Glucose Transporter Research Articles

Differential Effect of Simulated Microgravity on the Cellular Uptake of Small Molecules.

The space environment can affect the function of all physiological systems, including the properties of cell membranes. Our goal in this study was to explore the effect of simulated microgravity (SMG) on the cellular uptake of small molecules based on reported microgravity-induced changes in membrane properties. SMG was applied to cultured cells using a random-positioning machine for up to three hours. We assessed the cellular accumulation of compounds representing substrates of uptake and efflux transporters, and of compounds not shown to be transported by membrane carriers. Exposure to SMG led to an increase of up to 60% (p < 0.01) in the cellular uptake of efflux transporter substrates, whereas a glucose transporter substrate showed a decrease of 20% (p < 0.05). The uptake of the cathepsin activity-based probe GB123 (MW, 1198 g/mol) was also enhanced (1.3-fold, p < 0.05). Cellular emission of molecules larger than ~3000 g/mol was reduced by up to 50% in SMG (p < 0.05). Our findings suggest that short-term exposure to SMG could differentially affect drug distribution across membranes. Longer exposure to microgravity, e.g., during spaceflight, may have distinct effects on the cellular uptake of small molecules.

PSIX-24 Greater glucose transporter SLC2A1 expression in milk somatic cells as a compensatory milk production strategy in young prolific Pelibuey ewes

Abstract The number of lambs per birth expressed as prolificacy is a key trait that determines productive efficiency in sheep. However, the optimal litter size depends on the production system, since the milk production of the ewe impacts the postnatal development of lambs. Milk yield, in turn, is related to the expression of the SLC2A1 gene in mammary epithelial cells. This gene encodes the solute carrier/glucose transporter 1 and is upregulated in peak/mid lactation. To assess the productive efficiency of twinning ewes in regard to SLC2A1 expression, the objective of this study was to measure the mRNA levels of SLC2A1 in milk somatic cells (MSC) of Pelibuey ewes lambing twins. Healthy ewes (n = 8), three primiparous and five multiparous, were selected to quantify and compare abundance of SLC2A1 mRNA. Management was under feedlot conditions, and the milk samples were taken between 16 and 20 d post-lambing. Total RNA was purified from MSC and SLC2A1 mRNA abundance were measured by RT-qPCR, relative to β-actin as reference gene. The total birth weight (TBW) and weaning weight of their lambs were recorded, calculating the total weight of lamb weaned (TWLW). TBW, TWLW and relative expression of SLC2A1 were analyzed with PROC GLM of SAS, whereas the Pearson correlation coefficient between TWLW and relative expression of SLC2A1 was calculated using PROC CORR of SAS. Although there was no statistical difference in TBW (P = 0.13) and TWLW (P = 0.38) between lambing groups, a numerical difference was observed both in TBW (5.7 ± 0.54 and 6.9 ± 0.42) and in TWLW (21.5 ± 3.94 and 26.2 ± 3.05) for primiparous and multiparous, respectively. The abundance of SLC2A1 mRNA were 3.1-fold change (P = 0.0005) greater in MSC of primiparous ewes than in the multiparous ones (Figure 1). In multiparous ewes a positive correlation, r = 0.96 (P = 0.01) was found between TWLW and relative expression of SLC2A1. It is concluded that greater relative expression of SLC2A1 in young prolific ewes could be a compensatory mechanism to produce more milk to feed their lambs, even with a smaller udder volume. Such findings give way for further research on the subject.

Comparative Effects of Tumor Necrosis Factor Alpha, Lipopolysaccharide, and Palmitate on Mitochondrial Dysfunction in Cultured 3T3-L1 Adipocytes.

