S-Methyl Cysteine Sulfoxide Does Not Ameliorate Weight Gain or Hyperlipidemia in Mice Fed a High-Fat Diet.

SCOPE: Higher intake of cruciferous and allium vegetables is associated with lower cardiometabolic risk. Little research has investigated the cardiometabolic effects of S-methyl cysteine sulfoxide (SMCSO), found abundant in these vegetables. This study hypothesizes that SMCSO will blunt development of metabolic syndrome features in mice fed high-fat feed. METHODS AND RESULTS: Fifty C57BL/6 male mice are randomly assigned to standard-chow, high-fat, or high-fat supplemented with low-SMCSO (43 mg kg-1 body weight [BW] day-1), medium-SMCSO (153 mg kg-1 BW day-1), or high-SMCSO (256 mg kg-1 BW day-1) for 12-weeks. High-fat with SMCSO did not prevent diet-induced obesity, glucose intolerance, or hypercholesterolemia. Mice fed high-fat with SMCSO has higher hepatic lipids than mice fed standard-chow or high-fat alone. Urinary SMCSO increases at 6- and 12-weeks in the low-SMCSO group, before reducing 46% and 28% in the medium- and high-SMCSO groups, respectively, at 12-weeks, suggesting possible tissue saturation. Interestingly, two SMCSO-fed groups consume significantly more feed, without significant weight gain. Due to limitations in measuring consumed feed, caution should be taken interpreting these results. CONCLUSION: SMCSO (43-256 mg kg-1 BW day-1) does not ameliorate metabolic syndrome features in high-fat fed mice. Substantial knowledge gaps remain. Further studies should administer SMCSO separately (i.e., gavage), with metabolic studies exploring tissue levels to better understand its physiological action.

Cheese containing probiotic Lactobacillus brevis NJ42 isolated from stingless bee honey reduces weight gain, fat accumulation, and glucose intolerance in mice.

Background: The high occurrence of metabolic syndrome has driven a growing demand for natural resource-based therapeutic strategies, highlighting their potential efficacy in addressing the complexities of this condition. Probiotics are established to be useful in the prevention and treatment of diabetes and obesity. However, limited exploration exists regarding the application of the isolated Lactobacillus strain from stingless bee honey as a probiotic within dairy products, such as cheese. This study investigated the effect of a high-fat diet supplemented with cheese containing probiotic bacteria (Lactobacillus brevis strain NJ42) isolated from Heterotrigona itama honey (PCHFD) on the symptoms of metabolic disorder in C57BL/6 mice. Methods and results: Body weight, glucose intolerance, insulin resistance, and fat accumulation were measured during 12 weeks of feeding and compared to mice fed with a normal chow (NC) and high-fat diet (HFD). Over a 12-week feeding period, PCHFD-fed mice exhibited substantial reductions in several metabolic syndrome-associated features. They had a lower rate of weight gain (p = 0.03) than the HFD-fed mice. Additionally, they displayed a notable 39.2% decrease in gonadal fat mass compared to HFD-fed mice (p = 0.003). HFD-fed mice showed impaired glucose tolerance when compared to NC-fed mice (p = 0.00). Conversely, PCHFD-fed mice showed a reduction in glucose intolerance to a level close to that of the NC-fed mice group (p = 0.01). These positive effects extended to reductions in hepatic steatosis and adipocyte hypertrophy. Conclusion: These results indicated that L. brevis strain NJ42, isolated from H. itama honey, is a prospective probiotic to lower the risk of developing metabolic syndrome features induced by a high-fat diet. These positive findings suggest the prospect of enriching commonly consumed dietary components such as cheese with probiotic attributes, potentially offering an accessible means to alleviating the symptoms of metabolic diseases.

The Impact of SGLT2 Inhibitors in the Heart and Kidneys Regardless of Diabetes Status.

