Dietary interventions to combat non-communicable diseases focus on optimizing food intake but overlook the influence of food structure. Here, we investigate how food structure influences digestion. In a randomized crossover study, ten healthy participants were fitted with nasoenteric tubes that allow simultaneous gastric and duodenal sampling, before consuming iso-nutrient chickpea meals with contrasting cellular structures. The primary outcome is gut hormone response. Secondary outcomes are intestinal content analysis, blood glucose and insulin response, subjective appetite changes and ad libitum energy intake. We show that the 'Broken' and 'Intact' cell structures of meals result in different digestive and metabolomic profiles, leading to distinct postprandial gut hormones, glycaemia and satiety responses. 'Broken' meal structure elicits higher glucose-dependent insulinotropic peptide, glucagon-like peptide-1 and blood glycaemia, driven by high starch digestibility and a sharp rise in gastric maltose within 30 min. 'Intact' meal structure produces a prolonged release of glucagon-like peptide-1 and peptide-YY, elevated duodenal amino acids and undigested starch at 120 min. This work highlights how food structure alters upper gastrointestinal nutrient-sensing hormones, providing insights into the adverse effects of modern diets on obesity and type 2 diabetes. ISRCTN registration: ISRCTN18097249.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are oral antidiabetic agents that have shown significant improvements in cardiovascular and renal outcomes among patients with heart failure (HF), regardless of diabetic status, establishing them as a cornerstone therapy. In addition to glycemic control and the osmotic diuretic effect, the inhibition of SGLT2 improves endothelial function and vasodilation, optimizing myocardial energy metabolism and preserving cardiac contractility. Moreover, SGLT2 inhibitors may exhibit anti-inflammatory properties and attenuate acute myocardial ischemia/reperfusion injury, thereby reducing cardiac infarct size, enhancing left ventricular function, and mitigating arrhythmias. These pleiotropic effects have demonstrated efficacy across various cardiovascular conditions, ranging from acute to chronic coronary syndromes and extending to arrhythmias, valvular heart disease, cardiomyopathies, cardio-oncology, and cerebrovascular disease. This review provides an overview of the current literature on the potential mechanisms underlying the effectiveness of SGLT2 inhibitors across a wide range of cardiovascular diseases beyond HF.

The first sodium-glucose cotransporter-2 inhibitor (SGLT2I), canagliflozin, was approved by the U.S. Food and Drug Administration for the treatment of type 2 diabetes in 2013. Since then, other members of this drug class (such as dapagliflozin, empagliflozin, and ertugliflozin) have become widely used. Unlike classical antidiabetic agents, these drugs do not interfere with insulin secretion or action, but instead promote renal glucose excretion. Since their approval, many preclinical and clinical studies have been conducted to investigate the diverse effects of SGLT2Is. While originally introduced as antidiabetic agents, the SGLT2Is are now recognized as pillars in the treatment of heart failure and chronic kidney disease, in patients with or without diabetes. The beneficial cardiac effects of this class have been attributed to several mechanisms. Among these, SGLT2Is inhibit fibrosis, hypertrophy, apoptosis, inflammation, and oxidative stress. They regulate mitochondrial function and ion transport, and stimulate autophagy through several underlying mechanisms. This review details the potential effects of SGLT2Is on cardiac cells.

In recent years, the introduction of sodium-glucose transporter-2 inhibitors (SGLT2is) marked a significant advancement in the treatment of cardiovascular disease (CVD). Beyond their known effects on glycemic control and lipid profile, SGLT2is demonstrate notable benefits for cardiovascular morbidity and mortality, regardless of diabetic status. These agents are currently recommended as first-line therapies in patients with heart failure, both with reduced and preserved ejection fraction, as they improve symptoms and reduce the risk of hospitalization. While several studies have demonstrated that SGLT2is can reduce the incidence of major adverse cardiovascular events (MACEs), the true impact of these agents on atherosclerosis progression and myocardial ischemia remains to be fully understood. A global beneficial effect related to improved glycemic and lipid control could be hypothesized, even though substantial evidence shows a direct impact on molecular pathways that enhance endothelial function, exhibit anti-inflammatory properties, and provide myocardial protection. In this context, this narrative review summarizes the current knowledge regarding these novel anti-diabetic drugs in preventing and treating myocardial ischemia, aiming to define an additional area of application beyond glycemic control and heart failure.

Parkinson's disease (PD) is the second most common neurodegenerative disorder. PD patients exhibit varying degrees of abnormal glucose metabolism throughout disease stages. Abnormal glucose metabolism is closely linked to the PD pathogenesis and progression. Key glucose metabolism processes involved in PD include glucose transport, glycolysis, the tricarboxylic acid cycle, oxidative phosphorylation, the pentose phosphate pathway, and gluconeogenesis. Recent studies suggest that glucose metabolism is a potential therapeutic target for PD. In this review, we explore the connection between PD and abnormal glucose metabolism, focusing on the underlying pathophysiological mechanisms. We also summarize potential therapeutic drugs related to glucose metabolism based on results from current cellular and animal model studies.

Uric acid (UA) is mainly synthesized in the liver, intestine, and vascular endothelium and excreted by the kidney (70 %) and intestine (30 %). Hyperuricemia (HUA) occurs when UA production exceeds excretion. Many studies have found that elevated UA is associated with diabetic microvascular complications (DMC), including diabetic retinopathy (DR), diabetic nephropathy (DN), and diabetic peripheral neuropathy (DPN). In addition, too high or too low UA levels will promote the occurrence and development of chronic diseases, but the relationship between UA and diabetic microvascular complications (DMC) is not clear. Therefore, the rational treatment of UA in patients with diabetes is essential. In this review, we summarize and discuss the mechanism and treatment of UA and DMC and may provide potential advice for rational drug selection.

Metabolic reprogramming and altered cellular energetics have been recently established as an important cancer hallmark. The modulation of glucose metabolism is one of the important characteristic features of metabolic reprogramming in cancer. It contributes to oncogenic progression by supporting the increased biosynthetic and bio-energetic demands of tumor cells. This oncogenic transformation consequently results in elevated expression of glucose transporters in these cells. Moreover, various cancers exhibit abnormal transporter expression patterns compared to normal tissues. Recent investigations have underlined the significance of glucose transporters in regulating cancer cell survival, proliferation, and metastasis. Abnormal regulation of these transporters, which exhibit varying affinities for hexoses, could enable cancer cells to efficiently manage their energy supply, offering a crucial edge for proliferation. Exploiting the upregulated expression of glucose transporters, GLUTs, and Sodium Linked Glucose Transporters (SGLTs), could serve as a novel therapeutic intervention for anti-cancer drug discovery as well as provide a unique targeting approach for drug delivery to specific tumor tissues. This review aims to discussthe previous and emerging research on the expression of various types of glucose transporters in tumor tissues, the role of glucose transport inhibitors as a cancer therapy intervention as well as emerging GLUT/SGLT-mediated drug delivery strategies that can be therapeutically employed to target various cancers.

