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1.
Cardiovasc Diabetol ; 23(1): 157, 2024 May 07.
Article in English | MEDLINE | ID: mdl-38715111

ABSTRACT

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) and SGLT1 inhibitors may have additional beneficial metabolic effects on circulating metabolites beyond glucose regulation, which could contribute to a reduction in the burden of cerebral small vessel disease (CSVD). Accordingly, we used Mendelian Randomization (MR) to examine the role of circulating metabolites in mediating SGLT2 and SGLT1 inhibition in CSVD. METHODS: Genetic instruments for SGLT1/2 inhibition were identified as genetic variants, which were both associated with the expression of encoding genes of SGLT1/2 inhibitors and glycated hemoglobin A1c (HbA1c) level. A two-sample two-step MR was used to determine the causal effects of SGLT1/2 inhibition on CSVD manifestations and the mediating effects of 1400 circulating metabolites linking SGLT1/2 inhibition with CSVD manifestations. RESULTS: A lower risk of deep cerebral microbleeds (CMBs) and small vessel stroke (SVS) was linked to genetically predicted SGLT2 inhibition. Better white matter structure integrity was also achieved, as evidenced by decreased mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD), as well as lower deep (DWMH) and periventrivular white matter hyperintensity (PWMH) volume. Inhibiting SGLT2 could also lessen the incidence of severe enlarged perivascular spaces (EPVS) located at white matter, basal ganglia (BG) and hippocampus (HIP). SGLT1 inhibition could preserve white matter integrity, shown as decreased MD of white matter and DWMH volume. The effect of SGLT2 inhibition on SVS and MD of white matter through the concentration of 4-acetamidobutanoate and the cholesterol to oleoyl-linoleoyl-glycerol (18:1 to 18:2) ratio, with a mediated proportion of 30.3% and 35.5% of the total effect, respectively. CONCLUSIONS: SGLT2 and SGLT1 inhibition play protective roles in CSVD development. The SGLT2 inhibition could lower the risk of SVS and improve the integrity of white matter microstructure via modulating the level of 4-acetamidobutanoate and cholesterol metabolism. Further mechanistic and clinical studies research are needed to validate our findings.


Subject(s)
Biomarkers , Cerebral Small Vessel Diseases , Mendelian Randomization Analysis , Sodium-Glucose Transporter 1 , Sodium-Glucose Transporter 2 Inhibitors , Sodium-Glucose Transporter 2 , Humans , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Sodium-Glucose Transporter 2 Inhibitors/adverse effects , Sodium-Glucose Transporter 1/genetics , Sodium-Glucose Transporter 1/antagonists & inhibitors , Sodium-Glucose Transporter 1/metabolism , Cerebral Small Vessel Diseases/genetics , Cerebral Small Vessel Diseases/diagnostic imaging , Cerebral Small Vessel Diseases/drug therapy , Cerebral Small Vessel Diseases/blood , Cerebral Small Vessel Diseases/metabolism , Risk Factors , Sodium-Glucose Transporter 2/metabolism , Sodium-Glucose Transporter 2/genetics , Biomarkers/blood , Risk Assessment , Glycated Hemoglobin/metabolism , Pharmacogenomic Variants , Treatment Outcome , Phenotype , Cerebral Hemorrhage/genetics , Cerebral Hemorrhage/chemically induced , Cerebral Hemorrhage/epidemiology , Protective Factors , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/epidemiology , Genetic Predisposition to Disease
4.
Biosci Rep ; 44(6)2024 Jun 26.
Article in English | MEDLINE | ID: mdl-38747277

ABSTRACT

Endothelin (ET) receptor antagonists are being investigated in combination with sodium-glucose co-transporter-2 inhibitors (SGLT-2i). These drugs primarily inhibit the SGLT-2 transporter that, in humans, is thought to be mainly restricted to the renal proximal convoluted tubule, resulting in increased glucose excretion favouring improved glycaemic control and diuresis. This action reduces fluid retention with ET receptor antagonists. Studies have suggested SGLT-2 may also be expressed in cardiomyocytes of human heart. To understand the potential of combining the two classes of drugs, our aim was to compare the distribution of ET receptor sub-types in human kidney, with SGLT-2. Secondly, using the same experimental conditions, we determined if SGLT-2 expression could be detected in human heart and whether the transporter co-localised with ET receptors. METHODS: Immunocytochemistry localised SGLT-2, ETA and ETB receptors in sections of histologically normal kidney, left ventricle from patients undergoing heart transplantation or controls. Primary antisera were visualised using fluorescent microscopy. Image analysis was used to measure intensity compared with background in adjacent control sections. RESULTS: As expected, SGLT-2 localised to epithelial cells of the proximal convoluted tubules, and co-localised with both ET receptor sub-types. Similarly, ETA receptors predominated in cardiomyocytes; low (compared with kidney but above background) positive staining was also detected for SGLT-2. DISCUSSION: Whether low levels of SGLT-2 have a (patho)physiological role in cardiomyocytes is not known but results suggest the effect of direct blockade of sodium (and glucose) influx via SGLT-2 inhibition in cardiomyocytes should be explored, with potential for additive effects with ETA antagonists.


