Glucose Transporter Research Articles

Effect of sodium–glucose co-transporter-2 inhibitors on survival free of organ support in patients hospitalised for COVID-19 (ACTIV-4a): a pragmatic, multicentre, open-label, randomised, controlled, platform trial

Patients hospitalised for COVID-19 are at risk for multiorgan failure and death. Sodium-glucose co-transporter-2 (SGLT2) inhibitors provide cardiovascular and kidney protection in patients with cardiometabolic conditions and could provide organ protection during COVID-19. We aimed to investigate whether SGLT2 inhibitors can reduce the need for organ support in patients hospitalised for COVID-19. This pragmatic, multicentre, open-label, randomised, controlled, platform trial was conducted across 63 sites in the USA, Spain, Brazil, Italy, and Mexico. Patients aged at least 18 years hospitalised for COVID-19 (moderate or severe illness) were randomly assigned (1:1), via an interactive voice system or web-response system, to receive locally available SGLT2 inhibitor (administered orally, once daily) plus standard-of-care or standard-of-care for 30 days. The primary outcome was organ support-free days evaluated through 21 days, assessed using intention-to-treat approach. This trial is registered on ClinicalTrials.gov, NCT04505774. The first patient was randomly assigned to the SGLT2 inhibitor domain on Dec 3, 2021. On March 31, 2023, at the recommendation of the data and safety monitoring board, enrolment in the SGLT2 inhibitor domain for both moderately and severely ill hospitalised patients was stopped prematurely for futility due to a low likelihood of finding a treatment benefit. The final randomised population consisted of 575 patients (mean age 72 years [SD 13], 242 (42%) female and 154 (27%) Hispanic; 504 in the moderate illness group and 71 in the severe illness group). 573 patients had a known 21-day outcome; 215 (75%) of 285 patients in the SGLT2 inhibitor plus standard-of-care group did not require respiratory or cardiovascular organ support versus 231 (80%) of 288 patients in the standard-of-care group. The adjusted odds ratio (OR) for an SGLT2 inhibitor effect on organ support-free days was 0·74 (95% Credible Interval [CrI] 0·48-1·13; where OR higher than 1 indicated treatment benefit, yielding a posterior probability of futility P(OR <1·2) of 99% and a posterior probability of inferiority P(OR<1·0) of 91%). There were 37 deaths (13%) in the SGLT2 inhibitor plus standard-of-care group and 42 deaths (15%) in the standard-of-care group at 90 days (hazard ratio 0·91 [95% CrI 0·58-1·43], probability of hazard ratio <1 of 66%). No safety concerns were observed with SGLT2 inhibitors, including no cases of ketoacidosis. SGLT2 inhibitors did not significantly increase days free of organ support or reduce mortality in patients hospitalised with COVID-19. SGLT2 inhibitors were well tolerated with no observed safety concerns. Overall, these findings do not support the use of SGLT2 inhibitors as standard care in patients hospitalised with COVID-19. National Institutes of Health.

Exercise performance and health: Role of GLUT4

The glucose transporter GLUT4 is integral for optimal skeletal muscle performance during exercise, as well as for metabolic health. Physiological regulation of GLUT4 translocation during exercise and increased GLUT4 expression following exercise involves multiple, redundant signalling pathways. These include effects of reactive oxygen species (ROS). ROS contribute to GLUT4 translocation that increases skeletal muscle glucose uptake during exercise and stimulate signalling pathways that increase GLUT4 expression. Conversely, ROS can also inhibit GLUT4 translocation and expression in metabolic disease states. The opposing roles of ROS in GLUT4 regulation are ultimately linked to the metabolic state of skeletal muscle and the intricate mechanisms involved give insights into pathways critical for exercise performance and implicated in metabolic health and disease.

Sodium–glucose co-transporter type-2 inhibitors for hospitalised patients with COVID-19: safe but not protective

Sodium–glucose co-transporter type-2 inhibitors for hospitalised patients with COVID-19: safe but not protective

Antidiabetic potential of fenugreek (Trigonella foenum-graecum): A magic herb for diabetes mellitus.