Canagliflozin (CANA) is a sodium glucose cotransporter-2 inhibitor that reduces blood glucose levels. Sodium glucose cotransporter-2 is primarily expressed in the kidney, but not in any bone cells, therefore effects on the skeleton are likely to be non-cell autonomous. Originally developed to treat type II diabetes, CANA use has expanded to treat cardiovascular and renovascular disease. Clinical trials examining CANA in diabetic patients have produced contradictory reports on fracture risk, but there are limited data of CANA in nondiabetic conditions. In nondiabetic preclinical models, short-term treatment with CANA negatively affected trabecular bone whereas long-term treatment reduced cortical bone mineralization in male but not female mice. To investigate the skeletal effects of an intermediate period of CANA treatment, we treated male and female C57BL/6 J mice with CANA (180 ppm) for 6 months. Age at treatment initiation was also evaluated, with cohorts starting CANA prior to skeletal maturity (3-months-old) or in adulthood (6-months-old). Longitudinal assessments of bone mineral density revealed early benefits of CANA treatment in female mice. At euthanasia, both trabecular and cortical bone morphology were improved by CANA treatment in males and females. Bone formation was reduced at the endosteal surface. CANA decreased osteoblast number in male mice and bone marrow adiposity in females. Overall, more skeletal benefits were recorded in CANA-treated females than males. Urinary calcium output increased with CANA treatment, but parathyroid hormone was not changed. Despite reduced fasting blood glucose, body composition and whole-body metabolism were minimally changed by CANA treatment. For all outcome measures, limited differences were recorded based on age at treatment initiation. This study demonstrated that in nondiabetic C57BL/6 J mice, an intermediate period of CANA treatment improved bone morphology, but reduced osteoblast and bone marrow adipocyte number as well as serum procollagen type 1 N-terminal pro-peptide in a sex-specific manner.

Chronic kidney disease and end-stage kidney disease (ESKD) are well-established risk factors for cardiovascular disease (CVD), the leading cause of mortality in the dialysis population. Conventional therapies, such as statins, blood pressure control, and renin-angiotensin-aldosterone system blockade, have inadequately addressed this cardiovascular risk, highlighting the unmet need for effective treatment strategies. Sodium-glucose transporter 2 (SGLT2) inhibitors have demonstrated significant renal and cardiovascular benefits among patients with type 2 diabetes, heart failure, or CKD at risk of progression. Unfortunately, efficacy data in dialysis patients is lacking as ESKD was an exclusion criterion for all major clinical trials of SGLT2 inhibitors. This review explores the potential of SGLT2 inhibitors in improving cardiovascular outcomes among patients with ESKD, focusing on their direct cardiac effects.

Recent clinical and preclinical studies have shown promising data for the application of SGLT2 inhibitors to the dialysis population. SGLT2 inhibitors may provide cardiovascular benefits to dialysis patients, not only indirectly by preserving the remaining kidney function and improving anemia but also directly by lowering intracellular sodium and calcium levels, reducing inflammation, regulating autophagy, and alleviating oxidative stress and endoplasmic reticulum stress within cardiomyocytes and endothelial cells. This review examines the current clinical evidence and experimental data supporting the use of SGLT2 inhibitors, discusses its potential safety concerns, and outlines ongoing clinical trials in the dialysis population. Further research is needed to evaluate the safety and effectiveness of SGLT2 inhibitor use among patients with ESKD.

Background: Sodium-glucose co-transporter 2 (SGLT-2) inhibitors, initially designed for type 2 diabetes, promote glucose excretion and lower blood glucose. Newer analogs like empagliflozin and dapagliflozin improve cardiovascular outcomes through mechanisms other than glycemic control, including blood pressure reduction and anti-inflammatory effects. Given the high cardiovascular risk present in diabetes, our study aims to emphasize the cardioprotective benefits of SGLT-2 inhibitors as a preventive therapy for heart failure (HF) in high-risk T2DM patients. Methods: Using data from 2542 patients identified by the ICD-10 E11 code from 2016 to 2020, this longitudinal study excluded those with E10 codes or those undergoing insulin treatment to focus on non-insulin-dependent T2DM. a multiple logistic regression model assessed HF incidence while adjusting for demographics and HbA1c. Results: SGLT-2 inhibitor use significantly lowered the odds of heart failure events (OR = 0.55, 95% CI: 0.31-0.99, p = 0.046), with a significant difference by gender (OR = 0.45, 95% CI: 0.28-0.71, p = 0.001) and eGFR (OR = 0.98, 95% CI: 0.97-0.99, p = 0.004). Conclusions: The real-world data highlight SGLT-2 inhibitors as promising for HF prevention and broader cardiometabolic health in T2DM, with potential value in managing complex comorbid profiles.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are an innovative class of antidiabetic drugs that provide cardiovascular benefits to both diabetic and nondiabetic patients, surpassing those of other antidiabetic drugs. Although the roles of mitochondria and endoplasmic reticulum (ER) in cardiovascular research are increasingly recognized as promising therapeutic targets, the exact molecular mechanisms by which SGLT2 inhibitors influence mitochondrial and ER homeostasis in the heart remain incompletely elucidated. This review comprehensively summarizes and discusses the impacts of SGLT2 inhibitors on mitochondrial dysfunction and ER stress in heart diseases including heart failure, ischemic heart disease/myocardial infarction, and arrhythmia from preclinical and clinical studies. Based on the existing evidence, the effects of SGLT2 inhibitors may potentially involve the restoration of mitochondrial biogenesis and alleviation of ER stress. Such consequences are achieved by enhancing adenosine triphosphate (ATP) production, preserving mitochondrial membrane potential, improving the activity of electron transport chain complexes, maintaining mitochondrial dynamics, mitigating oxidative stress and apoptosis, influencing cellular calcium and sodium handling, and targeting the unfolded protein response (UPR) through three signaling pathways including inositol requiring enzyme 1α (IRE1α), protein kinase R like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6). Therefore, SGLT2 inhibitors have emerged as a promising target for treating heart diseases due to their potential to improve mitochondrial functions and ER stress.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have emerged as pivotal medications for heart failure, demonstrating remarkable cardiovascular benefits extending beyond their glucose-lowering effects. The unexpected cardiovascular advantages have intrigued and prompted the scientific community to delve into the mechanistic underpinnings of these novel actions. Preclinical studies have generated many mechanistic theories, ranging from their renal and extrarenal effects to potential direct actions on cardiac muscle cells, to elucidate the mechanisms linking these drugs to clinical cardiovascular outcomes. Despite the strengths and limitations of each theory, many await validation in human studies. Furthermore, whether SGLT2 inhibitors confer therapeutic benefits in specific subsets of cardiomyopathies akin to their efficacy in other heart failure populations remains unclear. By examining the shared pathological features between heart failure resulting from vascular diseases and other causes of cardiomyopathy, certain specific molecular actions of SGLT2 inhibitors (particularly those targeting cardiomyocytes) would support the concept that these medications will yield therapeutic benefits across a broad range of cardiomyopathies. This article aims to discuss the important mechanisms of SGLT2 inhibitors and their implications in hypertrophic and dilated cardiomyopathies. Furthermore, we offer insights into future research directions for SGLT2 inhibitor studies, which hold the potential to further elucidate the proposed biological mechanisms in greater detail.

