Changes In Glucose Metabolism Research Articles

Plasma Neurofilament Light Relates to Divergent Default and Salience Network Connectivity in Alzheimer's Disease and Behavioral Variant Frontotemporal Dementia.

Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) show differential vulnerability to large-scale brain functional networks. Plasma neurofilament light (NfL), a promising biomarker of neurodegeneration, has been linked in AD patients to glucose metabolism changes in AD-related regions. However, it is unknown whether plasma NfL would be similarly associated with disease-specific functional connectivity changes in AD and bvFTD. Our study examined the associations between plasma NfL and functional connectivity of the default mode and salience networks in patients with AD and bvFTD. Plasma NfL and neuroimaging data from patients with bvFTD (n = 16) and AD or mild cognitive impairment (n = 38; AD + MCI) were analyzed. Seed-based functional connectivity maps of key regions within the default mode and salience networks were obtained and associated with plasma NfL in these patients. We demonstrated divergent associations between NfL and functional connectivity in AD + MCI and bvFTD patients. Specifically, AD + MCI patients showed lower default mode network functional connectivity with higher plasma NfL, while bvFTD patients showed lower salience network functional connectivity with higher plasma NfL. Further, lower NfL-related default mode network connectivity in AD + MCI patients was associated with lower Montreal Cognitive Assessment scores and higher Clinical Dementia Rating sum-of-boxes scores, although NfL-related salience network connectivity in bvFTD patients was not associated with Neuropsychiatric Inventory Questionnaire scores. Our findings indicate that plasma NfL is differentially associated with brain functional connectivity changes in AD and bvFTD.

Exercise-induced changes in myocardial glucose utilization during periods of active cardiac growth

Exercise training can promote physiological cardiac growth, which has been suggested to involve changes in glucose metabolism to facilitate hypertrophy of cardiomyocytes. In this study, we used a dietary, in vivo isotope labeling approach to examine how exercise training influences the metabolic fate of carbon derived from dietary glucose in the heart during acute, active, and established phases of exercise-induced cardiac growth. Male and female FVB/NJ mice were subjected to treadmill running for up to 4 weeks and cardiac growth was assessed by gravimetry. Cardiac metabolic responses to exercise were assessed via in vivo tracing of [13C6]-glucose via mass spectrometry and nuclear magnetic resonance. We found that the half-maximal cardiac growth response was achieved by approximately 1 week of daily exercise training, with near maximal growth observed in male mice with 2 weeks of training; however, female mice were recalcitrant to exercise-induced cardiac growth and required a higher daily intensity of exercise training to achieve significant, albeit modest, increases in cardiac mass. We also found that increases in the energy charge of adenylate and guanylate nucleotide pools precede exercise-induced changes in cardiac size and were associated with higher glucose tracer enrichment in the TCA pool and in amino acids (aspartate, glutamate) sourced by TCA intermediates. Our data also indicate that the activity of collateral biosynthetic pathways of glucose metabolism may not be markedly altered by exercise. Overall, this study provides evidence that metabolic remodeling in the form of heightened energy charge and increased TCA cycle activity and cataplerosis precedes cardiac growth caused by exercise training in male mice.

Semaglutide combined with empagliflozin vs. monotherapy for non-alcoholic fatty liver disease in type 2 diabetes: Study protocol for a randomized clinical trial.

Nonalcoholic fatty liver disease (NAFLD) is strongly associated with type 2 diabetes mellitus (T2DM). Lifestyle intervention remains a preferred treatment modality for NAFLD. The glucagon-like peptide (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors have been developed as new glucose-lowering drugs, which can improve fatty liver via an insulin-independent glucose-lowering effect. However, studies exploring the efficacy of GLP-1 receptor agonists combined with SGLT-2 inhibitors in patients with NAFLD and T2DM are scanty. Thus, the present randomised controlled trial aims at comparing the efficacy and safety of semaglutide plus empagliflozin with each treatment alone in patients with NAFLD and T2DM. This 52-week double-blinded, randomised, parallel-group, active-controlled trial evaluates the effects of semaglutide, empagliflozin and semaglutide + empagliflozin in 105 eligible overweight/obese subjects with NAFLD and T2DM. The primary outcome will be a change from baseline to week 52 in the controlled attenuation parameter, free fatty acid and glucagon. Secondary endpoints include changes in liver stiffness measurement, liver enzymes, blood glucose, lipid levels, renal function, electrolyte balances, minerals and bone metabolism, cytokines, high-sensitivity C-reactive protein, ferritin, anthropometric indicators, nonalcoholic fatty liver fibrosis score, fibrosis 4 score and homeostatic model assessment for insulin resistance. In addition, intention-to-treat, interim analysis and safety analysis will be performed. This double-blinded, randomised, clinical trial involves a multi-disciplinary approach and aims to explore the synergistic effects of the combination of semaglutide and empagliflozin. The results can provide important insights into mechanisms of GLP-1 receptor agonists and/or SGLT-2 inhibitors in patients with NAFLD and T2DM. This study has been registered with Chinese Clinical Trial Registry (ChiCTR2300070674).

