Glucose Transporter Research Articles

ECLIPSES: Early initiation of sodium glucose cotransporter-2 inhibitors for cardiovascular protection in patients with type 2 diabetes following acute coronary syndrome and subsequent coronary artery bypass graft surgery.

There is a paucity of data evaluating early initiation of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in patients with diabetes following acute coronary syndrome (ACS) and coronary artery bypass graft surgery (CABG). To describe the efficacy and safety of SGLT2i initiated early after CABG in patients with type 2 diabetes who experienced ACS. This is a retrospective cohort study of patients with type 2 diabetes (T2DM) who experienced ACS and subsequent CABGwith follow up at 3 and 12 months. Patients who filled a SGLT2i prescription within 14 days of discharge were allocated to the SGLT2i group and those who did not were included in the no SGLT2i group. The primary efficacy end point was first occurrence of a 4-point Major Adverse Cardiovascular Event (MACE), and the primary safety end point was a composite of hypoglycemia, hypotension, diabetic ketoacidosis, acute kidney injury, and urinary tract infection. Secondary end points included a comparative analysis of the primary outcome, 30-day readmission rates, and subgroup analyses of key populations. A total of 1629 patients were included: 226 received a SGLT2i within 14 days of discharge and 1403 did not. At 12 months, 8.9% and 15.3% of patients experienced MACE in the SGLT2i and no SGLT2i groups, respectively (adjusted Hazard Ratio [aHR] 0.65, 95% confidence interval [CI] 0.41-1.04). The primary safety outcome occurred in 12.0% of the SGLT2i group and 19.1% of the no SGLT2i group at 12 months (aHR 0.68, 95% CI 0.45-1.01). Early initiation of SGLT2i use was not associated with a reduction in MACE in patients with T2DM who experienced ACS and underwent subsequent CABG surgery. However, no apparent safety concerns were identified. Adequately powered trials are required to confirm this finding.

Prolonged treatment of compactin, atorvastatin, lovastatin or simvastatin decreased glucose consumption and expressions of proteins for glucose metabolism and insulin signaling in L6 skeletal muscle cells

Statins inhibit mevalonate synthesis and successfully lower plasma cholesterol levels and decrease the risk of cardiovascular diseases in humans, but also lead to myalgia in some patients. We hypothesize that statins may modulate glucose metabolism and insulin signaling in the skeletal muscle cells during and after differentiation, and in turn lead to side effects. Here, differentiating and differentiated L6 muscle cells were treated with 1 μM of different class of statins (compactin, pravastatin, atorvastatin, lovastatin and simvastatin) with or without insulin or mevalonate for extended periods of time. The glucose consumption and expression levels of proteins for glucose metabolism and insulin receptor (IR)/Akt signaling were determined. The prolonged statin treatments (except pravastatin) decreased glucose consumption in L6 skeletal muscle cells. In differentiating L6 cells, compactin, lovastatin or simvastatin decreased the expression levels of proteins involved in glucose metabolism and insulin signaling, including glucose transporter 4 (GLUT4), pyruvate dehydrogenase (PDH), glycogen synthase (GS), glycogen synthase kinase 3β (GSK3β) and insulin receptor β subunit (IRβ). In differentiated L6 cells, long-term treatment of compactin or simvastatin also decreased levels of proteins in glucose metabolism and IR/Akt signaling, including GLUT4, GSK3β, IRβ and PI3K p110α. Insulin treatment restored statin-mediated impairments in L6 cells. The insulin-mediated phosphorylation of Akt Ser473 was attenuated in differentiating and differentiated L6 cells in the presence of atorvastatin (differentiated only), compactin, lovastatin or simvastatin. In addition, mevalonate supplementation reversed the statin-mediated impairments in differentiated and differentiating L6 cells. Statin affected glucose usage and insulin signaling by inhibiting mevalonate synthesis in L6 cells. Our results provides a possible mechanism of adverse effects of statins in skeletal muscle and calls for cautious use of the medication in patients with impaired insulin sensitivity and glucose metabolism.

