Inhibition Of Glucose Reabsorption Research Articles

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

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

Attenuated Effects of Topical Empagliflozin on Imiquimod-induced Model of Psoriasis in Mice

Empagliflozin is a sodium-glucose cotransporter inhibitor (SGLT2) that drops blood glucose levels by inhibiting glucose reabsorption and encouraging glucose excretion. Other benefits of empagliflozin include cardiovascular protection, lowering uric acid levels, and reducing liver damage brought on by non-alcoholic fatty liver disease (NAFLD). to investigate the possible influence of two different concentrations of empagliflozin gel on psoriasis induced via imiquimod in mice. dividing 40 mice into five groups (8 mice for each group). All groups gated imiquimod to induce psoriasis (except group I) for seven days. The induction group (Group II) received imiquimod cream for seven days. The rest of the groups gated Clobetasol propionate cream 0.05%, empagliflozin 1% gel, and empagliflozin 3% gel, respectively, once daily for seven days after seven days of induction by imiquimod. The outcomes exhibited that topical empagliflozin had important anti-psoriatic activity by diminishing the Psoriasis Area Severity Index (PASI) score and improving histological alterations during imiquimod application; moreover, it elevated anti-inflammatory biomarker IL-37 and lowered inflammatory biomarkers TNF-α and IL-17. Empagliflozin has substantial anti-psoriatic action against imiquimod-induced psoriasis through its anti-proliferative and anti-inflammatory effects. Also, empagliflozin has a restorative effect on the histopathological alterations of mice's skin induced by imiquimod

Sodium-glucose cotransporter 2 inhibitors ameliorate ER stress-induced pro-inflammatory cytokine expression by inhibiting CD36 in NAFLD progression in vitro

Sodium-dependent glucose cotransporter-2 (SGLT2) inhibitors, antidiabetic drugs that reduce blood sugar levels by inhibiting glucose reabsorption in the renal proximal tubules, also ameliorate nonalcoholic fatty liver disease (NAFLD). This study aimed to examine the effects of SGLT2 inhibition on hepatic steatosis and nonalcoholic steatohepatitis (NASH) using an in vitro model of NAFLD progression. HepG2 cells and a coculture of Hepa1c1c7 and Raw 264.7 cells were treated with 400 μM palmitic acid (PA), followed by treatment with or without 10 μM empagliflozin and dapagliflozin. In HepG2 cells, PA increased hepatic lipid accumulation, the expression of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β), exocytosis mediators (VAMP3 and SNAP23), and ER stress markers (GRP78, PERK, IRE1α, ATF6, ATF4, and CHOP), and the gene and protein expression of CD36. SGLT2 inhibitors reversed the effects of PA. SGLT2 inhibition via siRNA reduced proinflammatory-cytokine gene expression in thapsigargin-treated HepG2 cells. Transfection with CD36 siRNA reversed the elevated ATF4 and CHOP expression in PA-treated HepG2 cells. SGLT2 inhibition via an SGTL2 inhibitor and SGLT2 siRNA reduced CD36, Tnf-α, Il-6, Il-1β, Vamp2, Snap23, Atf4, and Chop expression in the PA-treated Hepa1c1c7–Raw 264.7 cell coculture and suppressed Tnf-α release in the Hepa1c1c7–Raw 264.7 cell coculture treated with lipopolysaccharide and PA. These findings indicate that SGLT2 inhibitors inhibited NAFLD progression by reducing hepatic lipid accumulation and inflammation.

Research progress on the effects of sodium-glucose linked transporter 2 inhibitors on multiple metabolic disorders in metabolic syndrome.

Metabolic syndrome is a complex group of metabolic disorders with an increasing global incidence rate, posing a serious threat to human health. Sodium-glucose linked transporter 2 (SGLT2) inhibitors are a new type of oral hypoglycemic drug. SGLT2 inhibitors not only lower blood glucose level in a non-insulin-dependent manner by inhibiting glucose reabsorption by renal proximal convoluted tubular epithelial cell to promote urinary glucose excretion, but also by improving islet β cell function, reducing inflammatory responses, and inhibiting oxidative stress. In addition, SGLT2 inhibitors can reduce body weight through osmotic diuresis and increase fat metabolism; reduce blood pressure by inhibiting excessive activation of sympathetic nervous system and by improving vascular function. They can also improve blood lipids by increasing degradation of triacylglycerol; reduce blood uric acid by promoting uric acid excretion in kidney and intestine, and by reducing uric acid synthesis. This article reviews the effects and mechanisms of SGLT2 inhibitors on multiple metabolic disorders in metabolic syndrome and explores their potential application in metabolic syndrome treatment.