We have previously reported that dysregulated lipid metabolism and inflammation in 3T3-L1 adipocytes is attributed to tumor necrosis factor alpha (TNFα) rather than lipopolysaccharide (LPS) and palmitate (PA). In this study, we further compared the modulative effects of TNFα, LPS, and PA on mitochondrial function by treating 3T3-L1 adipocytes with TNFα (10 ng/mL), LPS (100 ng/mL), and PA (0.75 mM) individually or in combination for 24 h. Results showed a significant reduction in intracellular adenosine triphosphate (ATP) content, mitochondrial bioenergetics, total antioxidant capacity, and the mRNA expression of citrate synthase (Cs), sirtuin 3 (Sirt3), protein kinase AMP-activated catalytic subunit alpha 2 (Prkaa2), peroxisome proliferator-activated receptor gamma coactivator 1 alpha (Ppargc1α), nuclear respiratory factor 1 (Nrf1), and superoxide dismutase 1 (Sod1) in cells treated with TNFα individually or in combination with LPS and PA. Additionally, TNFα treatments decreased insulin receptor substrate 1 (Irs1), insulin receptor substrate 2 (Irs2), solute carrier family 2, facilitated glucose transporter member 4 (Slc2a4), and phosphoinositide 3 kinase regulatory subunit 1 (Pik3r1) mRNA expression. Treatment with LPS and PA alone, or in combination, did not affect the assessed metabolic parameters, while the combination of LPS and PA increased lipid peroxidation. These results show that TNFα but not LPS and PA dysregulate mitochondrial function, thus inducing oxidative stress and impaired insulin signaling in 3T3-L1 adipocytes. This suggests that TNFα treatment can be used as a basic in vitro model for studying the pathophysiology of mitochondrial dysfunction and related metabolic complications and screening potential anti-obesity therapeutics in 3T3-L1 adipocytes.

Structure and mechanism of a phosphotransferase system glucose transporter

Glucose is the primary source of energy for many organisms and is efficiently taken up by bacteria through a dedicated transport system that exhibits high specificity. In Escherichia coli, the glucose-specific transporter IICBGlc serves as the major glucose transporter and functions as a component of the phosphoenolpyruvate-dependent phosphotransferase system. Here, we report cryo-electron microscopy (cryo-EM) structures of the glucose-bound IICBGlc protein. The dimeric transporter embedded in lipid nanodiscs was captured in the occluded, inward- and occluded, outward-facing conformations. Together with biochemical and biophysical analyses, and molecular dynamics (MD) simulations, we provide insights into the molecular basis and dynamics for substrate recognition and binding, including the gates regulating the binding sites and their accessibility. By combination of these findings, we present a mechanism for glucose transport across the plasma membrane. Overall, this work provides molecular insights into the structure, dynamics, and mechanism of the IICBGlc transporter in a native-like lipid environment.

Novel 99mTc-Labeled Mannose Derivative as a Highly Promising Single Photon Emission Computed Tomography Probe for Tumor Imaging.

18F-2-fluoro-2-deoxy-d-glucose ([18F]FDG) has been the most used positron emission tomography imaging agent for clinical applications. Single photon emission computed tomography (SPECT) imaging is cheaper and used more widely for diagnostic use, but there is no SPECT tumor imaging agent for clinical applications comparable to [18F]FDG. Mannose is a C2 epimer of glucose and can also be transported into tumor cells via glucose transporters (GLUTs). To develop a novel SPECT tumor imaging agent with satisfactory tumor uptake and tumor/nontarget ratios, here a mannose derivative (CN7DM) was synthesized and radiolabeled with technetium-99m to prepare [99mTc]Tc-CN7DM. The six-coordinated structure of [99mTc]Tc-CN7DM was confirmed by the corresponding rhenium compound (Re-CN7DM). [99mTc]Tc-CN7DM was transported into cancer cells via GLUTs and may be trapped in the cancer cells by electrostatic attraction. The probe exhibited high uptake in tumors and low uptake in nontarget tissues in mice bearing different tumors, indicating that [99mTc]Tc-CN7DM exhibited promising potential for SPECT tumor imaging and warranted further clinical investigation.

Endothelial metabolic control of insulin sensitivity through resident macrophages

Endothelial cells (ECs) not only form passive blood conduits but actively contribute to nutrient transport and organ homeostasis. The role of ECs in glucose homeostasis is, however, poorly understood. Here, we show that, in skeletal muscle, endothelial glucose transporter 1 (Glut1/Slc2a1) controls glucose uptake via vascular metabolic control of muscle-resident macrophages without affecting transendothelial glucose transport. Lowering endothelial Glut1 via genetic depletion (Glut1ΔEC) or upon a short-term high-fat diet increased angiocrine osteopontin (OPN/Spp1) secretion. This promoted resident muscle macrophage activation and proliferation, which impaired muscle insulin sensitivity. Consequently, co-deleting Spp1 from ECs prevented macrophage accumulation and improved insulin sensitivity in Glut1ΔEC mice. Mechanistically, Glut1-dependent endothelial glucose metabolic rewiring increased OPN in a serine metabolism-dependent fashion. Our data illustrate how the glycolytic endothelium creates a microenvironment that controls resident muscle macrophage phenotype and function and directly links resident muscle macrophages to the maintenance of muscle glucose homeostasis.