Disulfidptosis-related subtype and prognostic signature in prostate cancer

BackgroundDisulfidptosis refers to cell death caused by the accumulation and bonding of disulfide in the cytoskeleton protein of SLC7A11-high level cells under glucose deprivation. However, the role of disulfidptosis-related genes (DRGs) in prostate cancer (PCa) classification and regulation of the tumor microenvironment remains unclear.MethodsFirstly, we analyzed the expression and mutation landscape of DRGs in PCa. We observed the expression levels of SLC7A11 in PCa cells through in vitro experiments and assessed the inhibitory effect of the glucose transporter inhibitor BAY-876 on SLC7A11-high cells using CCK-8 assay. Subsequently, we performed unsupervised clustering of the PCa population and analyzed the differentially expressed genes (DEGs) between clusters. Using machine learning techniques to select a minimal gene set and developed disulfidoptosis-related risk signatures for PCa. We analyzed the tumor immune microenvironment and the sensitivity to immunotherapy in different risk groups. Finally, we validated the accuracy of the prognostic signatures genes using single-cell sequencing, qPCR, and western blot.ResultsAlthough SLC7A11 can increase the migration ability of tumor cells, BAY-876 effectively suppressed the viability of prostate cancer cells, particularly those with high SLC7A11 expression. Based on the DRGs, PCa patients were categorized into two clusters (A and B). The risk label, consisting of a minimal gene set derived from DEGs, included four genes. The expression levels of these genes in PCa were initially validated through in vitro experiments, and the accuracy of the risk label was confirmed in an external dataset. Cluster-B exhibited higher expression levels of DRG, representing lower risk, better prognosis, higher immune cell infiltration, and greater sensitivity to immune checkpoint blockade, whereas Cluster A showed the opposite results. These findings suggest that DRGs may serve as targets for PCa classification and treatment. Additionally, we constructed a nomogram that incorporates DRGs and clinical pathological features, providing clinicians with a quantitative method to assess the prognosis of PCa patients.ConclusionThis study analyzed the potential connection between disulfidptosis and PCa, and established a prognostic model related to disulfidptosis, which holds promise as a valuable tool for the management and treatment of PCa patients.

Molecular mechanisms underlying glucose-dependent insulinotropic polypeptide secretion in human duodenal organoids.

Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone secreted by enteroendocrine K cells in the proximal small intestine. This study aimed to explore the function of human K cells at the molecular and cellular levels. CRISPR-Cas9 homology-directed repair was used to insert transgenes encoding a yellow fluorescent protein (Venus) or an Epac-based cAMP sensor (Epac-S-H187) in the GIP locus in human duodenal-derived organoids. Fluorescently labelled K cells were purified by FACS for RNA-seq and peptidomic analysis. GIP reporter organoids were employed for GIP secretion assays, live-cell imaging of Ca2+ using Fura-2 and cAMP using Epac-S-H187, and basic electrophysiological characterisation. The G protein-coupled receptor genes GPR142 and CASR were knocked out to evaluate roles in amino acid sensing. RNA-seq of human duodenal K cells revealed enrichment of several G protein-coupled receptors involved in nutrient sensing, including FFAR1, GPBAR1, GPR119, CASR and GPR142. Glucose induced action potential firing and cytosolic Ca2+ elevation and caused a 1.8-fold increase in GIP secretion, which was inhibited by the sodium glucose co-transporter 1/2 (SGLT1/2) blocker sotagliflozin. Activation of the long-chain fatty acid receptor free fatty acid receptor 1 (FFAR1) induced a 2.7-fold increase in GIP secretion, while tryptophan and phenylalanine stimulated secretion by 2.8- and 2.1-fold, respectively. While CASR knockout blunted intracellular Ca2+ responses, a CASR/GPR142 double knockout was needed to reduce GIP secretory responses to aromatic amino acids. The newly generated human organoid K cell model enables transcriptomic and functional characterisation of nutrient-sensing pathways involved in human GIP secretion. Both calcium-sensing receptor (CASR) and G protein-coupled receptor 142 (GPR142) contribute to protein-stimulated GIP secretion. This model will be further used to identify potential targets for modulation of native GIP secretion in diabetes and obesity.

Comparison Between SGLT2 Inhibitors and Lactation: Implications for Cardiometabolic Health in Parous Women.

