SGLT1 and SGLT2 inhibition, circulating metabolites, and cerebral small vessel disease: a mediation Mendelian Randomization study.

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.

A Randomized Crossover Trial of Mixed Meal Tolerance Test Response in People with Type 1 Diabetes on Insulin Pump Therapy and YG1699 or Dapagliflozin.

YG1699 is a novel inhibitor of sodium-glucose cotransporter 1 (SGLT1) and SGLT2. This double-blind, 3-way crossover trial compared YG1699 to dapagliflozin as an adjunct to insulin in people with type 1 diabetes (T1D) on insulin pump therapy. Treatment periods included four mixed meal tolerance tests (MMTTs) and insulin withdrawal tests per person. Nineteen adults with T1D were randomized to YG1699 10 mg, YG1699 25 mg, and dapagliflozin 10 mg once daily for 1 week in different orders. The primary end point was the difference in area under the curve (AUC) in plasma glucose (AUC0-120min) after an MMTT between treatment groups. Mean change in plasma glucose after an MMTT (AUC0-120min) was lower for YG1699 10 mg vs. dapagliflozin (89.51% of baseline vs. 102.13%, 90% confidence interval (CI) vs. dapagliflozin, -6% to -16%, P = 0.0003) and for YG1699 25 mg (84.83% vs. 102.13%, 90% CI vs. dapagliflozin -13% to -22%, P < 0.0001). At 120 minutes, mean glucose values on no treatment, dapagliflozin, YG1699 10 mg, and YG1699 25 mg were 149 (SE 7.6), 141 (SE 6.1), 128 (SE 6.9), and 115 (SE 7.8) mg/dL, respectively. Insulin dose requirements were lower for YG1699 10 mg and 25 mg vs. dapagliflozin for bolus insulin, and for YG1699 10 mg vs. dapagliflozin for total daily insulin. Safety profiles were similar between treatment groups. YG1699 reduced post-prandial glucose more than dapagliflozin in people with T1D on insulin pump therapy. The results were consistent with dual SGLT1/SGLT2 inhibition by YG1699.

Dual SGLT1/SGLT2 inhibitor phlorizin reduces glucose transport in experimental peritoneal dialysis.

INTRODUCTION: Glucose absorption during peritoneal dialysis (PD) is commonly assumed to occur via paracellular pathways. We recently showed that SGLT2 inhibition did not reduce glucose absorption in experimental PD, but the potential role of glucose transport into cells is still unclear. Here we sought to elucidate the effects of phlorizin, a non-selective competitive inhibitor of sodium glucose co-transporters 1 and 2 (SGLT1 and SGLT2), in an experimental rat model of PD. METHODS: A 120-min PD dwell was performed in 12 anesthetised Sprague-Dawley rats using 1.5% glucose fluid with a fill volume of 20 mL with (n = 6) or without (n = 6) intraperitoneal phlorizin (50 mg/L). Several parameters for peritoneal water and solute transport were monitored during the treatment. RESULTS: Phlorizin markedly increased the urinary excretion of glucose, lowered plasma glucose and increased plasma creatinine after PD. Median glucose diffusion capacity at 60 min was significantly lower (p < 0.05) being 196 µL/min (IQR 178-213) for phlorizin-treated animals compared to 238 µL/min (IQR 233-268) in controls. Median fractional dialysate glucose concentration at 60 min (D/D 0) was significantly higher (p < 0.05) in phlorizin-treated animals being 0.65 (IQR 0.63-0.67) compared to 0.61 (IQR 0.60-0.62) in controls. At 120 min, there was no difference in solute or water transport across the peritoneal membrane. CONCLUSION: Our findings indicate that a part of glucose absorption during the initial part of the dwell occurs via transport into peritoneal cells.

The Role of Combined SGLT1/SGLT2 Inhibition in Reducing the Incidence of Stroke and Myocardial Infarction in Patients with Type 2 Diabetes Mellitus.