Subject(s)
Receptor, Endothelin A , Receptor, Endothelin B , Sodium-Glucose Transporter 2 , Humans , Sodium-Glucose Transporter 2/metabolism , Sodium-Glucose Transporter 2/genetics , Receptor, Endothelin A/metabolism , Receptor, Endothelin B/metabolism , Kidney/metabolism , Male , Sodium-Glucose Transporter 2 Inhibitors/pharmacology , Kidney Tubules, Proximal/metabolism , Kidney Tubules, Proximal/drug effects , Female , Myocardium/metabolism , Middle Aged
5.
Cell Mol Biol Lett ; 29(1): 80, 2024 May 29.
Article in English | MEDLINE | ID: mdl-38811901

ABSTRACT

BACKGROUND: Sodium-glucose transporter 2 (SGLT2) inhibitors (iSGLT2) are approved medications for type 2 diabetes. Recent studies indicate that iSGLT2 inhibit the growth of some cancer cells. However, the mechanism(s) remains to be fully elucidated. METHODS: The SGLT2 levels were determined in normal colon CCD 841 CoN and, HCT 116, HT-29, SW480 and LoVo colorectal cancer (CRC) cell lines by quantitative real-time PCR and western blot. The effect of iSGLT2 canagliflozin on cell proliferation was examined using CCK-8, as its role on CRC cells metabolism and tumorigenesis has been evaluated by XF HS Seahorse Bioanalyzer and flow cytometric analyses. Transient gene silencing experiments and analysis of protein-protein interaction network were conducted to evaluate the SGLT2 molecular targets in CRC cells. RESULTS: Data showed that the treatment with iSGLT2 (50 µM) for 72 h induced cell cycle arrest (p < 0.001), impaired glucose and energetic metabolism (p < 0.001), promoted apoptotic cell death and ER stress flowing into autophagy (p < 0.001) in HCT 116 and HT-29 cells. These cellular events were accompanied by sirtuin 3 (SIRT3) upregulation (p < 0.01), as also supported by SIRT3 transient silencing experiments resulting in the attenuation of the effects of iSGLT2 on the cellular metabolic/energetic alterations and the induction of programmed cell death. The identification and validation of dipeptidyl peptidase 4 (DPP4) as potential common target of SGLT2 and SIRT3 were also assessed. CONCLUSIONS: These results deepened knowledge on the iSGLT2 contribution in limiting CRC tumorigenesis unveiling the SGLT2/SIRT3 axis in the cytotoxic mechanisms.


Subject(s)
Apoptosis , Cell Proliferation , Colorectal Neoplasms , Endoplasmic Reticulum Stress , Mitochondria , Sodium-Glucose Transporter 2 Inhibitors , Sodium-Glucose Transporter 2 , Humans , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Colorectal Neoplasms/genetics , Sodium-Glucose Transporter 2 Inhibitors/pharmacology , Endoplasmic Reticulum Stress/drug effects , Mitochondria/metabolism , Mitochondria/drug effects , Cell Proliferation/drug effects , Sodium-Glucose Transporter 2/metabolism , Sodium-Glucose Transporter 2/genetics , Apoptosis/drug effects , Autophagy/drug effects , Cell Line, Tumor , Canagliflozin/pharmacology , HT29 Cells , HCT116 Cells , Sirtuin 3/metabolism , Sirtuin 3/genetics , Cell Cycle Checkpoints/drug effects , Glucose/metabolism
7.
Physiol Rep ; 12(7): e15990, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38575554

ABSTRACT

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are rapidly gaining ground in the treatment of heart failure (HF) with reduced ejection fraction (HFrEF) and acute myocardial infarction (AMI) by an unknown mechanism. Upregulation of Na+/H+ exchanger 1 (NHE1), SGLT1, and Ca2+/calmodulin-dependent protein kinase II (CaMKII) in the diseased hearts was found to be attenuated by prolonged SGLT2i treatment. Unfortunately, dapagliflozin is not well understood as to how Na+/Ca2+ homeostasis is affected in cardiomyocytes. In this study, we aimed to investigate whether mechanical stretch in cardiomyocytes upregulate SGLT2, resulted to loss of Na+/Ca2+ homeostasis via ERK and eNOS signaling. AMI (+) and AMI (-) serum levels were estimated using ELISA assays of TGFß-1 or endoglin (CD105). Human cardiomyocyte cell line AC16 was subjected to different stresses: 5% mild and 25% aggressive, at 1 Hz for 24 h. Immunofluorescence assays were used to estimate troponin I, CD105, SGLT1/2, eNOSS633, and ERK1/2T202/Y204 levels was performed for 5% (mild), and 25% elongation for 24 h. AMI (+) serum showed increased TGFß1 and CD105 compared to AMI (-) patients. In consistent, troponin I, CD105, SGLT1/2, eNOSS633 and ERK1/2T202/Y204 were upregulated after 25% of 24 h cyclic stretch. Dapagliflozin addition caused SGLT2 inhibition, which significantly decreased troponin I, CD105, SGLT1/2, eNOSS633, and ERK1/2T202/Y204 under 25% cyclic stretching. In summary, SGLT2 may have sensed mechanical stretch in a way similar to cardiac overloading as in vivo. By blocking SGLT2 in stretched cardiomyocytes, the AMI biomarkers (CD105, troponin I and P-ERK) were decreased, potentially to rescue eNOS production to maintain normal cellular function. This discovery of CD105 and SGLT2 increase in mechanically stretched cardiomyocytes suggests that SGLT2 may conceive a novel role in direct or indirect sensing of mechanical stretch, prompting the possibility of an in vitro cardiac overloaded cell model, an alternative to animal heart model.