Introduction: In recent decades, an increase in the incidence of type 2 diabetes mellitus (T2DM) in children and adolescents has been observed. Pediatric-onset T2DM differs from the adult-onset form, particularly regarding the durability of glycemic control and earlier appearance of complications. However, the scarcity of approved treatments and comprehensive studies on T2DM management in youth persists. Ongoing clinical trials seek to ascertain the efficacy and safety of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients aged between 10 and 24 years with T2DM. Therefore, we aimed to perform a meta-analysis exploring the efficacy and safety of SGLT2i in pediatric patients and young adults with T2DM. Methods: We searched PubMed, Embase, Cochrane, and Web of Science for randomized controlled clinical trials on the efficacy and safety of SGLT2i in children, adolescents, and young adults with T2DM compared with placebo. Statistical analysis was performed using RevMan 5.4 and R statistical software 4.2.1. Heterogeneity was assessed with I2 statistics. Results: We included three studies totaling 334 patients followed for 37.79 weeks. Reduction in HbA1C (MD = -0.93; 95% CI = -1.36 to -0.49; p  < 0.0001; I2  = 0%) was significantly higher in SGLT2i group compared with placebo. The proportion of patients requiring rescue or discontinuation of study medication due to lack of efficacy was statistically lower in SGLT2i group compared with placebo (RR = 0.64; 95% CI = 0.43-0.94; p= 0.02; I2  = 0%). SGLT2i and placebo were similar in terms of any adverse event (RR = 1.10; 95% CI = 0.96-1.27; p= 0.17; I2  = 0%), serious side effects (RR = 1.06; 95% CI = 0.44-2.57; p=0.90; I2  = 0%), and individual adverse effects. Conclusion: In children, adolescents, and young adults with T2DM, SGLT2i appears to be effective and safe for glycemic control.

Hyperglycaemia is common during acute coronary syndromes (ACS) irrespective of diabetic status and portends excess infarct size and mortality, but the mechanisms underlying this effect are poorly understood. We hypothesized that sodium/glucose linked transporter-1 (SGLT1) might contribute to the effect of high-glucose during ACS and examined this using an ex-vivo rodent heart model of ischaemia-reperfusion injury. Langendorff-perfused rat hearts were subjected to 35 min ischemia and 2 h reperfusion, with variable glucose and reciprocal mannitol given during reperfusion in the presence of pharmacological inhibitors of SGLT1. Myocardial SGLT1 expression was determined in rat by rtPCR, RNAscope and immunohistochemistry, as well as in human by single-cell transcriptomic analysis. High glucose in non-diabetic rat heart exacerbated reperfusion injury, significantly increasing infarct size from 45 ± 3 to 65 ± 4% at 11-22 mmol/L glucose, respectively (p < 0.01), an association absent in diabetic heart (32 ± 1-37 ± 5%, p = NS). Rat heart expressed SGLT1 RNA and protein in vascular endothelium and cardiomyocytes, with similar expression found in human myocardium by single-nucleus RNA-sequencing. Rat SGLT1 expression was significantly reduced in diabetic versus non-diabetic heart (0.608 ± 0.08 compared with 1.116 ± 0.13 probe/nuclei, p < 0.01). Pharmacological inhibitors phlorizin, canagliflozin or mizagliflozoin in non-diabetic heart revealed that blockade of SGLT1 but not SGLT2, abrogated glucose-mediated excess reperfusion injury. Elevated glucose is injurious to the rat heart during reperfusion, exacerbating myocardial infarction in non-diabetic heart, whereas the diabetic heart is resistant to raised glucose, a finding which may be explained by lower myocardial SGLT1 expression. SGLT1 is expressed in vascular endothelium and cardiomyocytes and inhibiting SGLT1 abrogates excess glucose-mediated infarction. These data highlight SGLT1 as a potential clinical translational target to improve morbidity/mortality outcomes in hyperglycemic ACS patients.

The rising prevalence of diabetes mellitus has casted a spotlight on one of its significant sequelae: cognitive impairment. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, originally developed for diabetes management, are increasingly studied for their cognitive benefits. These benefits may include reduction of oxidative stress and neuroinflammation, decrease of amyloid burdens, enhancement of neuronal plasticity, and improved cerebral glucose utilization. The multifaceted effects and the relatively favorable side-effect profile of SGLT2 inhibitors render them a promising therapeutic candidate for cognitive disorders. Nonetheless, the application of SGLT2 inhibitors for cognitive impairment is not without its limitations, necessitating more comprehensive research to fully determine their therapeutic potential for cognitive treatment. In this review, we discuss the role of SGLT2 in neural function, elucidate the diabetes-cognition nexus, and synthesize current knowledge on the cognitive effects of SGLT2 inhibitors based on animal studies and clinical evidence. Research gaps are proposed to spur further investigation.

The sodium-glucose cotransporter 2 (SGLT2) is a glucose transporter that is located within the proximal tubule of the kidney's nephrons. While it is typically associated with the kidney, it was later identified in various areas of the central nervous system, including areas modulating cardiorespiratory regulation like blood pressure. In the kidney, SGLT2 functions by reabsorbing glucose from the nephron's tubule into the bloodstream. SGLT2 inhibitors are medications that hinder the function of SGLT2, thus preventing the absorption of glucose and allowing for its excretion through the urine. While SGLT2 inhibitors are not the first-line choice, they are given in conjunction with other pharmaceutical interventions to manage hyperglycemia in individuals with diabetes mellitus. SGLT2 inhibitors also have a surprising secondary effect of decreasing blood pressure independent of blood glucose levels. The implication of SGLT2 inhibitors in lowering blood pressure and its presence in the central nervous system brings to question the role of SGLT2 in the brain. Here, we evaluate and review the function of SGLT2, SGLT2 inhibitors, their role in blood pressure control, the future of SGLT2 inhibitors as antihypertensive agents, and the possible mechanisms of SGLT2 blood pressure control in the central nervous system.