#2595 Evolution of hemoglobin and serum uric acid levels after SGLT2i initiation in patients with and without diabetic nephropathy

Abstract Background and Aims Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are glucose-lowering drugs that inhibit glucose reabsorption in the proximal tubule, enhancing urinary glucose excretion. SGLT2i exhibit significant cardio- and renoprotective effects due to their capacity to increase diuresis and weight loss and reduce intraglomerular and blood pressure. Moreover, recent studies have described the potential of SGLT2i to improve additional cardiovascular risk factors, such as anemia or hyperuricemia. In this study, we aimed to describe the evolution of hemoglobin (Hb) and serum uric acid (SUA) levels in CKD patients with and without diabetic nephropathy before and after the initiation of SGLT2i therapy. Method CKD patients with and without diabetic nephropathy that were followed in the outpatient clinic of a tertiary referral academic hospital during January 2020 to September 2023 and that started SGLT2i therapy during that period were randomly recruited in the study. Patient characteristics, CKD staging, and levels of Hb and SUA before and after SGLT2i initiation were compared between groups. Hb and SUA levels were averaged considering all available laboratory controls during the last 12 months before treatment initiation and any available controls after treatment start. Results Demographic and clinical characteristics of enrolled patients are summarized in Fig. 1. Subjects with diabetic nephropathy were significantly older, more commonly hypertensive, presented worse kidney function, had received SGLT2i for a lengthier time and had lower hemoglobin values. We observed no change in hemoglobin levels after the initiation of SGLT2i in our sample, independently of diabetic nephropathy status or CKD stage (Fig. 2A, C). In contrast, SUA levels decreased significantly both in patients with and without diabetic nephropathy (Fig. 2B). This effect was observed across all the spectrum of CKD in our sample (Fig. 2D). Conclusion In our sample, SGLT2i initiation was associated with a significant decrease in SUA levels, both in patients with and without diabetic nephropathy and independently of CKD stage, which may help to explain its cardio- and nephroprotective effects. No change in Hb levels was observed, possibly due to a low prevalence of anaemia in our sample.

Diabetic cardiomyopathy: a focus on sodium-glucose cotransporter type 2 inhibitors

Diabetic cardiomyopathy (DCM) is a complication of type 2 diabetes mellitus (T2DM) capable of progressing to the development of symptomatic heart failure (HF), independently of traditional risk factors for it, such as coronary artery disease and hypertension. There is no specific treatment for DCM; however, sodium-glucose cotransporter 2 inhibitors (SGLT2i) are hypoglycemic drugs that act on SGLT2 channels, inhibiting glucose reabsorption in the kidney. In addition, they have cardioprotective effects, which is why their mechanisms at the cardiac level have been studied. According to the results of preclinical studies, SGLT2i act by interfering in the pathophysiology of DCM. Their main effects are: improvement in diastolic function and left ventricular ejection fraction (LVEF), attenuation in the progress of cardiac fibrosis, reduction of oxidative stress and proinflammatory markers. The clinical trials in humans specifically with DCM that have been carried out are limited; however, randomized clinical trials in patients with HF have shown benefits with SGLT2i, regardless of glycemic control in the reduction of hospitalization for HF and mortality from cardiovascular causes. In summary, SGLT2i suggest a treatment in DCM due to their cardiovascular benefits, in preclinical and clinical models of DCM and in the glycemic control of T2DM.

In-silico screening and identification of glycomimetic as potential human sodium-glucose co-transporter 2 inhibitor

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

Role of SLC5A2 polymorphisms and effects of genetic polymorphism on sodium glucose cotransporter 2 inhibitorsinhibitor response.