Sodium-glucose cotransporter-2 (SGLT2) inhibition and lactation result in the excretion of large amounts of glucose in urine or milk and are associated with a lower risk of cardiovascular events. The respective mechanisms behind this association with cardiovascular protection are not clear. This review compares the contribution of noninsulin-mediated glucose transport during pharmacologic inhibition of SGLT2 with noninsulin-mediated glucose transport during lactation in terms of the implications for the cardiometabolic health of parous women. The search topics used to obtain information on SGLT2 inhibitors included mechanisms of action, atherosclerosis, and heart failure. The search topics used to obtain information on lactation included cardiovascular health and milk composition. Subsequent reference searches of retrieved articles were also used. Active treatment with SGLT2 inhibitors affects glucose and sodium transport in the kidneys and predominantly protects against hospitalization for heart failure soon after the onset of therapy. Active lactation stimulates glucose transport into the mammary gland and improves subclinical and clinical atherosclerotic vascular disease years after delivery. Both SGLT2 inhibitors and lactation have effects on a variety of glucose transporters. Several mechanisms have been proposed to explain the cardiometabolic benefits of SGLT2 inhibition and lactation. Learning from the similarities and differences between both processes will advance our understanding of cardiometabolic health for all people.

The poplar SWEET1c glucose transporter plays a key role in the ectomycorrhizal symbiosis.

The mutualistic interaction between ectomycorrhizal fungi and trees is characterized by the coordinated exchange of soil nutrients with soluble sugars. Despite the importance of this process, the precise mechanism by which sugars are transported from host roots to colonizing hyphae remains unclear. This study aimed to identify the specific membrane transporters responsible for the unloading of sugars at the symbiotic interface, with a focus on the role of the root Sugars Will Eventually Be Exported Transporter (SWEET) uniporters. Our study used RNA sequencing and quantitative PCR to identify PtaSWEET gene expression in Populus tremula × alba-Laccaria bicolor ectomycorrhizal root tips. Our results suggest that symbiosis-induced PtaSWEET1c is primarily responsible for transporting glucose and sucrose, as demonstrated by the yeast assays. Moreover, we used a promoter-YFP reporter to confirm the localization of the PtaSWEET1c expression in cortical cells of ectomycorrhizal rootlets, supporting its major role in supplying glucose at the symbiotic interface. Furthermore, our observations confirmed the localization of PtaSWEET1c-GFP in the plasma membrane. The inactivation of PtaSWEET1c reduced ectomycorrhizal root formation and 13C translocation to ectomycorrhizal roots. Our findings highlight the crucial role of PtaSWEET1c in facilitating glucose and sucrose transport at the symbiotic interface of Populus-L. bicolor symbiosis.

Model-based meta-analysis of HbA1c reduction across SGLT2 inhibitors using dose adjusted by urinary glucose excretion

This study was aimed to evaluate whether the dose–response relationship of the sodium glucose co-transporter-2 inhibitors (SGLT2is) in patients with type 2 diabetes mellitus (T2DM)—canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, luseogliflozin, and tofogliflozin—can be explained in a unified manner based on their ability to promote urinary glucose excretion (UGE). Information on HbA1c reduction at various doses of each SGLT2i was collected from literatures on randomized controlled trials and was normalized based on the daily UGE data from phase I studies. After normalizing doses, the dose–response relationship of HbA1c reduction of most of SGLT2is was represented by a unified nonlinear mixed-effect model, with the estimated maximum HbA1c (%) reduction (Emax) of 0.796 points, whereas covariate analysis showed that canagliflozin had a 1.33-fold higher Emax than those of the other drugs. Other covariates included baseline HbA1c levels, body weight, disease duration, prior treatment, and renal function. Findings from this study would influence drug selection and adjustment in clinical practice. As with SGLT2is, in cases where the efficacy cannot be easily evaluated but an appropriate pharmacodynamic marker was assessed in early clinical trials, similar approaches for other drug classes can guide strategic and evidence-based dose selection in phase III trials.

Gpr55 deficiency crucially alters cardiomyocyte homeostasis and counteracts angiotensin II induced maladaption in female mice.

Cannabis stimulates several G-protein-coupled-receptors and causes bradycardia and hypotension upon sustained consumption. Moreover, in vitro studies suggest an interference of cannabinoid-signalling with cardiomyocyte contractility and hypertrophy. We aimed at revealing a functional contribution of the cannabinoid-sensitive receptor GPR55 to cardiomyocyte homeostasis and neurohumorally induced hypertrophy in vivo. Gpr55-/- and wild-type (WT) mice were characterized after 28-day angiotensin II (AngII; 1·μg·kg-1min-1) or vehicle infusion. In isolated adult Gpr55-/- and WT cardiomyocytes, mitochondrial function was assessed under naïve conditions, while cytosolic Ca2+ handling was additionally determined following application of the selective GPR55 antagonist CID16020046. Gpr55 deficiency did not affect angiotensin II (AngII) mediated hypertrophic growth, yet, especially in females, it alleviated maladaptive pro-hypertrophic and -inflammatory gene expression and improved inotropy and adrenergic responsiveness compared to WT. In-depth analyses implied increased cytosolic Ca2+ concentrations and transient amplitudes, and accelerated sarcomere contraction kinetics in Gpr55-/- myocytes, which could be mimicked by GPR55 blockade with CID16020046 in female WT cells. Moreover, Gpr55 deficiency up-regulated factors involved in glucose and fatty acid transport independent of the AngII challenge, accelerated basal mitochondrial respiration and reduced basal protein kinase (PK) A, G and C activity and phospholemman (PLM) phosphorylation. Our study suggests GPR55 as crucial regulator of cardiomyocyte hypertrophy and homeostasis presumably by regulating PKC/PKA-PLM and PKG signalling, and identifies the receptor as potential target to counteract maladaptation, adrenergic desensitization and metabolic shifts as unfavourable features of the hypertrophied heart in females.