Glucose deprivation-induced disulfidptosis in human nucleus pulposus cells: a novel pathological mechanism of intervertebral disc degeneration

BackgroundLimited supply of certain nutrients and deregulation of nucleus pulposus (NP) plays a key role in the pathogenesis of intervertebral disc degeneration (IVDD). However, whether nutrient deprivation-induced cell death, particularly disulfidptosis, contributes to the depletion of NP cells and the development of IVDD, is unknown.MethodsRNA-seq, single-cell RNA-seq, and Genome-wide DNA methylation datasets of nucleus pulposus tissue were collected for bioinformatic analysis. Predictive models of disulfidptosis related genes in IVDD were constructed by machine learning and their differential expression was analyzed. In addition, we performed cell subsets identification analysis, cell-cell communications analysis, and functional enrichment analysis of key genes in the core subset based on single-cell RNA-seq data of NP tissues isolated from one normal sample and one IVDD sample. Finally, glucose deprivation-induced disulfidptosis in human NP cells (HNPCs) was verified by various cell death inhibitors and disulfidptosis-related molecular markers.ResultsWe found the disulfidptosis signal was significantly activated in the IVDD group. Using single-cell RNA-seq analysis, we focused on the chondrocytes and found that disulfidptosis-related genes significantly highly expressed in the IVDD C4 chondrocyte subset, which was identified as a new disulfidptosis-associated cell subset. Correlation analysis revealed the negative correlation between SLC7A11 (driving gene of disulfidptosis) and the glucose transporter GLUTs (SLC2A1-4) family genes (suppressing genes of disulfidptosis) in the IVDD group. We also found obvious cell death in HNPC upon glucose starvation, while employment of various cell death inhibitors could not inhibit glucose starvation-induced death in HNPCs. Moreover, the accumulation of disulfide bonds in cytoskeletal proteins was indicated by slowed migration in non-reducible protein blotting experiments. 2-DG, a key disulfidptosis inhibitor, significantly rescued cell death caused by glucose starvation through lowering the NADP+/NADPH ratio.ConclusionsWe validated the occurrence of disulfidptosis in HPNCs and identified a novel disulfidptosis-associated cell subset, followed by experimental verification of disulfidptosis in a glucose-limited context to mimic a fall in nutrient supply during the development disc degeneration. These findings provided new insights into the pathological mechanisms of IVDD and encourage us to explore potential therapeutic targets involved in the regulation of disulfidptosis for the prevention of intervertebral disc degeneration.Graphical

The Role of Sodium Glucose Co-Transporter 2 Inhibitors in Atrial Fibrillation: A Comprehensive Review.

Atrial fibrillation (AF) is the most prevalent arrhythmia among adults worldwide, frequently co-occurring with comorbidities such as Heart Failure (HF) and Type 2 Diabetes Mellitus (T2DM). This association contributes to increased morbidity and mortality, elevated healthcare costs, and diminished quality of life. Consequently, preventing or delaying the onset and recurrence of AF is crucial for reducing the incidence of complications. Sodium-glucose cotransporter 2 inhibitors (SGLT2is), due to their multifaceted pharmacological actions, have been proposed as potential therapeutic agents in the management of AF. However, current evidence from both animal models and clinical studies remains inconclusive. This narrative literature review aims to provide a comprehensive analysis of existing evidence on the impact of SGLT2is on the prevalence, incidence of new-onset, and recurrence of AF in diabetic populations and patients with HF. Numerous observational studies, predominantly retrospective, suggest a consistent reduction in AF risk with SGLT2is, while randomized controlled trials (RCTs) have yielded mixed results, with some demonstrating benefits and others not reaching statistical significance. The heterogeneity in study outcomes, population characteristics, follow-up duration, and specific SGLT2is used, as well as potential biases, underscore the need for further extensive and rigorous RCTs to establish definitive conclusions and elucidate the underlying mechanisms.