Abstract RF02-02: BBO-10203, a first-in-class, orally bioavailable, selective covalent small molecule that inhibits RAS-driven PI3Kalpha activity without affecting glucose metabolism

Abstract PI3Kα is the most mutated kinase and the second most mutated oncogene in human cancer. Activation of PI3Ka can be achieved by receptor tyrosine kinases such as insulin receptor and insulin-like growth factor receptor 1 and/or by directly interacting with RAS family members. Previous elegant preclinical studies have established that RAS-driven PI3Ka activation is important in tumor cells but may not be involved in cell types controlling glucose metabolism. Alpelisib, a small molecule inhibitor of the kinase activity of PI3Ka, has been approved for the treatment of ER+ PIK3CA mutant breast cancer in combination with fulvestrant after endocrine therapy in advanced or metastatic breast cancer based on an improvement in PFS versus fulvestrant alone. Inhibition of PI3Ka activity by alpelisib in normal tissues resulted in a severe (G3/4) hyperglycemia rate of 37% with frequent dose interruptions and discontinuations. Additionally, preclinical studies have demonstrated that the dysregulation of glucose homeostasis resulting from PI3Ka kinase inhibition leads to hyperinsulinemia that increases pathway flux, rendering kinase inhibitors less effective. Here, we report on a novel covalent small molecule designed to inhibit RAS-mediated activation of the AKT pathway via PI3Ka without the resultant hyperglycemia associated with direct inhibition of PI3Ka kinase activity. BBO-10203 disrupts the physical interaction between RAS and PI3Ka in tumor cells resulting in potent signaling pathway inhibition. This agent selectively binds to PI3Ka and disrupts its interaction with K-,H-, and N-RAS with low single digit nanomolar potency (~5 nM). Breaking the interaction between these two oncogenes inhibits basal pAKT cellular levels (BT-474/KYSE-410 IC50: ~5 nM) in HER2 amplified (HER2amp) and wild-type or mutant PI3Ka cell lines. Even though BBO-10203 does not inhibit the kinase activity of PI3Ka, its effects on cancer cell signaling inhibition and transcriptional regulation highly resemble those of alpelisib. BBO-10203 displays excellent drug-like properties and oral bioavailability. Single dose treatment of KYSE-410 (HER2amp/KRASG12C) tumor bearing mice with increasing doses (1-100 mg/kg, PO) of BBO-10203 results in dose and time dependent inhibition of pAKT in vivo. Maximal inhibition (~80%) is achieved at 30 mg/kg and lasts for 24 hours. Repeated dose treatment of tumor bearing mice with BBO-10203 is well tolerated and results in significant efficacy in PIK3CA mutant as well as HER2amp human xenograft models. In the KYSE-410 xenograft model, BBO-10203 daily oral dosing of 30 mg/kg results in significant tumor regressions. Importantly, treatment with BBO-10203 does not affect insulin signaling in differentiated adipocytes in vitro, nor does it impact glucose metabolism in vivo at 3-times the maximal efficacious dose level in xenograft studies. In conclusion, we have identified a novel approach to inhibit the PI3Ka signaling pathway by blocking its interaction with, and activation by RAS. This approach can achieve strong pAKT inhibition in tumor cells without changes in glucose metabolism. Clinical investigation of BBO-10203 for the treatment of both ER+/PIK3CA mutant and HER2amp breast cancer is warranted. Citation Format: Pedro Beltran, Simanshu Dhirendra, Rui Xu, Ming Chen, Daniel Czyzyk, Sofia Donovan, Siyu Feng, Cindy Feng, Lijuan Fu, Felice Lightstone, Ken Lin, Anna Maciag, Dwight Nissley, Erin Riegler, Kerstin Sinkevicius, Andrew Stephen, James Stice, David Turner, Bin Wang, Keshi Wang, Yue Yang, Cathy Zhang, Frank McCormick, Eli Wallace. BBO-10203, a first-in-class, orally bioavailable, selective covalent small molecule that inhibits RAS-driven PI3Kalpha activity without affecting glucose metabolism [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr RF02-02.