Chronic Kidney Disease (CKD) and Cardiovascular Disease (CVD) are two devastating diseases that may occur in nondiabetics or individuals with diabetes and, when combined, it is referred to as cardiorenal disease. The impact of cardiorenal disease on society, the economy and the healthcare system is enormous. Although there are numerous therapies for cardiorenal disease, one therapy showing a great deal of promise is sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors. The SGLT family member, SGLT2, is often implicated in the pathogenesis of a range of diseases, and the dysregulation of the activity of SGLT2 markedly effects the transport of glucose and sodium across the luminal membrane of renal cells. Inhibitors of SGLT2 were developed based on the antidiabetic action initiated by inhibiting renal glucose reabsorption, thereby increasing glucosuria. Of great medical significance, large-scale clinical trials utilizing a range of SGLT2 inhibitors have demonstrated both metabolic and biochemical benefits via numerous novel mechanisms, such as sympathoinhibition, which will be discussed in this review. In summary, SGLT2 inhibitors clearly exert cardio-renal protection in people with and without diabetes in both preclinical and clinical settings. This exciting class of inhibitors improve hyperglycemia, high blood pressure, hyperlipidemia and diabetic retinopathy via multiple mechanisms, of which many are yet to be elucidated.

SGLT1/2 inhibition improves glycemic control and multi-organ protection in type 1 diabetes.

Sodium glucose cotransporters (SGLTs) are transport proteins that are expressed throughout the body. Inhibition of SGLTs is a relatively novel therapeutic strategy to improve glycemic control and has been shown to promote cardiorenal benefits. Dual SGLT1/2 inhibitors (SGLT1/2i) such as sotagliflozin target both SGLT1 and 2 proteins. Sotagliflozin or vehicle was administered to diabetic Akimba mice for 8 weeks at a dose of 25 mg/kg/day. Urine glucose levels, water consumption, and body weight were measured weekly. Serum, kidney, pancreas, and brain tissue were harvested under terminal anesthesia. Tissues were assessed using immunohistochemistry or ELISA techniques. Treatment with sotagliflozin promoted multiple metabolic benefits in diabetic Akimba mice resulting in decreased blood glucose and improved polydipsia. Sotagliflozin also prevented mortalities associated with diabetes. Our data suggests that there is the possibility that combined SGLT1/2i may be superior to SGLT2i in controlling glucose homeostasis and provides protection of multiple organs affected by diabetes.

Multi-organ denervation: a novel approach to combat cardiometabolic disease.

Cardiometabolic disorders are associated with a substantial loss in quality of life and pose a large burden on healthcare systems worldwide. Overactivation of the sympathetic nervous system has been shown to be a key player in several aspects relating to cardiometabolic disturbances. While diet- and exercise-induced approaches to help reduce weight remains the main strategy to combat metabolic disorders, this is often difficult to achieve. Current pharmacological approaches result in variable responses in different patient cohorts and long-term efficacy may be limited by medication side effects and non-adherence in the long term. There is a clear clinical need for complementary therapies to curb the burden of cardiometabolic disease. One such approach may include interventional sympathetic neuromodulation of organs relevant to cardiometabolic control. Data from sham-controlled clinical trials demonstrate the feasibility, safety and efficacy of catheter-based renal denervation. In analogy, denervation of the common hepatic artery is now feasible in humans and may prove to be similarly useful in modulating sympathetic overdrive directed towards the liver, pancreas and duodenum. Such a targeted multi-organ neuromodulation strategy may beneficially influence multiple aspects of the cardiometabolic disease continuum including blood pressure, glucose and lipid control.

Comparing and Contrasting the Effects of the SGLT Inhibitors Canagliflozin and Empagliflozin on the Progression of Retinopathy.