Subject(s)
Benzhydryl Compounds , Glucosides , Heart Failure , Myocardial Infarction , Humans , Animals , Endoglin/metabolism , Heart Failure/metabolism , Up-Regulation , Sodium-Glucose Transporter 2/metabolism , Troponin I/metabolism , Stroke Volume , Myocytes, Cardiac/metabolism
8.
Front Biosci (Landmark Ed) ; 29(4): 145, 2024 Apr 09.
Article in English | MEDLINE | ID: mdl-38682194

ABSTRACT

Sodium-glucose cotransporters 2 (SGLT2) are high-capacity, low-affinity transporters, expressed mainly in the early portion of the proximal renal tube, mediating up to 90% of renal glucose uptake, while SGLT1 receptors are found mainly in the small intestine, facilitating glucose absorption. SGLT2 inhibitors (SGLT2i) originally emerged as agents for the treatment of type 2 diabetes mellitus; however, they soon demonstrated remarkable cardio- and renoprotective actions that led to their licensed use for the treatment of heart failure and chronic kidney disease, regardless of the diabetic status. Cardiovascular remodelling represents an umbrella term that encompasses changes that occur in the cardiovascular system, from the molecular and cellular level, to tissue and organs after local injury, chronic stress, or pressure. SGLT modulation has been shown to positively affect many of these molecular and cellular changes observed during pathological remodelling. Among the different pathophysiological mechanisms that contribute to adverse remodelling, various stem and progenitor cells have been shown to be involved, through alterations in their number or function. Recent studies have examined the effects of SGLT2i on stem and progenitor cell populations and more specifically on endothelial progenitor cells (EPCs). Although some found no significant effect, others showed that SGLT2i can modulate the morphology and function of EPCs. These preliminary observations of the effect of SGLT2i on EPCs may be responsible for some of the beneficial effects of gliflozins on pathological remodelling and, by extension, on cardiovascular disease. The purpose of this narrative review is to critically discuss recent evidence on the cardioprotective effects of SGLT2is, in the context of cardiac remodelling.


Subject(s)
Sodium-Glucose Transporter 2 Inhibitors , Humans , Sodium-Glucose Transporter 2 Inhibitors/pharmacology , Stem Cells/drug effects , Stem Cells/metabolism , Animals , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Ventricular Remodeling/drug effects , Cardiovascular System/drug effects , Sodium-Glucose Transporter 2/metabolism , Sodium-Glucose Transporter 2/genetics , Cardiovascular Diseases/metabolism , Cardiovascular Diseases/drug therapy , Cardiovascular Diseases/physiopathology , Heart Failure/drug therapy , Heart Failure/physiopathology , Heart Failure/metabolism
9.
Mitochondrion ; 76: 101878, 2024 May.
Article in English | MEDLINE | ID: mdl-38599300

ABSTRACT

Mitochondrial volume is maintained through the permeability of the inner mitochondrial membrane by a specific aquaporin and the osmotic balance between the mitochondrial matrix and cellular cytoplasm. Various electrolytes, such as calcium and hydrogen ions, potassium, and sodium, as well as other osmotic substances, affect the swelling of mitochondria. Intracellular glucose levels may also affect mitochondrial swelling, although the relationship between mitochondrial ion homeostasis and intracellular glucose is poorly understood. This article reviews what is currently known about how the Sodium-Glucose transporter (SGLT) may impact mitochondrial sodium (Na+) homeostasis. SGLTs regulate intracellular glucose and sodium levels and, therefore, interfere with mitochondrial ion homeostasis because mitochondrial Na+ is closely linked to cytoplasmic calcium and sodium dynamics. Recently, a large amount of data has been available on the effects of SGLT2 inhibitors on mitochondria in different cell types, including renal proximal tubule cells, endothelial cells, mesangial cells, podocytes, neuronal cells, and cardiac cells. The current evidence suggests that SGLT inhibitors (SGLTi) may affect mitochondrial dynamics regarding intracellular Sodium and hydrogen ions. Although the regulation of mitochondrial ion channels by SGLTs is still in its infancy, the evidence accumulated thus far of the effect of SGLTi on mitochondrial functions certainly will foster further research in this direction.