Glucose is the primary energy source for most mammalian cells and its transport is affected by a family of facilitative glucose transporters (GLUTs) encoded by the SLC2 gene. GLUT1 and GLUT3, highly expressed isoforms in the blood-brain barrier and neuronal membranes, respectively, are associated with multiple neurodevelopmental disorders including epilepsy, dyslexia, ADHD, and autism spectrum disorder (ASD). Dietary therapies, such as the ketogenic diet, are widely accepted treatments for patients with the GLUT1 deficiency syndrome, while ameliorating certain symptoms associated with GLUT3 deficiency in animal models. A ketogenic diet, high-fat diet, and calorie/energy restriction during prenatal and postnatal stages can also alter the placental and brain GLUTs expression with long-term consequences on neurobehavior. This review focuses primarily on the role of diet/energy perturbations upon GLUT isoform-mediated emergence of neurodevelopmental and neurodegenerative disorders.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i), a novel class of glucose-lowering drugs, have revolutionized the management of heart failure with reduced and preserved ejection fraction, regardless of the presence of diabetes, and are currently incorporated in the heart failure guidelines. While these drugs have consistently demonstrated their ability to decrease heart failure hospitalizations in several landmark clinical trials, their cardioprotective effects are far from having been completely elucidated. In the past decade, a growing body of experimental research has sought to address the molecular and cellular mechanisms of SGLT2i in order to provide a better understanding of the off-target acute and chronic cardiac benefits, beyond the on-target renal effect responsible for blood glucose reduction. The present narrative review addresses the direct cardioprotective effects of SGLT2i, delving into the off-target mechanisms of the drugs currently approved for heart failure therapy, and provides insights into future perspectives.

Endothelial dysfunction often precedes the development of cardiovascular diseases, including heart failure. The cardioprotective benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2is) could be explained by their favorable impact on the endothelium. In this review, we summarize the current knowledge on the direct in vitro effects of SGLT2is on endothelial cells, as well as the systematic observations in preclinical models. Four putative mechanisms are explored: oxidative stress, nitric oxide (NO)-mediated pathways, inflammation, and endothelial cell survival and proliferation. Both in vitro and in vivo studies suggest that SGLT2is share a class effect on attenuating reactive oxygen species (ROS) and on enhancing the NO bioavailability by increasing endothelial nitric oxide synthase activity and by reducing NO scavenging by ROS. Moreover, SGLT2is significantly suppress inflammation by preventing endothelial expression of adhesion receptors and pro-inflammatory chemokines in vivo, indicating another class effect for endothelial protection. However, in vitro studies have not consistently shown regulation of adhesion molecule expression by SGLT2is. While SGLT2is improve endothelial cell survival under cell death-inducing stimuli, their impact on angiogenesis remains uncertain. Further experimental studies are required to accurately determine the interplay among these mechanisms in various cardiovascular complications, including heart failure and acute myocardial infarction.

The hyperactivation of the sympathetic nervous system (SNS) is linked to obesity, hypertension, and type 2 diabetes, which are characterized by elevated norepinephrine (NE) levels. Previous research has shown increased sodium-dependent glucose cotransporter 1 (SGLT1) protein levels in kidneys of hypertensive rodents, prompting investigation into the expression of SGLT1 in various tissues, such as skeletal muscle. This study aimed to assess (i) whether skeletal muscle cells and tissue express SGLT1 and SGLT2 proteins; (ii) if NE increases SGLT1 levels in skeletal muscle cells, and (iii) whether the skeletal muscle of neurogenically hypertensive mice exhibits increased SGLT1 expression. We found that (i) skeletal muscle cells and tissue are a novel source of the SGLT2 protein and that (ii) NE significantly elevated SGLT1 levels in skeletal muscle cells. As SGLT2 inhibition (SGLT2i) with Empagliflozin increased SGLT1 levels, in vivo studies with the dual inhibitor SGLT1/2i, Sotagliflozin were warranted. The treatment of neurogenically hypertensive mice using Sotagliflozin significantly reduced blood pressure. Our findings suggest that SNS activity upregulates the therapeutic target, SGLT1, in skeletal muscle, potentially worsening cardiometabolic control. As clinical trial data suggest cardiorenal benefits from SGLT2i, future studies should aim to utilize SGLT1i by itself, which may offer a therapeutic strategy for conditions with heightened SNS activity, such as hypertension, diabetes, and obesity.

Coronary arterial diseases are a major contributor to disease and death worldwide and are most often compounded by several other underlying medical conditions. A key concern is type 2 diabetes mellitus (T2DM). Despite progress in medical advancements, these life-threatening illnesses are still underdiagnosed and undermanaged. A relatively newer class of anti-diabetic drugs, the sodium-glucose cotransporter-2 inhibitors (SGL2-Is), also termed gliflozins, have shown promising results in reducing cardiovascular risk, regardless of diabetic status. These drugs have on-target (promoting renal glycosuria and diuresis by acting on the SGLT-2 channels in the proximal convoluted tubule) and off-target effects contributing to the reported cardiovascular benefit. Some emerging theories about its impact on myocardial energetics, calcium balance, and renal physiology exist. In this review article, we explored three major cardiovascular outcome trials: the Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial, the CANagliflozin cardioVascular Assessment Study (CANVAS) program, and the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose (EMPA-REG OUTCOME) trial to evaluate the cardiovascular effects of SGLT2-Is.

Sodium-glucose cotransporter (SGLT) 2 inhibition is a well-known target for the treatment of type 2 diabetes, renal disease and chronic heart failure. The protein SGLT2 is encoded by SLC5A2 (Solute Carrier Family 5 Member 2), which is highly expressed in renal cortex, but also in the testes where glucose uptake may be essential for spermatogenesis and androgen synthesis. We postulated that in healthy males, SGLT2 inhibitor therapy may affect gonadal function. We examined the impact on gonadal and steroid hormones in a post-hoc analysis of a double-blind, randomized, placebo-controlled research including 26 healthy males who were given either placebo or empagliflozin 10 mg once daily for four weeks. After one month of empagliflozin, there were no discernible changes in androgen, pituitary gonadotropin hormones, or inhibin B. Regardless of BMI category, the administration of empagliflozin, a highly selective SGLT2 inhibitor, did not alter serum androgen levels in men without diabetes. While SGLT2 is present in the testes, its inhibition does not seem to affect testosterone production in Leydig cells nor inhibin B secretion by the Sertoli cells.