BACKGROUND: Diabetic retinopathy (DR) is a leading cause of end-stage blindness globally and is arguably one of the most disabling complications of both Type 1 and Type 2 diabetes. Sodium Glucose Cotransporter-2 (SGLT2) inhibitors have now been successfully introduced to clinical medicine and exert multiple beneficial effects in diabetic patients. Given the broad therapeutic application of SGLT2 inhibitors, we hypothesised that SGLT2 inhibition may alleviate the progression of DR. Therefore, we aimed to compare the effectiveness of two clinically available SGLT2 inhibitors, Empagliflozin and Canagliflozin, on the progression of Retinopathy and DR using well-characterised mouse models, Kimba and Akimba, respectively. METHODS: Empagliflozin, Canagliflozin (25 mg/kg/day) or vehicle was administered to 10-week-old mice via drinking water for 8-weeks. Urine glucose levels were measured to ascertain SGLT2 inhibition promoted glucose excretion. Weekly body weight and water intake measurements were obtained. After 8-weeks of treatment, body weight, daily water intake, fasting blood glucose levels were measured and eye tissue was harvested. The retinal vasculature was assessed using immunofluorescence. RESULTS: Empagliflozin treated Akimba mice exhibited metabolic benefits suggested by healthy body weight gain and significantly reduced fasting blood glucose levels. Treatment with Empagliflozin reduced retinal vascular lesions in both Kimba and Akimba mice. Canagliflozin improved body weight gain, reduced blood glucose levels in Akimba mice, and reduced the development of retinal vascular lesions in Kimba mice. CONCLUSIONS: Our data demonstrates that Empagliflozin has future potential as a therapeutic for Retinopathy and DR and should now be considered for human trials.

Corrigendum to "Microglia are both a source and target of extracellular cyclophilin A" [Heliyon 5(9) August 2019 e02390].

[This corrects the article DOI: 10.1016/j.heliyon.2019.e02390.].

The Sympathetic Nervous System Regulates Sodium Glucose Co-Transporter 1 Expression in the Kidney.

Hyperactivation of the sympathetic nervous system (SNS) has been demonstrated in various conditions including obesity, hypertension and type 2 diabetes. Elevated levels of the major neurotransmitter of the SNS, norepinephrine (NE), is a cardinal feature of these conditions. Increased levels of the sodium glucose cotransporter 1 (SGLT1) protein have been shown to occur in the parotid and submandibular glands of hypertensive rodents compared to normotensive controls. However, there was a need to examine SGLT1 expression in other tissues, such as the kidneys. Whether NE may directly affect SGLT1 protein expression has not yet been investigated, although such a link has been shown for sodium glucose cotransporter 2 (SGLT2). Hence, we aimed to determine (i) whether our murine model of neurogenic hypertension displays elevated renal SGLT1 expression and (ii) whether NE may directly promote elevations of SGLT1 in human proximal tubule (HK2) cells. We did indeed demonstrate that in vivo, in our mouse model of neurogenic hypertension, hyperactivation of the SNS promotes SGLT1 expression in the kidneys. In subsequent in vitro experiments in HK2 cells, we found that NE increased SGLT1 protein expression and translocation as assessed by both specific immunohistochemistry and/or a specific SGLT1 ELISA. Additionally, NE promoted a significant elevation in interleukin-6 (IL-6) levels which resulted in the promotion of SGLT1 expression and proliferation in HK2 cells. Our findings suggest that the SNS upregulates SGLT1 protein expression levels with potential adverse consequences for cardiometabolic control. SGLT1 inhibition may therefore provide a useful therapeutic target in conditions characterized by increased SNS activity, such as chronic kidney disease.

Evaluation of Circulating Platelet Extracellular Vesicles and Hypertension Mediated Organ Damage.

Elevated circulating platelet-derived extracellular vesicles (pEVs) have been associated with arterial hypertension. The role of hypertension-mediated organ damage (HMOD) to induce EV release is still unknown. We studied the micro- and macro-vascular changes (retinal vascular density and pulse wave velocity), endothelial function (flow-mediated vasodilation of brachial artery and finger plethysmography), and assessed the psychosocial status (anxiety and depression) in hypertensive patients to determine their relationship with EV release. Pulse wave velocity showed a significant positive correlation with pEVs (r = 0.33; p = 0.01). Systolic blood pressure (SBP) negatively correlated with retinal vascularity. The superficial retinal vascular plexus density in the whole image showed a significant negative correlation with 24 h SBP (r = −0.38, p < 0.01), day-SBP (r = −0.35, p = 0.01), and night-SBP (r = −0.27, p = 0.04). pEVs did not show significant associations with microvascular damage (retinal vascular density), endothelial function (flow-mediated vasodilation of brachial artery and finger plethysmography), or psychosocial status (anxiety and depression). Our results indicate that the pEV levels were associated with macrovascular damage measured by PWV, whereas no significant association between pEVs and microvascular damage, endothelial function, or emotional status could be detected. The potential utility of pEV in clinical practice in the context of HMOD may be limited to macrovascular changes.