Subject(s)
Mitochondria , Mitochondria/metabolism , Humans , Animals , Sodium/metabolism , Sodium-Glucose Transporter 2/metabolism , Glucose/metabolism , Sodium-Glucose Transporter 2 Inhibitors/pharmacology , Homeostasis
10.
Comput Biol Chem ; 110: 108074, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38678730

ABSTRACT

Sodium-glucose co-transporter 2 (SGLT2) is one of the important targets against type II diabetes mellitus. A typical SGLT2 inhibitor acts by inhibiting glucose reabsorption, thus lowering the blood glucose level. Unlike SGLT1, SGLT2 is responsible for almost 90% glucose reabsorption from glomerular filtrate. The current SGLT2 inhibitors include gliflozins, often prescribed as second or third-line agents in diabetes mellitus. The SGLT2 inhibitors also benefit patients with heart and kidney disease. Due to instability issues with the natural O-aryl glycoside analogues C-glycoside analogues were developed and showed improved stability. Despite enhanced bioavailability and selectivity of newer derivatives, some serious side effects are associated with gliflozin analogues. At the present study, we applied in-silico approaches to find new glycomimetic compounds as potent SGLT2 inhibitors that could show improvement in side effects associated with current analogues. This work applied both ligand-based and structure-based drug approaches to find potential compounds. We developed a 3D-QSAR method to screen potential inhibitors from a library of ten thousand compounds and performed docking studies. The compounds were ranked based on predicted pIC50 and docking score. An initial screening of five thousand compounds was conducted, and the subsequently selected top 12 compounds were based on binding free energy calculations. These selected compounds were subjected to molecular dynamics (MD) simulations. Remarkably, our simulations identified nine compounds that exhibited significant and sustained binding affinity compared to the co-crystallized Empagliflozin. Collectively, considering the anticipated pharmacokinetic profiles and toxicity assessments, several of these compounds emerged as promising candidates for further in-depth evaluation.


Subject(s)
Sodium-Glucose Transporter 2 Inhibitors , Sodium-Glucose Transporter 2 , Sodium-Glucose Transporter 2 Inhibitors/chemistry , Sodium-Glucose Transporter 2 Inhibitors/pharmacology , Humans , Sodium-Glucose Transporter 2/metabolism , Sodium-Glucose Transporter 2/chemistry , Molecular Docking Simulation , Quantitative Structure-Activity Relationship , Molecular Structure , Drug Evaluation, Preclinical , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Glycosides/chemistry , Glycosides/pharmacology
11.
Am J Physiol Renal Physiol ; 326(6): F1041-F1053, 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38660713

ABSTRACT

Beyond glycemic control, SGLT2 inhibitors (SGLT2is) have protective effects on cardiorenal function. Renoprotection has been suggested to involve inhibition of NHE3 leading to reduced ATP-dependent tubular workload and mitochondrial oxygen consumption. NHE3 activity is also important for regulation of endosomal pH, but the effects of SGLT2i on endocytosis are unknown. We used a highly differentiated cell culture model of proximal tubule (PT) cells to determine the direct effects of SGLT2i on Na+-dependent fluid transport and endocytic uptake in this nephron segment. Strikingly, canagliflozin but not empagliflozin reduced fluid transport across cell monolayers and dramatically inhibited endocytic uptake of albumin. These effects were independent of glucose and occurred at clinically relevant concentrations of drug. Canagliflozin acutely inhibited surface NHE3 activity, consistent with a direct effect, but did not affect endosomal pH or NHE3 phosphorylation. In addition, canagliflozin rapidly and selectively inhibited mitochondrial complex I activity. Inhibition of mitochondrial complex I by metformin recapitulated the effects of canagliflozin on endocytosis and fluid transport, whereas modulation of downstream effectors AMPK and mTOR did not. Mice given a single dose of canagliflozin excreted twice as much urine over 24 h compared with empagliflozin-treated mice despite similar water intake. We conclude that canagliflozin selectively suppresses Na+-dependent fluid transport and albumin uptake in PT cells via direct inhibition of NHE3 and of mitochondrial function upstream of the AMPK/mTOR axis. These additional targets of canagliflozin contribute significantly to reduced PT Na+-dependent fluid transport in vivo.NEW & NOTEWORTHY Reduced NHE3-mediated Na+ transport has been suggested to underlie the cardiorenal protection provided by SGLT2 inhibitors. We found that canagliflozin, but not empagliflozin, reduced NHE3-dependent fluid transport and endocytic uptake in cultured proximal tubule cells. These effects were independent of SGLT2 activity and resulted from inhibition of mitochondrial complex I and NHE3. Studies in mice are consistent with greater effects of canagliflozin versus empagliflozin on fluid transport. Our data suggest that these selective effects of canagliflozin contribute to reduced Na+-dependent transport in proximal tubule cells.


