Glucose Transporter Research Articles

Effect of empagliflozin on no-reflow in patients with st elevation myocardial infarction undergoing primary percutaneous coronary intervention

Abstract Background Primary percutaneous coronary intervention (PPCI) restores myocardial tissue perfusion successfully in over 90 % of ST-elevation myocardial infarction (STEMI) patients .However there remains a small proportion of patients who exhibit no-reflow.(1) Empagliflozin is a sodium glucose co-transporter 2 (SGLT2) inhibitor that acts as a powerful anti-oxidant and has beneficial effects on endothelial function and reducing burden of ischemia in-vitro.(2) Aim and Objectives: To Assess the effect of Empagliflozin preloading in non-diabetic STEMI patients before PPCI on procedural, in-hospital outcomes and short-term Major Adverse Cardiovascular events (MACE) in a single tertiary center. Patients and Methods: The study was carried out on 200 non-diabetic STEMI patients presenting to our university hospital within the first 8 hours of symptom onset. Patients were randomised into 2 groups , the intervention group received 10mg Empagliflozin before PPCI with the standard medical therapy while the control group received only the standard medical therapy. Patients were assessed for demographic data, risk factors, procedural outcomes, clinical and in-hospital outcomes, and short-term MACE up to 1 month. Results: Our study found a significant difference between the intervention and control groups regarding contrast volume with a mean of 131 ml in the intervention group and 144 ml in control group with a p value of 0.009, incidence of no-reflow with 34.5% in the control group and only 18.2% in the intervention group and a p value of 0.014 and myocardial blush grade (MBG) were 84.1% of the patients in intervention group had MBG III after PCI while only 65.5% of the patients in the control group showed the same results with a p value of 0.019. Also, there was a significant difference in St-segment resolution post PCI as 59.1% of patients in the intervention group had complete ST segment resolution and only 39.1% of the patients in the control group had complete resolution with a p-value of 0.027, and total MACE in the first month which affected 44.8% of the patients in the control group and only 28.4% of those in the intervention group with a p-value of 0.024. Conclusion Our study showed that pre-loading of STEMI patients with Empagliflozin resulted in improvement in procedural outcomes, decreasing the incidence of coronary no-reflow, improvement in patient’s course during hospital stay and short-term MACE. Improvement in MACE was mainly due to reduced HF hospitalisations and anginal symptoms.

Effects of empagliflozin on myocardial transcriptome in rats with aortic stenosis-induced heart failure

Abstract Introduction Aortic stenosis (AS) represents one of the most prevalent valvular heart diseases and an important cause of heart failure. Currently, no medical therapies influence the natural history of aortic stenosis. Although sodium glucose co-transporter 2 inhibitors (SGLT2i) have improved cardiovascular outcomes in heart failure patients with both reduced and preserved ejection fraction, their action mechanisms are not clear. Transcriptome analysis present great potential to identify biomarkers of disease and to gain insight into disease pathophysiology. In this study, we analyzed myocardial mRNA profile in aortic stenosis rats treated with empagliflozin. Methods Eighteen weeks after supra-aortic banding surgery, male Wistar rats were divided into 3 groups: Sham (n=15); aortic stenosis (AS, n=27); AS+empagliflozin (AS-EMP, n=27). Empagliflozin (10 mg/kg/day) was added to rat chow for 8 weeks. Transcriptome of left ventricle (LV) myocardium was studied by RNA-sequencing (sample size: 5 per group). Differential gene expression was analyzed in R environment using the DESeq2 package. Genes were considered differentially expressed (DEG) when they exhibited a log2 fold change (log2FC) higher than 1 (upregulated) or lower than -1 (downregulated), coupled with an adjusted p-value below 0.05. Functional enrichment analysis using gene ontology was performed by the online tool Enrich. Statistical analysis: ANOVA and Tukey. Results AS-EMP had lower LV diastolic diameter (Sham 8.39±0.57; AS 9.80±0.53*; AS-EMP 9.08±0.87# mm; p<0.05: * vs Sham; # vs AS), left atrium diameter (Sham 5.68±0.40; AS 9.67±1.00*; AS-EMP 8.97±1.36*# mm; p<0.05: * vs Sham; # vs AS), and LV mass (Sham 0.85±0.11; AS 2.19±0.27*; AS-EMP 1.76±0.34*# g; p<0.05: * vs Sham; # vs AS) than AS. A total of 1246 differentially expressed genes were identified, comprising 663 upregulated genes (70 genes in AS vs SHAM; 593 in AS-EMP vs AS) and 583 downregulated genes (35 genes in AS vs SHAM; 548 in AS-EMP vs AS). Most of the differentially expressed genes were enriched in processes such as extracellular matrix and structure organization, signal transduction regulation, and substrate-dependent cell migration (AS vs SHAM), as well as myocardial contraction, negative regulation of programmed cell death, and mitochondrial membrane organization (AS-EMP vs AS). The main upregulated genes were Loxl1, Mfap4, Postn, Col8a1, Pi16, and Nppa in AS vs SHAM; and Mxra8, Zfta, Pnisr, Thoc1, and Ralbp1 in AS-EMP vs AS comparison. The main downregulated genes were Mxra8, Ralbp1, and Tubgcp6 in AS vs SHAM; and Itgb5, Ltbp2, Tmem109, Plec, and Rorc in AS-EMP vs AS comparison. Conclusion We identified myocardial genes and biological processes that are potentially involved in aortic stenosis-induced heart failure. Empagliflozin attenuates cardiac remodeling and modulates myocardial genes involved with myocyte contraction, apoptosis, and mitochondrial organization in aortic stenosis rats.