PURPOSE: In patients with type 2 diabetes mellitus (T2DM), both sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide receptor agonists (GLP-1 RAs) have demonstrated significant improvements in cardiovascular and kidney outcomes independent of their glycemic benefits. This paper will briefly compare the effect of SGLT2is and GLP-1 RAs to that of the SGLT1/2 inhibitor sotagliflozin on the incidence of myocardial infarction (MI) and stroke in patients with T2DM and further postulate mechanisms to account for these findings. METHODS AND RESULTS: Thus far, the results from SCORED and SOLOIST (trials studying the SGLT1/2 inhibitor sotagliflozin) suggest that an increase in SGLT1 inhibition when added to SGLT2 inhibition may contribute to reductions in MI and stroke in patients with T2DM. This benefit is beyond what SGLT2is alone can accomplish and at least similar to GLP-1 RAs but with the added benefit of a reduction in hospitalizations and urgent visits for HF. Larger and longer studies are required to confirm the effectiveness of SGLT1/SGLT2 inhibition in reducing MI and stroke in patients with T2DM and elucidate the mechanisms associated with this finding. CONCLUSIONS: The role of SGLT1/2 inhibition as an addition to GLP-1 RAs in patients with and without T2DM at increased risk for MI and stroke requires further study. Regardless, the finding that a relative increase in SGLT1/2 inhibition reduces the risk of MI and stroke as well as hospitalizations and urgent visits for heart failure could improve quality of life and reduce the healthcare burden associated with T2DM.

Inhibition of SGLT1 Alleviates the Glycemic Variability-Induced Cardiac Fibrosis via Inhibition of Activation of Macrophage and Cardiac Fibroblasts.

Glycemic variability has been considered one of the predictors of diabetes complications in patients with diabetes mellitus (DM). In this work, we evaluated whether glycemic variability induces cardiac fibrosis through regulating cardiac fibroblast activation and macrophage polarization. Moreover, we determined whether glucose transporter sodium-glucose cotransporter 1 (SGLT1) plays an important role in this process. Glycemic variability-induced mice were established using DM mice (GVDM mice), and intermittent high-glucose (IHG) treatment was used to simulate glycemic variability in RAW264.7 macrophages and cardiac fibroblasts. The short hairpin RNA for SGLT1 was used to knock down SGLT1. The results showed that glycemic variability aggravated the cardiac fibrosis in GVDM mice. Additionally, glycemic variability promoted the expression of fibrogenic cytokine and the extracellular matrix proteins in left ventricular tissues and cardiac fibroblasts. GVDM mice showed a higher incidence of macrophage infiltration and M1 polarization in left ventricular tissues. Moreover, IHG-promoted RAW264.7 macrophages tended to differentiate to M1 phenotype. SGLT1 knockdown alleviated cardiac fibrosis in GVDM mice and inhibited activations of cardiac fibroblast and macrophage M1 polarization. Our results indicated that glycemic variability aggravates cardiac fibrosis through activating cardiac fibroblast and macrophage M1 polarization, which could be partially inhibited by SGLT1 knockdown.

New Therapeutic Horizons in Chronic Kidney Disease: The Role of SGLT2 Inhibitors in Clinical Practice.

Chronic kidney disease (CKD) is a serious, progressive condition associated with significant patient morbidity. Hypertension control and use of renin-angiotensin system blockers are the cornerstones of treatment for CKD. However, even with these treatment strategies, many individuals will progress towards kidney failure. Recently, sodium-glucose cotransporter 2 (SGLT2) inhibitor clinical trials with primary renal endpoints have firmly established SGLT2 inhibition, in addition to standard of care, as an effective strategy to slow down the progression of CKD and reduce some of its associated complications. The emergence of this new clinical evidence supports the use of SGLT2 inhibitors in the management of CKD in people with and without diabetes. As licensing and guidelines for SGLT2 inhibitors are updated, there is a need to adapt CKD treatment pathways and for this class of drugs to be included as part of standard care for CKD management. In this article, we have used consensus opinion alongside the available evidence to provide support for the healthcare community involved in CKD management, regarding the role of SGLT2 inhibitors in clinical practice. By highlighting appropriate prescribing and practical considerations, we aim to encourage greater and safe use of SGLT2 inhibitors for people with CKD, both with and without diabetes.

Sodium glucose cotransporter 1 (SGLT1) inhibitors in cardiovascular protection: Mechanism progresses and challenges.

In recent years, multiple clinical trials have shown that sodium glucose cotransporter 1 (SGLT1) inhibitors have significant beneficial cardiovascular effects. This includes reducing the incidence of cardiovascular deaths and heart failure hospitalizations in people with and without diabetes, as well as those with and without generalized heart failure. The exact mechanism responsible for these beneficial effects is not completely understood. To explain the cardiovascular protective effects of SGLT1 inhibitors, several potential arguments have been proposed, including decreasing oxidative stress, regulating cardiac glucose uptake, preventing ischemia/reperfusion injury, alleviating the activation of cardiac fibroblasts, attenuating apoptosis, reducing intermittent high glucose-induced pyroptosis, ameliorating cardiac hypertrophy, attenuating arrhythmic vulnerabilities, and improving left ventricular systolic disorder. This article reviews the advantages and disadvantages of these mechanisms, and attempts to synthesize and prioritize mechanisms related to the reduction of clinical events.