Subject(s)
Canagliflozin , Kidney Tubules, Proximal , Sodium-Glucose Transporter 2 Inhibitors , Sodium-Hydrogen Exchanger 3 , Animals , Kidney Tubules, Proximal/drug effects , Kidney Tubules, Proximal/metabolism , Kidney Tubules, Proximal/enzymology , Sodium-Hydrogen Exchanger 3/metabolism , Canagliflozin/pharmacology , Sodium-Glucose Transporter 2 Inhibitors/pharmacology , Mice , Male , Sodium-Glucose Transporter 2/metabolism , Endocytosis/drug effects , Mice, Inbred C57BL , Albumins/metabolism , Mitochondria/metabolism , Mitochondria/drug effects , Benzhydryl Compounds , Glucosides
12.
Oncol Res ; 32(5): 817-830, 2024.
Article in English | MEDLINE | ID: mdl-38686050

ABSTRACT

Cancer frequently develops resistance to the majority of chemotherapy treatments. This study aimed to examine the synergistic cytotoxic and antitumor effects of SGLT2 inhibitors, specifically Canagliflozin (CAN), Dapagliflozin (DAP), Empagliflozin (EMP), and Doxorubicin (DOX), using in vitro experimentation. The precise combination of CAN+DOX has been found to greatly enhance the cytotoxic effects of doxorubicin (DOX) in MCF-7 cells. Interestingly, it was shown that cancer cells exhibit an increased demand for glucose and ATP in order to support their growth. Notably, when these medications were combined with DOX, there was a considerable inhibition of glucose consumption, as well as reductions in intracellular ATP and lactate levels. Moreover, this effect was found to be dependent on the dosages of the drugs. In addition to effectively inhibiting the cell cycle, the combination of CAN+DOX induces substantial modifications in both cell cycle and apoptotic gene expression. This work represents the initial report on the beneficial impact of SGLT2 inhibitor medications, namely CAN, DAP, and EMP, on the responsiveness to the anticancer properties of DOX. The underlying molecular mechanisms potentially involve the suppression of the function of SGLT2.


Subject(s)
Apoptosis , Breast Neoplasms , Doxorubicin , Sodium-Glucose Transporter 2 Inhibitors , Female , Humans , Apoptosis/drug effects , Apoptosis/genetics , Benzhydryl Compounds/pharmacology , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Canagliflozin/pharmacology , Cell Cycle/drug effects , Cell Proliferation/drug effects , Doxorubicin/pharmacology , Drug Resistance, Neoplasm/drug effects , Drug Synergism , Glucose/metabolism , Glucosides/pharmacology , MCF-7 Cells , Sodium-Glucose Transporter 2/metabolism , Sodium-Glucose Transporter 2 Inhibitors/pharmacology
13.
Curr Probl Cardiol ; 49(6): 102563, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38599557

ABSTRACT

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have emerged as a novel category of blood glucose-lowering drugs in clinical recommendations for a wide range of diseases. SGLT2 inhibitors are promising anti-inflammatory agents by acting either indirectly via improving metabolism and reducing stress conditions or via direct modulation of inflammatory signaling pathways. The SGLT2 inhibitors empagliflozin and dapagliflozin better vascular function and avert vascular aging by decreasing the reactive oxygen species (ROS) content and increasing nitric oxide bioavailability, respectively. It was discovered that ipragliflozin has the ability to prevent dysfunction of the endothelium, and this effect was connected with oxidative stress. According to published data, SGLT2 inhibitors may delay vascular aging and arrest the development of endothelial dysfunction in animal models of type 2 diabetes (T2D) by reducing inflammation, oxidative stress, and glucose toxicity and increasing the survival of hyperglycemic endothelial cells. The adenosine monophosphate-activated protein kinase (AMPK) molecule plays a vital role in the regulation of bioenergy metabolism and is pivotal in our understanding of diabetes mellitus and other metabolic disorders. It has been hypothesized that SGLT2 inhibitors may indirectly affect AMPK to reduce mammalian target of rapamycin (mTOR) activity. Numerous studies have demonstrated that SGLT2 inhibitors can activate AMPK by restoring the AMP/ATP balance in favor of AMP, which is assumed to be the mechanism by which these medications have positive effects on the cardiac structure and microvessel.


Subject(s)
Diabetes Mellitus, Type 2 , Signal Transduction , Sodium-Glucose Transporter 2 Inhibitors , Sodium-Glucose Transporter 2 Inhibitors/pharmacology , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Humans , Signal Transduction/drug effects , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Animals , Cardiovascular Diseases/metabolism , Cardiovascular Diseases/prevention & control , Inflammation/metabolism , Inflammation/drug therapy , Oxidative Stress/drug effects , Glucosides/therapeutic use , Glucosides/pharmacology , Sodium-Glucose Transporter 2/metabolism , Benzhydryl Compounds/therapeutic use , Benzhydryl Compounds/pharmacology
14.
Cardiovasc Res ; 120(5): 443-460, 2024 Apr 30.
Article in English | MEDLINE | ID: mdl-38456601