Increased nitrate intake from beetroot juice does not alter soluble cellular adhesion molecules and circulating inflammatory cytokines in individuals with treated hypertension: a randomised, controlled trial.

Dietary nitrate, found predominantly in green leafy vegetables and other vegetables such as radish, celery, and beetroot, has been shown to beneficially modulate inflammatory processes and immune cell function in animals and healthy individuals. The impact of increased nitrate intake on soluble inflammatory mediators in individuals with hypertension is unclear. We assessed whether the daily consumption of dietary nitrate via beetroot juice for 1-week lowered levels of circulating inflammatory markers in men and women with treated hypertension. Twenty-seven male and female participants were recruited to a randomized, placebo-controlled, double-blind crossover trial. The effects of 1-week intake of nitrate-rich beetroot juice versus 1-week intake of nitrate-depleted beetroot juice (placebo) were investigated. Plasma concentrations of circulating soluble adhesion molecules (ICAM-1, VCAM-1, CD62E, CD62P), inflammatory cytokines (IL-1ß, IL-6, IL-10, IL-12p70, TNF-α) and chemokines (IL-8, MCP-1) were measured by multiplex flow cytometric bead array in samples collected on day 7 of each intervention period. Other outcomes included alterations in nitrate metabolism assessed by measuring nitrate and nitrite concentrations in plasma, saliva, and urine. One week of beetroot juice did not alter levels of the soluble adhesion markers or cytokines assessed. A 7-fold increase in salivary nitrite, an 8-fold increase in salivary nitrate, a 3-fold increase in plasma nitrate and nitrite, and a 4-fold increase in urinary nitrate and nitrite compared to the placebo was observed (p < 0.001 for all comparisons). Increasing dietary nitrate consumption over 7 days is not effective in reducing soluble inflammatory mediators in individuals with treated hypertension. This trial was registered at anzctr.org.au as ACTRN 12613000116729.

Association of Circulating Platelet Extracellular Vesicles and Pulse Wave Velocity with Cardiovascular Risk Estimation.

Elevated circulating platelet-derived extracellular vesicles (EVs) have been reported in conditions associated with thrombotic risk. The present study aimed to assess the relationship between circulating platelet-derived EV levels, cardiovascular risk stratification and vascular organ damage, as assessed by pulse wave velocity (PWV). A total of 92 patients were included in the present analysis. Platelet EV were evaluated by flow cytometry (CD41+/Annexin v+). The cardiovascular risk was determined using the 2021 ESC guideline stratification and SCORE2 and SCORE-OP. PWV was performed as a surrogate to assess macrovascular damage. Risk stratification revealed significant group differences in EV levels (ANOVA, p = 0.04). Post hoc analysis demonstrated significantly higher levels of EVs in the very high-risk group compared with the young participants (12.53 ± 8.69 vs. 7.51 ± 4.67 EV/µL, p = 0.03). Linear regression models showed SCORE2 and SCORE-OP (p = 0.04) was a predictor of EV levels. EVs showed a significant association with macrovascular organ damage measured by PWV (p = 0.01). PWV progressively increased with more severe cardiovascular risk (p < 0.001) and was also associated with SCORE2 and SCORE-OP (p < 0.001). Within the pooled group of subjects with low to moderate risk and young participants (<40 years), those with EV levels in the highest tertile had a trend towards higher nocturnal blood pressure levels, fasting glucose concentration, lipid levels, homocysteine and PWV. Levels of platelet-derived EVs were highest in those patients with very high CV risk. Within a pooled group of patients with low to moderate risk, an unfavourable cardiometabolic profile was present with higher EV levels.

Platelet-derived extracellular vesicles correlate with therapy-induced nocturnal blood pressure changes.