SGLT-1-specific inhibition ameliorates renal failure and alters the gut microbial community in mice with adenine-induced renal failure.

Sodium-dependent glucose cotransporters (SGLTs) have attracted considerable attention as new targets for type 2 diabetes mellitus. In the kidney, SGLT2 is the major glucose uptake transporter in the proximal tubules, and inhibition of SGLT2 in the proximal tubules shows renoprotective effects. On the other hand, SGLT1 plays a role in glucose absorption from the gastrointestinal tract, and the relationship between SGLT1 inhibition in the gut and renal function remains unclear. Here, we examined the effect of SGL5213, a novel and potent intestinal SGLT1 inhibitor, in a renal failure (RF) model. SGL5213 improved renal function and reduced gut-derived uremic toxins (phenyl sulfate and trimethylamine-N-oxide) in an adenine-induced RF model. Histological analysis revealed that SGL5213 ameliorated renal fibrosis and inflammation. SGL5213 also reduced gut inflammation and fibrosis in the ileum, which is a primary target of SGL5213. Examination of the gut microbiota community revealed that the Firmicutes/Bacteroidetes ratio, which suggests gut dysbiosis, was increased in RF and SGL5213 rebalanced the ratio by increasing Bacteroidetes and reducing Firmicutes. At the genus level, Allobaculum (a major component of Erysipelotrichaceae) was significantly increased in the RF group, and this increase was canceled by SGL5213. We also measured the effect of SGL5213 on bacterial phenol-producing enzymes that catalyze tyrosine into phenol, following the reduction of phenyl sulfate, which is a novel marker and a therapeutic target for diabetic kidney disease DKD. We found that the enzyme inhibition was less potent, suggesting that the change in the microbial community and the reduction of uremic toxins may be related to the renoprotective effect of SGL5213. Because SGL5213 is a low-absorbable SGLT1 inhibitor, these data suggest that the gastrointestinal inhibition of SGLT1 is also a target for chronic kidney diseases.

Inhibitory Effect of Tangeretin and Cardamonin on Human Intestinal SGLT1 Activity In Vitro and Blood Glucose Levels in Mice In Vivo.

Rapid postprandial blood glucose elevation can cause lifestyle-related diseases, such as type II diabetes. The absorption of food-derived glucose is primarily mediated by sodium/glucose cotransporter 1 (SGLT1). Moderate SGLT1 inhibition can help attenuate postprandial blood glucose elevation and prevent lifestyle-related diseases. In this study, we established a CHO cell line stably expressing human SGLT1 and examined the effects of phytochemicals on SGLT1 activity. Among the 50 phytochemicals assessed, tangeretin and cardamonin inhibited SGLT1 activity. Tangeretin and cardamonin did not affect the uptake of L-leucine, L-glutamate, and glycyl-sarcosine. Tangeretin, but not cardamonin, inhibited fructose uptake, suggesting that the inhibitory effect of tangeretin was specific to the monosaccharide transporter, whereas that of cardamonin was specific to SGLT1. Kinetic analysis suggested that the suppression of SGLT1 activity by tangeretin was associated with a reduction in Vmax and an increase in Km, whereas suppression by cardamonin was associated with a reduction in Vmax and no change in Km. Oral glucose tolerance tests in mice showed that tangeretin and cardamonin significantly suppressed the rapid increase in blood glucose levels. In conclusion, tangeretin and cardamonin were shown to inhibit SGLT1 activity in vitro and lower blood glucose level in vivo.

Mizagliflozin, a selective SGLT1 inhibitor, improves vascular cognitive impairment in a mouse model of small vessel disease.