Secondary erythrocytosis / polycythemia due to sodium glucose co-transporter 2 inhibitors: a real world heart failure cohort

Abstract Background Sodium glucose co-transporter 2 inhibitors (SGLT2-i) are one of the four pillars of guideline-directed medical therapy in heart failure with reduced ejection fraction and preserved ejection fraction according to the current ESC and AHA/ACC heart failure guidelines 1,2. As a result, there has been a significant increase in their use worldwide. Although SGLT2 inhibitors are known to increase hemoglobin and hematocrit levels, there is a lack of data on the burden of erythrocytosis or polycythemia in pivotal trials 3,4. Purpose In this retrospective cohort study, we investigated the prevalence and clinical outcomes of SGLT2-i related erythrocytosis in a tertiary heart failure outpatient clinic. Methods We reviewed clinical data from heart failure patients treated with an SGLT2 inhibitor at our tertiary centre between September 2019 and October 2023. Patients were included if they were taking SGLT2-i continuously for more than one month. Data were collected on Hb/Hct levels at baseline before initiation of SGLT2-i, at peak levels during therapy and at the last follow-up. Erythrocytosis was defined according to the 2017 WHO classification as Hb> 10.3 mmol/L and/or Hct> 49% in men and Hb> 10.0 mmol/L and/or Hct> 48% in females. Results A total of 173 patients with heart failure were included (median age 58 [49-66] years, 65% male). One hundred and fifty-six patients (90%) were using dapagliflozin, while 16 patients (9%) were using empagliflozin. The overall prevalence of SGLT2i related erythrocytosis was 39/173 (22.5%; median age 60 and 82% males). Eleven (6.3%) patients had pre-existing erythrocytosis at baseline. During a mean follow-up of 14±10 months, 28/173 (16.2%) patients developed new onset erythrocytosis. The median time to the peak of the Hb/Hct level was 6.5 months. Although the group with erythrocytosis had significantly higher Hb and Hct at baseline compared to the group without erythrocytosis (Hb 9.7 mmol/L ± 1.0 vs. 8.5 mmol/L ± 1.0; p<0.001 in men and 9.1 mmol/L ± 0.8 mmol/L vs. 8.1 ± 0.8; p=0.006 in females), they also experienced a significantly greater median increase in Hb from baseline to peak (1.05 mmol/L vs. 0.60mmol/L; p=0.01) (see Figure 1) There were significantly more males (82% vs 60%; p=0.01) in the erythrocytosis group compared to the non-erythrocytosis group. In addition, the prevalence of OSAS was significantly higher in the group with erythrocytosis compared to the group without erythrocytosis (31% vs. 8%; p<0.001). Conclusion Secondary erythrocytosis or polycythemia is common in patients with chronic heart failure. It is particularly common in men and in patients with obstructive sleep apnoea syndrome (OSAS). There were no excess thrombotic or thromboembolic events, probably because of the routine use of anticoagulants/antiplatelets and limited follow-up. To avoid unnecessary haematological referrals and potential clinical adverse events, increased awareness among clinicians is needed.Table 1.Baseline and clinical outcomesFig1.Hemoglobin levels over time

Guideline-directed medical therapy patterns in heart failure with reduced ejection fraction: the OPTIMA-HF registry

Abstract Background/Introduction European guidelines strongly recommend an optimized pharmacological treatment in patients with heart failure with reduced ejection fraction (HFrEF) with a fast introduction of the four-pillars. Purpose Aim of the Optimization of Therapy in the Italian Management of Heart Failure [OpTIMa-HF] Registry was to collect data on HF patients to describe the current Italian population of HF patients with a specific focus on HFrEF treatment adherence and prescription rates, according to the most recent European Guidelines. Methods OPTIMA-HF is an observational, cross-sectional, multicenter, real-life study conducted in two different clinical settings: HF outpatients’ clinics of Italian University Hospitals and territorial Italian Cardiology outpatients’ services, that enrolled patients with chronic HFrEF receiving at least 1 oral medication for management of HF. Patients were characterized by baseline use and dose of angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB)/angiotensin receptor neprilysin inhibitor (ARNI), beta-blocker, mineralocorticoid receptor antagonist (MRA) and sodium glucose co-transporter II inhibitor (SGLT2i). Patient-level factors associated with medication use were examined. Results Overall, 1390 patients from 29 ambulatory cardiology practices and university hospitals were included. Mean age was 69.5 ± 11.9 years, 24% were female, and median EF was 33 (28-37). Among enrolled patients, 72.2% were prescribed ARNI, 17.1% ACEI/ARB, 95% beta-blocker, 75.5% MRA and 63% SGLT2i therapy (Figure 1). Despite high prescription rates for each single class, a still not sufficient number of patients was on treatment with all four pillars, in particular 40.4% considering the presence ARNI and 6.2%. When medications were prescribed, few patients were receiving target doses of ACEI/ARB (31.7%), ARNI (16%), and beta-blocker (33.3%), whereas a higher proportion were receiving target doses of MRA therapy (38%), and all were receiving target dose for SGLT2i. Among patients eligible for all classes of medication, only 1.1% were simultaneously receiving target doses of ACE/ARB/ARNI, beta-blocker, MRA and SGLT2i. Prescription rates did not significantly differ between the type of center (University Hospital vs. territorial Cardiology outpatients’ services). As regards patients not on treatment with any of the four pillars, a small but still present amount of patients had no contraindications to these drugs (Figure 1). Conclusions In this contemporary outpatient HFrEF Italian registry, significant high prescription rates of the four-pillars were observed, however therapy combination rate is still not sufficient and drugs' titration need to be implemented to receive the greatest benefits from an optimized treatment. Strategies to improve guideline-directed use of HFrEF medications remain urgently needed, and these findings may inform targeted approaches to optimize outpatient medical therapy.

