New Class Of Antidiabetic Drugs Research Articles

Canagliflozin enhances endogenous eliminatiton of senescent cells through downregulation of PD-L1

Abstract Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been developed as a new class of anti-diabetic drug, and shown cardio- and renal-protective effects in patients with diabetes, heart failure, and chronic kidney diseases. Also, there's evidence that canagliflozin, one of the SGLT2 inhibitors has expanded lifespan in aged mice, but their detailed protective machinery is still to be clarified. Here we demonstrate that canagliflozin has a effect to eliminate senescent cells from pathological tissues, so-called "senolysis" in some murine disease models and alleviates their pathology. We treated canagliflozin mixed in food at 0.03% (w/w) to high-fat-diet(HFD)-fed obese mice and found that canagliflozin reduced senescent cells in visceral adipose tissue within 1 week. Also, we found that senolytic effect of canagliflozin was provided through enhancing endogenous senolytic function by NK or T cells. This machinery was mediated by enhanced AMPK signaling, which leads to the downregulation of PD-L1 expression on senescent cells. Furthermore, we treated canagliflozin to ApoE-knockout atherosclerotic mice with western diet feeding, progeroid mice and chronological aged mice. Canagliflozin reduced their senescent cell burden, resulting in alleviation of atherosclerosis, extended lifespan of progeroid, and altered physical function due to chronological aging. Our results would be promising evidence that SGLT2 inhibitors can be used as not only cardio- or renal-protective drugs but also anti-aging drugs.

Association between dapagliflozin, cardiac biomarkers, and cardiac remodeling in patients with diabetes mellitus and heart failure: a post-hoc analysis of a randomized study

Abstract Introduction Sodium-glucose Cotransporter-2 (SGLT-2) inhibitors are a relatively new class of antidiabetic drugs, which showed favorable effects in heart failure (HF) patients, irrespective of their left ventricular ejection fraction (LVEF). Recent studies have demonstrated the beneficial effects of empagliflozin on cardiac function and structure, however, less is known about dapagliflozin. Purpose To investigate the association between the use of dapagliflozin and cardiac biomarkers as well as cardiac structure in a cohort of patients with HF and diabetes mellitus (DM). Methods The present was a post-hoc analysis of a recently published randomized study, which included 110 patients (Dapagliflozin group n = 56, Control group n = 54) with HF and DM. Inclusion criteria included: age>18 years, history of DM and HF, regardless of LVEF, and hospitalization for HF exacerbation within 6 months. Exclusion criteria were previous treatment with SGLT2i or Glucagon-like Peptide-1 Receptor agonists, a GFR< 30 and life expectancy< 1 year. The evaluation of patients (at baseline, 6 and 12 months) included clinical assessment, laboratory blood tests, and echocardiography. In order to investigate the changes in biomarkers and ultrasound indexes throughout the follow-up period in the two groups, linear mixed regression analyses were conducted. The regression equation included terms for time, group, time-group interaction, age and heart rate (HR) at baseline. Adjusted regression coefficients (β) with standard errors (SE) were computed from the results of the mixed models. Statistical significance was set at p< 0.05 and analyses were conducted using STATA statistical software (version 13.0). Results After adjusting for age and baseline HR, troponin decreased significantly throughout the follow-up period in a similar degree in both groups. Brain Natriuretic peptide (BNP) decreased significantly across all follow-up time points in both groups. However, the degree of decrease was significantly greater in the SGLT2-inhibitor group (Figure 1A, Table 1). LVEF did not change significantly over the follow-up period in the Control group, while it increased significantly in the SGLT2-inhibitor group. Left atrium (LA) increased significantly throughout the follow-up period only in the Control group, while in the SGLT2-inhibitor group there was no significant change. LA Volume index (Figure 1B), LV end diastolic volume (LVEDV), LVEDV index (Figure 1C), LV end systolic volume (LVESV), LVESV index and Global longitudinal strain (GLS) (Figure 1D) increased significantly throughout the follow-up period in the Control group, while in the SGLT2-inhibitor group they decreased significantly. LV mass index increased significantly throughout the follow-up period in a similar degree in both groups. Conclusion(s) Dapagliflozin, an SGLT2i, was associated with a reduction in cardiac biomarkers and with reverse cardiac remodeling in patients with HF and DM.Figure1.Longitudinal changesTable1.Results of the mixed LR analysis