Maternal Neudesin Levels in Pregnant Women with Gestational Diabetes Mellitus.

Our aim was to investigate the changes in neudesin levels in pregnant women with GDM and the relationship between neudesin and metabolic parameters. Forty pregnant women diagnosed with GDM and forty age- and gestational week-matched control subjects were included in the study. Demographic data were obtained from records. Maternal lipid profiles, glucose levels, fasting insulin, HbA1C, and HOMA-IR results were compared between the groups. Correlation tests were performed to evaluate the relationship between neudesin and clinical and laboratory diagnostic parameters. p < 0.05 were interpreted as statistically significant. The human serum neudesin levels were significantly lower in the GDM group compared with the controls. The correlation tests showed statistically negative and weak correlations between the neudesin levels and the maternal age, 50 g OGCT, 100 g OGTT 3 hours, and HbA1C. The optimum neudesin cutoff value for a diagnosis of GDM disease is 6.94 ng/dL, with a sensitivity of 65.9% and a specificity of 63.2%. This study has shown that lower neudesin levels may occur as a reflection of changes in glucose metabolism during intrauterine life.

Characterization of tau propagation pattern and cascading hypometabolism from functional connectivity in Alzheimer's disease.

Tau pathology and its spatial propagation in Alzheimer's disease (AD) play crucial roles in the neurodegenerative cascade leading to dementia. However, the underlying mechanisms linking tau spreading to glucose metabolism remain elusive. To address this, we aimed to examine the association between pathologic tau aggregation, functional connectivity, and cascading glucose metabolism and further explore the underlying interplay mechanisms. In this prospective cohort study, we enrolled 79 participants with 18F-Florzolotau positron emission tomography (PET), 18F-fluorodeoxyglucose PET, resting-state functional, and anatomicalmagnetic resonance imaging (MRI) images in the hospital-based Shanghai Memory Study. We employed generalized linear regression and correlation analyses to assess the associations between Florzolotau accumulation, functional connectivity, and glucose metabolism in whole-brain and network-specific manners. Causal mediation analysis was used to evaluate whether functional connectivity mediates the association between pathologic tau and cascading glucose metabolism. We examined 22 normal controls and 57 patients with AD. In the AD group, functional connectivity was associated with Florzolotau covariance (β = .837, r = 0.472, p < .001) and glucose covariance (β = 1.01, r = 0.499, p < .001). Brain regions with higher tau accumulation tend to be connected to other regions with high tau accumulation through functional connectivity or metabolic connectivity. Mediation analyses further suggest that functional connectivity partially modulates the influence of tau accumulation on downstream glucose metabolism (mediation proportion: 49.9%). Pathologic tau may affect functionally connected neurons directly, triggering downstream glucose metabolism changes. This study sheds light on the intricate relationship between tau pathology, functional connectivity, and downstream glucose metabolism, providing critical insights into AD pathophysiology and potential therapeutic targets.

Effects of environmental enrichment on GLUT expression in the visual cortex of amblyopic rats

ObjectiveTo investigate the potential changes of glucose metabolism and glucose transporter protein (GLUT) in the visual cortex of formally deprived amblyopic rats, as well as the effects of enriched environments on the levels of nerve conduction and glucose metabolism in the visual cortex of amblyopic rats. Methods36 rats were randomly divided into three groups: CON + SE (n = 12), MD + SE (n = 12) and MD + EE (n = 12). The right eyelids of both MD + SE and MD + EE groups were sutured. After successful modelling, the MD + EE group was maintained in an enriched environment, and the other two groups were kept in the same environment. Pattern visual evoked potentials (PVEP) was used to confirm models' effect, glucose metabolism was analyzed by Micro-PET/CT (18F-FDG), and the protein as well as mRNA expression levels of GLUT were detected by Western Blot and quantitative RT-PCR (quantitative Reverse Transcription-Polymerase Chain Reaction) analyses, site of GLUT expression by immunofluorescence (IF). ResultsAfter suture modelling, both the MD + EE and MD + SE groups objective visual nerve conduction function decreased, the glucose metabolism in the visual cortex was markedly lower. After the enriched environment intervention, it recovered in the MD + EE group. The expression levels of GLUT1 and GLUT3 were increased in the MD + EE group in comparison with the MD + SE group. GLUT1 was primarily expressed on astrocytes and endothelial cells, but GLUT3 was mainly expressed on neurons. ConclusionEnrichment of the environment exhibited a therapeutic effect on amblyopia, which could be related to the enhancement of glucose metabolism and GLUT expression in the visual cortex.