The potential protective effect of dapagliflozin on the development of cardiotoxicity in cancer patients after one year of observation

Abstract Introduction Despite the widespread use of anthracyclines (ANT) and anti-HER2 agents as trastuzumab (TZB) in chemotherapy schemes, it is known the potential cardiotoxic effects that can limit the intensity and duration of treatments. The clinical trial "DECLARE-TIMI 58" (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58), demonstrated that dapagliflozin, a Sodium glucose cotransporter 2 inhibitor, reduces the composite end point of cardiovascular death/hospitalization for heart failure in a broad population of patients with type 2 diabetes mellitus. Purpose We aimed to study if dapagliflozin could exerts cardioprotective effects in anthracycline, carfilzomib and trastuzumab-induced cardiotoxicity through the analysis of ejection fraction (LVEF), global longitudinal strain (GLS) of both left and right ventricle, E/A ratio, E/e’ ratio, left atrium diameter, BNP/NT-pro-BNP and troponin I. Methods 32 diabetic patients were randomized (16 dapagliflozin;16 placebo). The groups were well-matched for baseline characteristics (age, diabetes duration, HbA1c, renal and heart function as well as chemotherapeutic agents ). Our patients who were diagnosed with cancer at our medical center, receiving potentially cardiotoxic treatment: 52% were treated with only trastuzumab, 34% were treated with only anthracycline and 14% carfilzomib. The primary endpoint was the development of cardiotoxicity after treatment with chemotherapy. Cardiotoxicity was defined as a decrease of LVEF by 5% or more to less than 55% in the presence of symptoms of heart failure or an asymptomatic decrease in LVEF by 10% or more to less than 55%. Results In the first year of observation patients treated with dapagliflozin didn’t show any deterioration of LV GLS (¬19.8±2.8 vs ¬19.3±4.1%, p=0.403) There was no change in LVEF (57.8±4.9% vs 59±6.8%) and GLS of right ventricle (20.3±2.8% vs 20.0±3.6%). Conversely, patients treated with placebo, presented a significant impairment of LV GLS (¬20.8±2.1% vs ¬18.5±2.2%, p=0,001) while a borderline deterioration of EF was noticed after treatment with placebo(60±5.4 vs 56.7±6.7%, p=0,045). Conclusions At the best of our knowledge, our study is the first to investigate the prophylactic use of dapagiflozin in the development of non-ischemic cardiomyopathy in diabetic patients receiving anthracycline or trastuzumab,carflilzomib therapies. Treatment with dapagliflozin prevented deterioration of myocardial function and preserved ejection fraction

Canagliflozin reduces oral loop diuretic intensification in patients with type 2 diabetes: a participant level pooled analysis of CREDENCE and CANVAS

Abstract Background Patients with type 2 diabetes often have coexistent heart failure or chronic kidney disease (CKD) that require treatment with loop diuretics; however, the prognostic implications of oral loop diuretic intensification are not well characterized. The sodium glucose cotransporter-2 inhibitor canagliflozin reduces the risk of hospitalization for heart failure or cardiovascular death and CKD progression among patients with type 2 diabetes at high cardiovascular risk or with concomitant CKD. Purpose To assess the prognostic implications of oral loop diuretic intensification and the treatment effects of canagliflozin versus placebo on loop diuretic use in high-risk patients with type 2 diabetes. Methods This was a post-hoc participant-level pooled analysis of the CANVAS Program and CREDENCE trial which enrolled patients with type 2 diabetes at high cardiovascular risk or with CKD. Oral loop diuretic intensification was defined as a composite of new loop diuretic initiation (among patients not receiving loop diuretics at baseline) or loop diuretic dose increase (among patients receiving loop diuretics at baseline). We assessed the association between the requirement for loop diuretic intensification and the incidence of subsequent all-cause death. The effect of canagliflozin versus placebo on the composite of loop diuretic intensification as well as its components were evaluated. We further examined the effect of canagliflozin on an expanded post hoc composite of cardiovascular death, hospitalization for heart failure or loop diuretic intensification. Results 2,263 (15.6%) of 14,543 patients were treated with loop diuretics at baseline. Over a median follow-up of 2.2 years, 1,264 patients (9.4%) required oral loop diuretic intensification, of which 981 (77.6%) patients required initiation of oral loop diuretics and 283 (22.4%) required oral loop diuretic dose increase. Patients requiring oral loop diuretic intensification experienced rates of subsequent mortality that were 3.5-fold higher (5.9[5.4-6.5] per 100 patient-years) than those not requiring oral loop diuretic intensification (1.7[1.6-1.9] per 100 patient-years). Treatment with canagliflozin reduced the need for oral loop diuretic intensification by 41% (HR 0.59; 95%CI: 0.53-0.66) including both new diuretic initiation (HR 0.65; 95%CI: 0.57-0.74) and diuretic dose increase (HR 0.42; 95%CI: 0.33-0.54); Figure 1. Treatment with canagliflozin similarly reduced an expanded composite of worsening heart failure inclusive of cardiovascular death, heart failure hospitalization or diuretic intensification (HR 0.64; 95%CI: 0.58-0.70). Conclusion Among high-risk patients with T2D, new oral loop diuretic intensification was frequent and associated with an increased risk of subsequent mortality. Treatment with canagliflozin significantly reduced the need for loop diuretic intensification.