Approaches targeting the sodium-glucose cotransporter (SGLT) could represent a promising future therapeutic strategy for numerous oncological and metabolic diseases. In this study, we evaluated the safety, biodistribution and radiation dosimetry of the glucose analogue positron emission tomography (PET) agent [18F] labeled alpha-methyl-4-deoxy-4-[18F]fluoro-D-glucopyranoside ([18F]Me4FDG) with high sodium-glucose cotransporter and low glucose transporter (GLUT) affinity. For this purpose, five healthy volunteers (1 man, 4 women) underwent multiple whole-body PET/computed tomography (CT) examinations starting with injection and up to 4 h after injection of averaged (2.4 ± 0.1) MBq/kg (range: 2.3-2.5 MBq/kg) administered activity. The PET/CT scans were conducted in 5 separate sessions, blood pressure and temperature were measured, and blood and urine samples were collected before the scans and one hour after injection to assess toxicity. Measurements of [18F]Me4FDG radioactivity in organs of interest were determined from the PET/CT scans at 5 time points. Internal dosimetry was performed on voxel level using a fast Monte Carlo approach.

All studied volunteers could well tolerate the [18F]Me4FDG and no adverse event was reported. The calculated effective dose was (0.013 ± 0.003) mSv/MBq. The organs with the highest absorbed dose were the kidneys with 0.05 mSv/MBq per kidney. The brain showed almost no uptake. After 60 min, (12 ± 15) % of the administered dose was excreted into the bladder.

Featuring an effective dose of only 0.013 ± 0.003 mSv/MBq and no occurrence of side effects, the glucose analogue [18F]Me4FDG seems to be a safe radio-tracer with a favorable biodistribution for PET imaging and also within several consecutive scans.

NCT03557138, Registered 22 February 2017, https://ichgcp.net/clinical-trials-registry/NCT03557138 .

Sodium-glucose cotransporter (SGLT) 2 inhibitors partially inhibit SGLT1 expression; however, whether a clinical dose of SGLT2 inhibitor abrogates ischemic preconditioning (IPC) is unknown, and the pharmacological cardioprotective effect under SGLT1 inhibition has not been examined. In this study, we investigated whether a clinical dose of tofogliflozin abrogates IPC and whether pharmacological preconditioning with olprinone has cardioprotective effects under SGLT1 inhibition.

Male Wistar rats were divided into seven groups (seven rats per group) and subjected to the following treatments before inducing ischemia/reperfusion (I/R; 30 minutes of coronary artery occlusion followed by 120 minutes of reperfusion): saline infusion control treatment (Con); ischemic preconditioning (IPC); IPC after phlorizin infusion (IPC+Phl); IPC after low-dose tofogliflozin infusion (IPC+L-Tof); IPC after high-dose tofogliflozin infusion (IPC+H-Tof); olprinone infusion (Olp); and Olp infusion after phlorizin infusion (Olp+Phl).

The infarct size was significantly decreased in the IPC group, but not in the IPC+Phl group. In contrast, the infarct size decreased in the IPC+L-Tof and IPC+H-Tof groups. Additionally, Olp reduced the infarct size, and the effect was preserved in Olp+Phl groups. Phosphorylated AMP-activated protein kinase (AMPK) expression was lower in the IPC+Phl group compared to that in the IPC group.

The cardioprotective effect of IPC was attenuated by strong SGLT1 inhibition, but the effect was preserved under a clinical dose of highly selective SGLT2 inhibitor. Olprinone exerts a cardioprotective effect even under strong SGLT1 inhibition.

Sotagliflozin is a dual sodium-glucose co-transporter 1 and 2 inhibitor that increases glucosuria and natriuresis in patients with type 2 diabetes mellitus (T2DM). However, the safety and efficacy in patients with concomitant chronic kidney disease (CKD) remains unclear. Therefore, we aimed to conduct a meta-analysis to evaluate the current evidence in this regard.

We searched PubMed, Embase, Cochrane, and Web of Science for randomized controlled clinical trials on the safety and efficacy of Sotagliflozin in patients with T2DM and CKD compared with placebo. Statistical analysis was performed using RevMan 5.4. Heterogeneity was assessed with I2 statistics. The study was recorded in PROSPERO registry (CRD42023449631). RESULTS : We included three studies totaling 11,648 patients followed for 15.7 ± 5.9 months. Reduction in HbA1C (mean difference - 0.33%; 95% CI [- 0.54, - 0.11]; p = 0.003; I2 = 100%) and weight (mean difference - 1.01 kg; 95% CI [- 1.17, - 0.86]; p < 0.00001; I2 = 96%) were significantly higher in the Sotagliflozin group compared with placebo. All-cause mortality (RR 0.98; 95% CI [0.81, 1.20]; p = 0.87; I2 = 0%) and major adverse cardiovascular events (RR 0.70; 95% CI [0.40, 1.21]; p = 0.20; I2 = 39%) were not significantly different between groups. However, estimated glomerular filtration rate reduction (mean difference - 0.95; 95% CI [- 1.32, - 0.58]; p < 0.00001; I2 = 98%), genital mycotic infections (RR 2.73; 95% CI [1.96, 3.79]; p < 0.00001; I2 = 0%), diarrhea (RR 1.42; 95% CI [1.24. 1.63]; p < 0.00001; I2 = 0%) and volume depletion (RR 1.31; 95% CI [1.11, 1.56]; p = 0.002; I2 = 0%) were more common with Sotagliflozin.

In patients with T2DM and CKD, Sotagliflozin appears to be effective for glycemic control and weight loss. Although the medication seemed safe concerning mortality and cardiovascular events, it induced estimated glomerular filtration rate reduction, and was associated with a higher risk of genital mycotic infections, diarrhea, and volume depletion.

Doxorubicin (Dox) exhibits a high efficacy in the treatment of numerous types of cancer. However, the beneficial cytotoxic effects of Dox are often accompanied by an increase in the risk of cardiotoxicity. Oxidative stress (OS) plays a key role in Dox‑induced cardiomyopathy (DIC). OS in cardiomyocytes disrupts endoplasmic reticulum (ER) function, leading to the accumulation of misfolded/unfolded proteins known as ER stress. ER stress acts as an adaptive mechanism; however, prolonged ER stress together with OS may lead to the initiation of cardiomyocyte apoptosis. The present study aimed to explore the potential of an anti‑diabetic drug, empagliflozin (EMPA), in mitigating Dox‑induced ER stress and cardiomyocyte apoptosis. In the present study, the effects of 1 h pretreatment of EMPA on Dox‑treated cardiomyocytes isolated from Sprague‑Dawley rats were investigated. After 24 h, EMPA pre‑treatment promoted cell survival in the EMPA + Dox group compared with the Dox group. Results of the present study also demonstrated that EMPA mitigated overall ER stress, as the increased expression of ER stress markers was reduced in the EMPA + Dox group. Additionally, OS, inflammation and expression of ER stress apoptotic proteins were also significantly reduced following EMPA pre‑treatment in the EMPA + Dox group. Thus, EMPA may exert beneficial effects on Dox‑induced ER stress and may exhibit potential changes that can be utilised to further evaluate the role of EMPA in mitigating DIC.