Cardiovascular and kidney benefits of SGLT-2is and GLP-1RAs according to baseline blood pressure in type 2 diabetes: a systematic meta-analysis of cardiovascular outcome trials

Objectives: Using a systematic meta-analysis, we investigated if patients with type 2 diabetes (T2D) and with varying baseline blood pressure (BP) differ in the cardiorenal benefits received from sodium–glucose co-transporter 2 inhibitors (SGLT-2is) and glucagon-like peptide 1 receptor agonists (GLP-1RAs). Design: Randomized, placebo-controlled, cardiovascular outcome trials (CVOTs) of SGLT-2is and GLP-1RAs were identified from MEDLINE, Embase, and the Cochrane Library up to April 2024. Hazard ratios (HRs) with 95% CIs were pooled. The differential treatment effect by baseline BP category within each trial was estimated as the ratio of the HR (RHR) and pooled. Results: Seventeen publications based on 9 unique CVOTs (4 SGLT-2is and 5 GLP-1RAs) were eligible. In participants with normal baseline BP, comparing SGLT-2is with placebo, the HRs (95% CIs) were 0.88 (0.79-0.97) for major adverse cardiovascular events (MACE), 0.73 (0.59-0.91) for heart failure (HF) hospitalization, 0.78 (0.65-0.94) for composite CVD death/HF hospitalization, and 0.55 (0.41-0.73) for composite renal outcome. The corresponding estimates for participants with higher baseline BP were 0.88 (0.81-0.96), 0.67 (0.57-0.79), 0.73 (0.65-0.82), and 0.61 (0.48-0.77), respectively. In participants with normal baseline BP, GLP-RAs had no strong effect on MACE, stroke and nephropathy, but reduced stroke and nephropathy risk in those with higher baseline BP. Estimated RHRs showed no statistical evidence that baseline BP modified the cardiorenal benefits of SGLT-2is and GLP-1RAs. Conclusions: In patients with T2D, the cardiorenal benefits of treatment with SGLT2-Is and GLP1-RAs were similar in patients with normal baseline BP compared to those with a higher baseline BP.

Neuroprotective effect of empagliflozin against doxorubicin-induced chemobrain in rats: Interplay between SIRT-1/MuRF-1/PARP-1/NLRP3 signaling pathways and enhanced expression of miRNA-34a and LncRNA HOTAIR

Chemobrain, a challenging side effect of doxorubicin (DOX)-based chemotherapy, impairs cognitive abilities in cancer survivors. DOX triggers chemobrain via oxidative stress, leading to inflammation and apoptosis. Empagliflozin (EMPA), a sodium glucose co-transporter-2 inhibitor, demonstrated neuroprotective effects by reducing reactive oxygen species (ROS) and inflammation, but its protective mechanisms against DOX-induced chemobrain is not fully known. Thus, this study aimed to investigate EMPA’s neuroprotective effects on DOX-induced chemobrain in rats and to uncover the underlying protective mechanisms. Fifty male Wistar rats were divided into control, EMPA, DOX (2 mg/kg, IP, once/week for 4 weeks), and two treated groups (DOX+ EMPA 5 and 10 mg/kg/day, PO, for 4 weeks). Behavioral tests showed improved memory, motor performance, and reduced anxiety in EMPA-treated groups compared to DOX, with superior results at the higher dose. Histopathological analysis revealed increased intact neurons in the cortex and hippocampus in EMPA-treated groups, with 346.4 % increase in CA3 (p < 0.0001), 19.1 % in dentate gyrus (p = 0.0006), and 362.6 % in cortex (p < 0.0001) in the high-dose EMPA group. Biochemical investigations of the high-dose EMPA group revealed significant decreases in inflammatory and apoptotic markers (JNK/PARP-1/NLRP3/MuRF-1/FOXO-1), increased SIRT-1 protein expression by 389.9 % (p < 0.0001), and reduced miRNA-34a and LncRNA HOTAIR gene expression (50.4 % and 53.4 % respectively, p < 0.0001) relative to DOX group. Conclusively, EMPA demonstrated superior behavioral and histopathological outcomes particularly at higher dose, positioning it as a promising neuroprotective candidate against DOX-induced chemobrain, possibly through modulating SIRT-1, NF-κb, NLRP3, and oxidative stress pathways.