Fenugreek (Trigonella foenum-graecum) is a widely grown dietary herb in Asia, and its seeds are traditionally used for several diseases, including diabetes. The seeds and leaves possess a variety of compounds that play an important role in regulating their hypoglycemic effect. However, so far, no extensive systematic review exists on its antidiabetic effect, highlighting the molecular mechanisms and isolated compounds. The purpose of this review is to summarize the preclinical and clinical antidiabetic properties of fenugreek and its isolated compounds by focusing on underlying mechanisms. PubMed, Google Scholar, Science Direct, and Scopus databases were searched to retrieve articles until June, 2024. Preclinical studies demonstrated that the antidiabetic effect of fenugreek was mostly associated with enhanced glucose transporter type-4 (GLUT4) translocation and hexokinase activity, decreased glucose-6-phosphatase and fructose-1,6-bisphosphatase activities, inhibited α-amylase and maltase activities, protected β cells, and increased insulin release. Furthermore, few studies have reported its role as a glucagon-like peptide-1 (GLP-1) modulator, 5'-AMP-activated kinase (AMPK) activator, and dipeptidyl peptidase-IV (DPP-IV) inhibitor. Further clinical trials showed that fenugreek seeds improved blood glucose levels, insulin resistance, insulin sensitivity, and lipid profiles. This study highlights significant evidence of the antidiabetic effect of fenugreek and its isolated compounds; therefore, it could be a potential therapy for diabetes.

Epicatechin and β-Glucan from Whole Highland Barley Grain Synergistic Benefit on Attenuating Hyperglycemia via Improving Hepatic Glucose Metabolism in Diabetic C57BL/6J Mice.

Our previous study proved that epicatechin (EC) and β-glucan (BG) from whole-grain highland barley synergistically modulate glucose metabolism in insulin-resistant HepG2 cells. However, the main target and the mechanism underlying the modulation of glucose metabolism in vivo remain largely unknown. In this study, cell transfection assay and microscale thermophoresis analysis revealed that EC and BG could directly bind to the insulin receptor (IR) and mammalian receptor for rapamycin (mTOR), respectively. Molecular dynamic analysis indicated that the key amino acids of binding sites were Asp, Met, Val, Lys, Ser, and Tys. EC supplementation upregulated the IRS-1/PI3K/Akt pathway, while BG upregulated the mTOR/Akt pathway. Notably, supplementation with EC + BG significantly increased Akt and glucose transporter type 4 (GLUT4) protein expressions, while decreasing glycogen synthase kinase 3β (GSK-3β) expression in liver cells as compared to the individual effects of EC and BG, indicating their synergistic effect on improving hepatic glucose uptake and glycogen synthesis. Consistently, supplementation with EC + BG significantly decreased blood glucose levels and improved oral glucose tolerance compared to EC and BG. Therefore, combined supplementation with EC and BG may bind to corresponding receptors, targeting synergistic activation of Akt expression, leading to the improvement of hepatic glucose metabolism and thereby ameliorating hyperglycemia in vivo.

A new perspective on the regulation of glucose and cholesterol transport by mitochondria-lysosome contact sites.

Mitochondria and lysosomes play a very important role in maintaining cellular homeostasis, and the dysfunction of these organelles is closely related to many diseases. Recent studies have revealed direct interactions between mitochondria and lysosomes, forming mitochondria-lysosome contact sites that regulate organelle network dynamics and mediate the transport of metabolites between them. Impaired function of these contact sites is not only linked to physiological processes such as glucose and cholesterol transport but also closely related to the pathological processes of metabolic diseases. Here, we highlight the recent progress in understanding the mitochondria-lysosome contact sites, elucidate their role in regulating metabolic homeostasis, and explore the potential implications of this pathway in metabolic disorders.

Pharmacologic LDH inhibition redirects intratumoral glucose uptake and improves antitumor immunity in solid tumor models.

Tumor reliance on glycolysis is a hallmark of cancer. Immunotherapy is more effective in controlling glycolysis-low tumors lacking lactate dehydrogenase (LDH) due to reduced tumor lactate efflux and enhanced glucose availability within the tumor microenvironment (TME). LDH inhibitors (LDHi) reduce glucose uptake and tumor growth in preclinical models, but their impact on tumor-infiltrating T cells is not fully elucidated. Tumor cells have higher basal LDH expression and glycolysis levels compared with infiltrating T cells, creating a therapeutic opportunity for tumor-specific targeting of glycolysis. We demonstrate that LDHi treatment (a) decreases tumor cell glucose uptake, expression of the glucose transporter GLUT1, and tumor cell proliferation while (b) increasing glucose uptake, GLUT1 expression, and proliferation of tumor-infiltrating T cells. Accordingly, increasing glucose availability in the microenvironment via LDH inhibition leads to improved tumor-killing T cell function and impaired Treg immunosuppressive activity in vitro. Moreover, combining LDH inhibition with immune checkpoint blockade therapy effectively controls murine melanoma and colon cancer progression by promoting effector T cell infiltration and activation while destabilizing Tregs. Our results establish LDH inhibition as an effective strategy for rebalancing glucose availability for T cells within the TME, which can enhance T cell function and antitumor immunity.