Previously, we showed that sodium/glucose cotransporter 1 (SGLT1) participates in vascular cognitive impairment in small vessel disease. We hypothesized that SGLT1 inhibitors can improve the small vessel disease induced-vascular cognitive impairment. We examined the effects of mizagliflozin, a selective SGLT1 inhibitor, and phlorizin, a non-selective SGLT inhibitor, on vascular cognitive impairment in a mouse model of small vessel disease. Small vessel disease was created using a mouse model of asymmetric common carotid artery surgery (ACAS). Two and/or 4 weeks after ACAS, all experiments were performed. Cerebral blood flow (CBF) was decreased in ACAS compared with sham-operated mice. Phlorizin but not mizagliflozin reversed the decreased CBF of ACAS mice. Both mizagliflozin and phlorizin reversed the ACAS-induced decrease in the latency to fall in a wire hang test of ACAS mice. Moreover, they reversed the ACAS-induced longer escape latencies in the Morris water maze test of ACAS mice. ACAS increased SGLT1 and proinflammatory cytokine gene expressions in mouse brains and phlorizin but not mizagliflozin normalized all gene expressions in ACAS mice. Hematoxylin/eosin staining demonstrated that they inhibited pyknotic cell death in the ACAS mouse hippocampus. In PC12HS cells, IL-1ß increased SGLT1 expression and decreased survival rates of cells. Both mizagliflozin and phlorizin increased the survival rates of IL-1ß-treated PC12HS cells. These results suggest that mizagliflozin and phlorizin can improve vascular cognitive impairment through the inhibition of neural SGLT1 and phlorizin also does so through the improvement of CBF in a mouse model of small vessel disease.

Polypharmacology of clinical sodium glucose co-transport protein 2 inhibitors and relationship to suspected adverse drug reactions.

Sodium glucose co-transporter 2 inhibitors (SGLT2i) are a promising second-line treatment strategy for type 2 diabetes mellitus (T2DM) with a developing landscape of both beneficial cardio- and nephroprotective properties and emerging adverse drug reactions (ADRs) including diabetic ketoacidosis (DKA), genetic mycotic infections, and amputations among others. A national register study (MHRA Yellow Card, UK) was used to quantify the SGLT2i's suspected ADRs relative to their Rx rate (OpenPrescribing, UK). The polypharmacology profiles of SGLT2i were data-mined (ChEMBL) for the first time. The ADR reports (n = 3629) and prescribing numbers (Rx n = 5,813,325) for each SGLT2i in the United Kingdom (from launch date to the beginning December 2019) were determined. Empagliflozin possesses the most selective SGLT2/SGLT1 inhibition profile at ~2500-fold, ~10-fold more selective than cangliflozin (~260-fold). Canagliflozin was found to also inhibit CYP at clinically achievable concentrations. We find that for overall ADR rates, empagliflozin versus dapagliflozin and empagliflozin versus canagliflozin are statistically significant (χ2 , p < .05), while dapagliflozin versus canagliflozin is not. In terms of overall ADRs, there is a greater relative rate for canagliflozin > dapagliflozin > empagliflozin. For fatalities, there is a greater relative rate for dapagliflozin > canagliflozin > empagliflozin. An organ classification that resulted in a statistically significant difference between SGLT2i was suspected infection/infestation ADRs between empagliflozin and dapagliflozin. Our findings at this stage of SGLT2i usage in the United Kingdom suggest that empagliflozin, the most selective SGLT2i, had the lowest suspected ADR incident rate (relative to prescribing) and in all reported classes of ADRs identified including infections, amputations, and DKA.

Effects of SGLT2 Inhibitors beyond Glycemic Control-Focus on Myocardial SGLT1.

Selective sodium-glucose cotransporter 2 (SGLT2) inhibitors reduced the risk of hospitalization for heart failure in patients with or without type 2 diabetes (T2DM) in large-scale clinical trials. The exact mechanism of action is currently unclear. The dual SGLT1/2 inhibitor sotagliflozin not only reduced hospitalization for HF in patients with T2DM, but also lowered the risk of myocardial infarction and stroke, suggesting a possible additional benefit related to SGLT1 inhibition. In fact, several preclinical studies suggest that SGLT1 plays an important role in cardiac pathophysiological processes. In this review, our aim is to establish the clinical significance of myocardial SGLT1 inhibition through reviewing basic research studies in the context of SGLT2 inhibitor trials.