ABSTRACT

An increasing number of individuals are at high risk of type 2 diabetes (T2D) and its cardiovascular complications, including heart failure (HF), chronic kidney disease (CKD), and eventually premature death. The sodium-glucose co-transporter-2 (SGLT2) protein sits in the proximal tubule of human nephrons to regulate glucose reabsorption and its inhibition by gliflozins represents the cornerstone of contemporary T2D and HF management. Herein, we aim to provide an updated overview of the pleiotropy of gliflozins, provide mechanistic insights and delineate related cardiovascular (CV) benefits. By discussing contemporary evidence obtained in preclinical models and landmark randomized controlled trials, we move from bench to bedside across the broad spectrum of cardio- and cerebrovascular diseases. With landmark randomized controlled trials confirming a reduction in major adverse CV events (MACE; composite endpoint of CV death, non-fatal myocardial infarction, and non-fatal stroke), SGLT2 inhibitors strongly mitigate the risk for heart failure hospitalization in diabetics and non-diabetics alike while conferring renoprotection in specific patient populations. Along four major pathophysiological axes (i.e. at systemic, vascular, cardiac, and renal levels), we provide insights into the key mechanisms that may underlie their beneficial effects, including gliflozins' role in the modulation of inflammation, oxidative stress, cellular energy metabolism, and housekeeping mechanisms. We also discuss how this drug class controls hyperglycaemia, ketogenesis, natriuresis, and hyperuricaemia, collectively contributing to their pleiotropic effects. Finally, evolving data in the setting of cerebrovascular diseases and arrhythmias are presented and potential implications for future research and clinical practice are comprehensively reviewed.


Subject(s)
Blood Glucose , Cardiovascular Diseases , Diabetes Mellitus, Type 2 , Sodium-Glucose Transporter 2 Inhibitors , Humans , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Sodium-Glucose Transporter 2 Inhibitors/adverse effects , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/mortality , Cardiovascular Diseases/prevention & control , Cardiovascular Diseases/drug therapy , Cardiovascular Diseases/mortality , Cardiovascular Diseases/metabolism , Animals , Treatment Outcome , Blood Glucose/metabolism , Blood Glucose/drug effects , Sodium-Glucose Transporter 2/metabolism , Risk Assessment , Risk Factors , Cardiovascular System/drug effects , Cardiovascular System/metabolism , Cardiovascular System/physiopathology , Biomarkers/blood
15.
Basic Clin Pharmacol Toxicol ; 134(5): 643-656, 2024 May.
Article in English | MEDLINE | ID: mdl-38409617

ABSTRACT

AIMS: Sodium glucose co-transporter-2 (SGLT2) inhibition lowers glucose levels independently of insulin, leading to reduced insulin secretion and increased lipolysis, resulting in elevated circulating free fatty acids (FFAs). While SGLT2 inhibition improves tissue insulin sensitivity, the increase in circulating FFAs could reduce insulin sensitivity in skeletal muscle and the liver. We aimed to investigate the effects of SGLT2 inhibition on substrate utilization in skeletal muscle and the liver and to measure beta-cell function and glucose tolerance. METHODS: Thirteen metformin-treated individuals with type 2 diabetes were randomized to once-daily empagliflozin 25 mg or placebo for 4 weeks in a crossover design. Skeletal muscle glucose and FFA uptake together with hepatic tissue FFA uptake were measured using [18F]FDG positron emission tomography/computed tomography (PET/CT) and [11C]palmitate PET/CT. Insulin secretion and action were estimated using the oral minimal model. RESULTS: Empagliflozin did not affect glucose (0.73 ± 0.30 vs. 1.16 ± 0.64, µmol/g/min p = 0.11) or FFA (0.60 ± 0.30 vs. 0.56 ± 0.3, µmol/g/min p = 0.54) uptake in skeletal muscle. FFA uptake in the liver (21.2 ± 10.1 vs. 19 ± 8.8, µmol/100 ml/min p = 0.32) was unaffected. Empagliflozin increased total beta-cell responsivity (20 ± 8 vs. 14 ± 9, 10-9 min-1, p < 0.01) and glucose effectiveness (2.6 × 10-2 ± 0.3 × 10-2 vs. 2.4 × 10-2 ± 0.3 × 10-2, dL/kg/min, p = 0.02). CONCLUSIONS: Despite improved beta-cell function and glucose tolerance, empagliflozin does not appear to affect skeletal muscle FFA or glucose uptake.


Subject(s)
Benzhydryl Compounds , Diabetes Mellitus, Type 2 , Glucosides , Insulin Resistance , Humans , Fatty Acids, Nonesterified , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Sodium-Glucose Transporter 2/metabolism , Positron Emission Tomography Computed Tomography , Glucose/metabolism , Insulin/metabolism , Muscle, Skeletal
16.
Int J Biol Macromol ; 263(Pt 2): 130375, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38403210