Sodium glucose cotransporter 2 inhibitors in the management of heart failure: Veni, Vidi, and Vici.

Heart failure (HF) is a chronic disease associated with high morbidity and mortality rates. Renin-angiotensin-aldosterone system blockers (including angiotensin receptor/neprilysin inhibitors), beta-blockers, and mineralocorticoid receptor blockers remain the mainstay of pharmacotherapy for HF with reduced ejection fraction (HFrEF). However, despite the use of guideline-directed medical therapy, the mortality from HFrEF remains high. HF with preserved ejection fraction (HFpEF) comprises approximately half of the total incident HF cases; however, unlike HFrEF, there are no proven therapies for this condition. Sodium glucose cotransporter-2 inhibitors (SGLT-2is) represent a new class of pharmacological agents approved for diabetes mellitus (DM) that inhibit SGLT-2 receptors in the kidney. A serendipitous finding from seminal trials of SGLT-2is in DM was the significant improvement in renal and cardiovascular (CV) outcomes. More importantly, the improvement in HF hospitalization (HHF) in the CV outcomes trials of SGLT-2is was striking. Multiple mechanisms have been proposed for the pleiotropic effects of SGLT-2is beyond their glycemic control. However, as patients with HF were not included in any of these trials, it can be considered as a primary intervention. Subsequently, two landmark studies of SGLT-2is in patients with HFrEF, namely, an empagliflozin outcome trial in patients with chronic HF and a reduced ejection fraction (EMPEROR-Reduced) and dapagliflozin and prevention of adverse outcomes in HF (DAPA-HF), demonstrated significant improvement in HHF and CV mortality regardless of the presence of DM. These impressive results pitchforked these drugs as class I indications in patients with HFrEF across major guidelines. Thereafter, empagliflozin outcome trial in patients with chronic HF with preserved ejection fraction (EMPEROR-Preserved) and dapagliflozin evaluation to improve the lives of patients with preserved ejection fraction HF (DELIVER) trials successively confirmed that SGLT-2is also benefit patients with HFpEF with or without DM. These results represent a watershed as they constitute the first clinically meaningful therapy for HFpEF in the past three decades of evolution of HF management. Emerging positive data for the use of SGLT-2is in acute HF and post-myocardial infarction scenarios have strengthened the pivotal role of these agents in the realm of HF. In a short span of time, these classes of drugs have captivated the entire scenario of HF.

Effectiveness and mechanisms of sodium-dependent glucose transporter 2 inhibitors in type 2 diabetes and heart failure patients.

We comment on an article by Grubić Rotkvić et al published in the recent issue of the World Journal of Cardiology. We specifically focused on possible factors affecting the therapeutic effectiveness of sodium-dependent glucose transporter inhibitors (SGLT2i) in patients with type 2 diabetes mellitus (T2DM) and their impact on comorbidities. SGLT2i inhibits SGLT2 in the proximal tubules of the kidneys, lowering blood glucose levels by inhibiting glucose reabsorption by the kidneys and causing excess glucose to be excreted in the urine. Previous studies have demonstrated a role of SGLT2i in cardiovascular function in patients with diabetes who take metformin but still have poor glycemic control. In addition, SGLT2i has been shown to be effective in anti-apoptosis, weight loss, and cardiovascular protection. Accordingly, it is feasible to treat patients with T2DM with cardiovascular or renal diseases using SGLT2i.

Promising Directions for Regulating Signaling Pathways Involved in the Type 2 Diabetes Mellitus Development

Many studies confirm that substances of natural origin have a pronounced affinity for type 2 diabetes mellitus (T2DM) therapeutic targets. At the moment, there is growing interest in bioactive peptides, phytochemicals, and drugs from other natural sources as highly effective, safe and promising antidiabetic agents. Natural sources are a promising resource for regulating several pathological pathways in T2DM. The review describes ways to mitigate insulin resistance and tissue sensitivity to glucose through PTP1β (protein tyrosine phosphatase 1β), GLP-1R (glucagon-like peptide receptor), DPP-4 (dipeptidyl peptidase-4), AMPK (adenosine monophosphate activated protein kinase), MAPK (mitogen-activated protein kinase). Regulation of obesity and oxidative stress development through CCN3 (nephroblastoma overexpressed gene), PPAR-γ (peroxisome proliferator-activated receptor γ), Nrf2 (nuclear factor erythroid-related factor 2), FFAR (free fatty acid receptors), 11β-HSD1 (11β-hydroxysteroid dehydrogenase). Regulation of hyperglycemia through alpha-amylase inhibitors, regulation of glucose metabolism through GFAT (glutamine fructose-6-phosphate aminotransferase), FOXO1 (forkhead box protein O1), GLUT4 (glucose transporter type 4), PGC-1α (receptor gamma coactivator 1α activating peroxisome proliferator). The review examines the use of natural sources, from which low-molecular-weight and peptide compounds are used as T2DM targets modulators.