Targeting SRSF10 might inhibit M2 macrophage polarization and potentiate anti-PD-1 therapy in hepatocellular carcinoma.

The efficacy of immune checkpoint blockade therapy in patients with hepatocellular carcinoma (HCC) remains poor. Although serine- and arginine-rich splicing factor (SRSF) family members play crucial roles in tumors, their impact on tumor immunology remains unclear. This study aimed to elucidate the role of SRSF10 in HCC immunotherapy. To identify the key genes associated with immunotherapy resistance, we conducted single-nuclear RNA sequencing, multiplex immunofluorescence, and The Cancer Genome Atlas and Gene Expression Omnibus database analyses. We investigated the biological functions of SRSF10 in immune evasion using in vitro co-culture systems, flow cytometry, various tumor-bearing mouse models, and patient-derived organotypic tumor spheroids. SRSF10 was upregulated in various tumors and associated with poor prognosis. Moreover, SRSF10 positively regulated lactate production, and SRSF10/glycolysis/ histone H3 lysine 18 lactylation (H3K18la) formed a positive feedback loop in tumor cells. Increased lactate levels promoted M2 macrophage polarization, thereby inhibiting CD8+ T cell activity. Mechanistically, SRSF10 interacted with the 3'-untranslated region of MYB, enhancing MYB RNA stability, and subsequently upregulating key glycolysis-related enzymes including glucose transporter 1 (GLUT1), hexokinase 1 (HK1), lactate dehydrogenase A (LDHA), resulting in elevated intracellular and extracellular lactate levels. Lactate accumulation induced histone lactylation, which further upregulated SRSF10 expression. Additionally, lactate produced by tumors induced lactylation of the histone H3K18la site upon transport into macrophages, thereby activating transcription and enhancing pro-tumor macrophage activity. M2 macrophages, in turn, inhibited the enrichment of CD8+ T cells and the proportion of interferon-γ+CD8+ T cells in the tumor microenvironment (TME), thus creating an immunosuppressive TME. Clinically, SRSF10 could serve as a biomarker for assessing immunotherapy resistance in various solid tumors. Pharmacological targeting of SRSF10 with a selective inhibitor 1C8 enhanced the efficacy of programmed cell death 1 (PD-1) monoclonal antibodies (mAbs) in both murine and human preclinical models. The SRSF10/MYB/glycolysis/lactate axis is critical for triggering immune evasion and anti-PD-1 resistance. Inhibiting SRSF10 by 1C8 may overcome anti-PD-1 tolerance in HCC.

Effects of Polyunsaturated Fatty Acid/Saturated Fatty Acid Ratio and Different Amounts of Monounsaturated Fatty Acids on Adipogenesis in 3T3-L1 Cells.