Association of short-term changes in HbA1c with body composition and the importance of muscle maintenance in patients with Type 2 diabetes

AimsThis study aimed to investigate the relationship between changes in glucose metabolism and body composition in patients with diabetes. MethodsWe included 380 patients with type 2 diabetes, who underwent bioelectrical impedance analysis, in this longitudinal study. Changes in HbA1c (ΔHbA1c) levels and body composition indices were compared between baseline and 6 months. A multivariate analysis was performed to examine the relationship between ΔHbA1c and changes in body composition. ResultsHbA1c levels were significantly decreased at 6 months (P < 0.01), but there was no significant change in BMI. A linear multiple regression analysis showed that ΔHbA1c was negatively correlated with changes in muscle mass (β = −0.18; P = 0.047) and bone mineral content (β = −0.28; P < 0.001), but there was no significant association between ΔHbA1c levels and a change in body fat percentage. ConclusionsThis study shows a limited association between short-term changes in glucose metabolism and changes in body composition in patients with type 2 diabetes. Therefore, interventions aimed at reducing adiposity may not affect glucose metabolism in the short term, while interventions focused on maintaining or enhancing muscle mass and bone mineral content may play an important role in diabetes management.

Genome-Wide Analysis Identifies Nuclear Factor 1C as a Novel Transcription Factor and Potential Therapeutic Target in SCLC

IntroductionRecent insights regarding mechanisms mediating stemness, heterogeneity, and metastatic potential of lung cancers have yet to be fully translated to effective regimens for the treatment of these malignancies. This study sought to identify novel targets for lung cancer therapy. MethodsTranscriptomes and DNA methylomes of 14 SCLC and 10 NSCLC lines were compared with normal human small airway epithelial cells (SAECs) and induced pluripotent stem cell (iPSC) clones derived from SAEC. SCLC lines, lung iPSC (Lu-iPSC), and SAEC were further evaluated by DNase I hypersensitivity (DHS-seq). Changes in chromatin accessibility and depths of transcription factor (TF) footprints were quantified using Bivariate analysis of Genomic Footprint. Standard techniques were used to evaluate growth, tumorigenicity, and changes in transcriptomes and glucose metabolism of SCLC cells after NFIC knockdown and to evaluate NFIC expression in SCLC cells after exposure to BET inhibitors. ResultsSignificant commonality of transcriptomes and DNA methylomes was observed between Lu-iPSC and SCLC; however, this analysis was uninformative regarding pathways unique to lung cancer. Linking results of DNase I hypersensitive site sequencing to RNA sequencing enabled identification of networks not previously associated with SCLC. When combined with footprint depth, NFIC, a transcription factor not previously associated with SCLC, had the highest score of occupancy at open chromatin sites. Knockdown of NFIC impaired glucose metabolism, decreased stemness, and inhibited growth of SCLC cells in vitro and in vivo. ChIP-seq analysis identified numerous sites occupied by BRD4 in the NFIC promoter region. Knockdown of BRD4 or treatment with Bromodomain and extra-terminal domain (BET) inhibitors (BETis) markedly reduced NFIC expression in SCLC cells and SCLC PDX models. Approximately 8% of genes down-regulated by BETi treatment were repressed by NFIC knockdown in SCLC, whereas 34% of genes repressed after NFIC knockdown were also down-regulated in SCLC cells after BETi treatment. ConclusionsNFIC is a key TF and possible mediator of transcriptional regulation by BET family proteins in SCLC. Our findings highlight the potential of genome-wide chromatin accessibility analysis for elucidating mechanisms of pulmonary carcinogenesis and identifying novel targets for lung cancer therapy.