Oregano essential oil and Bacillus subtilis role in enhancing broiler’s growth, stress indicators, intestinal integrity, and gene expression under high stocking density

This study investigates the role of dietary Bacillus subtilis and oregano essential oil in mitigating the effects of high stocking density on growth performance, carcass traits, physiological stress indicators, gene expression, and intestinal integrity in broiler chickens. A total of, 1250 one-day-old Ross 308 male broiler chicks were randomly allocated to five experimental groups, where each group had five replicates of 50 chicks. Group 1 (control, LSD): 15 chicks/m2 fed a basal diet without feed additive, group 2 (HSD): 20 chicks/m2 fed a basal diet without feed additive, group 3 (BHSD): 20 chicks/m2 fed a basal diet supplemented with B. subtilis (500 mg/kg diet), group 4 (OHSD): 20 chicks/m2 fed a basal diet supplemented with oregano essential oil (300 mg/kg diet), group 5 (CHSD): 20 chicks/m2 fed a basal diet supplemented with oregano essential oil and B. subtilis. At 35 days of age, there was a noticeable improvement in the growth performance of broilers fed CHSD under high stocking density through the increase in body weight gain, dressing percentage, and crude protein digestibility with a decrease in feed conversion rate compared to other groups. Adding CHSD enhanced the state of oxidation and immunity through increasing superoxide dismutase, glutathione peroxidase, and the relative weight of bursa of Fabricius, while decreasing malondialdehyde, in addition to increasing plasma triiodothyronine levels. The microbial structure and morphometric parameters improved in the group that received the CHSD compared to the other groups, where villus height and Lactobacillus population increased, whereas Escherichia coli and Clostridium perfringens population decreased. Glucose transporter 2 (GLUT2), fatty acid transporter 1 (FABP1), and amino acid transferase 1 (CAT1) gene expression levels significantly increased when feeding on oregano essential oil with B. subtilis. In conclusion, combining oregano essential oil and B. subtilis supplements mitigated the effects of high stocking density by enhancing growth performance, antioxidative status, and intestinal integrity, in addition to modifying the genetic expression of genes related to nutrient absorption.

ECLIPSES: Early initiation of sodium glucose cotransporter-2 inhibitors for cardiovascular protection in patients with type 2 diabetes following acute coronary syndrome and subsequent coronary artery bypass graft surgery.

There is a paucity of data evaluating early initiation of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in patients with diabetes following acute coronary syndrome (ACS) and coronary artery bypass graft surgery (CABG). To describe the efficacy and safety of SGLT2i initiated early after CABG in patients with type 2 diabetes who experienced ACS. This is a retrospective cohort study of patients with type 2 diabetes (T2DM) who experienced ACS and subsequent CABGwith follow up at 3 and 12 months. Patients who filled a SGLT2i prescription within 14 days of discharge were allocated to the SGLT2i group and those who did not were included in the no SGLT2i group. The primary efficacy end point was first occurrence of a 4-point Major Adverse Cardiovascular Event (MACE), and the primary safety end point was a composite of hypoglycemia, hypotension, diabetic ketoacidosis, acute kidney injury, and urinary tract infection. Secondary end points included a comparative analysis of the primary outcome, 30-day readmission rates, and subgroup analyses of key populations. A total of 1629 patients were included: 226 received a SGLT2i within 14 days of discharge and 1403 did not. At 12 months, 8.9% and 15.3% of patients experienced MACE in the SGLT2i and no SGLT2i groups, respectively (adjusted Hazard Ratio [aHR] 0.65, 95% confidence interval [CI] 0.41-1.04). The primary safety outcome occurred in 12.0% of the SGLT2i group and 19.1% of the no SGLT2i group at 12 months (aHR 0.68, 95% CI 0.45-1.01). Early initiation of SGLT2i use was not associated with a reduction in MACE in patients with T2DM who experienced ACS and underwent subsequent CABG surgery. However, no apparent safety concerns were identified. Adequately powered trials are required to confirm this finding.