INTRODUCTION: Elevated nocturnal blood pressure (BP) is closely associated with increased risk of cardiovascular (CV) events. Circulating extracellular vesicles (EVs) have been proposed as a potential CV risk biomarker and shown to correlate with BP. The present study aimed to assess whether a reduction in BP is paralleled by respective changes in EVs. METHODS: Fifty-five hypertensive patients (age: 57.7 ±â€Š14.1 years) were included in the study. EVs and BP were assessed at baseline and at 12 weeks follow-up. Interventions to lower BP included advice on life-style modification only or life-style advice combined with additional pharmacotherapy. EVs were evaluated by flow cytometry (CD41+/Annexin V+) and BP by unobserved automated office BP and ambulatory BP monitoring. RESULTS: Nocturnal systolic BP correlated with EV levels at baseline ( P  = 0.01). Multivariable regression models showed that changes in nocturnal systolic BP (adjusted R2  = 0.23; P  = 0.01) and diastolic BP (adjusted R2  = 0.18; P  = 0.02) were associated with respective changes in EV levels. Furthermore, intervention-induced improvement of systolic dipping was associated with a reduction in EVs in the univariate analysis (adjusted R2  = 0.06; P  = 0.03). In contrast, systolic office, 24 h- and daytime-BP did not show significant associations with EVs. Patients whose medication was up-titrated at baseline showed a trend towards lower EV levels at follow-up (absolute change of -1.7 ±â€Š1.3 EV/µl; P  = 0.057). CONCLUSIONS: Circulating platelet-derived EVs were positively associated with nocturnal BP and therapy-induced changes over a 12-week treatment period. EVs may provide an integrated measure of BP changes achieved with pharmacotherapy.

Circulating platelet-derived extracellular vesicles correlate with night-time blood pressure and vascular organ damage and may represent an integrative biomarker of vascular health.

Elevated office blood pressure (BP) has previously been associated with increased levels of circulating extracellular vesicles (EVs). The present study aimed to assess the relationship between levels of platelet derived EVs, ambulatory BP parameters, and pulse wave velocity as a marker of macrovascular organ damage. A total of 96 participants were included in the study. Platelet-derived extracellular vesicles (pEVs) were evaluated by flow cytometry (CD41+/Annexin v+). BP evaluation included unobserved automated office BP and ambulatory BP monitoring. Carotid-femoral pulse wave velocity (PWV) was measured as a marker of macrovascular damage. pEVs correlated with nocturnal systolic BP (r = 0.31; p = .003) and nocturnal dipping (r = -0.29; p = .01) in univariable analysis. Multivariable regression models confirmed robustness of the association of EVs and nocturnal blood pressure (p = .02). In contrast, systolic office, 24h- and daytime-BP did not show significant associations with pEVs. No correlations were found with diastolic BP. Circulating pEVs correlated with pulse wave velocity (r = 0.25; p = .02). When comparing different hypertensive phenotypes, higher levels of EVs and PWV were evident in patients with sustained hypertension compared to patients with white coat HTN and healthy persons. Circulating platelet derived EVs were associated with nocturnal BP, dipping, and PWV. Given that average nocturnal BP is the strongest predictor of CV events, platelet derived EVs may serve as an integrative marker of vascular health, a proposition that requires testing in prospective clinical trials.

Retinal Capillary Damage Is Already Evident in Patients With Hypertension and Prediabetes and Associated With HbA1c Levels in the Nondiabetic Range.

OBJECTIVE: We analyzed whether any change in capillary density in the retinal circulation could be detected in patients with hypertension in the prediabetic stage. RESEARCH DESIGN AND METHODS: In a cross-sectional analysis, we assessed capillary density in the foveal (CDF) and parafoveal retinal areas using optical coherence tomography-angiography in 62 patients with hypertension and normal glucose metabolism and 40 patients with hypertension and prediabetes. RESULTS: The CDF was lower in patients with prediabetes than in those with normal glucose metabolism. Moreover, we found a correlation between CDF and HbA1c and glucose levels for the entire cohort. In patients with HbA1c <6.5% (48 mmol/mol), CDF was lower in patients with HOMA for insulin resistance (HOMA-IR) ≥2.5 than in patients with HOMA-IR <2.5. CONCLUSIONS: Patients with hypertension and prediabetes display retinal capillary changes, and an association with markers of glucose metabolism exists, even within a nondiabetic HbA1c range.