EFFECTS OF PETROL CONTAMINATED DIET AND WATER ONGLUCOSE, LIVER GLYCOGEN, PLASMA LACTATE AND LIPID PROFILE IN MALE WISTAR RATS

Exposure to petrol have been shown to cause detrimental health effects. Literature is sparse on whether exposure to petrol causes metabolic disorders. This study investigated the effects of petrol contaminated diet andwater on blood glucose, liver glycogen, plasma lactate, triglycerides and lipid profile in male Wistar rats. The study was divided into two phases. Phase one study consisted of 15 male Wistar rats divided into three groups (n = 5/group). Groups 1-3 were given distilled water, petrol-contaminated diet (20 mL petrol/200 g rodent chow PCD), and petrol-contaminated water (0.5 mL/kg PCW) orally and respectively for .two weeks. In the phase two study, 15 male Wistar rats were divided into three groups (n = 5/group), animals in groups 1-3 received distilled water, petrol contaminated diet, and petrol-contaminated water orally and respectively for four weeks.At the end of the experiment, fasting blood glucose, liver glycogen, plasma lactate, triglycerides and lipid profie were measured.The results of this study showed that the administration of petrol contaminated diet and water caused significant increase in plasma lactate levels, triglycerides (TG),total cholesterol (TC), low density lipoprotein (LDL), very low density lipoprotein (VLDL)and a significant reduction in liver glycogen and high density lipoprotein( HDL) in male Wistar rats. In conclusion, the study revealed that, exposure of rats to petrol contaminated diet and water caused changes in lipid profile, altered glucose and lipid metabolism in male Wistar rats. Exposure to petrol should therefore be restricted or avoided.

13C Metabolic Flux Analysis in Chondrocytes Reveals a Novel Switch in Metabolic Phenotype.

Chondrocytes are typically known for their anaerobic metabolism both in vivo and under culture conditions in vitro. However, chondrocytes have been shown to display greater biosynthetic activity when subjected to conditions that elicit aerobic metabolism. We have previously shown that tissue formation by chondrocytes can be upregulated by controlling nutrient availability and that this response arises from changes in glucose metabolism. The aim of the present study was to further characterize these changes through 13C-metabolic flux analysis (13C-MFA), as well as to determine the most optimal response. Primary bovine chondrocytes were grown in scaffold-free high-density tissue culture. [U-13C] glucose labeling experiments were combined with a tissue-specific metabolic network model to carry out 13C-MFA under varying levels of nutrient availability. 13C-MFA results demonstrated that when subjected to increasing nutrient availability, chondrocytes switch from a predominately anaerobic to a mixed aerobic-anaerobic phenotype. This metabolic switch was attributed to the saturation of the lactate fermentation pathway and metabolite overflow toward the tricarboxylic acid cycle. This effect appears to be similar to, but the inverse of, the Crabtree effect ("inverse Crabtree effect"). The relationships between metabolic flux and nutrient availability were then utilized to identify culture conditions that promote enhanced tissue formation. This novel metabolic effect presents a simple but effective approach for enhancing the biosynthetic response of chondrocytes-a key requirement to develop functional engineered cartilaginous tissue for joint resurfacing.

Abstract 6612: Therapy-resistant endocycling cancer cells alter mitochondrial structure and metabolism to survive therapeutic stress