Abstract 14285: Sodium Glucose Co-Transporter 2 Inhibition Eliminates Senescent Cells Through Downregulation of PD-L1 and Improves Pathological Aging

Introduction: Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been developed as a new class of anti-diabetic drug, and shown cardio- and renal-protective effects in patients with diabetes, heart failure, and chronic kidney diseases. SGLT2 inhibitor also has effect to expand lifespan in aged mice, suggesting anti-aging effect. But the detailed machinery of these protective effects is still to be clarified. Here we demonstrate that canagliflozin has a effect to eliminate senescent cells from pathological tissues, so-called "senolysis" in murine aging or age-related disease models. Methods: Canagliflozin mixed in food at 0.03% (w/w) was administered for up to 4 weeks to high-fat-fed diabetic mice, for 2 weeks to ApoE-knockout atherosclerotic mice model, for 20 weeks for chronological aged mice, and for lifetime to Zmpste-knockout progeroid mice. Burden of senescent cell accumilation as well as pathological or aged phenotype were measured in each mice model. Results: Canagliflozin reduced senescent cells in visceral adipose tissue within 1 week. Also, we found that senolytic effect of canagliflozin was provided through enhancing endogenous senolytic function by immune cells such as CD8+T cells. This machinery was mediated by enhanced AMPK signaling through incrase of endogenous AICAR production, which leads to the downregulation of PD-L1 expression on senescent cells. Oppositely, inhibition of AMPK signaling with Compound C administration (10mg/kg ip daily) resulted in abolishing senolytic effect of canagliflozin. Furthermore, canagliflozin reduced their senescent cell burden and alleviated atherosclerosis in ApoE-knockout mice, extended lifespan in progeroid mice, and altered physical function in aged mice. Conclusions: Our results showed new aspect of protective efficacy of SGLT2 inhibitors and would be promising evidence that SGLT2 inhibitors can be used as not only cardio- or renal-protective drugs but also anti-aging drugs.

Association between Dapagliflozin, Cardiac Biomarkers and Cardiac Remodeling in Patients with Diabetes Mellitus and Heart Failure.

Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are a relatively new class of antidiabetic drugs that have shown favorable effects in heart failure (HF) patients, irrespective of the left ventricular ejection fraction (LVEF). Recent studies have demonstrated the beneficial effects of empagliflozin on cardiac function and structure; however, less is known about dapagliflozin. The purpose of the current work was to investigate the association between the use of dapagliflozin and cardiac biomarkers as well as the cardiac structure in a cohort of patients with HF and diabetes mellitus (DM). The present work was an observational study that included 118 patients (dapagliflozin group n = 60; control group n = 58) with HF and DM. The inclusion criteria included: age > 18 years, a history of DM and HF, regardless of LVEF, and hospitalization for HF exacerbation within the previous 6 months. The exclusion criteria were previous treatment with SGLT2i or glucagon-like peptide-1 receptor agonists, a GFR< 30 and life expectancy < 1 year. The evaluation of patients (at baseline, 6 and 12 months) included a clinical assessment, laboratory blood tests and echocardiography. The Mann-Whitney test was used for the comparison of continuous variables between the two groups, while Friedman's analysis of variance for repeated measures was used for the comparison of continuous variables. Troponin (p < 0.001) and brain natriuretic peptide (BNP) (p < 0.001) decreased significantly throughout the follow-up period in the dapagliflozin group, but not in the control group (p > 0.05 for both). The LV end-diastolic volume index (p < 0.001 for both groups) and LV end-systolic volume index (p < 0.001 for both groups) decreased significantly in the dapagliflozin and the control group, respectively. The LVEF increased significantly (p < 0.001) only in the dapagliflozin group, whereas the global longitudinal strain (GLS) improved in the dapagliflozin group (p < 0.001) and was impaired in the control group (p = 0.021). The left atrial volume index decreased in the dapagliflozin group (p < 0.001) but remained unchanged in the control group (p = 0.114). Lastly, the left ventricular mass index increased significantly both in the dapagliflozin (p = 0.003) and control group (p = 0.001). Dapagliflozin, an SGLT2i, was associated with a reduction in cardiac biomarkers and with reverse cardiac remodeling in patients with HF and DM.

SGLT2 Inhibitors as Potential Anticancer Agents.