The Effect of SGLT2 Inhibition on Diabetic Kidney Disease in a Model of Diabetic Retinopathy.

Diabetic kidney disease (DKD) is a chronic disorder characterized by elevated urine albumin excretion, reduced glomerular filtration rate, or both. At present, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are the standard care for the treatment of DKD, resulting in improved outcomes. However, alternative treatments may be required because although the standard treatments have been found to slow the progression of DKD, they have not been found to halt the disease. In the past decade, sodium glucose co-transporter 2 (SGLT2) inhibitors have been widely researched in the area of cardiovascular disease and diabetes and have been shown to improve cardiovascular outcomes. SGLT2 inhibitors including canagliflozin and dapagliflozin have been shown to slow the progression of kidney disease. There is currently an omission of literature where three SGLT2 inhibitors have been simultaneously compared in a rodent diabetic model. After diabetic Akimba mice were treated with SGLT2 inhibitors for 8 weeks, there was not only a beneficial impact on the pancreas, signified by an increase in the islet mass and increased plasma insulin levels, but also on the kidneys, signified by a reduction in average kidney to body weight ratio and improvement in renal histology. These findings suggest that SGLT2 inhibition promotes improvement in both pancreatic and kidney health.

Targeting Features of the Metabolic Syndrome Through Sympatholytic Effects of SGLT2 Inhibition.

PURPOSE OF REVIEW: The moderate glucose-lowering effect of sodium glucose co-transporter 2 (SGLT2) inhibitors is unlikely to explain SGLT2 inhibitor-mediated beneficial outcomes, and unravelling the underlying mechanisms is a high priority in the research community. Given the dominant pathophysiologic role of the sympathetic nervous system activation in conditions such as hypertension and perturbed glucose homeostasis, it is pertinent to postulate that SGLT2 inhibitors may exert their beneficial effects at least in part via sympathetic inhibition. RECENT FINDINGS: SGLT2 inhibitors have shown enormous potential to improve cardiovascular outcomes in patients with type 2 diabetes, and their therapeutic potential is currently being investigated in a range of associated comorbidities such as heart failure and chronic kidney disease. Indeed, recent experimental data in relevant animal models highlight a bidirectional interaction between sympathetic nervous system activation and SGLT2 expression, and this facilitates several of the features associated with SGLT2 inhibition observed in clinical trials including improved glucose metabolism, weight loss, increased diuresis, and lowering of blood pressure. Currently available data highlight the various levels of interaction between the sympathetic nervous system and SGLT2 expression and explores the potential for SGLT2 inhibition as a therapeutic strategy in conditions commonly characterised by sympathetic activation.

Determining the role of SGLT2 inhibition with Empagliflozin in the development of diabetic retinopathy.

Diabetes mellitus is a chronic metabolic disease that occurs when the pancreas is not producing enough insulin or when the insulin that it does produce is not able to be used effectively in the body. This results in hyperglycemia and if the blood sugars are not controlled, then it can lead to serious damage of various body systems, especially the nerves and the blood vessels. Uncontrolled diabetes is a major cause of kidney failure, heart attacks, stroke and amputation. One of the most devastating complications for patients is diabetic retinopathy (DR) which represents the leading cause of preventable vision loss in people between 20 and 65 years of age. Sodium glucose transporter 2 (SGLT2) inhibitors have been shown to reduce the risk for cardiovascular and renal events, however literature highlighting their potential role to prevent DR is limited. We therefore used a relevant mouse model (Akimba) to explore the effects of the SGLT2 inhibitor, Empagliflozin (EMPA), on the development of diabetic retinal changes. Here we show that when given in the early stages of type 1 diabetes (T1D), EMPA reduced the weight loss usually associated with T1D, decreased diabetes-associated polydipsia, lowered fasting blood glucose levels, decreased kidney-to-body weight ratios and, most importantly in the current context, substantially reduced retinal abnormalities associated with DR. We show that EMPA reduces vascular leakage indicated by lower albumin staining in the vitreous humor and diminishes expression of the pathogenic factor VEGF in the retina. Additionally, EMPA significantly alters the retinal genetic signature. Our findings suggest that SGLT2 inhibition may be a useful therapeutic approach to prevent the development of DR and its severity if given early in the disease process.