Type 2 diabetes mellitus (T2DM) is a complex metabolic disease characterized by hyperglycaemia. T2DM is a highly heterogeneous polygenic disease. Due to genetic variation, variations in lifestyle and other environmental exposures, there are certain variations in the phenotype of T2DM patients. Sodium glucose cotransporter 2 (SGLT2) inhibitors are novel hypoglycaemic agents that increase urinary glucose excretion by inhibiting glucose reabsorption in the proximal tubules of the kidney. For glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors, studies have confirmed a variety of gene variants that may modify their effects. For SGLT2 inhibitors, research has focused on the SLC5A2 gene encoding SGLT2 and UGT1A9 gene polymorphisms affecting SGLT2 inhibitor metabolism. The SLC5A2 polymorphism rs9934336 have been associated with decreased HbA1c during the oral glucose tolerance test. Common variants of the SLC5A2 gene are related to blood glucose and insulin concentrations, but not glucagon concentrations. SLC5A2 rs9934336 and rs3116150 are related to a lower risk of heart failure. SGLT2 inhibitor exposure of UGT1A9*3 carriers is commonly higher than that of noncarriers, while these effects commonly have no obvious clinical significance on SGLT2 inhibitor pharmacokinetics. In terms of efficacy, general SLC5A2 variants show no significant effect on the response to the SGLT2 inhibitor empagliflozin. At present, research on the relationship between genetic polymorphisms and the efficacy of SGLT2 inhibitors is limited. The main purpose of this review is to elucidate the general effects of SGLT2 polymorphisms and the association between polymorphisms and the treatment response to SGLT2 inhibitors.

In silico Prediction of Sodium-Glucose Co-Transporter-2 (SGLT2) Inhibition Activity by Allium Fistulosum Compound Based on SkelSpheres Molecular Descriptor

The Sodium-Glucose co-transporter-2 (SGLT2) inhibitor represents a novel agent for the treatment of type 2 diabetes. Drugs of this class function by inhibiting glucose reabsorption in the kidneys, thereby controlling blood glucose levels. It is known that SGLT2 inhibitors activate the AMPK signaling pathway by increasing the expression and activity of AMP-activated protein kinase (AMPK). In vivo tests have demonstrated that ethanolic and aqueous extracts of Welsh onion leaves (Allium fistulosum L) can reduce body weight, liver weight, adipocyte size, and enhance AMP-activated protein kinase (AMPK) expression. In this study, the inhibitory activity (IC50) of compounds within Allium fistulosum against SGLT2 was predicted using the Support Vector Regression (SVR) predictive model and the SkelSpheres descriptor. The results of the predicted IC50 measurements for compounds present in the 70% ethanol extract of Allium fistulosum in silico indicate that 4 tyramine derivatives and 1 decursidate compound exhibit Excellent or Potent inhibitor activity criteria (IC50 < 1 µM). Among these, the four tyramine group compounds are the isomers N-trans-feruloyltyramine and N-cis-feruloyltyramine, as well as the isomers N-trans-feruloyl-3'-methoxytyramine and N-cis-feruloyl-3'-methoxytyramine. The findings of this study suggest that the ability of Allium fistulosum to enhance AMPK expression is possibly achieved through the inhibition of SGLT2.

Cardiorenal Protections of SGLT2 Inhibitors in the Treatment of Type 2 Diabetes.

Cardiovascular disease and renal complications raise the risk of death and morbidity in patients with type 2 diabetes (T2D). Sodium/glucose cotransporter-2 inhibitors (SGLT2i) are a novel class of glucose-lowering drug that increases urine glucose excretion while decreasing blood glucose levels in type 2 diabetes patients by inhibiting glucose reabsorption. In the present article, we review the discovery and development of SGLT2i as a new T2D treatment approach for T2D; thereafter, we consider different cell-based methods for the evaluation of SGLT2i. Finally, we provide evidences from both clinical and experimental studies which bring up the cardio-renal protective effects of SGLT2i. We performed a literature search using PubMed, Google Scholar, and Web of Science to identify publications on preclinical and clinical studies of cardiorenal protective action of SGLT2i and their suggested mechanisms. SGLT2i have shown good effects in the improvement of cardiovascular and renal complications independent of glucose lowering effects. Besides controlling blood glucose levels, SGLT2i were found to exhibit therapeutic benefits on the kidney and cardiovascular system by lowering diabetic glomerular hyperfiltration, blood pressure (BP), body weight, uric acid concentrations, lipid peroxidation, inflammation, etc. As a result of their distinct mode of action, SGLT2i have emerged as a promising treatment option for T2D and maybe T1D due to their increased urine excretion of glucose. It has been demonstrated that SGLT2i have considerable protective effects on diabetic nephropathy (DN) and cardiomyopathy in well-designed experimental and clinical investigations.