Sodium-glucose cotransporter 2 (SGLT2) serves as a critical glucose transporter that has been reported to be overexpressed in cancer models, followed by increased glucose uptake in both mice and humans. Inhibition of its expression can robustly thwart tumor development in vitro and in vivo. SGLT2 inhibitors are a comparatively new class of antidiabetic drugs that have demonstrated anticancer effects in several malignancies, including breast, liver, pancreatic, thyroid, prostate, and lung cancers. This review aims to assess the extent of SGLT involvement in different cancer cell lines and discuss the pharmacology, mechanisms of action, and potential applications of SGLT2 inhibitors to reduce tumorigenesis and its progression. Although these agents display a common mechanism of action, they exhibit distinct affinity towards the SGLT type 2 transporter compared to the SGLT type 1 transporter and varying extents of bioavailability and half-lives. While suppression of glucose uptake has been attributed to their primary mode of antidiabetic action, SGLT2 inhibitors have demonstrated several mechanistic ways to combat cancer, including mitochondrial membrane instability, suppression of β-catenin, and PI3K-Akt pathways, increase in cell cycle arrest and apoptosis, and downregulation of oxidative phosphorylation. Growing evidence and ongoing clinical trials suggest a potential benefit of combination therapy using an SGLT2 inhibitor with the standard chemotherapeutic regimen. Nevertheless, further experimental and clinical evidence is required to characterize the expression and role of SGLTs in different cancer types, the activity of different SGLT subtypes, and their role in tumor development and progression.

MYOCARDIAL REDUCTION OF SYMPATHETIC ACTIVITY IS INVOLVED IN THE ANTIFIBROTIC AND ANTIHYPERTROPHIC EFFECTS OF SGLT2 INHIBITION IN ANGIOTENSIN II-DEPENDENT HYPERTENSION

Objective: The beneficial myocardial effects of SGLT2 inhibitors, a new class of antidiabetic drugs, have been described not only in diabetic patients, but also in heart diseases not associated with diabetes. The positive effects of these drugs go beyond glycemic control and involve multiple mechanisms. In the present study we investigate whether the cardioprotective effects of empagliflozin, a SGLT2 inhibitor, may be dependent on myocardial sympathetic activity in experimental model of angiotensin II-dependent hypertension. Design and method: Experiments were performed in Sprague Dawley rats (n = 26) followed for 4 weeks and divided in the following groups: a) Angiotensin II-treated group (Ang II, 200 ng/kg/min, osmotic minipumps s.c, n = 7); b) Ang II +Empagliflozin-treated group (Empa, 10 mg/kg/day, per os, n = 6); c) control group (physiological saline s.c., n = 7); d) Control+Empagliflozin-treated group (n = 6). Systolic blood pressure was measured by tail cuff method. At the end of the experimental period myocardial interstitial fibrosis (Sirius Red staining) and myocardial hypertrophy were measured by histomorphometric analysis. Myocardial tyrosine hydroxylase expression, used as marker of sympathetic activity, was measured by immunohistochemistry. Results: Ang II caused a significant increase of blood pressure (p&lt;0.0001), myocardial interstitial fibrosis (p&lt;0.01), hypertrophy (p&lt;0.01), and tyrosine hydroxylase expression (p&lt;0.01) as compared to control groups. Empagliflozin treatment did not modify blood glucose in the different groups of rats. Empagliflozin administration did not modify the increase in blood pressure in Ang II treated rats, but prevented the development of myocardial fibrosis, hypertrophy, and tyrosine hydroxylase over-expression. Conclusions: These data demonstrate that in Ang II dependent hypertension Empagliflozin administration prevented the onset of myocardial fibrosis and hypertrophy through the reduction of local sympathetic activity. This effect is independent on the modulation of blood pressure and blood glucose levels.

Sodium Glucose Cotransporter-2 Inhibitor Empagliflozin Increases Antioxidative Capacity and Improves Renal Function in Diabetic Rats.

