph Magnes

Int. J. Mol. Sci. 2022, 23(14), 7966; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23147966 - 19 Jul 2022

Cited by 8 | Viewed by 2867

Abstract

(1) The cardio-reno-metabolic benefits of the SGLT2 inhibitors canagliflozin (cana), dapagliflozin (dapa), ertugliflozin (ertu), and empagliflozin (empa) have been demonstrated, but it remains unclear whether they exert different off-target effects influencing clinical profiles. (2) We aimed to investigate the effects of SGLT2 inhibitors on mitochondrial function, cellular glucose-uptake (GU), and metabolic pathways in human-umbilical-vein endothelial cells (HUVECs). (3) At 100 µM (supra-pharmacological concentration), cana decreased ECAR by 45% and inhibited GU (IC5o: 14 µM). At 100 µM and 10 µM (pharmacological concentration), cana increased the ADP/ATP ratio, whereas dapa and ertu (3, 10 µM, about 10× the pharmacological concentration) showed no effect. Cana (100 µM) decreased the oxygen consumption rate (OCR) by 60%, while dapa decreased it by 7%, and ertu and empa (all 100 µM) had no significant effect. Cana (100 µM) inhibited GLUT1, but did not significantly affect GLUTs’ expression levels. Cana (100 µM) treatment reduced glycolysis, elevated the amino acids supplying the tricarboxylic-acid cycle, and significantly increased purine/pyrimidine-pathway metabolites, in contrast to dapa (3 µM) and ertu (10 µM). (4) The results confirmed cana´s inhibition of mitochondrial activity and GU at supra-pharmacological and pharmacological concentrations, whereas the dapa, ertu, and empa did not show effects even at supra-pharmacological concentrations. At supra-pharmacological concentrations, cana (but not dapa or ertu) affected multiple cellular pathways and inhibited GLUT1. Full article

(This article belongs to the Special Issue SGLT2 Inhibitors: Emerging "Magic Bullets" beyond Glycemic Control (Volume 2))

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14 pages, 4160 KiB

Open AccessArticle

Blocking of SGLT2 to Eliminate NADPH-Induced Oxidative Stress in Lenses of Animals with Fructose-Induced Diabetes Mellitus

by Ying-Ying Chen, Tsung-Tien Wu, Chiu-Yi Ho, Tung-Chen Yeh, Gwo-Ching Sun, Ching-Jiunn Tseng and Pei-Wen Cheng

Int. J. Mol. Sci. 2022, 23(13), 7142; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23137142 - 27 Jun 2022

Cited by 9 | Viewed by 2209

Abstract

Chronic hyperglycemia triggers an abnormal rise in reactive oxygen species (ROS) that leads to blindness in patients with diabetes mellitus (DM) and cataracts. In this study, the effects of dapagliflozin, metformin and resveratrol on ROS production were investigated in lens epithelial cells (LECs) of animals with fructose-induced DM. LECs were isolated from patients without DM, or with DM devoid of diabetic retinopathy. Animals were treated with 10% fructose for 8 weeks to induce DM, which was verified by monitoring blood pressure and serum parameters. For drug treatments, 1.2 mg/day of dapagliflozin was given for 2 weeks, 500 mg/kg/day of metformin was given, and 10 mg/kg/day of resveratrol was given. Dihydroethidium was used to stain endogenous O₂˙⁻ production in vivo of the LECs. Superoxide production was expressed in the cataract of DM, or patients without DM. Sodium–glucose cotransporter 2 (SGLT2), glucose transporter 1 (GLUT1), GLUT5, the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit p47/p67-phox, NOX4 and RAGE were significantly increased in LECs with DM. In addition, the dapagliflozin treatment reduced GLUT5, p47/p67-phox, NADPH oxidase 4 (NOX4) and receptor for advanced glycation end products (RAGE) expressions. On the contrary, metformin or resveratrol inhibited p47-phox, GLUT5, and SGLT2 expressions, but not nuclear factor erythroid 2–related factor 2 (NRF2). In summary, dapagliflozin, metformin or resveratrol down-regulated p47-phox expression through SGLT2 inactivation and ROS reduction. These important findings imply that SGLT2 can be blocked to ameliorate oxidative stress in the cataracts of DM patients. Full article

(This article belongs to the Special Issue SGLT2 Inhibitors: Emerging "Magic Bullets" beyond Glycemic Control (Volume 2))