878-P: Absolute Amount of Urinary Glucose Excretion, Not the Change, Is the Measure Determinant for the Effects of SGLT2 inhibitors

SGLT2 inhibitors exhibit hypoglycemic effect via increased urinary glucose excretion (UGE) by inhibiting glucose reabsorption in the kidney. Although the effects of SGLT2 inhibitors are theoretically dependent on UGE, clinical trials have shown renoprotective effect even in severely impaired kidney function. Thus, we aimed to investigate the relationship between UGE and various parameters before and after the administration of SGLT2 inhibitors. The patients newly administered SGLT2 inhibitors and measured 24-hour UGE before and after the administration during hospitalization for diabetes education were included. Body weight (BW), blood ketone levels, hematocrit (Ht), eGFR, and 7-point SMBG (DBG) were measured, and the correlations between the parameters before(b-), after (a-) and the change (Δ-) were analyzed by simple linear regression. A total of 32 patients (age 59.3±10.9 years, 19 males) were included (empagliflozin 5, tohogliflozin 6, dapagliflozin 2, canagliflozin 4, luseogliflozin 15). The mean A1C and BW were 8.8±1.2% and 77.7±11.5kg, and mean UGE, average of DBG at baseline were 15.4 ± 27.5g/day and 10.3±2.0mM/L, respectively. As shown in table, ΔDBG showed correlation only with UGE before and after administration but not with ΔUGE. In conclusion, hypoglycemic effect of SGLT2 inhibitors is dependent on absolute amount of UGE but not on ΔUGE after administration. Disclosure Y.Hamamoto: None. Y.Yamada: Speaker's Bureau; Novo Nordisk Pharma Ltd., Teijin Pharma Limited, Ono Pharmaceutical Co., Ltd., Sumitomo Pharma Co., Ltd. Y.Seino: Research Support; Terumo Corporation, Nippon Boehringer Ingelheim, Arkray Marketing, Taisho Pharmaceutical Holdings Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Speaker's Bureau; Merck & Co., Inc., Nippon Boehringer Ingelheim, Arkray Marketing, Taisho Pharmaceutical Holdings Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd.

Evolution of sodium-glucose co-transporter 2 inhibitors from a glucose-lowering drug to a pivotal therapeutic agent for cardio-renal-metabolic syndrome.

Cardio-renal-metabolic (CRM) syndrome, which involves type 2 diabetes mellitus (T2DM), chronic kidney disease (CKD), and heart failure (HF), is a serious healthcare issue globally, with high morbidity and mortality. The disorders that comprise CRM syndrome are independent can mutually affect and accelerate the exacerbation of each other, thereby substantially increasing the risk of mortality and impairing quality of life. To manage CRM syndrome by preventing vicious interactions among individual disorders, a holistic treatment approach that can simultaneously address multiple disorders underpinning CRM syndrome is of great importance. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) lower blood glucose levels by inhibiting glucose reabsorption in the renal proximal tubule and were first indicated for the treatment of T2DM. Several cardiovascular outcome trials have demonstrated that SGLT2i not only lower blood glucose but also reduce the risk of hospitalization for HF and worsening renal function in patients with T2DM. Results have also suggested that the observed cardiorenal benefits of SGLT2i may be independent of their blood glucose-lowering effects. Several randomized controlled trials subsequently assessed the efficacy and safety of SGLT2i in patients without T2DM, and revealed considerable benefits of SGLT2i treatment against HF and CKD, regardless of the presence of T2DM. Thus, SGLT2i have become an essential therapeutic option to prevent the onset, slow the progression, and improve the prognosis of CRM syndrome. This review assesses the evolution of SGLT2i from a glucose-lowering drug to a therapeutic agent for CRM syndrome by evaluating epoch-making clinical studies, including randomized control trials and real-world studies.