Translocation renal cell carcinoma (tRCC) most commonly involves an ASPSCR1-TFE3 fusion, but molecular mechanisms remain elusive and animal models are lacking. Here, we show that human ASPSCR1-TFE3 driven by Pax8-Cre (a credentialed clear cell RCC driver) disrupted nephrogenesis and glomerular development, causing neonatal death, while the clear cell RCC failed driver, Sglt2-Cre, induced aggressive tRCC (as well as alveolar soft part sarcoma) with complete penetrance and short latency. However, in both contexts, ASPSCR1-TFE3 led to characteristic morphological cellular changes, loss of epithelial markers, and an epithelial-mesenchymal transition. Electron microscopy of tRCC tumors showed lysosome expansion, and functional studies revealed simultaneous activation of autophagy and mTORC1 pathways. Comparative genomic analyses encompassing an institutional human tRCC cohort (including a hitherto unreported SFPQ-TFEB fusion) and a variety of tumorgraft models (ASPSCR1-TFE3, PRCC-TFE3, SFPQ-TFE3, RBM10-TFE3, and MALAT1-TFEB) disclosed significant convergence in canonical pathways (cell cycle, lysosome, and mTORC1) and less established pathways such as Myc, E2F, and inflammation (IL-6/JAK/STAT3, interferon-γ, TLR signaling, systemic lupus, etc.). Therapeutic trials (adjusted for human drug exposures) showed antitumor activity of cabozantinib. Overall, this study provides insight into MiT/TFE-driven tumorigenesis, including the cell of origin, and characterizes diverse mouse models available for research.

Peritoneal dialysis (PD) and prolonged exposure to PD fluids (PDF) induce peritoneal membrane (PM) fibrosis and hypervascularity, leading to functional PM degeneration. 2-deoxy-glucose (2-DG) has shown potential as PM antifibrotic by inhibiting hyper-glycolysis induced mesothelial-to-mesenchymal transition (MMT). We investigated whether administration of 2-DG with several PDF affects the permeability of mesothelial and endothelial barrier of the PM. The antifibrotic effect of 2-DG was confirmed by the gel contraction assay with embedded mesothelial (MeT-5A) or endothelial (EA.hy926) cells cultured in Dianeal® 2.5 % (CPDF), BicaVera® 2.3 % (BPDF), Balance® 2.3 % (LPDF) with/without 2-DG addition (0.2 mM), and qPCR for αSMA, CDH2 genes. Moreover, 2-DG effect was tested on the permeability of monolayers of mesothelial and endothelial cells by monitoring the transmembrane resistance (RTM), FITC-dextran (10, 70 kDa) diffusion and mRNA expression levels of CLDN-1 to -5, ZO1, SGLT1, and SGLT2 genes. Contractility of MeT-5A cells in CPDF/2-DG was decreased, accompanied by αSMA (0.17 ± 0.03) and CDH2 (2.92 ± 0.29) gene expression fold changes. Changes in αSMA, CDH2 were found in EA.hy926 cells, though αSMA also decreased under LPDF/2-DG incubation (0.42 ± 0.02). Overall, 2-DG mitigated the PDF-induced alterations in mesothelial and endothelial barrier function as shown by RTM, dextran transport and expression levels of the CLDN-1 to -5, ZO1, and SGLT2. Thus, supplementation of PDF with 2-DG not only reduces MMT but also improves functional permeability characteristics of the PM mesothelial and endothelial barrier.

Coronary heart disease is a narrowing or obstruction of the vascular cavity caused by atherosclerosis of the coronary arteries, which leads to myocardial ischemia and hypoxia. At present, percutaneous coronary intervention (PCI) is an effective treatment for coronary atherosclerotic heart disease. Restenosis is the main limiting factor of the long-term success of PCI, and it is also a difficult problem in the field of intervention. Sodium-glucose cotransporter 2 (SGLT2) inhibitor is a new oral glucose-lowering agent used in the treatment of diabetes in recent years. Recent studies have shown that SGLT2 inhibitors can effectively improve the prognosis of patients after PCI and reduce the occurrence of restenosis. This review provides an overview of the clinical studies and mechanisms of SGLT2 inhibitors in the prevention of restenosis, providing a new option for improving the clinical prognosis of patients after PCI.

SY-009 produces a hypoglycemic effect via inhibiting sodium/glucose cotransporter 1 (SGLT1) in type 2 diabetes mellitus (T2DM) patients. This randomized, double-blind, placebo-controlled, and multiple-dose escalation clinical trial aimed to evaluate the pharmacokinetic and pharmacodynamical characteristics as well as the safety and tolerability of SY-009 in T2DM patients.

Fifty T2DM patients were randomized into experimental and placebo groups, and hospitalized for 9 days managed with a unified diet and rest management. Subjects were given SY-009 or placebo from day 1 to day 7 at different frequencies and dosages. Single dose cohort was defined as the first dose on day 1 and multiple dose cohort included all the dose from day 1 to 7. Blood samples were collected for pharmacokinetic analysis. Mixed meal tolerance tests were performed. Blood samples were collected to determine glucose, C-peptide, insulin, glucagon-like peptide-1 (GLP-1), and gastric inhibitory polypeptide (GIP).

PK parameters were not obtained because blood SY-009 concentrations were below the limit of quantitation in all subjects. SY-009 decreased the postprandial glucose. Blood glucose was controlled within 4 hours after taking the drug. Short-term administration of SY-009 (7 days) had no significant effects on fasting glucose but reduced the secretion of C-peptide, insulin, and GIP and increased GLP-1 secretion. The most common adverse event was gastrointestinal disorder manifesting abdominal pain, diarrhea, and bloating.

Plasma exposure of SY-009 and its metabolites was fairly low in T2DM patients at doses of 1.0-4.0 mg. SY-009 reduced postprandial glucose, C-peptide, and insulin levels, showing relative safety and tolerability in the dose range of 1.0-4.0 mg.

ClinicalTrials.gov Identifier: NCT04345107.

