Dysregulation Of Glucose Metabolism Research Articles

Diabetic Cardiomyopathy: An Update on Emerging Pathological Mechanisms.

Diabetic Cardiomyopathy (DCM) is a notable consequence of diabetes mellitus, distinguished by cardiac dysfunction that occurs separately from coronary artery disease or hypertension. A recent study has revealed an intricate interaction of pathogenic processes that contribute to DCM. Important aspects involve the dysregulation of glucose metabolism, resulting in heightened oxidative stress and impaired mitochondrial function. In addition, persistent high blood sugar levels stimulate inflammatory pathways, which contribute to the development of heart fibrosis and remodelling. Additionally, changes in the way calcium is managed and the presence of insulin resistance are crucial factors in the formation and advancement of DCM. This may be due to the involvement of many molecular mechanistic pathways such as NLRP3, NF- κB, PKC, and MAPK with their downstream associated signaling pathways. Gaining a comprehensive understanding of these newly identified pathogenic pathways is crucial in order to design precise therapy approaches that can enhance the results for individuals suffering from diabetes. In addition, this review offers an in-depth review of not just pathogenic pathways and molecular mechanistic pathways but also diagnostic methods, treatment options, and clinical trials.

Mendelian randomization and multi-omics approach analyses reveal impaired glucose metabolism and oxidative phosphorylation in visceral adipose tissue of women with polycystic ovary syndrome.

What is the significance of visceral adipose tissue (VAT) in the pathogenesis of polycystic ovary syndrome (PCOS) and its impact on the regulation of metabolic disorders in women with PCOS? We revealed a potentially causal relationship between increased genetically predicted VAT and PCOS-related traits, and found that VAT exhibited impaired glucose metabolism and mitochondrial oxidative phosphorylation (OXPHOS) in women with PCOS. PCOS is a common reproductive endocrine disorder accompanied by many metabolic abnormalities. Adipose tissue is a metabolically active endocrine organ that regulates multiple physiological processes, and VAT has a much stronger association with metabolism than subcutaneous adipose tissue does. Mendelian randomization (MR) analysis was used to investigate the potential causal association between genetically predicted VAT and the risk of PCOS. Data for MR analysis were extracted from European population cohorts. VAT samples from sixteen PCOS patients and eight control women who underwent laparoscopic surgery were collected for proteomics and targeted metabolomics analyses. PCOS was diagnosed according to the 2003 Rotterdam Criteria. The control subjects were women who underwent laparoscopic investigation for infertility or benign indications. Proteomics was performed by TMT labeling and liquid chromatography-tandem mass spectrometry analysis, and targeted metabolomics was performed by ultra-performance liquid chromatography-tandem mass spectrometry analysis. The key differentially expressed proteins (DEPs) were validated by immunoblotting. MR analysis revealed a potentially causal relationship between increased genetically predicted VAT and PCOS, as well as related traits, such as polycystic ovaries, total testosterone, bioavailable testosterone, and anti-Müllerian hormone, while a negative relationship was found with sex hormone-binding globulin. Enrichment pathway analysis of DEPs indicated the inhibition of glycolysis and activation of mitochondrial OXPHOS in the VAT of PCOS patients. MR analysis revealed that key DEPs involved in glycolysis and OXPHOS were significantly linked to PCOS and its related traits. Dot blot assay confirmed a significant decrease in glycolysis enzymes PKM2 and HK1, and an increase in mitochondrial Complex I and III subunits, NDUFS3 and UQCR10. Moreover, metabolomics analysis confirmed down-regulated metabolites of energy metabolic pathways, in particular glycolysis. Further analysis of PCOS and control subjects of normal weight revealed that dysregulation of glucose metabolism and OXPHOS in VAT of women with PCOS was independent of obesity. The mass spectrometry proteomics data have been deposited to the iProX database (http://www.iprox.org) with the iProX accession: IPX0005774001. There may be an overlap in some exposure and outcome data, which might affect the results in the MR analysis. The changes in protein expression of key enzymes affect their activities and disrupt the energy metabolic homeostasis in VAT, providing valuable insight for identifying potential intervention targets of PCOS. This work was supported by the National Key Research and Development Project of China (2021YFC2700402), the National Natural Science Foundation of China (82071608, 82271665), the Key Clinical Projects of Peking University Third Hospital (BYSY2022043), and the CAMS Innovation Fund for Medical Sciences (2019-I2M-5-001). All authors report no conflict of interest. N/A.