The impact of hypoxic training at different altitudes on human physiology, biochemistry, and cytogenetics

This study investigated the impact of dosed hypoxic normobaric exercises on the physio-biochemical parameters of blood and lymph circulation, as well as cytogenetic changes in red blood cells (RBC), using a Sprague Dawley Rat Model. Hypoxic training was conducted in an animal hypoxic chamber. The session lasted 34-35 minutes. The O2 content was 20.5% at the beginning of the session; then, it dropped to 14.8% within 4-5 minutes, corresponding to a rise to an altitude of 2,900-3,000 m, and was maintained at that level until the end of the session. The hypoxic training cycle increased the RBC count by 4.1%, the hemoglobin count by 4.2%, the blood oxygen capacity by 8.3%, the circulating blood volume by 16.7%, and interstitial metabolism and lymph circulation by 30.6%. A cytogenetic study revealed an increase in erythropoiesis-reticulocyte count by 40.3% and a slightly higher frequency of micronucleated erythrocytes. We observed economization of the heart, respiration, activation of glucose transport by 33.5%, increased lipid utilization, and increased antioxidant protection. These parameters especially changed when hypoxic training was combined with physical activity. Hypoxic training with physical activity expands the body’s compensatory and adaptive capabilities by increasing the reserves of the respiratory, cardiovascular, and lymphatic systems.

Meta-analysis of sotagliflozin, a dual sodium-glucose-cotransporter 1/2 inhibitor, for heart failure in type 2 diabetes.

Sodium-glucose co-transporters (SGLTs) mediate sodium and glucose transport across cell membranes. SGLT2 inhibitors have a recognized place within heart failure (HF) guidelines. We evaluated the effect of sotagliflozin on HF and cardiovascular outcomes in participants with type 2 diabetes. Scopus, Medline, Embase and Central were searched from inception until 2 June 2023. Randomized controlled trials evaluating sotagliflozin in type 2 diabetes participants and reporting HF events were selected. Major adverse cardiovascular events (MACE) and systolic blood pressure were evaluated. The Cochrane risk of bias tool (RoB 2.0) was used. Pooled mean difference (MD), relative risk (RR), 95% confidence intervals and the number needed to treat (NNT) were estimated (PROSPERO: CRD42023432732). We selected nine studies (n=15320 participants: n=8040 intervention and n=7280 control). The median follow-up was 13.4months (Q1=13, Q3=21). One study recruited participants with HF at baseline. After a follow-up of >52weeks, sotagliflozin significantly reduced the risk of HF [n=8 studies; RR=0.66 (0.64, 0.69)], stroke [n=6 studies; RR=0.75 (0.58, 0.97)] and MACE [n=8 studies; RR=0.73 (0.66, 0.81)]. The NNT was 20 and 26 for HF and MACE, respectively. Sotagliflozin lowered systolic blood pressure [n=7; MD=-2.38mmHg (-2.79, -1.97)]. No dose-dependent effect was identified for HF [200mg: RR=0.38 (0.16, 0.89), 400mg: RR=0.57 (0.39, 0.85), P-value=0.22]. The high risk of bias was a limitation of this review. Sotagliflozin reduced HF and cardiovascular events in type 2 diabetes participants. Research exploring its effects in HF and comparisons with SGLT2 inhibitors is warranted to determine if dual SGLT inhibition surpasses selective inhibition.

Quinic acid as an inhibitor of α‐glucosidase activity, nonenzymatic glycosylation, and glucose transport in Caco‐2 cells

Quinic acid as an inhibitor of α‐glucosidase activity, nonenzymatic glycosylation, and glucose transport in Caco‐2 cells

Hyperglycemia selectively increases cerebral non-oxidative glucose consumption without affecting blood flow.