The prevalence and burden of diabetes are on the rise in India, making it 'the diabetes capital of the world'. Comorbidities such as obesity, cardiovascular (CV) complications, chronic kidney disease (CKD), non-alcoholic fatty liver disease (NAFLD), and neurodegenerative diseases are common in patients with diabetes. Recent breakthroughs in diabetes medications and continuous glucose monitoring have resulted in a paradigm shift in diabetes care. Hence, a review in the Indian context is warranted. This review focuses on the existing evidence (gathered by a systematic literature search utilising online databases such as PubMed) on the metabolic, cardio-renoprotective, and hepatoprotective effects of sodium-glucose co-transporter 2 (SGLT2) inhibition, particularly in the Indian setting. The study revealed that the SGLT2 inhibitors (SGLT2i), with their numerous pleiotropic benefits, have received considerable attention recently as a novel class of antihyperglycaemic agents (AHAs) for the management of diabetes. SGLT2i play a crucial role in the transition from glycaemic control to metabolic care, particularly in the context of obesity, CV disease and renal disease. In addition to improving glycaemic control, SGLT2i have been shown to promote weight loss, reduce blood pressure and improve lipid profiles, which are key components of metabolic health. Moreover, SGLT2i have demonstrated renal protective effects, including a reduction in albuminuria and a slower decline in the estimated glomerular filtration rate (eGFR), suggesting a potential role in the management of renal dysfunction.

Myocardial ischaemia reperfusion injury (MIRI) determines infarct size and long-term outcomes after acute myocardial infarction (AMI). Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, alleviates MIRI in animal models.

We investigated the potential mechanisms underlying the cardioprotective effect of dapagliflozin against MIRI, focusing on mitochondrial injury and mitophagy. MIRI mouse and H9C2 cell models were established.

2,3,5-Triphenyltetrazolium chloride (TTC) staining showed a significant alleviation of MIRI after pre-treatment of dapagliflozin compared to the model group (14.91 ± 1.76 vs. 40.47 ± 3.69%). Data from the pre-treatment dapagliflozin group showed a significant decrease in left ventricular ejection fraction (LVEF) (44.8 ± 2.7 vs. 28.5 ± 5.3%, P<0.01), left ventricular end-diastolic volume (LVEDV) (70.6 ± 9.5 vs. 93.5 ± 13.8 ul, P<0.05), and left ventricular end-systolic volume (LVESV) (39.0 ± 8.3 vs. 67.9 ± 13.7 ul, P<0.05) compared to the model group. Dapagliflozin also reduced the levels of reactive oxygen species (ROS) and fragmented mitochondrial DNA, reversed the decrease in mitochondrial membrane potential, and suppressed apoptosis. Further study showed that dapagliflozin could protect against mitochondrial injury by rapidly clearing damaged mitochondria via mitophagy in a phosphatase and tensin homologue (PTEN)-induced putative kinase 1 (PINK1)/parkindependent manner. Dapagliflozin regulated mitophagy in cardiomyocytes by suppressing the adenosine 5'monophosphate-activated protein kinase (AMPK)-PINK1/parkin signalling pathway, resulting in attenuated MIRI.

Dapagliflozin alleviated MIRI by activating mitophagy via the AMPK-PINK1/parkin signalling pathway.

Sodium/glucose cotransporter (SGLT) 1 and 2 expression in carcinoma cells was recently examined, but their association with the clinicopathological factors of the patients and their biological effects on breast carcinoma cells have remained remain virtually unknown. Therefore, in this study, we explored the expression status of SGLT1 and SGLT2 in breast cancer patients and examined the effects of SGLT1 inhibitors on breast carcinoma cells in vitro.

SGLT1 and SGLT2 were immunolocalized and we first correlated the findings with clinicopathological factors of the patients. We then administered mizagliflozin and KGA-2727, SGLT1 specific inhibitors to MCF-7 and MDA-MB-468 breast carcinoma cell lines, and their growth-inhibitory effects were examined. Protein arrays were then used to further explore their effects on the growth factors.

The SGLT1 high group had significantly worse clinical outcome including both overall survival and disease-free survival than low group. SGLT2 status was not significantly correlated with clinical outcome of the patients. Both mizagliflozin and KGA-2727 inhibited the growth of breast cancer cell lines. Of particular interest, mizagliflozin inhibited the proliferation of MCF-7 cells, even under very low glucose conditions. Mizagliflozin downregulated vascular endothelial growth factor receptor 2 phosphorylation.

High SGLT1 expression turned out as an adverse clinical prognostic factor in breast cancer patient. This is the first study demonstrating that SGLT1 inhibitors suppressed breast carcinoma cell proliferation. These results indicated that SGLT1 inhibitors could be used as therapeutic agents for breast cancer patients with aggressive biological behaviors.

The human intestinal tract reacts to extensive resection with spontaneous intestinal adaptation. We analyzed whether gene expression analyses or intestinal permeability (IP) testing could provide biomarkers to describe regulation mechanisms in the intestinal barrier in short bowel syndrome (SBS) patients during adaptive response or treatment with the glucagon-like peptide-2 analog teduglutide.

Relevant regions of the GLP-2 receptor gene were sequenced. Gene expression analyses and immunohistochemistry were performed from mucosal biopsies. IP was assessed using a carbohydrate oral ingestion test.

The study includes 59 SBS patients and 19 controls. Increases in gene expression with teduglutide were received for sucrase-isomaltase, sodium/glucose cotransporter 1, and calcium/calmodulin serine protein kinase. Mannitol recovery was decreased in SBS but elevated with teduglutide (Δ 40%), showed a positive correlation with remnant small bowel and an inverse correlation with parenteral support.

Biomarkers predicting clinical and functional features in human SBS are very limited. Altered specific gene expression was shown for genes involved in nutrient transport but not for genes controlling tight junctions. However, mannitol recovery proved useful in describing the absorptive capacity of the gut during adaptation and treatment with teduglutide.

Designing oral drug delivery systems using intestinal glucose transporters (IGTs) may be one of the strategies for improving oral bioavailability of drugs. However, little is known about the biological factors affecting the drug transport capacity of IGTs. Gastrodin is a sedative drug with a structure very similar to glucose. It is a highly water-soluble phenolic glucoside. It can hardly enter the intestine through simple diffusion but exhibits good oral bioavailability of over 80%. We confirmed that gastrodin is absorbed via the intestinal glucose transport pathway. It has the highest oral bioavailability among the reported glycosides' active ingredients through this pathway. Thus, gastrodin is the most selective drug substrate of IGTs and can be used to evaluate the drug transport capacity of IGTs. Obviously, strain is one of the main biological factors affecting drug absorption. This study firstly compared the drug transport capacity of IGTs between SD rats and Wistar rats and between C57 mice and KM mice by pharmacokinetic experiments and single-pass intestinal perfusion experiments of gastrodin. Then, the sodium-dependent glucose transporter type 1 (SGLT1) and sodium-independent glucose transporters type 2 (GLUT2) in the duodenum, jejunum, ileum and colon of these animals were quantified using RT-qPCR and Western blot. The results showed that the oral bioavailability of gastrodin in Wistar rats was significantly higher than in SD rats and significantly higher in KM mice than in C57 mice. Gastrodin absorption significantly differed among different intestinal segments in SD rats, C57 mice and KM mice, except Wistar rats. RT-qPCR and Western blot demonstrated that the intestinal expression distribution of SGLT1 and GLUT2 in SD rats and C57 mice was duodenum ≈ jejunum > ileum > colon. SGLT1 expression did not differ among different intestinal segments in KM mice, whereas the intestinal expression distribution of GLUT2 was duodenum ≈ jejunum ≈ ileum > colon. However, the expression of SGLT1 and GLUT2 did not differ among different intestinal segments in Wistar rats. It was reported that the intestinal expression distribution of SGLT1 and GLUT2 in humans is duodenum > jejunum > ileum > colon. Hence, the intestinal expression distribution of SGLT1 and GLUT2 of SD rats and C57 mice was more similar to that in humans. In conclusion, the drug transport capacity of IGTs differs in different strains of rats and mice. SD rats and C57 mice are more suitable for evaluating the pharmacokinetics of glycosides' active ingredients absorbed via the intestinal glucose transport pathway.