Nicotinamide Mononucleotide Improves Endometrial Homeostasis in a Rat Model of Polycystic Ovary Syndrome by Decreasing Insulin Resistance and Regulating the Glylytic Pathway.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder that can lead to insulin resistance (IR) and dysregulation of glucose metabolism, resulting in an imbalance in the endometrial environment, which is unfavorable for embryo implantation of PCOS. This study aims to investigate whether nicotinamide mononucleotide (NMN) improves the stability of the endometrium in a rat model of PCOS and identifies whether it is related to reduce IR and increase glycolysis levels and its potential signaling pathway. Female Sprague-Dawley (SD) rats are fed letrozole and a high-fat diet (HFD) to form the PCOS model, then the model rats are treated with or without NMN. It randomly divided into control, PCOS, and PCOS-NMN groups according to the feeding and treating method. Compared with the PCOS group, the regular estrous cycles are restored, the serum androgen (p<0.01) and fasting insulin levels (p<0.05) are reduced, and endometrial morphology (p<0.05) is improved in NMN-PCOS group. Furthermore, NMN inhibits endometrial cell apoptosis, improves endometrial decidualization transition, reduces IR, restores the expression of glycolysis rate-limiting enzymes, and activates the PI3K/AKT pathway in the uterus. These results suggest that NMN enhances endometrial tissue homeostasis by decreasing uterine IR and regulating the glycolysis through the PI3K/AKT pathway.

The Relationship Between Age at Diabetes Onset and Clinical Outcomes in Newly Diagnosed Type 2 Diabetes: A Real-World Two-Center Study.

This study was developed with the goal of clarifying whether there is any relationship between type 2 diabetes mellitus (T2DM) age of onset and clinical outcomes for patients in National Metabolic Management Centers (MMC). From September 2017 - June 2022, 864 total T2DM patients were recruited in MMC and assigned to those with early-onset and late-onset diabetes (EOD and LOD) based on whether their age at disease onset was ≤ 40 or > 40 years. All patients received standardized management. Baseline and 1-year follow-up data from these two groups of patients were assessed. Associations between onset age and other factors were evaluated with a multivariate linear regression approach, adjusting for appropriate covariates. Outcomes in particular subgroups were also assessed in stratified analyses. Markers of dysregulated glucose metabolism and BMI values were significantly higher among EOD patients as compared to LOD patients. Subjects in both groups exhibited significant improvements in several disease-related parameters on 1-year follow-up after undergoing metabolic management. EOD patients exhibited significantly greater percentage reductions in HbA1c levels (-28.49 (-44.26, -6.45)% vs -13.70 (-30.15,-1.60)%, P =0.017) relative to LOD patients following adjustment for confounders. Significant differences were also detected between these groups when focused on subgroups of patients who were male, exhibited a BMI ≥ 25, an HbA1c ≥ 9, or had a follow-up frequency < 2. Data from a 1-year follow-up time point suggest that a standardized metabolic disease management model can promote effective metabolic control in newly diagnosed T2DM patients, particularly among individuals with EOD.

Effects of Chronotherapeutic Interventions in Adults With ADHD and Delayed Sleep Phase Syndrome (DSPS) on Regulation of Appetite and Glucose Metabolism