(1) Background: Adipose tissue serves as a central repository for energy storage and is an endocrine organ capable of secreting various adipokines, including leptin and adiponectin. These adipokines exert profound influences on diverse physiological processes such as insulin sensitivity, appetite regulation, lipid metabolism, energy homeostasis, and body weight. Given the integral role of adipose tissue in metabolic regulation, it is imperative to investigate the effects of varying proportions and types of dietary fats on adipocyte function. In addition, our previous study showed that P/S = 5 and MUFA = 60% appeared to be beneficial in preventing white adipose tissue accumulation by decreasing plasma insulin levels and increasing hepatic lipolytic enzyme activities involved in β-oxidation. Therefore, the objective of this study was to explore the effects of a polyunsaturated fatty acid (PUFA) to saturated fatty acid (SFA) ratio of 5 and varying levels of monounsaturated fatty acids (MUFA = 30% or 60%) on lipogenesis. (2) Methods: We cultured 3T3-L1 mouse embryo fibroblasts in Dulbecco's modified Eagle's medium (DMEM) containing 10% bovine calf serum until confluent. Varying ratios of palmitic acid (PA), oleic acid (OA), and linoleic acid (LA) were first bound with bovine serum albumin (BSA) before being applied to 3T3-L1 adipocytes in low doses and in high doses. (3) Results: Low doses of P/S ratio = 5, MUFA = 60% (M60) fatty acids decreased the accumulation of triglycerides in mature adipocytes by decreasing the mRNA expression of adipogenic factors, such as peroxisome proliferator-activated receptors (PPARs), lipoprotein lipase (LPL), and glucose transporter-4 (GLUT-4), while increasing lipolytic enzyme (hormone-sensitive lipase, HSL) expression when compared to high doses of P/S ratio = 5, MUFA = 60% (M60), low and high doses of P/S ratio = 5, MUFA = 30% (M30). Furthermore, the treatment of M60 in low doses also decreased the secretion of leptin and increased the secretion of adiponectin in adipocytes. (4) Conclusions: The composition of P/S = 5, MUFA = 60% fatty acid in low doses appeared to result in anti-adipogenic effects on 3T3-L1 adipocytes due to the down-regulation of adipogenic effects and the transcription factor.

HIV-1 Elite Controllers are Characterised by Elevated Levels of CD69-Expressing Natural Killer Cells.

Human immunodeficiency virus type 1 (HIV-1) elite controllers (ECs) are a rare subset of people living with HIV-1 (PLWH) who control viral replication in the absence of antiretroviral therapy (ART) and may provide a model for a functional cure. We investigated the role of natural killer (NK) cells in HIV-1 ECs from South Africa. Phenotypic (CD69, CD38, CD57, PD-1), functional (CD107a, IFN-γ), and nutrient transporter profiles (glucose transporter 1, CD98) of NK cells from ECs (n=20), viraemic progressors (VPs; n=19), people living with HIV-1 (PLWH) on ART (n=20), and people without HIV-1 (PWOH; n=21) were analysed using flow cytometry. The Kruskal-Wallis test followed by the Mann-Whitney U test were used to determine differences among the study groups. The Spearman's rank correlation coefficient was used to determine significant associations. Compared to the other study groups, the percentage of CD69-expressing NK cells was higher in ECs, whereas the percentage of CD38-expressing NK cells was higher in VPs. Percentages of CD69+CD38- NK cells were elevated in ECs compared to VPs (p = 0.003), but were not different to PLWH on ART and PWOH. Differentiation, exhaustion, and metabolic profiles were not different in ECs compared with PLWH on ART and PWOH, however, NK cell function was lower than in PWOH. These findings demonstrate that NK cells from ECs have an activated, mature profile with low levels of immune exhaustion and a reduced metabolic phenotype suggesting functional competence. This insight could inform the development of novel immunotherapeutic strategies for treating HIV-1.

The use of sodium–glucose co-transporter-2 inhibitors in heart failure: a practical overview

Heart failure is a major global healthcare concern. The condition is associated with high morbidity, high mortality and a reduced quality of life. The prognosis of heart failure is poor, with a 5-year survival rate close to 50%. Pharmacological treatment is a cornerstone of heart failure care, helping to improve outcomes and quality of life for people living with the condition. The sodium–glucose co-transporter-2 (SGLT2) inhibitors dapagliflozin and empagliflozin have been approved for patients who have heart failure with reduced ejection fraction, mildly reduced ejection fraction and preserved ejection fraction. This article discusses the evidence base, mechanism of action, clinical indications and practical considerations for the use of SGLT2 inhibitors in the treatment of heart failure.

Abstract P227: Potential roles of vascular glucose transporter 1 in development of abdominal aortic aneurysm induced by angiotensin II