There are several pathologic mechanisms involved in diabetic nephropathy, but the role of oxidative stress seems to be one of the most important. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a relatively new class of antidiabetic drugs that might also have some other effects in addition to lowering glucose. The aim of this study was to evaluate the possible effects of the SGLT2 inhibitor empagliflozin on oxidative stress and renal function in diabetes. Male Wistar rats were randomly divided into four groups: control, control-treated, diabetic, and diabetic-treated (n = 8 per group). Diabetes was induced by a single intraperitoneal dose of streptozotocin (50 mg/kg). The treated animals received empagliflozin for 5 weeks (20 mg/kg/day/po). All groups were sacrificed on the 36th day, and blood and tissue samples were collected. Serum levels of urea, uric acid, creatinine, and glucose levels were determined. The level of malondialdehyde (MDA) and glutathione (GLT), as well as the activity of catalase (CAT) and superoxide dismutase (SOD), was measured in all groups. Data were analyzed using one-way Anova and paired T-tests, and p ≤ 0.05 was considered significant. Diabetes significantly increased urea (p < 0.001), uric acid (p < 0.001), and creatinine (p < 0.001) in the serum, while the activities of CAT (p < 0.001) and SOD (p < 0.001) were reduced. GLT was also reduced (p < 0.001), and MDA was increased (p < 0.001) in non-treated animals. Treatment with empagliflozin improved renal function, as shown by a reduction in the serum levels of urea (p = 0.03), uric acid (p = 0.03), and creatinine (p < 0.001). Empagliflozin also increased the antioxidant capacity by increasing CAT (p = 0.035) and SOD (p = 0.02) activities and GLT content (p = 0.01) and reduced oxidative damage by lowering MDA (p < 0.001). It seems that uncontrolled diabetes induces renal insufficiency by decreasing antioxidant defense mechanisms and inducing oxidative stress. Empagliflozin might have additional benefits in addition to lowering glucose--reversing these processes, improving antioxidative capacity, and improving renal function.

Quantitative analysis of low content polymorphic impurities in canagliflozin tablets by PXRD, NIR, ATR-FITR and Raman solid-state analysis techniques combined with stoichiometry

Canagliflozin (CFZ) was a commercially new class of anti-diabetic drug, which had various anhydrate crystal forms and two hydrate crystal forms (Canagliflozin hemihydrate (Hemi-CFZ) and Canagliflozin monohydrate (Mono-CFZ) crystal form). Commercially available CFZ tablets’ active pharmaceutical ingredient (API) was Hemi-CFZ, which was easy conversion to CFZ or Mono-CFZ under the influence of temperature, pressure, humidity and other factors in tablets processing, storage, and transportation, thus affected bioavailability and efficacy of tablets. Therefore, quantitative analysis low content of CFZ and Mono-CFZ in tablets was essential to control tablets’ quality. The main objective of this study was to examine the feasibility of Powder X-ray Diffraction (PXRD), Near Infrared Spectroscopy (NIR), Attenuated Total Reflectance Fourier Transform Infrared Spectroscopy (ATR-FTIR) and Raman for quantitative analysis the low content of CFZ or Mono-CFZ in ternary mixtures. PLSR calibration models for low content of CFZ and Mono-CFZ were established by the solid analysis techniques of PXRD, NIR, ATR-FTIR and Raman combined with various pretreatments (such as Multiplicative Scatter Correction (MSC), Standard Normal Variate (SNV), Savitzky-Golay First Derivative (SG1st), Savitzky-Golay Second Derivative (SG2nd) and Wavelet Transform (WT)), and the correction models were verified. However, compared with PXRD, ATR-FTIR and Raman, NIR due to its water sensitivity was the most suitable for the quantitative analysis low content of CFZ or Mono-CFZ in tablets. Partial Least Squares Regression (PLSR) model for quantitative analysis low content of CFZ in tablets was as follow: Y = 0.0480 + 0.9928 X, R2 = 0.9986, LOD = 0.1596 %, LOQ = 0.4838 %, SG1st + WT pretreated. And that of Mono-CFZ were Y = 0.0050 + 0.9996 X, R2 = 0.9996, LOD = 0.0164 %, LOQ = 0.0498 %, MSC + WT pretreated and Y = 0.0051 + 0.9996 X, R2 = 0.9996, LOD = 0.0167 %, LOQ = 0.0505 %, SNV + WT pretreated, respectively. That can be used for quantitative analysis of impurity crystal content in drug production to ensure drug quality.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors and non-small cell lung cancer survival.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a relatively new class of antidiabetic drugs with demonstrated renal and cardiovascular disease benefit. This study evaluates the role of SGLT2 inhibitors on the survival of non-small cell lung cancer (NSCLC) patients. We used National Surveillance, Epidemiology and End Results (SEER)-Medicare linked data. Twenty four thousand nine hundred fifteen NSCLC patients newly diagnosed between 2014 and 2017 with pre-exiting diabetes and aged 66 years or older were included and followed to the end of 2019. Information on SGLT2 inhibitors use was extracted from the Medicare Part D file. SGLT2 inhibitor use was associated with significantly reduced mortality risk after adjusting for potential confounders (HR = 0.68, 95% CI = 0.60-0.77) with stronger association for longer duration of use (HR = 0.54, 85% CI = 0.44-0.68). Further, we found that SGLT2 inhibitor use was associated with a significant reduced risk of mortality regardless of patients' demographic, tumour characteristics and cancer treatments. Our large SEER-Medicare linked data study indicates that SGLT2 inhibitors use was associated with improved overall survival of NSCLC patients with pre-existing diabetes. Further studies are needed to confirm our findings and elucidate the possible mechanisms behind the association.