ABSTRACT

Sodium-glucose cotransporter 2 (SGLT2) plays a pivotal role in mediating glucose reabsorption within the renal filtrate, representing a well-known target in type 2 diabetes and heart failure. Recent emphasis has been directed toward designing SGLT2 inhibitors, with C-glycoside inhibitors emerging as front-runners. The architecture of SGLT2 has been successfully resolved using cryo-electron microscopy. However, comprehension of the pharmacophores within the binding site of SGLT2 remains unclear. Here, we use machine learning and molecular dynamics simulations on SGLT2 bound with its inhibitors in preclinical or clinical development to shed light on this issue. Our dataset comprises 1240 SGLT2 inhibitors amalgamated from diverse sources, forming the basis for constructing machine learning models. SHapley Additive exPlanation (SHAP) elucidates the crucial fragments that contribute to inhibitor activity, specifically Morgan_3, 162, 310, 325, 366, 470, 597, 714, 926, and 975. Furthermore, the computed binding free energies and per-residue contributions for SGLT2-inhibitor complexes unveil crucial fragments of inhibitors that interact with residues Asn-75, His-80, Val-95, Phe-98, Val-157, Leu-274, and Phe-453 in the binding site of SGLT2. This comprehensive investigation enhances understanding of the binding mechanism for SGLT2 inhibitors, providing a robust framework for evaluating and discovering novel lead scaffolds within this domain.


Subject(s)
Diabetes Mellitus, Type 2 , Sodium-Glucose Transporter 2 Inhibitors , Humans , Sodium-Glucose Transporter 2 Inhibitors/pharmacology , Diabetes Mellitus, Type 2/metabolism , Sodium-Glucose Transporter 2/metabolism , Molecular Dynamics Simulation , Cryoelectron Microscopy , Glucose/metabolism , Hypoglycemic Agents/pharmacology
17.
Diabetes ; 73(5): 763-779, 2024 May 01.
Article in English | MEDLINE | ID: mdl-38394641

ABSTRACT

The beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on kidney function are well-known; however, their molecular mechanisms are not fully understood. We focused on 78-kDa glucose-regulated protein (GRP78) and its interaction with SGLT2 and integrin-ß1 beyond the chaperone property of GRP78. In streptozotocin (STZ)-induced diabetic mouse kidneys, GRP78, SGLT2, and integrin-ß1 increased in the plasma membrane fraction, while they were suppressed by canagliflozin. The altered subcellular localization of GRP78/integrin-ß1 in STZ mice promoted epithelial mesenchymal transition (EMT) and fibrosis, which were mitigated by canagliflozin. High-glucose conditions reduced intracellular GRP78, increased its secretion, and caused EMT-like changes in cultured HK2 cells, which were again inhibited by canagliflozin. Urinary GRP78 increased in STZ mice, and in vitro experiments with recombinant GRP78 suggested that inflammation spread to surrounding tubular cells and that canagliflozin reversed this effect. Under normal glucose culture, canagliflozin maintained sarco/endoplasmic reticulum (ER) Ca2+-ATPase (SERCA) activity, promoted ER robustness, reduced ER stress response impairment, and protected proximal tubular cells. In conclusion, canagliflozin restored subcellular localization of GRP78, SGLT2, and integrin-ß1 and inhibited EMT and fibrosis in DKD. In nondiabetic chronic kidney disease, canagliflozin promoted ER robustness by maintaining SERCA activity and preventing ER stress response failure, and it contributed to tubular protection.


Subject(s)
Endoplasmic Reticulum Chaperone BiP , Sodium-Glucose Transporter 2 Inhibitors , Animals , Mice , Canagliflozin , Fibrosis , Glucose/pharmacology , Integrins/metabolism , Sodium-Glucose Transporter 2/metabolism , Sodium-Glucose Transporter 2 Inhibitors/pharmacology
18.
J Clin Pharmacol ; 64(6): 672-684, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38363006

ABSTRACT

The aim of this study was to use a combination of physiologically based pharmacokinetic (PBPK) modeling and urinary glucose excretion (UGE) modeling to predict the time profiles of pharmacokinetics (PK) and UGE for the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (EMP). Additionally, the study aims to explore the compensatory effect of SGLT1 in renal glucose reabsorption (RGR) when SGLT2 is inhibited. The PBPK-UGE model was developed using physicochemical and biochemical properties, renal physiological parameters, binding kinetics, glucose, and Na+ reabsorption kinetics by SGLT1/2. For area under the plasma concentration-time curve, maximum plasma concentration, and cumulative EMP excretion in urine, the predicted values fell within a range of 0.5-2.0 when compared to observed data. Additionally, the simulated UGE data also matched well with the clinical data, further validating the accuracy of the model. According to the simulations, SGLT1 and SGLT2 contributed approximately 13% and 87%, respectively, to RGR in the absence of EMP. However, in the presence of EMP at doses of 2.5 and 10 mg, the contribution of SGLT1 to RGR significantly increased to approximately 76%-82% and 89%-93%, respectively, in patients with type 2 diabetes mellitus. Furthermore, the model supported the understanding that the compensatory effect of SGLT1 is the underlying mechanism behind the moderate inhibition observed in total RGR. The PBPK-UGE model has the capability to accurately predict the PK and UGE time profiles in humans. Furthermore, it provides a comprehensive analysis of the specific contributions of SGLT1 and SGLT2 to RGR in the presence or absence of EMP.