Multiple studies have shown that hyperglycemia increases the cerebral metabolic rate of glucose (CMRglc) in subcortical white matter. This observation remains unexplained. Using positron emission tomography (PET) and euinsulinaemic glucose clamps, we found, for the first time, that acute hyperglycemia increases non-oxidative CMRglc (i.e., aerobic glycolysis (AG)) in subcortical white mater as well as in medial temporal lobe structures, cerebellum and brainstem, all areas with low euglycemic CMRglc. Surprisingly, hyperglycemia did not change regional cerebral blood flow (CBF), the cerebral metabolic rate of oxygen (CMRO2), or the blood-oxygen-level-dependent (BOLD) response. Regional gene expression data reveal that brain regions where CMRglc increased have greater expression of hexokinase 2 (HK2). Simulations of glucose transport revealed that, unlike hexokinase 1, HK2 is not saturated at euglycemia, thus accommodating increased AG during hyperglycemia.

Electronic Health Record Alert With Heart Failure Risk and Sodium Glucose Cotransporter 2 Inhibitor Prescriptions in Diabetes: A Randomized Clinical Trial.

Sodium glucose cotransporter 2 inhibitors (SGLT2i) prevent heart failure (HF) in patients with type 2 diabetes mellitus (T2DM) but prescription rates are low. The effect of an electronic health record (EHR) alert notifying providers of patients' estimated risk of developing HF on SGTL2i prescriptions is unknown. This was a pragmatic, randomized clinical trial that compared an EHR alert and usual care among patients with T2DM and no history of HF or SGLT2i use at a single center. The EHR alert notified providers of their patient's HF risk and recommended HF prevention strategies. Randomization was performed at the provider level across general and subspecialty internal medicine as well as family medicine outpatient clinics. The primary outcome was proportion of SGLT2i prescriptions within 30 days. Proportion of natriuretic peptide (NP) tests within 90 days was also assessed. A total of 1524 patients (median age 75 years, 45% women, 23% Black) were enrolled between September 28, 2021, and April 29, 2022 from 189 outpatient clinics. SGLT2i were prescribed to 1.2% (9/780) of patients in the EHR alert group and 0% (0/744) of those in the usual care group (P value = 0.009). Natriuretic peptide testing was performed within 90 days among 10.8% (84/780) of patients in the EHR alert group and 7.3% (54/744) of patients in the usual care group (P value = 0.02). In a single-center trial with low overall SGLT2i use, an EHR alert incorporating HF risk information significantly increased SGLT2i prescriptions and NP testing although the absolute rates were low.

Antagonistic insulin-like signaling influencing glucose regulation in C. elegans

The insulin/ IGF-signaling (IIS) is an evolutionary conserved signaling pathway within eukaryotic organisms that regulates glucose metabolism and cell division. The nematode, C. elegans is an excellent model for exploring IIS as they have 40 insulin-like peptides that act on a single receptor, DAF-2. We aim to explore the relationships between IIS and glucose metabolism, focusing on the antagonistic insulin-like peptide, INS-17 and its influence over FDGT-1 (facilitated glucose transporter 1). FDGT-1 is expressed throughout the nematode, including the basolateral membrane of intestinal cells and where it is theorized to export glucose to the surrounding somatic cells rather than absorb it from the intestinal tract. We hypothesize that IIS controls transcription of FDGT-1 and antagonistic peptides should lead to a decrease in FDGT-1 transcription, resulting in the increased lifespan and increased fat accumulation observed in daf-2(lf) loss of function and ins-17(oe) over expressing strains. In this study, survival assays are used to assess the impact which high-glucose content has on lifespan, along with Oil Red O (ORO) lipid staining to visualize lipid accumulation amongst conditions and protein quantification of FDGT-1:GFP to evaluate FDGT-1 protein levels. Our findings are consistent with the idea of low insulin signaling leading to extended lifespan as daf-2(lf) lived significantly longer than WT in both 0% and 2% glucose conditions and ins-17(oe) living significantly longer than wildtype in 2% glucose conditions. The ORO lipid staining revealed that high glucose conditions and low insulin signaling result in lipid accumulation within the nematode. Using the fdgt-1:gfp strain, we were able to determine an increase in the FDGT-1 in the presence of glucose, suggesting FDGT-1 expression is influenced by glucose. These findings aim to further our understanding of IIS regulating glucose uptake and metabolism, along with the significance of the FDGT-1 glucose transporter.