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28 pages, 7893 KiB

Open AccessArticle

Col4a3^-/- Mice on Balb/C Background Have Less Severe Cardiorespiratory Phenotype and SGLT2 Over-Expression Compared to 129x1/SvJ and C57Bl/6 Backgrounds

by Camila I. Irion, Monique Williams, Jose Condor Capcha, Trevor Eisenberg, Guerline Lambert, Lauro M. Takeuchi, Grace Seo, Keyvan Yousefi, Rosemeire Kanashiro-Takeuchi, Keith A. Webster, Karen C. Young, Joshua M. Hare and Lina A. Shehadeh

Int. J. Mol. Sci. 2022, 23(12), 6674; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23126674 - 15 Jun 2022

Cited by 4 | Viewed by 2591

Abstract

Alport syndrome (AS) is a hereditary renal disorder with no etiological therapy. In the preclinical Col4a3^-/- model of AS, disease progression and severity vary depending on mouse strain. The sodium-glucose cotransporter 2 (SGLT2) is emerging as an attractive therapeutic target in cardiac/renal pathologies, but its application to AS remains untested. This study investigates cardiorespiratory function and SGLT2 renal expression in Col4a3^-/- mice from three different genetic backgrounds, 129x1/SvJ, C57Bl/6 and Balb/C. male Col4a3^-/- 129x1/SvJ mice displayed alterations consistent with heart failure with preserved ejection fraction (HFpEF). Female, but not male, C57Bl/6 and Balb/C Col4a3^-/- mice exhibited mild changes in systolic and diastolic function of the heart by echocardiography. Male C57Bl/6 Col4a3^-/- mice presented systolic dysfunction by invasive hemodynamic analysis. All strains except Balb/C males demonstrated alterations in respiratory function. SGLT2 expression was significantly increased in AS compared to WT mice from all strains. However, cardiorespiratory abnormalities and SGLT2 over-expression were significantly less in AS Balb/C mice compared to the other two strains. Systolic blood pressure was significantly elevated only in mutant 129x1/SvJ mice. The results provide further evidence for strain-dependent cardiorespiratory and hypertensive phenotype variations in mouse AS models, corroborated by renal SGLT2 expression, and support ongoing initiatives to develop SGLT2 inhibitors for the treatment of AS. Full article

(This article belongs to the Special Issue SGLT2 Inhibitors: Emerging "Magic Bullets" beyond Glycemic Control (Volume 2))

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25 pages, 4641 KiB

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Empagliflozin Treatment Attenuates Hepatic Steatosis by Promoting White Adipose Expansion in Obese TallyHo Mice

by Ryan Kurtz, Andrew Libby, Bryce A. Jones, Komuraiah Myakala, Xiaoxin Wang, Yichien Lee, Grace Knoer, Julia N. Lo Cascio, Michaela McCormack, Grace Nguyen, Elijah N. D. Choos, Olga Rodriguez, Avi Z. Rosenberg, Suman Ranjit, Christopher Albanese, Moshe Levi, Carolyn M. Ecelbarger and Blythe D. Shepard

Int. J. Mol. Sci. 2022, 23(10), 5675; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105675 - 18 May 2022

Cited by 7 | Viewed by 3392

Abstract

Sodium-glucose co-transporters (SGLTs) serve to reabsorb glucose in the kidney. Recently, these transporters, mainly SGLT2, have emerged as new therapeutic targets for patients with diabetes and kidney disease; by inhibiting glucose reabsorption, they promote glycosuria, weight loss, and improve glucose tolerance. They have also been linked to cardiac protection and mitigation of liver injury. However, to date, the mechanism(s) by which SGLT2 inhibition promotes systemic improvements is not fully appreciated. Using an obese TallyHo mouse model which recapitulates the human condition of diabetes and nonalcoholic fatty liver disease (NAFLD), we sought to determine how modulation of renal glucose handling impacts liver structure and function. Apart from an attenuation of hyperglycemia, Empagliflozin was found to decrease circulating triglycerides and lipid accumulation in the liver in male TallyHo mice. This correlated with lowered hepatic cholesterol esters. Using in vivo MRI analysis, we further determined that the reduction in hepatic steatosis in male TallyHo mice was associated with an increase in nuchal white fat indicative of “healthy adipose expansion”. Notably, this whitening of the adipose came at the expense of brown adipose tissue. Collectively, these data indicate that the modulation of renal glucose handling has systemic effects and may be useful as a treatment option for NAFLD and steatohepatitis. Full article

(This article belongs to the Special Issue SGLT2 Inhibitors: Emerging "Magic Bullets" beyond Glycemic Control (Volume 2))