Prolonged treatment of compactin, atorvastatin, lovastatin or simvastatin decreased glucose consumption and expressions of proteins for glucose metabolism and insulin signaling in L6 skeletal muscle cells

Statins inhibit mevalonate synthesis and successfully lower plasma cholesterol levels and decrease the risk of cardiovascular diseases in humans, but also lead to myalgia in some patients. We hypothesize that statins may modulate glucose metabolism and insulin signaling in the skeletal muscle cells during and after differentiation, and in turn lead to side effects. Here, differentiating and differentiated L6 muscle cells were treated with 1 μM of different class of statins (compactin, pravastatin, atorvastatin, lovastatin and simvastatin) with or without insulin or mevalonate for extended periods of time. The glucose consumption and expression levels of proteins for glucose metabolism and insulin receptor (IR)/Akt signaling were determined. The prolonged statin treatments (except pravastatin) decreased glucose consumption in L6 skeletal muscle cells. In differentiating L6 cells, compactin, lovastatin or simvastatin decreased the expression levels of proteins involved in glucose metabolism and insulin signaling, including glucose transporter 4 (GLUT4), pyruvate dehydrogenase (PDH), glycogen synthase (GS), glycogen synthase kinase 3β (GSK3β) and insulin receptor β subunit (IRβ). In differentiated L6 cells, long-term treatment of compactin or simvastatin also decreased levels of proteins in glucose metabolism and IR/Akt signaling, including GLUT4, GSK3β, IRβ and PI3K p110α. Insulin treatment restored statin-mediated impairments in L6 cells. The insulin-mediated phosphorylation of Akt Ser473 was attenuated in differentiating and differentiated L6 cells in the presence of atorvastatin (differentiated only), compactin, lovastatin or simvastatin. In addition, mevalonate supplementation reversed the statin-mediated impairments in differentiated and differentiating L6 cells. Statin affected glucose usage and insulin signaling by inhibiting mevalonate synthesis in L6 cells. Our results provides a possible mechanism of adverse effects of statins in skeletal muscle and calls for cautious use of the medication in patients with impaired insulin sensitivity and glucose metabolism.

Disulfidptosis-related subtype and prognostic signature in prostate cancer

BackgroundDisulfidptosis refers to cell death caused by the accumulation and bonding of disulfide in the cytoskeleton protein of SLC7A11-high level cells under glucose deprivation. However, the role of disulfidptosis-related genes (DRGs) in prostate cancer (PCa) classification and regulation of the tumor microenvironment remains unclear.MethodsFirstly, we analyzed the expression and mutation landscape of DRGs in PCa. We observed the expression levels of SLC7A11 in PCa cells through in vitro experiments and assessed the inhibitory effect of the glucose transporter inhibitor BAY-876 on SLC7A11-high cells using CCK-8 assay. Subsequently, we performed unsupervised clustering of the PCa population and analyzed the differentially expressed genes (DEGs) between clusters. Using machine learning techniques to select a minimal gene set and developed disulfidoptosis-related risk signatures for PCa. We analyzed the tumor immune microenvironment and the sensitivity to immunotherapy in different risk groups. Finally, we validated the accuracy of the prognostic signatures genes using single-cell sequencing, qPCR, and western blot.ResultsAlthough SLC7A11 can increase the migration ability of tumor cells, BAY-876 effectively suppressed the viability of prostate cancer cells, particularly those with high SLC7A11 expression. Based on the DRGs, PCa patients were categorized into two clusters (A and B). The risk label, consisting of a minimal gene set derived from DEGs, included four genes. The expression levels of these genes in PCa were initially validated through in vitro experiments, and the accuracy of the risk label was confirmed in an external dataset. Cluster-B exhibited higher expression levels of DRG, representing lower risk, better prognosis, higher immune cell infiltration, and greater sensitivity to immune checkpoint blockade, whereas Cluster A showed the opposite results. These findings suggest that DRGs may serve as targets for PCa classification and treatment. Additionally, we constructed a nomogram that incorporates DRGs and clinical pathological features, providing clinicians with a quantitative method to assess the prognosis of PCa patients.ConclusionThis study analyzed the potential connection between disulfidptosis and PCa, and established a prognostic model related to disulfidptosis, which holds promise as a valuable tool for the management and treatment of PCa patients.

Molecular mechanisms underlying glucose-dependent insulinotropic polypeptide secretion in human duodenal organoids.

Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone secreted by enteroendocrine K cells in the proximal small intestine. This study aimed to explore the function of human K cells at the molecular and cellular levels. CRISPR-Cas9 homology-directed repair was used to insert transgenes encoding a yellow fluorescent protein (Venus) or an Epac-based cAMP sensor (Epac-S-H187) in the GIP locus in human duodenal-derived organoids. Fluorescently labelled K cells were purified by FACS for RNA-seq and peptidomic analysis. GIP reporter organoids were employed for GIP secretion assays, live-cell imaging of Ca2+ using Fura-2 and cAMP using Epac-S-H187, and basic electrophysiological characterisation. The G protein-coupled receptor genes GPR142 and CASR were knocked out to evaluate roles in amino acid sensing. RNA-seq of human duodenal K cells revealed enrichment of several G protein-coupled receptors involved in nutrient sensing, including FFAR1, GPBAR1, GPR119, CASR and GPR142. Glucose induced action potential firing and cytosolic Ca2+ elevation and caused a 1.8-fold increase in GIP secretion, which was inhibited by the sodium glucose co-transporter 1/2 (SGLT1/2) blocker sotagliflozin. Activation of the long-chain fatty acid receptor free fatty acid receptor 1 (FFAR1) induced a 2.7-fold increase in GIP secretion, while tryptophan and phenylalanine stimulated secretion by 2.8- and 2.1-fold, respectively. While CASR knockout blunted intracellular Ca2+ responses, a CASR/GPR142 double knockout was needed to reduce GIP secretory responses to aromatic amino acids. The newly generated human organoid K cell model enables transcriptomic and functional characterisation of nutrient-sensing pathways involved in human GIP secretion. Both calcium-sensing receptor (CASR) and G protein-coupled receptor 142 (GPR142) contribute to protein-stimulated GIP secretion. This model will be further used to identify potential targets for modulation of native GIP secretion in diabetes and obesity.