Dapagliflozin efficacy as an add-on therapy in double and triple-drug regimens: A meta-analysis of randomized control trial

Background: Diabetes is one of the most common diseases compared to others. There are many drugs available in the market to treat diabetes. Still, most of them have adverse drug reactions like hypoglycemia, weight gain, and subtherapeutic drug concentrations. SGLT-2 inhibitors are a new class of drugs used as add-on therapy to treat type-2 Diabetes Mellitus. They act by inhibiting glucose reabsorption and increasing glucose excretion via the kidneys. In an average adult, two kidneys filter about 180g of glucose per day. About 98% of the glucose filtered in the kidneys get reabsorbed in the proximal convoluted tubule back into the bloodstream, which can be inhibited by SGLT-2 inhibitors.
 Method: A systematic review and meta-analysis were performed on randomized clinical trial data, extracted from PubMed, Cochrane and Embase. All data, including baseline and shift of baseline, standard deviation, and number of participants, were recorded for HbA1c, Fasting blood glucose (FBG), Bodyweight and SBP/DBP.
 Results: Twelve randomized clinical trials, including 8000 participants, were compared and divided into three groups of drugs: SAXA+DAPA+MET, SAXA+MET and DAPA+MET. The comparison is done for HbA1c (WMD:-6.78; 95% CI:-8.28; P <0.00001) (WMD:-4.88; 95% CI:-6.93; P <0.00001), FBG (SMD: -6.50; 95% CI: -8.55, -4.45; P <0.00001) (SMD: -7.75; 95% CI: -8.84, -6.66; P<0.00005,), body weight (SMD: 0.30; 95% CI: 0.27, 0.33; P =1.00) (SMD: -1.00; 95% CI: -1.90, -0.10; P<0.00001). Conclusion: Dapagliflozin, when given in combination, shows a major improvement in HbA1c and FBG levels and does not affect body weight. It was shown to be more effective when given in triple combination therapy.
 Keywords: Dapagliflozine, meta-analysis, Sexagliptine, Metformin, Type two diabetes mellitus (T2DM), Sodium-glucose Cotransporter-2 (SGLT2)

ACTING EARLY TO PROTECT RENAL: BEYOND GLYCEMIC CONTROL OF SGLT2 INHIBITORS

Type 2 Diabetes Mellitus (T2DM) is the leading cause of chronic kidney disease (CKD), accounting for almost half of all cases of kidney failure that necessitate replacement therapy. Cardiovascular disease (CVD) is the leading cause of death in patients with T2DM and CKD. To lower blood glucose levels by inhibiting glucose reabsorption in the proximal tubule, sodium/glucose cotransporter 2 inhibitors (SGLT2-i) were developed. Consistent reductions in risks for secondary kidney disease end points (albuminuria and a composite of serum creatinine doubling or 40% estimated glomerular filtration rate decline, kidney failure, or death) were recognized in clinical trials designed to demonstrate the CVD safety of SGLT2i in type 2 diabetes mellitus (T2DM), as well as reductions in CVD events. The DECLARE-TIMI58 (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58, or DECLARE) trial in patients with T2DM, urinary albumin-creatinine ratio >300 mg/g, and estimated glomerular filtration rate of 30 to 90 mL/min/1.73 m2 established the kidney and CVD benefits of dapagliflozin in patients with CKD. SGLT2i boost glomerular hemodynamic function and are figured to augment other local and systemic processes that contribute to the development of CKD and CVD. According to latest Indonesian Society of Endocrinologist’s guideline, patients with T2DM was recommended to use SGLT2i to reduce their risk of CKD and CVD, in accordance with the clinical trial entry criteria. To achieve widespread use of these life-saving medications, effective implementation strategies are required.

SGLT2 inhibitor empagliflozin promotes revascularization in diabetic mouse hindlimb ischemia by inhibiting ferroptosis.