Protective effect of SGL5213, a potent intestinal sodium-glucose cotransporter 1 inhibitor, in nonalcoholic fatty liver disease in mice.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic disease. SGL5213, which is minimally absorbed and is restricted to the intestinal tract, is a potent intestinal sodium-glucose cotransporter 1 (SGLT1) inhibitor. In this study, we investigated the protective effect of SGL5213 in a rodent model of NAFLD. METHODS: Using a rodent model of NAFLD, we compared SGL5213 efficacy with miglitol, which is an α-glucosidase inhibitor. We used a high-fat and high-sucrose diet-induced NAFLD model. RESULTS: SGL5213 and miglitol improved obesity, liver dysfunction, insulin resistance, and the NAFLD severity. To further investigate the effects of SGL5213, we analyzed the mRNA expression of genes involved in lipid metabolism, inflammation, and liver fibrosis, and cecal pH levels. SGL5213 and miglitol treatment significantly decreased mRNA expression of factors involved in inflammation and liver fibrosis. SGL5213 treatment significantly decreased cecal pH levels, which did not occur with miglitol. CONCLUSIONS: SGL5213 had a protective effect on the pathogenesis of NAFLD in a rodent model. We considered that inhibiting glucose absorption and increasing glucose content in the gastrointestinal tract with SGL5213 might have contributed to the protective effect in NAFLD. SGL5213 is a promising therapeutic agent for NAFLD with obesity and insulin resistance.

Implications of SGLT Inhibition on Redox Signalling in Atrial Fibrillation.

Atrial fibrillation (AF) is the most common sustained (atrial) arrhythmia, a considerable global health burden and often associated with heart failure. Perturbations of redox signalling in cardiomyocytes provide a cellular substrate for the manifestation and maintenance of atrial arrhythmias. Several clinical trials have shown that treatment with sodium-glucose linked transporter inhibitors (SGLTi) improves mortality and hospitalisation in heart failure patients independent of the presence of diabetes. Post hoc analysis of the DECLARE-TIMI 58 trial showed a 19% reduction in AF in patients with diabetes mellitus (hazard ratio, 0.81 (95% confidence interval: 0.68-0.95), n = 17.160) upon treatment with SGLTi, regardless of pre-existing AF or heart failure and independent from blood pressure or renal function. Accordingly, ongoing experimental work suggests that SGLTi not only positively impact heart failure but also counteract cellular ROS production in cardiomyocytes, thereby potentially altering atrial remodelling and reducing AF burden. In this article, we review recent studies investigating the effect of SGLTi on cellular processes closely interlinked with redox balance and their potential effects on the onset and progression of AF. Despite promising insight into SGLTi effect on Ca2+ cycling, Na+ balance, inflammatory and fibrotic signalling, mitochondrial function and energy balance and their potential effect on AF, the data are not yet conclusive and the importance of individual pathways for human AF remains to be established. Lastly, an overview of clinical studies investigating SGLTi in the context of AF is provided.

Investigation of Hypoglycemic Peptides Derived from Conserved Regions of adMc1 to Reveal Their Antidiabetic Activities.

Diabetes mellitus is the most common chronic disorder and leading cause of renal, neurological, and gastrointestinal manifestations in developed and developing countries. Despite of many drugs and combinational therapies, the complications of diabetes are still listed due to severe consequences of those drugs. In past few years, plant-derived drugs draw special attention due to their higher efficacy and fewer side-effects. Momordica charantia also known as bitter melon is referred as an antidiabetic and hypoglycemic plant in native populations of Asia and East Africa. In current study, an in silico approach was used to evaluate the interactions and binding patterns of plant-derived peptides devised from a hypoglycemic protein adMc1 of M. charantia as potential inhibitor of DPP-IV, SGLT1, and GLUT2 receptor proteins. The study has described a novel approach to investigate hypoglycemic peptides to cure diabetes. A total of eighty tetra-, penta-, and hexapeptides were devised from conserved regions of adMc1 homologs. The molecular docking approach using MOE software was employed to reveal inhibiting potentials of devised peptides against three selected proteins. Out of 30 shortlisted ligands six peptides (i.e. SMCG, DECC, TTIT, RTTI, ARNL and TVEV) accomplished the criteria of being good drug candidates against selected receptor proteins following the drugability assessment test. The overall results are acceptable on the basis of ADMET profiling for being good drug candidates against selected proteins.