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Review

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SGLT2 Inhibitors: A New Therapeutical Strategy to Improve Clinical Outcomes in Patients with Chronic Kidney Diseases

by Assunta Di Costanzo, Giovanni Esposito, Ciro Indolfi and Carmen Anna Maria Spaccarotella

Int. J. Mol. Sci. 2023, 24(10), 8732; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24108732 - 13 May 2023

Cited by 5 | Viewed by 4634

Abstract

The purpose of this manuscript is to review the effects of sodium-glucose cotransport protein 2 inhibitors (SGLT2is) in patients with chronic kidney disease according to basic mechanisms, current recommendations, and future perspectives. Based on growing evidence from randomized, controlled trials, SGLT2is have proven their benefit on cardiac and renal adverse complications, and their indications expanded into the following five categories: glycemic control, reduction in atherosclerotic cardiovascular disease (ASCVD), heart failure, diabetic kidney disease, and nondiabetic kidney disease. Although kidney disease accelerates the progression of atherosclerosis, myocardial disease, and heart failure, so far, no specific drugs were available to protect renal function. Recently, two randomized trials, the DAPA-CKD and EMPA-Kidney, demonstrated the clinical benefit of the SGLT2is dapagliflozin and empagliflozin in improving the outcome in patients with chronic kidney disease. For the consistently positive results in cardiorenal protection, the SGLT2i represents an effective treatment to reduce the progression of kidney disease or death from cardiovascular causes in patients with and without diabetes mellitus. Full article

(This article belongs to the Special Issue SGLT2 Inhibitors: Emerging "Magic Bullets" beyond Glycemic Control (Volume 2))

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11 pages, 447 KiB

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Mouse Models with SGLT2 Mutations: Toward Understanding the Role of SGLT2 beyond Glucose Reabsorption

by Keiko Unno, Kyoko Taguchi, Yoshiichi Takagi, Tadashi Hase, Shinichi Meguro and Yoriyuki Nakamura

Int. J. Mol. Sci. 2023, 24(7), 6278; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24076278 - 27 Mar 2023

Cited by 4 | Viewed by 1923

Abstract

The sodium–glucose cotransporter 2 (SGLT2) mainly carries out glucose reabsorption in the kidney. Familial renal glycosuria, which is a mutation of SGLT2, is known to excrete glucose in the urine, but blood glucose levels are almost normal. Therefore, SGLT2 inhibitors are attracting attention as a new therapeutic drug for diabetes, which is increasing worldwide. In fact, SGLT2 inhibitors not only suppress hyperglycemia but also reduce renal, heart, and cardiovascular diseases. However, whether long-term SGLT2 inhibition is completely harmless requires further investigation. In this context, mice with mutations in SGLT2 have been generated and detailed studies are being conducted, e.g., the SGLT2^−/− mouse, Sweet Pee mouse, Jimbee mouse, and SAMP10-ΔSglt2 mouse. Biological changes associated with SGLT2 mutations have been reported in these model mice, suggesting that SGLT2 is not only responsible for sugar reabsorption but is also related to other functions, such as bone metabolism, longevity, and cognitive functions. In this review, we present the characteristics of these mutant mice. Moreover, because the relationship between diabetes and Alzheimer’s disease has been discussed, we examined the relationship between changes in glucose homeostasis and the amyloid precursor protein in SGLT2 mutant mice. Full article

(This article belongs to the Special Issue SGLT2 Inhibitors: Emerging "Magic Bullets" beyond Glycemic Control (Volume 2))

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28 pages, 2140 KiB

Open AccessReview

Unlocking the Full Potential of SGLT2 Inhibitors: Expanding Applications beyond Glycemic Control

by Mahmoud E. Youssef, Galal Yahya, Mihaela Simona Popoviciu, Simona Cavalu, Marwa A. Abd-Eldayem and Sameh Saber

Int. J. Mol. Sci. 2023, 24(7), 6039; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24076039 - 23 Mar 2023