It has been reported that pharmacological inhibition of glycolysis attenuated abdominal aortic aneurysm (AAA) development in mice. Glucose transporters (GLUTs) incorporate glucose as a first step of glycolysis. GLUT1 over-expression in vascular smooth muscle cell (VSMC) appears to enhance atherosclerosis in a mouse model. In angiotensin II (AngII) plus BAPN model of mouse AAA, silencing of VSMC AngII type 1 rec receptors attenuated AAA development and rupture which was associated with less immune cell infiltration to the aortas. However, the role of VSMC GLUT1 in AAA remains elusive. Here we tested our hypothesis that VSMC GLUT1 deletion attenuates AAA development and rupture in mice. Rat aortic VSMC were obtained by the explant method. Media glucose consumption of cultured VSMCs was evaluated in the presence or absence of angiotensin II (AngII, 100 nM) stimulation and GLUT1 inhibitor BAY-876. GLUT1 floxed mice were crossed with tamoxifen-inducible SMMHC-Cre mice. At 6 weeks of age, mice were injected with 2 mg/kg tamoxifen for 5 days. Significant vascular GLUT1 silencing was confimed with immunofluorescent chemistry. As a control, tamoxifen-treated SMMHC-Cre male mice were utilized. At 8 weeks, AngII (1 μg/kg/min) was delivered for 4 weeks. In addition, mice were received 1 mg/mL BAPN during the first 2 weeks of AngII infusion. After 4weeks, all animals were euthanized and maximal external diameter of the abdominal aorta was measured. In cultured VSMC, glucose consumption increased by AngII was attenuated by pretreatment of 100 nM BAY-876. AngII plus BAPN significantly developed AAA in control mice. However, silencing of VSMC GLUT1 did not affect AAA development by AngII plus BAPN. The survival rate due to aortic rupture in VSMC GLUT1 silenced mice and control mice treated with BAPN and AngII were 60.0% and 57.1%, respectively. AngII induced hypertension in control mice and VSMC GLUT1 silenced mice. Although GLUT1 may be a primary VSMC GLUT to enhance glucose utilization in response to AngII stimulation, VSMC GLUT1 silencing did not alter AngII-dependent AAA development or rupture in a mouse model. Since pharmacological inhibition of GLUT attenuated AAA and associated macrophage infiltration, it is possible that GLUT1 or other GLUT expressed in macrophages may contribute to development of AAA. In conclusion, VSMC GLUT1 silencing did not alter AngII-dependent AAA development or rupture in a mouse model.

Promising Influences of Moringa oleifera in Functional Foods against Metabolic Syndrome: A Comprehensive and Mechanistic Review.

Metabolic syndrome (MetS) is now considered a global issue with a growing financial and health impact. Numerous herbal alternatives have been examined and researched due to the ever-increasing demand for new medications to treat metabolic syndrome disorders. People have empirically employed Moringa oleifera (MO), a native plant to several Asian nations, for a variety of diseases. We sought to examine recent research on MO in MetS and its potential mechanism of action in the current review. Four databases, including PubMed, Scopus, Web of Sciences, and Google Scholar, were thoroughly searched, and the data were then compiled. In total, 146 papers covering nonclinical and clinical MO investigations in metabolic syndromerelated disorders are included in this study. Numerous research confirmed MO's positive impact on the control of blood glucose, blood pressure, hyperlipidemia, and obesity. Many molecular processes have been investigated, including increasing glucose transporter type 4 (GLUT4) expression, inhibition of β-Hydroxy-β-methylglutaryl-coenzyme A (HMG-CoA), α-glucosidase inhibiting, AMP-activated protein kinase (AMPK) activation, and other suggested mechanisms. The current review established much data favoring MO's potential advantages in metabolic syndrome. However, further research involving human studies is required in this area to determine whether Moringa can effectively treat metabolic syndrome.

Dual Targeting of Syndecan-1 and Glucose Transporter-1 with a Novel Lipid-Based Delivery System Enhances Therapeutic Efficacy and Overcomes Chemoresistance in Pancreatic Ductal Adenocarcinoma

Dual Targeting of Syndecan-1 and Glucose Transporter-1 with a Novel Lipid-Based Delivery System Enhances Therapeutic Efficacy and Overcomes Chemoresistance in Pancreatic Ductal Adenocarcinoma

Diabetes Pharmacotherapy and its effects on the Skeletal Muscle Energy Metabolism.

The disorders of skeletal muscle metabolism in patients with Type 2 diabetes mellitus (T2DM), such as mitochondrial defection and glucose transporters (GLUTs) translocation dysfunctions, are not uncommon. Therefore, when anti-diabetic drugs were used in various chronic diseases associated with hyperglycemia, the impact on skeletal muscle should not be ignored. However, current studies mainly focus on muscle mass rather than metabolism or functions. Anti-diabetic drugs might have a harmful or beneficial impact on skeletal muscle. In this review, we summarize the upto- date studies on the effects of anti-diabetic drugs and some natural compounds on skeletal muscle metabolism, focusing primarily on emerging data from pre-clinical to clinical studies. Given the extensive use of anti-diabetic drugs and the common sarcopenia, a better understanding of energy metabolism in skeletal muscle deserves attention in future studies.