A DISEASE-BASED PERSPECTIVE OF THE RELATIONSHIP BETWEEN NEUROINFLAMMATION AND IMPAIRED GLUCOSE METABOLISM

Neuroinflammation is a significant contributor to the pathogenesis of several central nervous system disorders including Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, and amyotrophic lateral sclerosis. Neuroinflammation is the immune response of the central nervous system against central or peripheral abnormalities disturbed by foreign agents, molecules, metabolic activities, or various diseases. Astrocytes and microglia activation are the main activators of neuroinflammation. The polarization changes of these defender cells have some key roles in bodily metabolism as much as neuronal behavior. The blood-brain barrier is known as the first defender of brain parenchyma. Neuroinflammation disrupts blood-brain barrier integrity and may cause blood-brain barrier breakdown. Glucose is the main energy source of brain and glucose uptake is achieved through the blood-brain barrier. Altered glucose metabolism may have detrimental effects on brain functions and may cause brain disorders. Also, it has been suggested that neuroinflammation may have crucial roles in glucose metabolism. The distribution of the blood-brain barrier in vascular endothelial cells of neurons, astrocytes, and microglia contributes to the transport of glucose to the cells of brain. Microglia and astrocyte polarization are suggested as the two main underlying mechanisms in neuroinflammation. It’s obviously determined that neuroinflammation-caused neurodegenerative diseases are tightly linked with the brain insulin resistance and disrupted cerebral and peripheral glucose metabolism. However, there is lacking knowledge about glucose metabolism deficiencies and microglia/astrocyte polarization. Herein this review, we summarized the neuroinflammation and glucose metabolism with the most common neurological diseases and the possible effects of microglia/astrocyte polarization on glucose metabolism.

Astrocytic GLUT1 reduction paradoxically improves central and peripheral glucose homeostasis.

Astrocytes are considered an essential source of blood-borne glucose or its metabolites to neurons. Nonetheless, the necessity of the main astrocyte glucose transporter, i.e., GLUT1, for brain glucose metabolism has not been defined. Unexpectedly, we found that brain glucose metabolism was paradoxically augmented in mice with astrocytic GLUT1 reduction (GLUT1ΔGFAP mice). These mice also exhibited improved peripheral glucose metabolism especially in obesity, rendering them metabolically healthier. Mechanistically, we observed that GLUT1-deficient astrocytes exhibited increased insulin receptor-dependent ATP release, and that both astrocyte insulin signaling and brain purinergic signaling are essential for improved brain function and systemic glucose metabolism. Collectively, we demonstrate that astrocytic GLUT1 is central to the regulation of brain energetics, yet its depletion triggers a reprogramming of brain metabolism sufficient to sustain energy requirements, peripheral glucose homeostasis, and cognitive function.

Activation of the WNT7B/β-Catenin Pathway Initiates GLUT1 Expression and Promotes Aerobic Glycolysis in Colorectal Cancer Cells

Glucose is an important energy source for tumors, however the molecular mechanisms by which tumor cells regulate glucose uptake remain unclear. In this study, we aimed to investigate the regulation mechanism of the WNT7B/β-catenin pathway for glucose transporter 1 (GLUT1)-mediated glucose metabolism in colorectal cancer. Here, we found that WNT7B expression levels were significantly increased in colorectal cancer tissues and closely associated with the clinical stage and lymph node metastasis in patients with colorectal cancer. Next, we confirmed that WNT7B significantly increased the glucose consumption and lactic acid levels in SW480 cells by overexpressing WNT7B. Additionally, gene and protein levels of GLUT1 were increased in WNT7B-overexpressing SW480 cells. However, WNT7B knockdown reversed these effects. WNT7B also enhanced GLUT1-mediated cell proliferation, invasion, and migration. WNT7B overexpression inhibited the effect of glucose deprivation on apoptosis. The WNT/β-catenin signaling pathway inhibitor, LGK974, inhibited WNT7B secretion, leading to GLUT1 levels downregulation and promotion of cell apoptosis. Ectopic tumor xenograft model experiments revealed that WNT7B promoted tumor progression in mice. Overall, our results suggest that WNT7B promotes β-catenin entry into the nucleus to initiates GLUT1 transcription, increases glucose transport and consumption, and enhances aerobic glycolysis, thus promoting tumor progression in colorectal cancer cells.