Subject(s)
Benzhydryl Compounds , Glucosides , Models, Biological , Sodium-Glucose Transporter 1 , Sodium-Glucose Transporter 2 Inhibitors , Glucosides/pharmacokinetics , Humans , Benzhydryl Compounds/pharmacokinetics , Benzhydryl Compounds/urine , Sodium-Glucose Transporter 1/metabolism , Sodium-Glucose Transporter 2 Inhibitors/pharmacokinetics , Sodium-Glucose Transporter 2 Inhibitors/pharmacology , Glucose/metabolism , Male , Sodium-Glucose Transporter 2/metabolism , Adult , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/pharmacology , Renal Reabsorption/drug effects , Kidney/metabolism , Glycosuria , Female , Middle Aged
19.
Mol Cell Endocrinol ; 584: 112156, 2024 Apr 15.
Article in English | MEDLINE | ID: mdl-38278341

ABSTRACT

The imbalance between T helper 17 (Th17) and regulatory T (Treg) cells is an important mechanism in the pathogenesis of diabetic nephropathy (DN). Serum/glucocorticoid regulated kinase 1 (SGK1) is a serine-threonine kinase critical for stabilizing the Th17 cell phenotype. Sodium-glucose cotransporter 2 (SGLT2) is a glucose transporter that serves as a treatment target for diabetes. Our study investigated the regulatory role of SGLT2 in the development of DN. The results revealed that SGLT2 knockdown suppressed high glucose-induced excessive secretion of sodium (Na+) and inflammatory cytokines in mouse renal tubular epithelial TCMK-1 cells. High Na+ content induced Th17 differentiation and upregulated SGK1, phosphorylated forkhead box protein O1 (p-FoxO1), and the interleukin 23 receptor (IL-23 R) in primary mouse CD4+ T cells. Co-culture of CD4+ T cells with the culture medium of TCMK-1 cells with insufficient SGLT2 expression significantly suppressed cell migration ability, reduced the production of pro-inflammatory cytokines, and inhibited Th17 differentiation possibly by downregulating SGK1, p-FoxO1, and IL-23 R. In addition, in vivo data demonstrated that SGLT2 knockdown markedly downregulated SGK1 in db/db mice. Insufficient SGLT2 or SGK1 expression also ameliorated the Th17/Treg imbalance, suppressed the development of DN, and regulated the expression of IL-23 R and p-FoxO1. In conclusion, this study showed that SGLT2 knockdown restored the Th17/Treg balance and suppressed DN possibly by regulating the SGK1/p-FoxO1/IL-23 R axis by altering Na+ content in the local environment. These findings highlight the potential use of SGLT2 and SGK1 for the management of DN.


Subject(s)
Diabetes Mellitus , Diabetic Nephropathies , Immediate-Early Proteins , Protein Serine-Threonine Kinases , Sodium-Glucose Transporter 2 , Animals , Mice , Cytokines/metabolism , Diabetes Mellitus/metabolism , Diabetic Nephropathies/genetics , Diabetic Nephropathies/metabolism , Glucocorticoids/metabolism , Glucose/metabolism , Interleukin-23/metabolism , Mice, Inbred Strains , Sodium/metabolism , Sodium-Glucose Transporter 2/metabolism , T-Lymphocytes, Regulatory , Protein Serine-Threonine Kinases/metabolism , Immediate-Early Proteins/metabolism
20.
J Diabetes Complications ; 38(2): 108687, 2024 02.
Article in English | MEDLINE | ID: mdl-38266571

ABSTRACT

AIMS: Diabetic nephropathy (DN) complicates diabetes Mellitus and intimately relates to intrarenal renin-angiotensin system (RAS) activity. Dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), has been validated to improve renal outcomes in diabetic patients from clinical research by elusive mechanisms. This study explored the presumption that the eagerness activity of intrarenal RAS in DN generated oxidative stress to promote renal fibrosis, and the process can be interrupted by dapagliflozin. METHODS: A streptozotocin-induced DN model was established in male C57BL/6J mice. Mice were treated with dapagliflozin or losartan for 14 weeks. Biochemical data, renal fibrosis, oxidative stress, and RAS were measured. RESULTS: DN mice were characterized by overtly low body weight, high levels of blood glucose, and renal injury. Interrupting SGLT2 and RAS significantly improved renal dysfunction and pathological lesions in DN mice. Consistent with these favorable effects, dapagliflozin revoked the local RAS/oxidative stress and the succeeding transforming growth factor beta (TGFß) signaling. CONCLUSIONS: This research clarifies that intrarenal RAS activity triggers renal injury in DN, and dapagliflozin attenuates renal fibrosis by suppressing Angiotensin II/TGFß signaling. It unravels a novel insight into the role of prevention and treatment of SGLT2 inhibitors to DN.


Subject(s)
Benzhydryl Compounds , Diabetes Mellitus, Experimental , Diabetic Nephropathies , Glucosides , Humans , Male , Mice , Animals , Angiotensin II , Sodium-Glucose Transporter 2/metabolism , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/metabolism , Transforming Growth Factor beta , Mice, Inbred C57BL , Diabetic Nephropathies/drug therapy , Diabetic Nephropathies/prevention & control , Diabetic Nephropathies/metabolism , Kidney/pathology , Fibrosis
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