Oligodendroglial fatty acid metabolism as a central nervous system energy reserve

Brain function requires a constant supply of glucose. However, the brain has no known energy stores, except for glycogen granules in astrocytes. In the present study, we report that continuous oligodendroglial lipid metabolism provides an energy reserve in white matter tracts. In the isolated optic nerve from young adult mice of both sexes, oligodendrocytes survive glucose deprivation better than astrocytes. Under low glucose, both axonal ATP levels and action potentials become dependent on fatty acid β-oxidation. Importantly, ongoing oligodendroglial lipid degradation feeds rapidly into white matter energy metabolism. Although not supporting high-frequency spiking, fatty acid β-oxidation in mitochondria and oligodendroglial peroxisomes protects axons from conduction blocks when glucose is limiting. Disruption of the glucose transporter GLUT1 expression in oligodendrocytes of adult mice perturbs myelin homeostasis in vivo and causes gradual demyelination without behavioral signs. This further suggests that the imbalance of myelin synthesis and degradation can underlie myelin thinning in aging and disease.

Insulin injection rotation and Diabetes Mellitus nutritional management education

The management of Diabetes Mellitus (DM) involves implementing a healthy lifestyle and pharmacological interventions through the administration of anti-hyperglycemia drugs. An essential aspect of treating DM patients is insulin administration, which facilitates glucose transportation into cells. This study evaluated the effectiveness of insulin injection rotation and nutritional management education for DM.The literature search utilized the keywords "education,"AND "insulin injection," AND "nutritional management," AND "DM", ranged 2021-2023 Searches were conducted on various databases, including Proquest, NCBI, BMC, ScienceDirect, and other relevant platforms such as Google Scholar.Ten journal articles pertinent to the subject matter were identified in the study. Findings indicate that nutritional education facilitates overall health improvement in individuals with DM, contributing to maintaining average body weight and near-normal blood glucose levels. It also enhances lipid profile and insulin receptor sensitivity while being a preventive measure against acute or chronic complications such as hyperglycemia. It is noted that selecting the appropriate injection site can significantly impact patients' blood glucose levels. While it is recommended to administer injections at consistent locations, repetitive use of the same site may pose risks of side effects, such as lipodystrophy.After conducting a comprehensive review of ten journal articles, it has been concluded that insulin injection rotation and nutritional management education are effective for managing DM.

Rural-Urban Disparities in the Uptake of New Diabetes Medications

OBJECTIVE This study assessed rural-urban differences in the uptake and use of glucagon-like peptide 1 (GLP-1) receptor agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors, and sodium–glucose cotransporter 2 (SGLT2) inhibitors among U.S. adults with diabetes. RESEARCH DESIGN AND METHODS We calculated person-level annual total and out-of-pocket (OOP) expenditures for new, other, and all diabetes medications in the Medical Expenditure Panel Survey. We defined newer diabetes medications as GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT2 inhibitors. The primary outcome was whether a person received a new diabetes medication during the year, and secondary outcomes were medication expenditures. The key independent variable was metropolitan statistical area (MSA) status. Logistic regression was used to estimate use rates of new diabetes medications by MSA status, and a two-part model was used to estimate individual-level annual total and OOP expenditures on new, other, and all diabetes medications. RESULTS We observed no significant difference (adjusted odds ratio 0.943, P = 0.37) in newer diabetes medication use. Individuals with diabetes in non-MSA areas were more likely to have spending (probit coefficient 0.058, P = 0.06) and to spend more on other diabetes medications (combined marginal effect $103.13, P = 0.09), although this result was not statistically significant. This imbalance increased from $81.33 (P = 0.09) in 2003–2006 to $136.66 (P = 0.08) in 2017–2020. CONCLUSIONS Rural-urban diabetes outcome disparities are not likely to be the result of differences in the uptake of GLP-1 receptor agonist, DPP-4 inhibitor, and SGLT2 inhibitor medications.