1,5-Anhydro-D-fructose (1,5-AF) is a bioactive monosaccharide that is produced by the glycogenolysis in mammalians and is metabolized to 1,5-anhydro-D-glucitol (1,5-AG). 1,5-AG is used as a marker of glycemic control in diabetes patients. 1,5-AF has a variety of physiological activities, but its effects on energy metabolism, including feeding behavior, are unclarified. The present study examined whether 1,5-AF possesses the effect of satiety. Peroral administration of 1,5-AF, and not of 1,5-AG, suppressed daily food intake. Intracerebroventricular (ICV) administration of 1,5-AF also suppressed feeding. To investigate the neurons targeted by 1,5-AF, we investigated c-Fos expression in the hypothalamus and brain stem. ICV injection of 1,5-AF significantly increased c-Fos positive oxytocin neurons and mRNA expression of oxytocin in the paraventricular nucleus (PVN). Moreover, 1,5-AF increased cytosolic Ca²⁺ concentration of oxytocin neurons in the PVN. Furthermore, the satiety effect of 1,5-AF was abolished in oxytocin knockout mice. These findings reveal that 1,5-AF activates PVN oxytocin neurons to suppress feeding, indicating its potential as the energy storage monitoring messenger to the hypothalamus for integrative regulation of energy metabolism.

Hyperglycaemia-induced oxidative stress and inflammation contribute to vascular cell dysfunction and subsequent cardiovascular events in T2DM. Selective sodium-glucose co-transporter-2 (SGLT-2) inhibitor empagliflozin significantly improves cardiovascular mortality in T2DM patients (EMPA-REG trial). Since SGLT-2 is known to be expressed on cells other than the kidney cells, we investigated the potential ability of empagliflozin to regulate glucose transport and alleviate hyperglycaemia-induced dysfunction of these cells.

Primary human monocytes were isolated from the peripheral blood of T2DM patients and healthy individuals. Primary human umbilical vein endothelial cells (HUVECs) and primary human coronary artery endothelial cells (HCAECs), and fetoplacental endothelial cells (HPECs) were used as the EC model cells. Cells were exposed to hyperglycaemic conditions in vitro in 40 ng/mL or 100 ng/mL empagliflozin. The expression levels of the relevant molecules were analysed by RT-qPCR and confirmed by FACS. Glucose uptake assays were carried out with a fluorescent derivative of glucose, 2-NBDG. Reactive oxygen species (ROS) accumulation was measured using the H₂DFFDA method. Monocyte and endothelial cell chemotaxis were measured using modified Boyden chamber assays.

Both primary human monocytes and endothelial cells express SGLT-2. Hyperglycaemic conditions did not significantly alter the SGLT-2 levels in monocytes and ECs in vitro or in T2DM conditions. Glucose uptake assays carried out in the presence of GLUT inhibitors revealed that SGLT-2 inhibition very mildly, but not significantly, suppressed glucose uptake by monocytes and endothelial cells. However, we detected the significant suppression of hyperglycaemia-induced ROS accumulation in monocytes and ECs when empagliflozin was used to inhibit SGLT-2 function. Hyperglycaemic monocytes and endothelial cells readily exhibited impaired chemotaxis behaviour. The co-treatment with empagliflozin reversed the PlGF-1 resistance phenotype of hyperglycaemic monocytes. Similarly, the blunted VEGF-A responses of hyperglycaemic ECs were also restored by empagliflozin, which could be attributed to the restoration of the VEGFR-2 receptor levels on the EC surface. The induction of oxidative stress completely recapitulated most of the aberrant phenotypes exhibited by hyperglycaemic monocytes and endothelial cells, and a general antioxidant N-acetyl-L-cysteine (NAC) was able to mimic the effects of empagliflozin.

This study provides data indicating the beneficial role of empagliflozin in reversing hyperglycaemia-induced vascular cell dysfunction. Even though both monocytes and endothelial cells express functional SGLT-2, SGLT-2 is not the primary glucose transporter in these cells. Therefore, it seems likely that empagliflozin does not directly prevent hyperglycaemia-mediated enhanced glucotoxicity in these cells by inhibiting glucose uptake. We identified the reduction of oxidative stress by empagliflozin as a primary reason for the improved function of monocytes and endothelial cells in hyperglycaemic conditions. In conclusion, empagliflozin reverses vascular cell dysfunction independent of glucose transport but could partially contribute to its beneficial cardiovascular effects.

Understanding the regulatory mechanisms of PD-L1 expression in tumors provides key clues for improving immune checkpoint blockade efficacy or developing novel oncoimmunotherapy. Here, we showed that the FDA-approved sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin dramatically suppressed PD-L1 expression and enhanced T cell-mediated cytotoxicity. Mechanistic study revealed that SGLT2 colocalized with PD-L1 at the plasma membrane and recycling endosomes and thereby prevented PD-L1 from proteasome-mediated degradation. Canagliflozin disturbed the physical interaction between SGLT2 and PD-L1 and subsequently allowed the recognition of PD-L1 by Cullin3SPOP E3 ligase, which triggered the ubiquitination and proteasome-mediated degradation of PD-L1. In mouse models and humanized immune-transformation models, either canagliflozin treatment or SGLT2 silencing significantly reduced PD-L1 expression and limited tumor progression - to a level equal to the PD-1 mAb - which was correlated with an increase in the activity of antitumor cytotoxic T cells. Notably, prolonged progression-free survival and overall survival curves were observed in the group of PD-1 mAb-treated patients with non-small cell lung cancer with high expression of SGLT2. Therefore, our study identifies a regulator of cell surface PD-L1, provides a ready-to-use small-molecule drug for PD-L1 degradation, and highlights a potential therapeutic target to overcome immune evasion by tumor cells.