Unlocking the medicinal arsenal of Cissus assamica: GC-MS/MS, FTIR, and molecular docking insights.

This study investigated the biochemical components present in the leaves of Cissus assamica. The primary aim was to analyze these components using advanced techniques and assess their potential therapeutic applications. Fourier Transform Infrared (FT-IR) spectroscopy, Gas Chromatography-Mass Spectrometry (GC-MS), and Mass Spectral analysis were employed to identify and characterize the compounds in Cissus assamica leaves. The mass spectra of each compound were compared with data from the Wiley and NIST libraries to determine their names, molecular masses, and chemical structures. FT-IR analysis identified characteristic functional groups by their specific frequencies. FT-IR spectroscopic analysis revealed significant molecular vibrations at frequencies of 3265.63, 2853.81, 1638.60, 1469.21, and 1384.95 cm⁻¹, indicating the presence of specific functional groups. The GC-MS analysis identified distinct compounds, such as "aR-Turmerone," "Curlone," "7,8-Epoxylanostan-11-ol, 3-acetoxy-," "13-Docosenamide, (Z)-," "Phenol, 3,5-bis(1,1-dimethylethyl)-," "9,19-Cyclolanostan-3-ol, 24,24-epoxymethano-, acetate," and "Quinoline-5,8-dione-6-ol, 7-[[(4-cyclohexylbutyl)amino]methyl]-." These compounds exhibited potential therapeutic applications. Their cytotoxic, antimicrobial, antidiarrheal, anti-hyperglycemic, and pain-relieving properties were evaluated by comparing them with reference ligands targeting specific receptors, including dihydrofolate reductase (DHFR), epidermal growth factor receptor (EGFR), kappa opioid receptor (KOR), glucose transporter 3 (GLUT 3), and cyclooxygenase 2 (COX-2). The results of this study suggest that Cissus assamica leaves contain bioactive compounds with potential therapeutic benefits for treating infections, diarrhea, hyperglycemia, and pain. However, further research is needed to conduct comprehensive phytochemical screening and establish the precise mechanisms of action for the crude extract or the plant-derived compounds.

Abstract P138: Diet Influences the Expression of Renal Sodium-Glucose Cotransporters in Juvenile Male Rats

Poor nutrition and metabolic dysfunction are becoming more prevalent among children, as evident by increasing childhood obesity in recent years. The kidney sodium-glucose cotransporter 2 (SGLT2) is a contributor to overall metabolic homeostasis, with inhibition of SGLT2 significantly reducing circulating glucose and lipids. The study objective was to determine if diet influences the expression of renal glucose transporters in young rats. Weanling male Wistar Kyoto rats received 1) standard laboratory chow, 2) AIN-93G diet, or 3) a high-fat diet (60% kcal, HFD). Each dietary group was then further subdivided to receive either filtered water or 5% (w/v) sucrose solution ad libitum . Four weeks later, animals were euthanized and kidneys were collected and processed. mRNA expression of Sglt1 , Sglt2 , Sqstm1 , and Nlrp3 was determined using gene specific primers and RT-PCR. Renal SGLT2 protein expression was visualized using immunohistochemistry and quantified using Imagej software. Diet significantly influenced the renal expression of both Sglt1 ( P =0.005) and Sglt2 (P=0.046), while beverage did not have a significant effect on either ( P =0.7 and P =0.4, respectively). Rats fed the HFD had more than 30% reduction in Sglt1 mRNA expression as compared to rats fed chow, and ~20% reduction in Sglt2 as compared to rats fed AIN. Preliminary data suggest that diet and beverage significantly altered renal protein expression of SGLT2, with rats fed chow having the lowest renal expression that was slightly increased with sugar consumption (1.5% versus 2.7%, respectively). Rats fed AIN had the greatest expression, but was drastically reduced in rats consuming sugar (4% versus 1.2%, respectively). To determine if autophagy and inflammasome activation is involved, the expression of Sqstm1 and Nlrp3 was measured by RT-PCR. Similarly, rats fed HFD had the lowest expression of both Sqstm1 ( P&lt;0.001) and Nlrp3 ( P=0.03). Sqstm1 and Nlrp3 mRNA expression was decreased with sugar consumption in rats fed chow and AIN, whereas Sqstm1 ( P =0.01) and Nlrp3 ( P &lt;0.001) mRNA expression was increased in rats fed HFD with sugar beverage. Our data suggest that diet significantly influences renal glucose transporter expression in juvenile rats in a way that may be mediated by autophagic impairment. The modulatory effect of sugar consumption on SGLT2 protein, Sqstm1, and Nlrp3 was diet-dependent, highlighting the importance of nutrition to renal physiology within weeks after weaning.