Comparison Between SGLT2 Inhibitors and Lactation: Implications for Cardiometabolic Health in Parous Women.

Sodium-glucose cotransporter-2 (SGLT2) inhibition and lactation result in the excretion of large amounts of glucose in urine or milk and are associated with a lower risk of cardiovascular events. The respective mechanisms behind this association with cardiovascular protection are not clear. This review compares the contribution of noninsulin-mediated glucose transport during pharmacologic inhibition of SGLT2 with noninsulin-mediated glucose transport during lactation in terms of the implications for the cardiometabolic health of parous women. The search topics used to obtain information on SGLT2 inhibitors included mechanisms of action, atherosclerosis, and heart failure. The search topics used to obtain information on lactation included cardiovascular health and milk composition. Subsequent reference searches of retrieved articles were also used. Active treatment with SGLT2 inhibitors affects glucose and sodium transport in the kidneys and predominantly protects against hospitalization for heart failure soon after the onset of therapy. Active lactation stimulates glucose transport into the mammary gland and improves subclinical and clinical atherosclerotic vascular disease years after delivery. Both SGLT2 inhibitors and lactation have effects on a variety of glucose transporters. Several mechanisms have been proposed to explain the cardiometabolic benefits of SGLT2 inhibition and lactation. Learning from the similarities and differences between both processes will advance our understanding of cardiometabolic health for all people.

The poplar SWEET1c glucose transporter plays a key role in the ectomycorrhizal symbiosis.

The mutualistic interaction between ectomycorrhizal fungi and trees is characterized by the coordinated exchange of soil nutrients with soluble sugars. Despite the importance of this process, the precise mechanism by which sugars are transported from host roots to colonizing hyphae remains unclear. This study aimed to identify the specific membrane transporters responsible for the unloading of sugars at the symbiotic interface, with a focus on the role of the root Sugars Will Eventually Be Exported Transporter (SWEET) uniporters. Our study used RNA sequencing and quantitative PCR to identify PtaSWEET gene expression in Populus tremula × alba-Laccaria bicolor ectomycorrhizal root tips. Our results suggest that symbiosis-induced PtaSWEET1c is primarily responsible for transporting glucose and sucrose, as demonstrated by the yeast assays. Moreover, we used a promoter-YFP reporter to confirm the localization of the PtaSWEET1c expression in cortical cells of ectomycorrhizal rootlets, supporting its major role in supplying glucose at the symbiotic interface. Furthermore, our observations confirmed the localization of PtaSWEET1c-GFP in the plasma membrane. The inactivation of PtaSWEET1c reduced ectomycorrhizal root formation and 13C translocation to ectomycorrhizal roots. Our findings highlight the crucial role of PtaSWEET1c in facilitating glucose and sucrose transport at the symbiotic interface of Populus-L. bicolor symbiosis.

Model-based meta-analysis of HbA1c reduction across SGLT2 inhibitors using dose adjusted by urinary glucose excretion

This study was aimed to evaluate whether the dose–response relationship of the sodium glucose co-transporter-2 inhibitors (SGLT2is) in patients with type 2 diabetes mellitus (T2DM)—canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, luseogliflozin, and tofogliflozin—can be explained in a unified manner based on their ability to promote urinary glucose excretion (UGE). Information on HbA1c reduction at various doses of each SGLT2i was collected from literatures on randomized controlled trials and was normalized based on the daily UGE data from phase I studies. After normalizing doses, the dose–response relationship of HbA1c reduction of most of SGLT2is was represented by a unified nonlinear mixed-effect model, with the estimated maximum HbA1c (%) reduction (Emax) of 0.796 points, whereas covariate analysis showed that canagliflozin had a 1.33-fold higher Emax than those of the other drugs. Other covariates included baseline HbA1c levels, body weight, disease duration, prior treatment, and renal function. Findings from this study would influence drug selection and adjustment in clinical practice. As with SGLT2is, in cases where the efficacy cannot be easily evaluated but an appropriate pharmacodynamic marker was assessed in early clinical trials, similar approaches for other drug classes can guide strategic and evidence-based dose selection in phase III trials.

Gpr55 deficiency crucially alters cardiomyocyte homeostasis and counteracts angiotensin II induced maladaption in female mice.