Background: ADHD is highly comorbid with Delayed Sleep Phase Syndrome (DSPS). Both are associated with obesity and diabetes, which can be caused by long-term dysregulations of appetite and glucose metabolism. This study explores hormones involved in these processes and the effects of chronotherapeutic interventions in a small sample of adults with ADHD and DSPS. Methods: Exploratory, secondary analysis of data from the PhASE study, a three-armed randomized clinical trial, are presented, including 37 adults (18–53 years) with ADHD and DSPS receiving three weeks of 0.5 mg/day (1) placebo, (2) melatonin, or (3) melatonin plus 30 minutes of bright light therapy (BLT). Leptin (appetite-suppressing), ghrelin (appetite-stimulating), insulin, insulin-like growth factor-1 (IGF-1), and glucose were measured from blood collected at 08:00 hours. Salivary cortisol was collected during the first 30 minutes after awakening and self-reported appetite was assessed. Results: Baseline leptin and IGF-1 levels were higher than reference ranges, and ghrelin and cortisol levels were lower, while insulin and glucose were normal. Melatonin treatment decreased leptin and insulin. Other outcomes remained unchanged and melatonin + BLT had no effects. Conclusion: Due to the small sample size and exploratory nature of the study, results should be interpreted with caution. Overall, these results show no strong indications for dysregulation of appetite and glucose metabolism to suggest high risk of obesity and diabetes in this small sample of adults with ADHD and DSPS. However, baseline appetite was suppressed, likely because measurements took place in the early morning which could be considered the biological night for this study population. Melatonin treatment seemed to cause subtle changes in appetite-regulating hormones suggesting increased appetite. Chronotherapeutic treatment may affect appetite-regulating hormones by advancing the biological rhythm and/or altering eating behaviors, but this remains to be investigated in larger samples using detailed food diaries.

Dietary oxygenated water mitigates type 2 diabetes mellitus by modulating gut microbiota and enhancing glucose metabolism in skeletal muscle

Type 2 diabetes mellitus (T2DM) is a significant health concern resulting from dysregulation of glucose metabolism, emphasizing the need for effective dietary interventions. Emerging evidence suggests a correlation between diabetes and hypoxia, indicating that oxygenated water (ORW) may hold promise in mitigating T2DM. This study employed a multifaceted approach involving physiological, genomic, metabolomic, transcriptomic, and molecular biological analyses to investigate the effects of ORW on T2DM and its underlying mechanisms. The results demonstrated that ORW effectively ameliorated key symptoms of T2DM by improving polydipsia and polyphagia, reducing fasting blood glucose, enhancing glucose tolerance, and increasing insulin levels. Notably, the beneficial effects of ORW appeared to be mediated through modulation of gut-muscle interactions by influencing gut microbiota composition and metabolite profiles. Transcriptomic and molecular analyses revealed that ORW activated the Akt signaling pathway and upregulated key genes involved in glucose uptake and utilization in skeletal muscle, as evidenced by increased p-AKT/AKT ratio and upregulation of Irs1, Glut4, Hk2, and Pfk. Collectively, these findings demonstrate that ORW alleviates T2DM by modulating gut microbiota while enhancing glucose uptake/utilization in skeletal muscle, supporting its potential use as an effective adjuvant strategy for targeted regulation of T2DM.

Degraded sweet corn cob polysaccharides modulate T2DM-induced abnormalities in hepatic lipid metabolism via the bile acid-related FXR-SHP and FXR-FGF15-FGFR4 pathways

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by dysregulation of glucose and lipid metabolism. This study aimed to elucidate the mechanism through which a degraded sweet corn cob polysaccharide (UE-DSCCP-A) mitigates T2DM by modulating hepatic lipid metabolism. Biochemical indices pertinent to lipid metabolism were assessed, and liver pathology was examined in T2DM mice following UE-DSCCP-A treatment. Additionally, metabolomics, PCR, and Western blot analyses were employed to investigate the underlying mechanisms involved. These findings indicated that UE-DSCCP-A ameliorated hepatic lipid metabolism disorders, decreased lipid accumulation, and mitigated hepatic fibrosis. Untargeted metabolomics analysis revealed that UE-DSCCP-A modulated pathways associated with steroid biosynthesis and bile acid synthesis and metabolism in T2DM mice. The bile acid assay results demonstrated that UE-DSCCP-A treatment reduced bile acid levels in both the serum and liver but increased fecal bile acid levels in T2DM mice. Furthermore, alterations in bile acid distribution within the liver were observed. UE-DSCCP-A has the capacity to activate the hepatic FXR-SHP pathway as well as the gut-liver axis involving FXR-FGF15-FGFR4 signaling. Consequently, UE-DSCCP-A is capable of modulating critical target genes and proteins associated with bile acid synthesis and metabolism, regulating steroid biosynthesis, and influencing bile acid synthesis and transport within the liver. Additionally, it has beneficial effects on lipid metabolism disorders in individuals with T2DM. Thus, UE-DSCCP-A represents a promising candidate for functional foods with inherent hypoglycemic properties.