Blood glucose control with different treatment regimens in type 2 diabetes patients hospitalized with COVID-19 infection: A retrospective study.

Coronavirus disease (COVID-19) is closely associated with hyperglycemia and a worse prognosis in patients with a previous diagnosis of type 2 diabetes mellitus. A few studies investigated the effects of diabetes treatment regimens in these patients during hospitalization. Here, we evaluate the impact of insulin and non-insulin therapy on glucose control in patients with type 2 diabetes admitted with COVID-19. This is a retrospective study including 359 COVID-19 patients with type 2 diabetes. Patients were divided into 2 groups according to diabetes treatment during hospitalization. The first group included patients treated with insulin only, and the second group patients treated with other antidiabetic agents with or without insulin. Average blood glucose was higher in the insulin-only treatment group (201 ± 66 mg/dL vs 180 ± 71 mg/dL, P = .004), even after excluding mechanically ventilated patients (192 ± 69 vs 169 ± 59 mg/dL, P = .003). In patients with moderate severity of COVID-19, average blood glucose was also significantly higher in the insulin-only treated group (197 ± 76 vs 168 ± 51 mg/dL, P = .001). Most patients (80%) in the combination treatment group received metformin. Moderately affected COVID-19 patients with type 2 diabetes could safely be treated with antihyperglycemic medications with or without insulin.

Psoriasiform lesions as a side effect of SGLT-2 therapy

SGLT-2 inhibitors (flozins) are one of the new classes of anti-diabetic drugs, used from 2012. They are highly recommended in case of intolerance or contraindication of metformin, but in Poland they are used usually as third-line drug after metformin and sulfonylurea. They growing popularity is caused by their significance in cardiovascular risk reduction and preventive role in according to diabetes complications like chronic kidney disease, or diabetes-induced dementia. The aid of this article is to summarize the knowledge on the risk of psoriasis development in diabetic patients cured with flozins.&#x0D; In according to the newest studies, flozins may be considered as a pro-psoriatic factor, increasing the risk of this skin disease, especially in patients with diabetic kidney disease. But on the other hand, SGLT-2 inhibitors have significantly decreasing effect on cardiovascular risk, which is increased in psoriatic patients.

Intensified Multifactorial Intervention in Patients with Type 2 Diabetes Mellitus.

In the management of diabetes mellitus, one of the most important goals is to prevent its micro- and macrovascular complications, and to that end, multifactorial intervention is widely recommended. Intensified multifactorial intervention with pharmacotherapy for associated risk factors, alongside lifestyle modification, was first shown to be efficacious in patients with microalbuminuria (Steno-2 study), then in those with less advanced microvascular complications (the Anglo-Danish-Dutch Study of Intensive Treatment In People with Screen Detected Diabetes in Primary Care [ADDITION]-Europe and the Japan Diabetes Optimal Treatment study for 3 major risk factors of cardiovascular diseases [J-DOIT3]), and in those with advanced microvascular complications (the Nephropathy In Diabetes-Type 2 [NID-2] study and Diabetic Nephropathy Remission and Regression Team Trial in Japan [DNETT-Japan]). Thus far, multifactorial intervention led to a reduction in cardiovascular and renal events, albeit not necessarily significant. It should be noted that not only baseline characteristics but also the control status of the risk factors and event rates during intervention among the patients widely varied from one trial to the next. Further evidence is needed for the efficacy of multifactorial intervention in a longer duration and in younger or elderly patients. Moreover, now that new classes of antidiabetic drugs are available, it should be addressed whether strict and safe glycemic control, alongside control of other risk factors, could lead to further risk reductions in micro- and macrovascular complications, thereby decreasing all-cause mortality in patients with type 2 diabetes mellitus.