Interaction between sodium-glucose co-transporter 2 and the sympathetic nervous system.

PURPOSE OF REVIEW: Sodium-glucose co-transporter 2 (SGLT2) inhibitors have taken centre stage in research and therapeutic efforts to modulate hard clinical outcomes in patients with heightened cardiovascular and renal risk profiles. Sympathetic nervous system (SNS) activation is a prominent feature across several cardiovascular and renal disease states. This review reflects on the remarkable clinical impact of SGLT2 inhibitors on cardiorenal outcomes, and navigates the evidence for a proposed clinically relevant interaction between SGLT2 and the SNS. RECENT FINDINGS: SGLT2 inhibitors exert several pleiotropic effects beyond glucose-lowering. These include, but are not limited to, diuresis and natriuresis, blood pressure lowering, reduction in inflammation and oxidative stress, stimulation of erythropoiesis, and improvement in cardiac energetics. Treatment with SGLT2 inhibitors is associated with significant improvement in cardiorenal outcomes irrespective of diabetes status. In addition, evidence from preclinical studies points to a strong signal of a bidirectional temporal association between SGLT2 inhibition and reduction in SNS activation. SUMMARY: Ongoing preclinical and clinical trials aimed at unravelling the proposed interaction between SGLT and SNS will enhance our understanding of their individual and/or collective contributions to cardiovascular disease progression and guide future targeted therapeutic interventions.

Determining the Role of SGLT2 Inhibition with Dapagliflozin in the Development of Diabetic Retinopathy.

BACKGROUND: Diabetic retinopathy (DR) is a major cause of blindness globally. Sodium Glucose Cotransporter-2 (SGLT2) inhibitors have been demonstrated to exert cardiorenal protection in patients with diabetes. However, their potential beneficial effect on DR is less well studied. The aim of the present study was to determine the effects of the SGLT2 inhibition with Dapagliflozin (DAPA) on DR in well-characterised DR mouse models and controls. METHODS: Dapagliflozin was administered to mice with and without diabetes for 8 weeks via their drinking water at 25 mg/kg/day. Urine glucose levels were measured weekly and their response to glucose was tested at week 7. After 8 weeks of treatment, eye tissue was harvested under terminal anaesthesia. The retinal vasculature and neural structure were assessed using immunofluorescence, immunohistochemistry and electron microscopy techniques. RESULTS: Dapagliflozin treated DR mice exhibited metabolic benefits reflected by healthy body weight gain and pronounced glucose tolerance. Dapagliflozin reduced the development of retinal microvascular and neural abnormalities, increased the beneficial growth factor FGF21 (Fibroblast Growth Factor 21). We highlight for the first time that SGLT2 inhibition results in the upregulation of SGLT1 protein in the retina and that SGLT1 is significantly increased in the diabetic retina. CONCLUSIONS: Blockade of SGLT2 activity with DAPA may reduce retinal microvascular lesions in our novel DR mouse model. In conclusion, our data demonstrates the exciting future potential of SGLT1 and/or SGLT2 inhibition as a therapeutic for DR.

A standarized protocol for evaluation of large extracellular vesicles using the attune™ NXT system.

Extracellular vesicles (EVs) represent a promising biomarker in several medical areas. Flow cytometry (FC) is one of the most widely-used methods to characterize EVs, providing quantitative information and determination of EV subtypes. EV evaluation represents a challenge as no standardized methods are available to facilitate assessment across different research centers. This is principally because their size falls below the detection limit of most standard flow cytometers and a thorough optimization process is required to ensure instrument-specific sensitivity. We provide an overview of a standardized method to evaluate large EVs using the Attune™ Nxt Acoustic Focusing Flow Cytometer system (Thermo Fisher Scientific).