"Emerging clinical approaches in diabetic cardiomyopathy: insights from clinical trials and future directions".

We aim to explore the potential of diverse treatments, including perhexiline, calcium channel blockers, anti-hypertensives, PDE5 inhibitors, anti-anginal drugs, aldose reductase inhibitors, and SGLT-2 inhibitors, supported by clinical evidence. Additionally, this review seeks to identify novel therapeutic targets and future avenues for improving cardiovascular outcomes in diabetic populations. We performed a comprehensive literature review of English-language studies across multiple electronic databases, such as PubMed, ScienceDirect, Scopus, and Google Scholar, focusing on clinical trials. The search utilized keywords including 'Anti-hyperglycaemic drug,' 'Diabetic cardiomyopathy,' 'DPP-4 inhibitors,' 'GLP-1 receptor agonists,' 'Heart failure,' and 'SGLT-2 inhibitors.' We assessed clinical investigations in the treatment of cardiomyopathy and diabetes mellitus (DM) that are enhancing our understanding through trials evaluating the Polypill, Perhexiline, Eplerenone, IMB-1018972, AT-001, tadalafil, and dapagliflozin inhibitors. The development of new targeted interventions is of paramount importance due to the overlooked early symptoms, the complexity of the cellular and molecular pathways involved, and the absence of effective drug therapies. Pharmacological treatments like GLP-1 agonists, SGLT-2 inhibitors, NHE-1, NHE-3, and PPAR-γ agonists show promise for treating DCM. These treatments improve myocardial glucose absorption, address dysregulated glucose and lipid metabolism, and lower heart failure and cardiovascular events. Further research is needed to confirm effectiveness and safety.

Examining the liver-pancreas crosstalk reveals a role for the molybdenum cofactor in β-cell regeneration.

Regeneration of insulin-producing β-cells is an alternative avenue to manage diabetes, and it is crucial to unravel this process in vivo during physiological responses to the lack of β-cells. Here, we aimed to characterize how hepatocytes can contribute to β-cell regeneration, either directly or indirectly via secreted proteins or metabolites, in a zebrafish model of β-cell loss. Using lineage tracing, we show that hepatocytes do not directly convert into β-cells even under extreme β-cell ablation conditions. A transcriptomic analysis of isolated hepatocytes after β-cell ablation displayed altered lipid- and glucose-related processes. Based on the transcriptomics, we performed a genetic screen that uncovers a potential role of the molybdenum cofactor (Moco) biosynthetic pathway in β-cell regeneration and glucose metabolism in zebrafish. Consistently, molybdenum cofactor synthesis 2 (Mocs2) haploinsufficiency in mice indicated dysregulated glucose metabolism and liver function. Together, our study sheds light on the liver-pancreas crosstalk and suggests that the molybdenum cofactor biosynthesis pathway should be further studied in relation to glucose metabolism and diabetes.

Fucoxanthin Mitigates High-Fat-Induced Lipid Deposition and Insulin Resistance in Skeletal Muscle through Inhibiting PKM1 Activity.

Glucose and lipid metabolism dysregulation in skeletal muscle contributes to the development of metabolic disorders. The efficacy of fucoxanthin in alleviating lipid metabolic disorders in skeletal muscle remains poorly understood. In this study, we systematically investigated the impact of fucoxanthin on mitigating lipid deposition and insulin resistance in skeletal muscle employing palmitic acid-induced lipid deposition in C2C12 cells and ob/ob mice. Fucoxanthin significantly alleviated PA-induced skeletal muscle lipid deposition and insulin resistance. In addition, fucoxanthin prominently upregulated the expression of lipid metabolism-related genes (Pparα and Cpt-1), promoting fatty acid β-oxidation metabolism. Additionally, fucoxanthin significantly increased the expression of Pgc-1α and Tfam, elevated the mtDNA/nDNA ratio, and reduced ROS levels. Further, we identified pyruvate kinase muscle isozyme 1 (PKM1) as a high-affinity protein for fucoxanthin by drug affinity-responsive target stability and LC-MS and confirmed their robust interaction by CETSA, microscale thermophoresis, and circular dichroism. Supplementation with pyruvate, the product of PKM1, significantly attenuated the beneficial effects of fucoxanthin on lipid deposition and insulin resistance. Mechanistically, fucoxanthin reduced glucose glycolysis rate and enhanced mitochondrial biosynthesis and fatty acid β-oxidation through inhibiting PKM1 activity, thereby alleviating lipid metabolic stress. These findings present a novel clinical strategy for treating metabolic diseases using fucoxanthin.