Role of Sodium Glucose Cotransporter 2 Inhibitor in Hypertension

Review Role of Sodium Glucose Cotransporter 2 Inhibitor in Hypertension Zhitong Zhou, Dao Wen Wang, Junfang Wu * Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan 430030, China. * Correspondence: Junfang.wu@tjh.tjmu.edu.cn Received: 17 October 2022 Accepted: 15 November 2022 Published: 21 December 2022 Abstract: Sodium glucose cotransporter 2 inhibitors (SGLT-2i) are a new class of antidiabetic drugs that act by inhibiting the reabsorption of glucose in the proximal renal tubule, which results in lowering the level of blood and urinary glucose. Besides the glucose-lowing effect, some clinical trials found the benefits of SGLT2i in treating heart failure with or without diabetes. In 2021, SGLT2i were recommended by the European Society of Cardiology in treating of heart failure. Compared to heart failure, hypertension is a common cardiovascular disease with an increasing prevalence globally. There is also clinical evidence indicating that SGLT2i can lower blood pressure. Here we focused on addressing the role of SGLT-2i in treating hypertension and its possible mechanism in this review.

Sodium-glucose cotransporter inhibitors and kidney fibrosis: review of the current evidence and related mechanisms.

Sodium-glucose cotransporter inhibitors (SGLT2i) are a new class of anti-diabetic drugs that have beneficial cardiovascular and renal effects. These drugs decrease proximal tubular glucose reabsorption and decrease blood glucose levels as a main anti-diabetic action. Furthermore, SGLT2i decreases glomerular hyperfiltration by a tubuloglomerular feedback mechanism. However, the renal benefits of these agents are independent of glucose-lowering and hemodynamic factors, and SGLT2i also impacts the kidney structure including kidney fibrosis. Renal fibrosis is a common pathway and pathological marker of virtually every type of chronic kidney disease (CKD), and amelioration of renal fibrosis is of utmost importance to reduce the progression of CKD. Recent studies have shown that SGLT2i impact many cellular processes including inflammation, hypoxia, oxidative stress, metabolic functions, and renin-angiotensin system (RAS) which all are related with kidney fibrosis. Indeed, most but not all studies showed that renal fibrosis was ameliorated by SGLT2i through the reduction of inflammation, hypoxia, oxidative stress, and RAS activation. In addition, less known effects on SGLT2i on klotho expression, capillary rarefaction, signal transducer and activator of transcription signaling and peptidylprolyl cis/trans isomerase (Pin1) levels may partly explain the anti-fibrotic effects of SGLT2i in kidneys. It is important to remember that some studies have not shown any beneficial effects of SGLT2i on kidney fibrosis. Given this background, in the current review, we have summarized the studies and pathophysiologic aspects of SGL2 inhibition on renal fibrosis in various CKD models and tried to explain the potential reasons for contrasting findings.

Dapagliflozin Prevents High-Glucose-Induced Cellular Senescence in Renal Tubular Epithelial Cells.

Gliflozins are a new class of antidiabetic drugs with renoprotective properties. In cultures of primary human renal tubular epithelial cells (RPTECs) subjected to high-glucose conditions in the presence or absence of dapagliflozin, we evaluated cellular senescence pathways. High glucose increased sodium-glucose cotransporter-2 (SGLT-2) expression and glucose consumption, enhancing reactive oxygen species production. The latter induced DNA damage, ataxia telangiectasia mutated kinase (ATM), and p53 phosphorylation. Stabilized p53 increased the cell cycle inhibitor p21, resulting in cell cycle arrest and increasing the cellular senescence marker beta-galactosidase (GLB-1). RPTECs under high glucose acquired a senescence-associated secretory phenotype, which was detected by the production of IL-1β, IL-8, and TGF-β1. By decreasing SGLT-2 expression and glucose consumption, dapagliflozin inhibited the above pathway and prevented RPTEC senescence. In addition, dapagliflozin reduced the cell cycle inhibitor p16 independently of the glucose conditions. Neither glucose concentration nor dapagliflozin affected the epithelial-to-mesenchymal transition when assessed with α-smooth muscle actin (α-SMA). Thus, high glucose induces p21-dependent RPTEC senescence, whereas dapagliflozin prevents it. Since cellular senescence contributes to the pathogenesis of diabetic nephropathy, delineating the related molecular mechanisms and the effects of the widely used gliflozins on them is of particular interest and may lead to novel therapeutic approaches.