Cannabis stimulates several G-protein-coupled-receptors and causes bradycardia and hypotension upon sustained consumption. Moreover, in vitro studies suggest an interference of cannabinoid-signalling with cardiomyocyte contractility and hypertrophy. We aimed at revealing a functional contribution of the cannabinoid-sensitive receptor GPR55 to cardiomyocyte homeostasis and neurohumorally induced hypertrophy in vivo. Gpr55-/- and wild-type (WT) mice were characterized after 28-day angiotensin II (AngII; 1·μg·kg-1min-1) or vehicle infusion. In isolated adult Gpr55-/- and WT cardiomyocytes, mitochondrial function was assessed under naïve conditions, while cytosolic Ca2+ handling was additionally determined following application of the selective GPR55 antagonist CID16020046. Gpr55 deficiency did not affect angiotensin II (AngII) mediated hypertrophic growth, yet, especially in females, it alleviated maladaptive pro-hypertrophic and -inflammatory gene expression and improved inotropy and adrenergic responsiveness compared to WT. In-depth analyses implied increased cytosolic Ca2+ concentrations and transient amplitudes, and accelerated sarcomere contraction kinetics in Gpr55-/- myocytes, which could be mimicked by GPR55 blockade with CID16020046 in female WT cells. Moreover, Gpr55 deficiency up-regulated factors involved in glucose and fatty acid transport independent of the AngII challenge, accelerated basal mitochondrial respiration and reduced basal protein kinase (PK) A, G and C activity and phospholemman (PLM) phosphorylation. Our study suggests GPR55 as crucial regulator of cardiomyocyte hypertrophy and homeostasis presumably by regulating PKC/PKA-PLM and PKG signalling, and identifies the receptor as potential target to counteract maladaptation, adrenergic desensitization and metabolic shifts as unfavourable features of the hypertrophied heart in females.

Cardiovascular and kidney benefits of SGLT-2is and GLP-1RAs according to baseline blood pressure in type 2 diabetes: a systematic meta-analysis of cardiovascular outcome trials

Objectives: Using a systematic meta-analysis, we investigated if patients with type 2 diabetes (T2D) and with varying baseline blood pressure (BP) differ in the cardiorenal benefits received from sodium–glucose co-transporter 2 inhibitors (SGLT-2is) and glucagon-like peptide 1 receptor agonists (GLP-1RAs). Design: Randomized, placebo-controlled, cardiovascular outcome trials (CVOTs) of SGLT-2is and GLP-1RAs were identified from MEDLINE, Embase, and the Cochrane Library up to April 2024. Hazard ratios (HRs) with 95% CIs were pooled. The differential treatment effect by baseline BP category within each trial was estimated as the ratio of the HR (RHR) and pooled. Results: Seventeen publications based on 9 unique CVOTs (4 SGLT-2is and 5 GLP-1RAs) were eligible. In participants with normal baseline BP, comparing SGLT-2is with placebo, the HRs (95% CIs) were 0.88 (0.79-0.97) for major adverse cardiovascular events (MACE), 0.73 (0.59-0.91) for heart failure (HF) hospitalization, 0.78 (0.65-0.94) for composite CVD death/HF hospitalization, and 0.55 (0.41-0.73) for composite renal outcome. The corresponding estimates for participants with higher baseline BP were 0.88 (0.81-0.96), 0.67 (0.57-0.79), 0.73 (0.65-0.82), and 0.61 (0.48-0.77), respectively. In participants with normal baseline BP, GLP-RAs had no strong effect on MACE, stroke and nephropathy, but reduced stroke and nephropathy risk in those with higher baseline BP. Estimated RHRs showed no statistical evidence that baseline BP modified the cardiorenal benefits of SGLT-2is and GLP-1RAs. Conclusions: In patients with T2D, the cardiorenal benefits of treatment with SGLT2-Is and GLP1-RAs were similar in patients with normal baseline BP compared to those with a higher baseline BP.

Neuroprotective effect of empagliflozin against doxorubicin-induced chemobrain in rats: Interplay between SIRT-1/MuRF-1/PARP-1/NLRP3 signaling pathways and enhanced expression of miRNA-34a and LncRNA HOTAIR

Chemobrain, a challenging side effect of doxorubicin (DOX)-based chemotherapy, impairs cognitive abilities in cancer survivors. DOX triggers chemobrain via oxidative stress, leading to inflammation and apoptosis. Empagliflozin (EMPA), a sodium glucose co-transporter-2 inhibitor, demonstrated neuroprotective effects by reducing reactive oxygen species (ROS) and inflammation, but its protective mechanisms against DOX-induced chemobrain is not fully known. Thus, this study aimed to investigate EMPA’s neuroprotective effects on DOX-induced chemobrain in rats and to uncover the underlying protective mechanisms. Fifty male Wistar rats were divided into control, EMPA, DOX (2 mg/kg, IP, once/week for 4 weeks), and two treated groups (DOX+ EMPA 5 and 10 mg/kg/day, PO, for 4 weeks). Behavioral tests showed improved memory, motor performance, and reduced anxiety in EMPA-treated groups compared to DOX, with superior results at the higher dose. Histopathological analysis revealed increased intact neurons in the cortex and hippocampus in EMPA-treated groups, with 346.4 % increase in CA3 (p < 0.0001), 19.1 % in dentate gyrus (p = 0.0006), and 362.6 % in cortex (p < 0.0001) in the high-dose EMPA group. Biochemical investigations of the high-dose EMPA group revealed significant decreases in inflammatory and apoptotic markers (JNK/PARP-1/NLRP3/MuRF-1/FOXO-1), increased SIRT-1 protein expression by 389.9 % (p < 0.0001), and reduced miRNA-34a and LncRNA HOTAIR gene expression (50.4 % and 53.4 % respectively, p < 0.0001) relative to DOX group. Conclusively, EMPA demonstrated superior behavioral and histopathological outcomes particularly at higher dose, positioning it as a promising neuroprotective candidate against DOX-induced chemobrain, possibly through modulating SIRT-1, NF-κb, NLRP3, and oxidative stress pathways.