An Overview of Cardiovascular Risk in Pituitary Disorders.

Cardiovascular comorbidities owing to hormonal excess or deficiency are the main cause of mortality in patients with pituitary disorders. In patients with Cushing's Disease, there is an increased prevalence of cardiovascular diseases and/or risk factors including visceral obesity, insulin resistance, atherosclerosis, arterial hypertension, dyslipidaemia, hypercoagulability as well as structural and functional changes in the heart, like cardiac hypertrophy and left ventricle (LV) dysfunction. Notably, these demonstrate limited reversibility even after remission. Furthermore, patients with acromegaly may manifest insulin resistance but also structural and functional heart changes, also known as "acromegalic cardiomyopathy". Patients with prolactinomas demonstrate an aggravation of metabolic parameters, obesity, dysregulation of glucose and lipid metabolism as well as endothelial dysfunction. Hypopituitarism and conventional hormonal replacement therapy may also contribute to an unhealthy metabolic status, which promotes atherosclerosis and may lead to premature mortality. This review discusses the literature on cardiovascular risk in patients with pituitary disorders to increase physician awareness regarding this aspect of management in patients with pituitary disorders.

Potential of Sorghum Seeds in Alleviating Hyperglycemia, Oxidative Stress, and Glycation Damage.

Diabetes mellitus, characterized by dysregulated glucose metabolism, oxidative stress, and the formation of advanced glycation end products, poses a significant global health burden. In this study, we explored the potential of sorghum (Sorghum bicolor) seeds, known for their abundant phytochemical composition, as a natural remedy for diabetes and its associated damage. High-performance liquid chromatography/high-resolution mass spectrometry analysis revealed a remarkable phenolic richness in sorghum grains, including gallic acid, quercetin, and the predominant procyanidin B-1, with ecotype-specific variations in flavonoid distribution. Elemental analysis by ICP showed an abundance of macro-elements (Ca, K, Mg), trace elements (Fe, Mn, Si, Zn), and ultra-trace elements (B, Co, Cr, Cu, Mo, Se, V) essential for human health, supporting its therapeutic and nutritional potential. Additionally, the results demonstrated variable total phenolic contents (188-297 mg GAE/g dE) and total flavonoid contents (66-78 mg QE/g dE), with corresponding differences in antioxidant activities across the five ecotypes. Treatment with sorghum seed extract (SE1) significantly reduced oxidative stress markers, such as malondialdehyde (MDA)by 40% and hydrogen peroxide (H2O2) by 63%, in diabetic mice, compared to untreated diabetic controls. Moreover, sorghum extracts exhibited a remarkable increase in antioxidant enzyme activities, including a 50% increase in superoxide dismutase (SOD) activity and a 60% increase in glutathione peroxidase (GPx) activity, indicating their potential to bolster antioxidant defenses against diabetes-induced oxidative stress. These findings underscore the therapeutic potential of sorghum seeds in diabetes management and prevention, paving the way for the development of functional foods with enhanced health benefits.

Tissue Inhibitor of Metalloproteinase 3 (TIMP3) mutations increase glycolytic activity and dysregulate glutamine metabolism in RPE cells