TMET-37. SODIUM-DEPENDENT GLUCOSE TRANSPORTER 2 (SGLT2) IS OVEREXPRESSED IN THE MAJORITY OF ATRTS AND A SUBSET OF PEDIATRIC PATIENTS WITH HIGH-GRADE GLIOMA; A POTENTIAL IMAGING AND THERAPEUTIC TARGET

Abstract Sodium glucose cotransporters (SGLT) are a class of glucose transporters independent of the conventional glucose transporters (GLUT). Like the GLUT, SGLT2 plays an important role in glucose uptake in many solid cancers. Importantly, SGLT2 inhibitors are a new class of anti-diabetic drugs and have recently been investigated as a potential anti-cancer therapy in a variety of solid cancers. In fact, a recent study in adult high-grade gliomas showed that an SGLT-specific PET imaging probe ([18F] Me-4FDG) is sensitive for visualization of high-grade glioma (HGG) with superior tumor-normal brain uptake relative to 18F-FDG-PET. We aimed to investigate the expression of SGLT2 within pediatric brain tumor subtypes using RNA sequencing data from PedcBioPortal and immunohistochemistry of tissue microarrays (TMAs). Using the RNA sequencing data from 603 patients with pediatric brain tumors, we found that HGGs have the highest SGLT2 expression (Z score=0.13± 1.03) and were significantly higher compared to low-grade gliomas (Z score= -0.12, p=0.049), medulloblastomas (Z score=-0.28, p=0.001), and ependymomas (Z score=-0.30, p=0.002). Atypical teratoid rhabdoid tumors (ATRT) also had significantly higher Z score (0.10±0.67) compared to medulloblastomas (p=0.038), and ependymomas (p=0.049). There was no significant difference between HGGs and ATRTs in SGLT2 expression (p=0.899). Analysis of 4 TMAs including HGGs, medulloblastomas, ependymomas, and ATRTs after SGLT2 immunohistochemistry demonstrated strong membranous staining in a small subset and moderate-weak staining in the majority of HGGs. The majority of ATRTs were positive. The majority of medulloblastomas and ependymomas were negative, noting that the membranous nature of the staining may be a limiting factor in evaluation of tumors with less cytoplasm. In conclusion, our work demonstrates that SGLT2 has heterogeneous expression in pediatric brain tumors and is overexpressed in the majority of ATRTs, and a subset of pediatric HGGs, and may represent a compelling paradigm that integrates metabolic imaging and therapy of these tumors.

Remission as an Emerging Therapeutic Target in Type 2 Diabetes in the Era of New Glucose-Lowering Agents: Benefits, Challenges, and Treatment Approaches.

Type 2 diabetes mellitus (T2DM) is a progressive disease with a growing prevalence, associated with an increased risk of complications. The introduction of new classes of antidiabetic drugs into clinical practice has dramatically changed the landscape of diabetes therapy. However, despite the progress made in the pharmacotherapy of T2DM, mitigating the burden of the disease on individuals, societies and health care systems remains a challenge. Remission has recently emerged as a therapeutic target in T2DM, achievable through a wide range of interventions. Recent studies have shown that extensive lifestyle changes, such as weight reduction, bariatric surgery, and intensive glucose lowering therapy, can prompt the remission of diabetes, but some unanswered questions remain regarding its long-term effects on diabetic complications. Metabolic surgery and novel classes of glucose-lowering medications are currently the most effective interventions to induce weight loss and by extension remission in patients with diabetes; however, the ideal strategy to achieve the long-term maintenance of remission remains doubtful. In this narrative review, we discuss the available therapeutic approaches to target the remission of diabetes through personalized multimodal care, based on the latest evidence.