GLUT1 and cerebral glucose hypometabolism in human focal cortical dysplasia is associated with hypermethylation of key glucose regulatory genes.

Focal cortical dysplasia (FCD) is recognized as a significant etiological factor in pharmacoresistant intractable epilepsy, linked with disturbances in neurovascular metabolism. Our study investigated regulation of glucose-transporter1 (GLUT1) and cerebral hypometabolism within FCD subtypes. Surgically excised human brain specimens underwent histopathological categorization. A subset of samples (paired with matching blood) was assessed for DNA methylation changes of glucose metabolism-related genes. We evaluated GLUT1, VEGFα, MCT2, and mTOR expression by western blot analysis, measured glucose-lactate concentrations, and established correlations with patients' demographic and clinical profiles. Furthermore, we investigated the impact of DNA methylation inhibitor decitabine and hypometabolic condition on the uptake of [ 3 H]-2-deoxyglucose and ATPase in epileptic brain endothelial cells (EPI-EC). We observed hypermethylation of GLUT1 and glucose metabolic genes in FCD brain/blood samples and could distinguish FCDIIa/b from mMCD, MOGHE and non-lesional types in brain. Low GLUT1 and glucose-lactate ratios corresponded to elevated VEGFα and MCT2 in FCDIIa/b vs non-lesional tissues, independent of age, gender, seizure-onset, or duration of epilepsy. Increased mTOR signaling in FCDIIa/b tissues was evident. Decitabine stimulation increased GLUT1, decreased VEGFα expression, restored glucose uptake and ATPase activity in EPI-ECs and reduced mTOR and MCT2 levels in HEK cells. We demonstrated: 1) hypermethylation of glucose regulatory genes distinguish FCDIIa/b from mMCD, MOGHE and non-lesional types, 2) glucose uptake reduction is due to GLUT1 suppression mediated possibly by a GLUT1-mTOR mechanism; and 3) DNA methylation regulates cellular glucose update and metabolism. Together, these studies may lead to GLUT1-mediated biomarkers, glucose metabolism and identify early intervention strategies in FCD.

SPINK4 modulates inhibition of glycolysis against colorectal cancer progression.

Dysregulation of glycolysis is frequently linked to aggressive tumor activity in colorectal cancer (CRC). Although serine peptidase inhibitor, Kazal type 4 (SPINK4) has been linked to CRC, its exact linkage to glycolytic processes and gene expression remains unclear. Differentially expressed genes (DEGs) were screened from two CRC-related datasets (GSE32323 and GSE141174), followed by expression and prognostic analysis of SPINK4. In vitro techniques such as flow cytometry, western blotting, transwell assay, and quantitative real-time polymerase chain reaction (qRT-PCR) were used to assess SPINK4 expression in CRC cells. Its effects on apoptosis, glycolysis, and the cell cycle were also investigated. Finally, the impact of SPINK4 overexpression on tumor development was assessed using a xenograft model, while histological and immunohistochemical analyses characterized SPINK4 expression patterns in CRC tissues. SPINK4 expression was downregulated in CRC, correlating with poor patient prognosis. In vitro assays confirmed that overexpression of SPINK4 reduced CRC cell proliferation, invasion, and migration, while its knockdown promoted these processes and caused G1 arrest. SPINK4 also regulated apoptosis by altering caspase activation and Bcl-2 expression. Besides, SPINK4 overexpression altered glycolytic activity, reduced 2-Deoxy-D-glucose (2-DG) absorption, and controlled critical glycolytic enzymes, resulting in alterations in metabolic pathways, whereas SPINK4 knockdown reversed this effect. SPINK4 overexpression significantly reduced tumor volume in vivo, indicating its inhibitory role in carcinogenesis. Moreover, high expression of SPINK4, hexokinase 2 (HK2), glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), and pyruvate kinase M2 (PKM2) was observed in CRC tissues. As a key inhibitor of glycolytic metabolism in CRC, SPINK4 promises metabolic intervention in CRC therapy due to its impact on tumor growth and cell proliferation.