ObjectivesMutations in Tissue Inhibitor of Metalloproteinases 3 (TIMP3) cause Sorsby's Fundus Dystrophy (SFD), a dominantly inherited, rare form of macular degeneration that results in vision loss. TIMP3 is synthesized primarily by retinal pigment epithelial (RPE) cells, which constitute the outer blood-retinal barrier. One major function of RPE is the synthesis and transport of vital nutrients, such as glucose, to the retina. Recently, metabolic dysfunction in RPE cells has emerged as an important contributing factor in retinal degenerations. We set out to determine if RPE metabolic dysfunction was contributing to SFD pathogenesis. MethodsQuantitative proteomics was conducted on RPE of mice expressing the S179C variant of TIMP3, known to be causative of SFD in humans. Proteins found to be differentially expressed (P < 0.05) were analyzed using statistical overrepresentation analysis to determine enriched pathways, processes, and protein classes using g:profiler and PANTHER Gene Ontology. We examined the effects of mutant TIMP3 on RPE metabolism using human ARPE-19 cells expressing mutant S179C TIMP3 and patient-derived induced pluripotent stem cell-derived RPE (iRPE) carrying the S204C TIMP3 mutation. RPE metabolism was directly probed using isotopic tracing coupled with GC/MS analysis. Steady state [U–13C6] glucose isotopic tracing was preliminarily conducted on S179C ARPE-19 followed by [U–13C6] glucose and [U–13C5] glutamine isotopic tracing in SFD iRPE cells. ResultsQuantitative proteomics and enrichment analysis conducted on RPE of mice expressing mutant S179C TIMP3 identified differentially expressed proteins that were enriched for metabolism-related pathways and processes. Notably these results highlighted dysregulated glycolysis and glucose metabolism. Stable isotope tracing experiments with [U–13C6] glucose demonstrated enhanced glucose utilization and glycolytic activity in S179C TIMP3 APRE-19 cells. Similarly, [U–13C6] glucose tracing in SFD iRPE revealed increased glucose contribution to glycolysis and the TCA cycle. Additionally, [U–13C5] glutamine tracing found evidence of altered malic enzyme activity. ConclusionsThis study provides important information on the dysregulation of RPE glucose metabolism in SFD and implicates a potential commonality with other retinal degenerative diseases, emphasizing RPE cellular metabolism as a therapeutic target.

Vagus Nerve Suppression in Ischemic Stroke by Carotid Artery Occlusion: Implications for Metabolic Regulation, Cognitive Function, and Gut Microbiome in a Gerbil Model.

The vagus nerve regulates metabolic homeostasis and mediates gut-brain communication. We hypothesized that vagus nerve dysfunction, induced by truncated vagotomy (VGX) or carotid artery occlusion (AO), would disrupt gut-brain communication and exacerbate metabolic dysregulation, neuroinflammation, and cognitive impairment. This study aimed to test the hypothesis in gerbils fed a high-fat diet. The gerbils were divided into four groups: AO with VGX (AO_VGX), AO without VGX (AO_NVGX), no AO with VGX (NAO_VGX), and no AO without VGX (NAO_NVGX). After 5 weeks on a high-fat diet, the neuronal cell death, neurological severity, hippocampal lipids and inflammation, energy/glucose metabolism, intestinal morphology, and fecal microbiome composition were assessed. AO and VGX increased the neuronal cell death and neurological severity scores associated with increased hippocampal lipid profiles and lipid peroxidation, as well as changes in the inflammatory cytokine expression and brain-derived neurotrophic factor (BDNF) levels. AO and VGX also increased the body weight, visceral fat mass, and insulin resistance and decreased the skeletal muscle mass. The intestinal morphology and microbiome composition were altered, with an increase in the abundance of Bifidobacterium and a decrease in Akkermansia and Ruminococcus. Microbial metagenome functions were also impacted, including glutamatergic synaptic activity, glycogen synthesis, and amino acid biosynthesis. Interestingly, the effects of VGX were not significantly additive with AO, suggesting that AO inhibited the vagus nerve activity, partly offsetting the effects of VGX. In conclusion, AO and VGX exacerbated the dysregulation of energy, glucose, and lipid metabolism, neuroinflammation, and memory deficits, potentially through the modulation of the gut-brain axis. Targeting the gut-brain axis by inhibiting vagus nerve suppression represents a potential therapeutic strategy for ischemic stroke.

Regulation of Fructose Metabolism in Nonalcoholic Fatty Liver Disease.