CMTM6 mediates the Warburg effect and promotes the liver metastasis of colorectal cancer

Liver metastasis of colorectal cancer (CRC) is a leading cause of death among cancer patients. The overexpression of glucose transporter 1 (Glut1) and enhanced glucose uptake that are associated with the Warburg effect are frequently observed in CRC liver metastases, but the underlying mechanisms remain poorly understood. CKLF-like MARVEL transmembrane domain-containing protein 6 (CMTM6) regulates the intracellular trafficking of programmed death-ligand-1 (PD-L1); therefore, we investigated whether CMTM6 regulates Glut1 trafficking and the Warburg effect in CRC cells. We found that knocking down of CMTM6 by shRNA induced the lysosomal degradation of Glut1, decreased glucose uptake and glycolysis in CRC cells, and suppressed subcutaneous CRC growth in nude mice and liver metastasis in C57BL/6 mice. Mechanistically, CMTM6 forms a complex with Glut1 and Rab11 in the endosomes of CRC cells, and this complex is required for the Rab11-dependent transport of Glut1 to the plasma membrane and for the protection of Glut1 from lysosomal degradation. Multiomics revealed global transcriptomic changes in CMTM6-knockdown CRC cells that affected the transcriptomes of adjacent cancer-associated fibroblasts from CRC liver metastases. As a result of these transcriptomic changes, CMTM6-knockdown CRC cells exhibited a defect in the G2-to-M phase transition, reduced secretion of 60 cytokines/chemokines, and inability to recruit cancer-associated fibroblasts to support an immunosuppressive CRC liver metastasis microenvironment. Analysis of TCGA data confirmed that CMTM6 expression was increased in CRC patients and that elevated CMTM6 expression was associated with worse patient survival. Together, our data suggest that CMTM6 plays multiple roles in regulating the Warburg effect, transcriptome, and liver metastasis of CRC.

Antidiabetic Potential of Apiaceae Family Plants- A Critical Update

Apiaceae is one of the biggest and most important plant families, comprising about 3700 species and 434 genera. Most of them are aromatic, flowering plants. The plants in this family are beneficial for everyday use and treating diseases. They are a rich source of nutraceuticals and secondary metabolites attributed to different pharmacological activities. Some plants under this family possess antidiabetic activity through different mechanisms, such as inhibiting carbohydrate hydrolyzing enzymes, stimulating insulin secretion, and regulating glucose transporters. Diabetes mellitus has become a chronic metabolic disorder whose management is of utmost importance in recent days. The present review aims to establish the use of Apiaceae family plants in treating diabetes mellitus. The availability of plants, their bio-constituents, mode of action, and experimental studies have also been briefly described here.

Obesity-Related Glomerulopathy: Epidemiology, Pathogenesis, and Current Treatments

Obesity-related glomerulopathy (ORG) is a kidney disease characterized by glomerulomegaly with or without focal segmental glomerulosclerosis. With the increase in worldwide obesity rates, the number of ORG patients has also risen rapidly. Approximately 10% of ORG patients have been found to progress to the end stage of renal disease 6.2 years after diagnosis. The pathogenesis of ORG is complex, involving altered renal hemodynamics, activation of the renin–angiotensin–aldosterone system, insulin resistance, and abnormal lipid metabolism and adipokines. Despite the numerous strategies to lose weight as treatment for ORG, ranging from lifestyle and diet changes to bariatric surgery and medications, approved and marketed weight-loss drugs often have potential side effects and perform below expectations. Recently, new glucose-lowering drugs that also reduce body weight and improve kidney function have garnered attention. In particular, several large clinical trials have confirmed the efficacy and safety of sodium–glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists in reducing weight and preserving kidney function. This article provides a brief review of the epidemiology, pathogenesis, and treatment strategies of ORG.