Gintonin Stimulates Glucose Uptake in Myocytes: Involvement of Calcium and Extracellular Signal-Regulated Kinase Signaling.

Ginseng has anti-hyperglycemic effects. Gintonin, a glycolipoprotein derived from ginseng, also stimulates insulin release from pancreatic beta cells. However, the role of gintonin in glucose metabolism within skeletal muscle is unknown. Here, we showed the effect of gintonin on glucose uptake, glycogen content, glucose transporter (GLUT) 4 expression, and adenosine triphosphate (ATP) content in C2C12 myotubes. Gintonin (3-30 μg/mL) dose-dependently stimulated glucose uptake in myotubes. The expression of GLUT4 on the cell membrane was increased by gintonin treatment. Treatment with 1-3 μg/mL of gintonin increased glycogen content in myotubes, but the content was decreased at 30 μg/mL of gintonin. The ATP content in myotubes increased following treatment with 10-100 μg/mL gintonin. Gintonin transiently elevated intracellular calcium concentrations and increased the phosphorylation of extracellular signal-regulated kinase (ERK). Gintonin-induced transient calcium increases were inhibited by treatment with the lysophosphatidic acid receptor inhibitor Ki16425, the phospholipase C inhibitor U73122, and the inositol 1,4,5-trisphosphate receptor antagonist 2-aminoethoxydiphenyl borate. Gintonin-stimulated glucose uptake was decreased by treatment with U73122, the intracellular calcium chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl) ester, and the ERK inhibitor PD98059. These results show that gintonin plays a role in glucose metabolism by increasing glucose uptake through transient calcium increases and ERK signaling pathways. Thus, gintonin may be beneficial for glucose metabolism control.

Calcium ATPase (PMCA) and GLUT-4 Upregulation in the Transverse Tubule Membrane of Skeletal Muscle from a Rat Model of Chronic Heart Failure.

Intolerance to exercise is a symptom associated with chronic heart failure (CHF) resulting in SM waste and weakness in humans. The effect of CHF on skeletal muscle (SM) arose from experimental evidence in rat models to explain the underlying mechanism. We investigated SM mechanical and metabolic properties in sham rats and with coronary ligation-induced CHF. After twelve weeks of CHF, rats were catheterized to measure right auricular pressure, SM mechanical properties, SERCA-ATPase activity and plasma membrane Ca2+-ATPase (PMCA) hydrolytic activity in isolated sarcoplasmic reticulum (SR) and transverse tubule (TT membrane), respectively, in the sham and CHF. The right auricular pressure and plasma nitrite concentration in CHF increased two-fold with respect to the sham. Pleural effusion and ascites were detected in CHF, confirming CHF. SERCA activity was conserved in CHF. In TT membranes from CHF, the glucose transporter GLUT4 increased seven-fold, and the PMCA hydrolytic activity increased five-fold, but in isolated muscle, the mechanical properties were unaffected. The absence of a deleterious effect of coronary ligation-induced CHF in the rat model on SM could be explained by the increased activity of PMCA and increased presence of GLUT-4 on the TT membrane, which may be involved in the mechanical outcome of the EDL.

Targeting Sodium in Heart Failure.

A dominant event determining the course of heart failure (HF) includes the disruption of the delicate sodium (Na+) and water balance leading to (Na+) and water retention and edema formation. Although incomplete decongestion adversely affects outcomes, it is unknown whether interventions directly targeting (Na+), such as strict dietary (Na+) restriction, intravenous hypertonic saline, and diuretics, reverse this effect. As a result, it is imperative to implement (Na+)-targeting interventions in selected HF patients with established congestion on top of quadruple therapy with angiotensin receptor neprilysin inhibitor, β-adrenergic receptor blocker, mineralocorticoid receptor antagonist, and sodium glucose cotransporter 2 inhibitor, which dramatically improves outcomes. The limited effectiveness of (Na+)-targeting treatments may be partly due to the fact that the current metrics of HF severity have a limited capacity of foreseeing and averting episodes of congestion and guiding (Na+)-targeting treatments, which often leads to dysnatremias, adversely affecting outcomes. Recent evidence suggests that spot urinary sodium measurements may be used as a guide to monitor (Na+)-targeting interventions both in chronic and acute HF. Further, the classical (2)-compartment model of (Na+) storage has been displaced by the (3)-compartment model emphasizing the non-osmotic accumulation of (Na+), chiefly in the skin. 23(Na+) magnetic resonance imaging (MRI) enables the accurate and reliable quantification of tissue (Na+). Another promising approach enabling tissue (Na+) monitoring is based on wearable devices employing ion-selective electrodes for electrolyte detection, including (Na+) and (Cl-). Undoubtably, further studies using 23(Na+)-MRI technology and wearable sensors are required to learn more about the clinical significance of tissue (Na+) storage and (Na+)-related mechanisms of morbidity and mortality in HF.