Elevations in fructose consumption have been reported to contribute significantly to an increased incidence of obesity and metabolic diseases in industrial countries. Mechanistically, a high fructose intake leads to the dysregulation of glucose, triglyceride, and cholesterol metabolism in the liver, and causes elevations in inflammation and drives the progression of nonalcoholic fatty liver disease (NAFLD). A high fructose consumption is considered to be toxic to the body, and there are ongoing measures to develop pharmaceutical therapies targeting fructose metabolism. Although a large amount of work has summarized the effects fructose exposure within the intestine, liver, and kidney, there remains a gap in our knowledge regarding how fructose both indirectly and directly influences immune cell recruitment, activation, and function in metabolic tissues, which are essential to tissue and systemic inflammation. The most recent literature demonstrates that direct fructose exposure regulates oxidative metabolism in macrophages, leading to inflammation. The present review highlights (1) the mechanisms by which fructose metabolism impacts crosstalk between tissues, nonparenchymal cells, microbes, and immune cells; (2) the direct impact of fructose on immune cell metabolism and function; and (3) therapeutic targets of fructose metabolism to treat NAFLD. In addition, the review highlights how fructose disrupts liver tissue homeostasis and identifies new therapeutic targets for treating NAFLD and obesity.

Novel Hexokinase 1 Genetic Mutation Presenting with Recurrent Fever and Developmental Delay: Possible Insight on the Role of Glucose Metabolism Dysregulation and Autoinflammation

Novel Hexokinase 1 Genetic Mutation Presenting with Recurrent Fever and Developmental Delay: Possible Insight on the Role of Glucose Metabolism Dysregulation and Autoinflammation

Dysregulated energy and protein homeostasis and the loss of GABAergic amacrine cells in aging retina

Aging is a major risk factor for the development or the worsening of retinal degenerative conditions. The intricate network of the neural retina determined that the retinal aging is a complicated process. The aim of this study is to delineate the transcriptomic changes of major retinal neurons during aging in C57BL/6 mice at single-cell level. We analyzed the transcriptional profiles of the photoreceptor, bipolar, amacrine, and Müller glial cells of 1.5–2 and 24–30 months old mice using single-cell RNA sequencing technique. We selectively confirmed the differences in gene expression using immunofluorescence staining and RNA in situ hybridization analysis. We found that each retinal cell type had unique changes upon aging. However, they all showed signs of dysregulated glucose and energy metabolism, and perturbed proteostasis. In particular, old Müller glia exhibited the most profound changes, including the upregulation of cell metabolism, stress-responses, antigen-presentation and immune responses and metal ion homeostasis. The dysregulated gliogenesis and differentiation was confirmed by the presence of Müller glia expressing rod-specific genes in the inner nuclear layer and the outer plexiform layer of the old retina. We further pinpointed the specific loss of GABAergic amacrine cells in old retina. Our study emphasized changes of amacrine and Müller glia during retinal aging, provided resources for further research on the molecular and cellular regulatory mechanisms underlying aging-associated retinal deterioration.

Exploring the Interplay between the Warburg Effect and Glucolipotoxicity in Cancer Development: A Novel Perspective on Cancer Etiology.

The Warburg effect, first observed by Otto Warburg in the 1920s, delineates a metabolic phenomenon in which cancer cells exhibit heightened glucose uptake and lactate production, even under normoxic conditions. This metabolic shift towards glycolysis, despite the presence of oxygen, fuels the energy demands of rapidly proliferating cancer cells. Dysregulated glucose metabolism, characterized by the overexpression of glucose transporters and the redirection of metabolic pathways towards glycolysis, lies at the crux of this metabolic reprogramming. Consequently, the accumulation of lactate as a byproduct contributes to the creation of an acidic tumor microenvironment, fostering tumor progression and metastasis. However, recent research, notably proposed by Maher Akl, introduces a novel perspective regarding the role of glycolipids in cancer metabolism. Akl's glucolipotoxicity hypothesis posits that aberrant glycolipid metabolism, specifically the intracellular buildup of glycolipids, significantly influences tumor initiation and progression. This hypothesis underscores the disruptive impact of accumulated glycolipids on cellular homeostasis, thereby activating oncogenic pathways and promoting carcinogenesis. This perspective aims to synthesize the intricate mechanisms underlying both the Warburg effect and glucolipotoxicity, elucidating their collective contributions to tumor growth and malignancy. By comprehensively understanding these metabolic aberrations, novel avenues for therapeutic intervention targeting the fundamental drivers of cancer initiation and progression emerge, holding promise for more efficacious treatment strategies in the future.