Gliflozins are known as SGLT2 inhibitors, which are used to treat diabetic patients by inhibiting glucose reabsorption in kidney proximal tubules. Recent studies show that gliflozins may exert other effects independent of SGLT2 pathways. In this study we investigated their effects on skeletal muscle cell viability and paracrine function, which were crucial for promoting revascularization in diabetic hindlimb ischemia (HLI). We showed that treatment with empagliflozin (0.1-40 μM) dose-dependently increased high glucose (25 mM)-impaired viability of skeletal muscle C2C12 cells. Canagliflozin, dapagliflozin, ertugliflozin, ipragliflozin and tofogliflozin exerted similar protective effects on skeletal muscle cells cultured under the hyperglycemic condition. Transcriptomic analysis revealed an enrichment of pathways related to ferroptosis in empagliflozin-treated C2C12 cells. We further demonstrated that empagliflozin and other gliflozins (10 μM) restored GPX4 expression in high glucose-treated C2C12 cells, thereby suppressing ferroptosis and promoting cell viability. Empagliflozin (10 μM) also markedly enhanced the proliferation and migration of blood vessel-forming cells by promoting paracrine function of skeletal muscle C2C12 cells. In diabetic HLI mice, injection of empagliflozin into the gastrocnemius muscle of the left hindlimb (10 mg/kg, every 3 days for 21 days) significantly enhanced revascularization and blood perfusion recovery. Collectively, these results reveal a novel effect of empagliflozin, a clinical hypoglycemic gliflozin drug, in inhibiting ferroptosis and enhancing skeletal muscle cell survival and paracrine function under hyperglycemic condition via restoring the expression of GPX4. This study highlights the potential of intramuscular injection of empagliflozin for treating diabetic HLI.

SGLT2 inhibitors: suggestions from the amphibian world

Sodium-glucose cotransporter 2 inhibitors are a class of antidiabetic drugs that inhibit glucose reabsorption in the proximal renal tubules. In many trials these drugs have shown unpredictable major cardio- and nephroprotective properties. Multiple hypotheses have been raised to elucidate the mechanisms underlying the last effects. Some authors suggest they may be due to the contemporary urinary loss of energy (as glucose) and water (by osmotic diuresis). This particular condition could induce metabolic changes resulting in more efficient energetics at cardiac and renal levels and in less oxidative stress. These changes might really be part of a series of evolutionarily conserved metabolic switches that allow organisms to survive in arid habitats with restricted nutrients and water availability, well studied in amphibians and collectively named “estivation”.

Empagliflozin Treatment Attenuates Hepatic Steatosis by Promoting White Adipose Expansion in Obese TallyHo Mice.

Sodium-glucose co-transporters (SGLTs) serve to reabsorb glucose in the kidney. Recently, these transporters, mainly SGLT2, have emerged as new therapeutic targets for patients with diabetes and kidney disease; by inhibiting glucose reabsorption, they promote glycosuria, weight loss, and improve glucose tolerance. They have also been linked to cardiac protection and mitigation of liver injury. However, to date, the mechanism(s) by which SGLT2 inhibition promotes systemic improvements is not fully appreciated. Using an obese TallyHo mouse model which recapitulates the human condition of diabetes and nonalcoholic fatty liver disease (NAFLD), we sought to determine how modulation of renal glucose handling impacts liver structure and function. Apart from an attenuation of hyperglycemia, Empagliflozin was found to decrease circulating triglycerides and lipid accumulation in the liver in male TallyHo mice. This correlated with lowered hepatic cholesterol esters. Using in vivo MRI analysis, we further determined that the reduction in hepatic steatosis in male TallyHo mice was associated with an increase in nuchal white fat indicative of “healthy adipose expansion”. Notably, this whitening of the adipose came at the expense of brown adipose tissue. Collectively, these data indicate that the modulation of renal glucose handling has systemic effects and may be useful as a treatment option for NAFLD and steatohepatitis.

Canagliflozin Regulates Human Endothelial Cell Function: Role of Heme Oxygenase‐1