Cited by 17 | Viewed by 6928

Abstract

The number of diabetic patients has risen dramatically in recent decades, owing mostly to the rising incidence of type 2 diabetes mellitus (T2DM). Several oral antidiabetic medications are used for the treatment of T2DM including, α-glucosidases inhibitors, biguanides, sulfonylureas, meglitinides, GLP-1 receptor agonists, PPAR-γ agonists, DDP4 inhibitors, and SGLT2 inhibitors. In this review we focus on the possible effects of SGLT2 inhibitors on different body systems. Beyond the diabetic state, SGLT2 inhibitors have revealed a demonstrable ability to ameliorate cardiac remodeling, enhance myocardial function, and lower heart failure mortality. Additionally, SGLT2 inhibitors can modify adipocytes and their production of cytokines, such as adipokines and adiponectin, which enhances insulin sensitivity and delays diabetes onset. On the other hand, SGLT2 inhibitors have been linked to decreased total hip bone mineral deposition and increased hip bone resorption in T2DM patients. More data are needed to evaluate the role of SGLT2 inhibitors on cancer. Finally, the effects of SGLT2 inhibitors on neuroprotection appear to be both direct and indirect, according to scientific investigations utilizing various experimental models. SGLT2 inhibitors improve vascular tone, elasticity, and contractility by reducing oxidative stress, inflammation, insulin signaling pathways, and endothelial cell proliferation. They also improve brain function, synaptic plasticity, acetylcholinesterase activity, and reduce amyloid plaque formation, as well as regulation of the mTOR pathway in the brain, which reduces brain damage and cognitive decline. Full article

(This article belongs to the Special Issue SGLT2 Inhibitors: Emerging "Magic Bullets" beyond Glycemic Control (Volume 2))

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32 pages, 1306 KiB

Open AccessReview

Could SGLT2 Inhibitors Improve Exercise Intolerance in Chronic Heart Failure?

by Suzanne N. Voorrips, Huitzilihuitl Saucedo-Orozco, Pablo I. Sánchez-Aguilera, Rudolf A. De Boer, Peter Van der Meer and B. Daan Westenbrink

Int. J. Mol. Sci. 2022, 23(15), 8631; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23158631 - 03 Aug 2022

Cited by 9 | Viewed by 3495

Abstract

Despite the constant improvement of therapeutical options, heart failure (HF) remains associated with high mortality and morbidity. While new developments in guideline-recommended therapies can prolong survival and postpone HF hospitalizations, impaired exercise capacity remains one of the most debilitating symptoms of HF. Exercise intolerance in HF is multifactorial in origin, as the underlying cardiovascular pathology and reactive changes in skeletal muscle composition and metabolism both contribute. Recently, sodium-related glucose transporter 2 (SGLT2) inhibitors were found to improve cardiovascular outcomes significantly. Whilst much effort has been devoted to untangling the mechanisms responsible for these cardiovascular benefits of SGLT2 inhibitors, little is known about the effect of SGLT2 inhibitors on exercise performance in HF. This review provides an overview of the pathophysiological mechanisms that are responsible for exercise intolerance in HF, elaborates on the potential SGLT2-inhibitor-mediated effects on these phenomena, and provides an up-to-date overview of existing studies on the effect of SGLT2 inhibitors on clinical outcome parameters that are relevant to the assessment of exercise capacity. Finally, current gaps in the evidence and potential future perspectives on the effects of SGLT2 inhibitors on exercise intolerance in chronic HF are discussed. Full article

(This article belongs to the Special Issue SGLT2 Inhibitors: Emerging "Magic Bullets" beyond Glycemic Control (Volume 2))

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13 pages, 914 KiB

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SGLT2 Inhibitors and Their Antiarrhythmic Properties

by Ewald Kolesnik, Daniel Scherr, Ursula Rohrer, Martin Benedikt, Martin Manninger, Harald Sourij and Dirk von Lewinski

Int. J. Mol. Sci. 2022, 23(3), 1678; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031678 - 31 Jan 2022

Cited by 23 | Viewed by 5018

Abstract

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are gaining ground as standard therapy for heart failure with a class-I recommendation in the recently updated heart failure guidelines from the European Society of Cardiology. Different gliflozins have shown impressive beneficial effects in patients with and without diabetes mellitus type 2, especially in reducing the rates for hospitalization for heart failure, yet little is known on their antiarrhythmic properties. Atrial and ventricular arrhythmias were reported by clinical outcome trials with SGLT2 inhibitors as adverse events, and SGLT2 inhibitors seemed to reduce the rate of arrhythmias compared to placebo treatment in those trials. Mechanistical links are mainly unrevealed, since hardly any experiments investigated their impact on arrhythmias. Prospective trials are currently ongoing, but no results have been published so far. Arrhythmias are common in the heart failure population, therefore the understanding of possible interactions with SGLT2 inhibitors is crucial. This review summarizes evidence from clinical data as well as the sparse experimental data of SGLT2 inhibitors and their effects on arrhythmias. Full article

(This article belongs to the Special Issue SGLT2 Inhibitors: Emerging "Magic Bullets" beyond Glycemic Control (Volume 2))

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