Sitagliptin alleviates renal steatosis and endoplasmic reticulum stress in high fat diet-induced obese rats by targeting SREBP-1/CD36 signaling pathway

High fat diet (HFD) consumption can cause dysregulation of glucose and lipid metabolism, coupled with increased ectopic lipid deposition in renal tissue leading to steatosis and dysfunction. Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor clinically used for type II diabetes therapy; however its effect on renal steatosis in obese state is still uncertain. Herein, obesity was induced by feeding male Wistar rats HFD for 18 weeks, thereafter received either drug vehicle, or sitagliptin (10 mg/kg, PO) along with HFD for further 6 weeks and compared with age-matched rats receiving normal chow diet (NCD). After 24 weeks, serum and kidneys were collected for histological and biochemical assessments. Compared to NCD-fed group, HFD-fed rats displayed marked weight gain, increased fat mass, insulin resistance, dyslipidemia, impaired kidney functions and renal histological alterations. Sitagliptin effectively ameliorated obesity and related metabolic perturbations and improved kidney architecture and function. There were increased levels of triglycerides and cluster of differentiation 36 (CD36) in kidneys of obese rats, that were lowered by sitagliptin therapy. Sitagliptin significantly repressed the expression of lipogenesis genes, while up-regulated genes involved in mitochondrial biogenesis and fatty acid oxidation in kidneys of HFD-fed rats. Sitagliptin was found to induce down-regulation of endoplasmic reticulum (ER) stress and apoptotic markers in kidneys of obese rats. These findings together may emphasize a novel concept that sitagliptin can be an effective therapeutic approach for halting obesity-related renal steatosis and CKD.

Combining bioinformatics and multiomics strategies to investigate the key microbiota and active components of Liupao tea ameliorating hyperlipidemia

Ethnopharmacological relevanceHyperlipidemia as a major health issue has attracted much public attention. As a geographical indication product of China, Liupao tea (LPT) is a typical representative of traditional Chinese dark tea that has shown good potential in regulating glucose and lipid metabolism. LPT has important medicinal value in hyperlipidemia prevention. However, the active ingredients and metabolic mechanisms by which LPT alleviates hyperlipidemia remain unclear. Aim of the studyThis study aimed to systematically investigate the metabolic mechanisms and active ingredients of LPT extract in alleviating hyperlipidemia. Materials and methodsFirstly, we developed a mouse model of hyperlipidemia to study the pharmacodynamics of LPT. Subsequently, network pharmacology and molecular docking were performed to predict the potential key active ingredients and core targets of LPT against hyperlipidemia. LC-MS/MS was used to validate the identity of key active ingredients in LPT with chemical standards. Finally, the effect and metabolic mechanisms of LPT extract in alleviating hyperlipidemia were investigated by integrating metabolomic, lipidomic, and gut microbiome analyses. ResultsResults showed that LPT extract effectively improved hyperlipidemia by suppressing weight gain, remedying dysregulation of glucose and lipid metabolism, and reducing hepatic damage. Network pharmacology analysis and molecular docking suggested that four potential active ingredients and seven potential core targets were closely associated with roles for hyperlipidemia treatment. Ellagic acid, catechin, and naringenin were considered to be the key active ingredients of LPT alleviating hyperlipidemia. Additionally, LPT extract modulated the mRNA expression levels of Fxr, Cyp7a1, Cyp8b1, and Cyp27a1 associated with bile acid (BA) metabolism, mitigated the disturbances of BA and glycerophospholipid (GP) metabolism in hyperlipidemia mice. Combining fecal microbiota transplantation and correlation analysis, LPT extract effectively improved species diversity and abundance of gut microbiota, particularly the BA and GP metabolism-related gut microbiota, in the hyperlipidemia mice. ConclusionsLPT extract ameliorated hyperlipidemia by modulating GP and BA metabolism by regulating Lactobacillus and Dubosiella, thereby alleviating hyperlipidemia. Three active ingredients of LPT served as the key factors in exerting an improvement on hyperlipidemia. These findings provide new insights into the active ingredients and metabolic mechanisms of LPT in improving hyperlipidemia, suggesting that LPT can be used to prevent and therapeutic hyperlipidemia.