Sodium‐glucose cotransporter‐2 (SGLT2) inhibitors are the newest class of glucose lowering drugs that act by inhibiting glucose reabsorption in the proximal tubule of the kidney. Recent clinical trials found that SGLT2 inhibitors reduce cardiovascular disease and mortality in patients with diabetes. The mechanism underlying the salutary actions of these drugs is not completely clear; however, it does not involve differential improvements in glycemic control. Given the critical role that endothelial cells (ECs) play in maintaining vascular homeostasis, the present study investigated the effect of the SGLT2 inhibitor canagliflozin on EC function. It also determined if the vasoprotective protein heme oxygenase‐1 (HO‐1) contributes to the cellular actions of the drug. Treatment of human umbilical vein ECs with clinically relevant concentrations of canagliflozin blocked cell proliferation, and this was associated with a pronounced decline in DNA synthesis. Canagliflozin also inhibited the migration of ECs following scrape injury in a concentration‐dependent manner. Incubation of ECs with a high concentration of glucose (25mM) and oxidized low‐density lipoprotein (oxLDL;50mg/L), which mimics the diabetic milieu, stimulated the adhesion of monocytes to ECs. However, treatment of ECs with canagliflozin markedly reduced the binding of monocytes to these cells. In addition, canagliflozin increased the expression of HO‐1 in a time and concentration‐dependent fashion, leading to a significant rise in endothelial HO‐1 activity. Finally, inhibition of HO‐1 activity or expression increased the adhesion of monocytes to glucose/oxLDL‐challenged ECs exposed to canagliflozin but had no effect on the proliferative or migratory response of canagliflozin‐treated ECs. In conclusion, the present study identifies canagliflozin as a key regulator of EC function. Moreover, it demonstrates that the induction of HO‐1 by canagliflozin contributes to the anti‐inflammatory action the drug. Thus, canagliflozin may exert some of its favorable effects in diabetes by limiting endothelial inflammation via the upregulation of HO‐1.

SGLT2 Inhibitors as the Most Promising Influencers on the Outcome of Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD), the most frequent liver disease in the Western world, is a common hepatic manifestation of metabolic syndrome (MetS). A specific cure has not yet been identified, and its treatment is currently based on risk factor therapy. Given that the initial accumulation of triglycerides in the liver parenchyma, in the presence of inflammatory processes, mitochondrial dysfunction, lipotoxicity, glucotoxicity, and oxidative stress, can evolve into non-alcoholic steatohepatitis (NASH). The main goal is to identify the factors contributing to this evolution because, once established, untreated NASH can progress through fibrosis to cirrhosis and, ultimately, be complicated by hepatocellular carcinoma (HCC). Several drugs have been tested in clinical trials for use as specific therapy for NAFLD; most of them are molecules used to cure type 2 diabetes mellitus (T2DM), which is one of the main risk factors for NAFLD. Among the most studied is pioglitazone, either alone or in combination with vitamin E, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors. Actually, the most promising category seems to be sodium-glucose cotransporter (SGLT2) inhibitors. Their action is carried out by inhibiting glucose reabsorption in the proximal renal tubule, leading to its increased excretion in urine and decreased levels in plasma. Experimental studies in animal models have suggested that SGLT2 inhibitors may have beneficial modulatory effects on NAFLD/NASH, and several trials in patients have proven their beneficial effects on liver enzymes, BMI, blood lipids, blood glucose, and insulin resistance in NAFLD patients, thus creating strong expectations for their possible use in preventing the evolution of liver damage in these patients. We will review the main pathogenetic mechanisms, diagnostic modalities, and recent therapies of NAFLD, with particular attention to the use of SGLT2 inhibitors.

Ipragliflozin attenuates non-alcoholic steatohepatitis development in an animal model.

Non-alcoholic steatohepatitis (NASH) is a common chronic liver disease with no decisive treatment. The sodium glucose cotransporter 2 (SGLT2) inhibitor ipragliflozin was developed as a new oral hypoglycemic drug, which can improve NASH via an insulin-independent glucose-lowering effect by inhibiting glucose reabsorption in the renal proximal tubules. However, ipragliflozin appears to modulate steatosis or inflammation via different pathways. To elucidate the new mechanism of ipragliflozin for the treatment of NASH, we evaluated its effects in a NASH mouse model (STAM mice) with beta cell depletion, and compared the expression of microRNAs (miRNAs) in STAM mice treated with or without ipragliflozin (16.7 μg/day for 5 weeks). Ipragliflozin reduced aspartate transaminase and alanine aminotransferase levels, along with reduced hepatic steatosis, hepatocyte ballooning, lobular inflammation, and liver fibrosis. In addition, ipragliflozin upregulated mitochondrial transport-related and antioxidant defensive system-related genes in the liver. Among 2555 mouse miRNA probes, miR-19b-3p was commonly differentially expressed with ipragliflozin treatment for 5 weeks in both the liver and serum but in different directions, with a decrease in the liver and increase in the serum. Therefore, ipragliflozin can improve NASH development likely through the antioxidative stress pathway and by regulating miR-19b-3p.