Therapeutic efficacy of dapagliflozin on diabetic kidney disease in rats

AimDiabetic kidney disease (DKD) is one of the severe microvascular complications of type 2 diabetes mellitus (T2DM), which eventually leads to irreversible renal damage and develops into end-stage renal disease (ESRD). Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a new class of antidiabetic drugs that act on the kidney to reduce glucose reabsorption. Increasing evidence confirms that dapagliflozin exerts a protective effect on DKD, but the mechanisms have not been reported. The aims of this study were to observe the therapeutic efficacy of dapagliflozin on DKD and investigate the possible immunological mechanism. Materials and methodsT2DM was modeled by a high-sugar and high-fat diet combined with STZ. Then, rats were treated with 10 mg/kg dapagliflozin for 8 weeks. The protective efficacy of dapagliflozin was evaluated by observing body weight, blood glucose, blood serum creatinine, blood urea nitrogen, 24-h urine protein, renal histology and ultrastructure, and oxidative stress levels. The immunological mechanisms were monitored by measuring the levels of TLR2/Myd88/NF-κB by immunohistochemical staining, RT-qPCR and Western blotting. ResultsAfter treatment with dapagliflozin, renal damage was greatly improved. The levels of blood glucose, renal function and proteinuria were significantly decreased, and renal pathological and ultrastructural damage was obviously extenuated, possibly due to the reduction in inflammation and the levels of oxidative stress. ConclusionsDapagliflozin has therapeutic potential for DKD. This effect was possibly mediated by inhibiting inflammation and oxidative stress levels.

Unfavorable effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on the skeletal system of nondiabetic rats

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic drugs, acting by inhibiting the reabsorption of glucose in the kidneys. They turned out to improve cardiovascular and renal outcomes not only in patients with type 2 diabetes but also in nondiabetic patients. At present, they are more and more widely used in patients without diabetes. Since there were concerns that SGLT2 inhibitors may increase fracture risk in diabetes, the aim of the study was to examine the effect of dapagliflozin and canagliflozin on the musculoskeletal system of nondiabetic, healthy rats. The experiments were carried out on mature female rats, divided into the control rats and rats treated with dapagliflozin (1.4 mg/kg p.o.) or canagliflozin (4.2 mg/kg p.o.) for 4 weeks. Serum bone turnover markers, skeletal muscle strength and mass, bone mass, density, histomorphometric parameters and mechanical properties were determined. Administration of the drugs did not affect the skeletal muscle mass and strength. There was no effect on serum bone turnover markers, and bone mass and composition. However, administration of both drugs resulted in disorders of cancellous bone microarchitecture and worsening of bone mechanical properties. In conclusion, both SGLT2 inhibitors unfavorably affected the skeletal system of healthy rats.

Sodium-glucose cotransporter 2 (SGLT2) inhibitor initiation and hepatocellular carcinoma prognosis.

IntroductionSodium-glucose cotransporter 2 (SGLT2) inhibitors are a relatively new class of antidiabetic drugs. Emerging findings from laboratory studies indicate that SGLT2 inhibitors can improve liver function and suppress the proliferation of hepatocellular carcinoma (HCC) cells. The aim of this study was to test the hypothesis that initiation of SGLT2 inhibitors improves HCC prognosis in a human population.MethodsWe used National Surveillance, Epidemiology and End Results (SEER)—Medicare linked data in the United States to evaluate the role of SGLT2 inhibitor initiation on the survival of HCC patients. 3,185 HCC patients newly diagnosed between 2014 and 2017 aged 66 years or older with pre-existing type 2 diabetes were included and followed to the end of 2019. Information on SGLT2 inhibitor initiation was extracted from the Medicare Part D file.ResultsSGLT2 inhibitor initiation was associated with significantly lower mortality risk after adjusting for potential confounders (HR = 0.68, 95% CI = 0.54–0.86) with stronger association for longer duration of use (HR = 0.60, 95% CI = 0.41–0.88). Further, we found that SGLT2 inhibitor initiation was associated with a lower risk mortality risk ranging from 14% to 60% regardless of patient demographic variables, tumor characteristics, and cancer treatments.ConclusionOur large SEER-Medicare linked data study indicates that SGLT2 inhibitor initiation was associated with improved overall survival of HCC patients with pre-existing type 2 diabetes compared with no SGLT2 inhibitor use. Further studies are needed to confirm our findings and elucidate the possible mechanisms behind the association.