Baicalein Ameliorates Insulin Resistance of HFD/STZ Mice Through Activating PI3K/AKT Signal Pathway of Liver and Skeletal Muscle in a GLP-1R-Dependent Manner.

Insulin resistance (IR) is the principal pathophysiological change occurring in diabetes mellitus (DM). Baicalein, a bioactive flavonoid primarily extracted from the medicinal plant Scutellaria baicalensis Georgi, has been shown in our previous research to be a potential natural glucagon-like peptide-1 receptor (GLP-1R) agonist. However, the exact therapeutic effect of baicalein on DM and its underlying mechanisms remain elusive. In this study, we investigated the therapeutic effects of baicalein on diabetes and sought to clarify its underlying molecular mechanisms. Our results demonstrated that baicalein improves hyperglycemic, hyperinsulinemic, and glucometabolic disorders in mice with induced diabetes via GLP-1R. This was confirmed by the finding that baicalein's effects on improving IR were largely diminished in mice with whole-body Glp1r ablation. Complementarily, network pharmacology analysis highlighted the pivotal involvement of the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) insulin signaling pathway in the therapeutic actions of baicalein on IR. Our mechanism research significantly confirmed that baicalein mitigates hepatic and muscular IR through the PI3K/AKT signal pathway, both in vitro and in vivo. Furthermore, we demonstrated that baicalein enhances glucose uptake in skeletal muscle cells under IR conditions through the Ca2+/calmodulin-dependent protein kinase II (CaMKII)-adenosine 5'-monophosphate-activated protein kinase (AMPK)-glucose transporter 4 (GLUT4) signaling pathway in a GLP-1R-dependent manner. In conclusion, our findings confirm the therapeutic effects of baicalein on IR and reveal that it improves IR in liver and muscle tissues through the PI3K/AKT insulin signaling pathway in a GLP-1R dependent manner. Moreover, we clarified that baicalein enhances the glucose uptake in skeletal muscle tissue through the Ca2+/CaMKII-AMPK-GLUT4 signal pathway.

Dysregulated renal tubular handling of filtered glucose in patients with type 2 diabetes mellitus: a descriptive study

Objective: To determine the frequency of suspected dysregulated renal tubular handling of filtered glucose, and its association with blood glucose levels in type 2 diabetes mellitus. Method: The analytical, cross-sectional study was conducted from November 2022 to June 2023 at the Department of Medicine along with the Department of Pathology and Biochemistry, Pakistan Railway Hospital, Islamic International Medical College, Rawalpindi, Pakistan, and comprised diabetics aged 19-80 years. Blood and urinary glucose were assessed at the point of contact. Blood glucose 80-180mg/dl was considered glucose in range and &gt;180mg/dl glucose above range. Hyper-function of sodium glucose transport receptors was suspected if urinary glucose was &lt;++ and the function of these receptors was considered normal if urinary sugar was ++ or more. Association of suspected receptors and their association with blood glucose levels was determined. Data was analysed using SPSS 26. Results: Of the 159 diabetics, 91(57%) were females and 68(43%) were males. The overall mean age was 57±11 years (range: 46-68 years). Of the total, 43(27%) patients had glucose in range and 116(73%) had glucose above range. Of the diabetics with glucose above range, 54(47%) patients had hyper-functioning sodium glucose transport receptors, and 62(53%) had normal functioning sodium glucose transport receptors. Of the patients with glucose in range, 11(26%) had hyper-functioning sodium glucose transport receptors, and 32(74%) had normal functioning sodium glucose transport receptors. There was a significant association between sodium glucose transport receptors’ function and blood glucose levels (p&lt;0.001). Conclusion: Dysfunction of sodium glucose transport receptors affected the secretion of glucose in the urine, resulting in impaired glucose regulation in type 2 diabetes mellitus cases. Key Words: Blood glucose, Diabetes, Glycosuria, Sodium-glucose transporter 2.