Efficacy of Metformin plus Sodium Glucose Transporter-2 inhibitors (SGLT-2i) in Obese Type 2

Efficacy of Metformin plus Sodium Glucose Transporter-2 inhibitors (SGLT-2i) in Obese Type 2

Sodium–glucose co-transporter-2 inhibitors for hospitalised patients with COVID-19: a prospective meta-analysis of randomised trials

Sodium-glucose co-transporter-2 (SGLT2) inhibitors have been proposed as a potential treatment for adults hospitalised with COVID-19, due to their potential anti-inflammatory and endothelial protective effects. Published evidence from randomised control trials (RCTs) does not provide evidence of benefit. We aimed to estimate the effect of oral administration of SGLT2 inhibitors compared with usual care or placebo in adults hospitalised with COVID-19. Eligible RCTs that estimated the effect of oral administration of SGLT2 inhibitors compared with usual care or placebo on 28-day all-cause mortality (primary outcome) were included in this prospective meta-analysis. The primary safety outcome was ketoacidosis by 28 days. Trials were identified through systematic searches of ClinicalTrials.gov, EudraCT, and the WHO ISRCTN registry between Nov 1, 2022 and Jan 31, 2023. The search terms were "random*" AND "COVID" AND each SGLT2i, not restricted by trial status or language. Individual searches were then combined. Prespecified summary outcome data, overall and within subgroups of interest, were provided by each trial. The primary analyses were inverse variance weighted meta-analysis of odds ratios (ORs). Risk of bias was assessed using the Cochrane Risk of Bias tool. This study was registered with PROSPERO, CRD42023406442. Three eligible trials randomly assigned 6096 participants (3025 to the SGLT2 inhibitor group and 3071 to the usual care or placebo group). 2381 (39%) patients were women and 1547 (25%) had type 2 diabetes at randomisation. By 28 days, there were 351 deaths in the SGLT2 inhibitor group and 382 deaths in the usual care or placebo group (summary OR 0·93 [95% CI 0·79-1·08]; p=0·33, I2 for inconsistency across trials 0%). The risk of bias was assessed as being low. Ketoacidosis was observed in seven participants in the SGLT2 inhibitor group and two patients in the usual care or placebo group. Although administration of SGLT2 inhibitor was safe, we found no clear evidence that adding SGLT2 inhibitor therapy improved outcomes in patients hospitalised with COVID-19 compared with usual care or placebo. These data do not support the use of SGLT2 inhibitors as standard treatment in adults hospitalised for COVID-19. None.

Reduction of hyperglycemia in STZ-induced diabetic mice by prophylactic treatment with heat-killed Mycobacterium aurum: possible effects on glucose utilization, mitochondrial uncoupling, and oxidative stress in liver and skeletal muscle.

In addition to conventional treatment and modifications in physical activity and diet, alternative strategies have been investigated to manage, prevent, or delay diabetes in humans. In this regard, one strategy has relied on the immunomodulatory properties of mycobacteria, whereby Bacillus Calmette-Guerin, an attenuated live strain of Mycobacterium bovis, has been shown to improve glycemic control in patients with diabetes and to alleviate hyperglycemia in selected murine models of diabetes. A novel heat-killed (HK) whole-cell preparation of Mycobacterium aurum (M. aurum) is currently under development as a potential food supplement; nevertheless, its potential bioactivity remains largely unknown. Thus, the present study investigated the potential prophylactic anti-diabetic effects of HK M. aurum in streptozotocin (STZ)-induced diabetic mice. Mice were divided into three groups: the STZ-induced diabetic group was injected with a single intraperitoneal high dose of STZ, the HK M. aurum-treated diabetic group was prophylactically treated with three doses of HK M. aurum 6 weeks before STZ injection, and the control non-diabetic group was given three intradermal injections of borate-buffered saline and an intraperitoneal injection of citrate buffer. Liver lactate dehydrogenase (LDH), uncoupling protein 2 (UCP2), and glucose transporter 2 (GLUT2) and skeletal muscle LDH, UCP3, and GLUT4 protein expression levels in different mouse groups were determined by Western blot. Our results indicated that HK M. aurum did not cause any significant changes in glycemic levels of normal non-diabetic mice. Prophylactic administration of three doses of HK M. aurum to diabetic mice resulted in a significant reduction in their blood glucose levels when compared to those in control diabetic mice. Prophylactic treatment of diabetic mice with HK M. aurum significantly restored their disturbed protein expression levels of liver UCP2 and LDH as well as of skeletal muscle UCP3. On the other hand, prophylactic treatment of diabetic mice with HK M. aurum had no significant effect on their liver GLUT2 and skeletal muscle GLUT4 and LDH protein expression levels. Our findings provide the first evidence that HK M. aurum possesses a hyperglycemia-lowering capacity and might support its future use as a food supplement for the amelioration of diabetes.