Angiotensin II-induced upregulation of SGLT1 and 2 contributes to human microparticle-stimulated endothelial senescence and dysfunction: protective effect of gliflozins.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduced cardiovascular risk in type 2 diabetes patients independently of glycemic control. Although angiotensin II (Ang II) and blood-derived microparticles are major mediators of cardiovascular disease, their impact on SGLT1 and 2 expression and function in endothelial cells (ECs) and isolated arteries remains unclear. METHODS: ECs were isolated from porcine coronary arteries, and arterial segments from rats. The protein expression level was assessed by Western blot analysis and immunofluorescence staining, mRNA levels by RT-PCR, oxidative stress using dihydroethidium, nitric oxide using DAF-FM diacetate, senescence by senescence-associated beta-galactosidase activity, and platelet aggregation by aggregometer. Microparticles were collected from blood of patients with coronary artery disease (CAD-MPs). RESULTS: Ang II up-regulated SGLT1 and 2 protein levels in ECs, and caused a sustained extracellular glucose- and Na+-dependent pro-oxidant response that was inhibited by the NADPH oxidase inhibitor VAS-2780, the AT1R antagonist losartan, sotagliflozin (Sota, SGLT1 and SGLT2 inhibitor), and empagliflozin (Empa, SGLT2 inhibitor). Ang II increased senescence-associated beta-galactosidase activity and markers, VCAM-1, MCP-1, tissue factor, ACE, and AT1R, and down-regulated eNOS and NO formation, which were inhibited by Sota and Empa. Increased SGLT1 and SGLT2 protein levels were observed in the rat aortic arch, and Ang II- and eNOS inhibitor-treated thoracic aorta segments, and were associated with enhanced levels of oxidative stress and prevented by VAS-2780, losartan, Sota and Empa. CAD-MPs promoted increased levels of SGLT1, SGLT2 and VCAM-1, and decreased eNOS and NO formation in ECs, which were inhibited by VAS-2780, losartan, Sota and Empa. CONCLUSIONS: Ang II up-regulates SGLT1 and 2 protein expression in ECs and arterial segments to promote sustained oxidative stress, senescence and dysfunction. Such a sequence contributes to CAD-MPs-induced endothelial dysfunction. Since AT1R/NADPH oxidase/SGLT1 and 2 pathways promote endothelial dysfunction, inhibition of SGLT1 and/or 2 appears as an attractive strategy to enhance the protective endothelial function.

New insight in understanding the contribution of SGLT1 in cardiac glucose uptake: evidence for a truncated form in mice and humans.

Although sodium glucose cotransporter 1 (SGLT1) has been identified as one of the major SGLT isoforms expressed in the heart, its exact role remains elusive. Evidence using phlorizin, the most common inhibitor of SGLTs, has suggested its role in glucose transport. However, phlorizin could also affect classical facilitated diffusion via glucose transporters (GLUTs), bringing into question the relevance of SGLT1 in overall cardiac glucose uptake. Accordingly, we assessed the contribution of SGLT1 in cardiac glucose uptake using the SGLT1 knockout mouse model, which lacks exon 1. Glucose uptake was similar in cardiomyocytes isolated from SGLT1-knockout (Δex1KO) and control littermate (WT) mice either under basal state, insulin, or hyperglycemia. Similarly, in vivo basal and insulin-stimulated cardiac glucose transport measured by micro-PET scan technology did not differ between WT and Δex1KO mice. Micromolar concentrations of phlorizin had no impact on glucose uptake in either isolated WT or Δex1KO-derived cardiomyocytes. However, higher concentrations (1 mM) completely inhibited insulin-stimulated glucose transport without affecting insulin signaling nor GLUT4 translocation independently from cardiomyocyte genotype. Interestingly, we discovered that mouse and human hearts expressed a shorter slc5a1 transcript, leading to SGLT1 protein lacking transmembrane domains and residues involved in glucose and sodium bindings. In conclusion, cardiac SGLT1 does not contribute to overall glucose uptake, probably due to the expression of slc5a1 transcript variant. The inhibitory effect of phlorizin on cardiac glucose uptake is SGLT1-independent and can be explained by GLUT transporter inhibition. These data open new perspectives in understanding the role of SGLT1 in the heart.NEW & NOTEWORTHY Ever since the discovery of its expression in the heart, SGLT1 has been considered as similar as the intestine and a potential contributor to cardiac glucose transport. For the first time, we have demonstrated that a slc5a1 transcript variant is present in the heart that has no significant impact on cardiac glucose handling.

Effects of sodium-glucose cotransporter 1 and 2 inhibitors on cardiovascular and kidney outcomes in type 2 diabetes: A meta-analysis update.

In this report, we aim to provide an updated meta-analysis of the sodium-glucose cotransporter 2 (SGLT2) inhibitors trial data with the new trial data on sotagliflozin, a first-in-class dual SGLT1 and SGLT2 inhibitor. We searched Medline, Cochrane library, and Embase databases for randomized clinical trials comparing cardiovascular and kidney outcomes between SGLT2 and dual SGLT1/2 inhibitors and placebo. Nine randomized clinical trials with a total of 60,914 patients with type 2 diabetes were included. In patients with type 2 diabetes, the use of SGLT2 and dual SGLT1/2 inhibitors improves the cardiovascular and kidney outcome.