Abstract Therapy resistance is responsible for 90% of cancer-related deaths. We identified a novel mechanism of therapy resistance in which cancer cells enter an endocycling cell state, undergoing repeated S and G phases without dividing. As a result, resistant endocycling cells are 40 times larger than mitotic cancer cell controls. Interestingly, we observed that these non-proliferative endocycling cells can eventually give rise to proliferative progeny weeks after chemotherapy is removed, modeling cancer recurrence. We hypothesize that this endocycling cancer cell state is a critical driver of therapy resistance and cancer lethality. We evaluated oxidative stress in endocycling cells that survived the days and weeks following chemotherapy treatment using DCF-DA staining. We found increased levels of reactive oxygen species (ROS) in endocycling prostate cancer cells compared to untreated mitotic cells when normalized to cell size. Given that mitochondria are major producers and regulators of ROS, we hypothesize that cells surviving in this resistant state alter mitochondrial structure and function in response to increased oxidative stress. We performed immunofluorescence and confocal microscopy on mitochondria in untreated cells and cells following chemotherapy treatment to observe their morphology. Surviving endocycling cells had increased mitochondrial fragmentation when compared to the untreated group, a result that was further supported by reduced expression of phospho-DRP1 Ser637 via western blot. To assess changes in glucose metabolism, we then utilized isotope tracing-based metabolomics with [U-13C]glucose on untreated and surviving endocycling cells following chemotherapy. Endocycling cells had decreased labeling of 13C in TCA cycle metabolites, suggesting a decrease in mitochondrial function when compared to untreated cells. Ongoing work involves further studying metabolic reprogramming as cells enter this resistant state with parallel labeling experiments using [1,2-13C]glucose and [U-13C]glutamine to perform mathematical modeling-based 13C-metabolic flux analysis. In addition, we engineered a cell line to track mitochondria in real-time to quantify mitochondrial dynamics underlying the morphology observed in untreated and surviving cells. Our goal is to characterize how this therapy-resistant cell state alters its mitochondrial structure and function to survive therapeutic stress. Identifying vulnerabilities of this phenotype will enable new approaches for eliminating drug resistance in cancer. Citation Format: Melvin Li, Sarah R. Amend, Kenneth J. Pienta. Therapy-resistant endocycling cancer cells alter mitochondrial structure and metabolism to survive therapeutic stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6612.

PDGFRβ + cell HIF2α is dispensable for white adipose tissue metabolic remodeling and hepatic lipid accumulation in obese mice

BackgroundObesity is associated with extensive white adipose tissue (WAT) expansion and remodeling. Healthy WAT expansion contributes to the maintenance of energy balance in the liver, thereby ameliorating obesity-related hepatic steatosis. Tissue-resident mesenchymal stromal cell populations, including PDGFRβ + perivascular cells, are increasingly recognized pivotal as determinants of the manner in which WAT expands. However, the full array of regulatory factors controlling WAT stromal cell functions remains to be fully elucidated. Hypoxia-inducible factors (HIFs) are critical regulators in WAT stromal cell populations such as adipocyte precursor cells (APCs). It is revealed that HIF1α activation within PDGFRβ + stromal cells results in the suppression of de novo adipogenesis and the promotion of a pro-fibrogenic cellular program in obese animals. However, the role of HIF2α in PDGFRβ + cells remains undetermined in vivo.MethodsNew genetic models were employed in which HIF1α (encoded by the Hif1a gene) and HIF2α (encoded by the Epas1 gene) are selectively inactivated in PDGFRβ + cells in an inducible manner using tamoxifen (TAM). With these models, both in vitro and in vivo functional analysis of PDGFRβ + cells lacking HIF proteins were performed. Additionally, comprehensive metabolic phenotyping in diet-induced mouse models were performed to investigate the roles of PDGFRβ + cell HIF proteins in WAT remodeling, liver energy balance and systemic metabolism.ResultsUnlike HIF1α inactivation, the new findings in this study suggest that inducible ablation of HIF2α in PDGFRβ + cells does not cause apparent effects on WAT expansion induced by obesogenic diet. The adipogenic ability of PDGFRβ + APCs is not significantly altered by genetic HIF2α ablation. Moreover, no difference of key parameters associated with healthy WAT remodeling such as improvements of WAT insulin sensitivity, reduction in metabolic inflammation, as well as changes in liver fat accumulation or systemic glucose metabolism, is detected in PDGFRβ + cell Epas1-deficient mice.ConclusionThe new findings in this study support that, in contrast to HIF1α, PDGFRβ + cell HIF2α appears dispensable for WAT metabolic remodeling and the resulting effects on liver metabolic homeostasis in diet-induced obesity, underscoring the isoform-specific roles of HIFα proteins in the regulation of adipose tissue biology.

Non-invasive assessment of stimulation-specific changes in cerebral glucose metabolism with functional PET.

Functional positron emission tomography (fPET) with [18F]FDG allows quantification of stimulation-induced changes in glucose metabolism independent of neurovascular coupling. However, the gold standard for quantification requires invasive arterial blood sampling, limiting its widespread use. Here, we introduce a novel fPET method without the need for an input function. We validated the approach using two datasets (DS). For DS1, 52 volunteers (23.2 ± 3.3years, 24 females) performed Tetris® during a [18F]FDG fPET scan (bolus + constant infusion). For DS2, 18 participants (24.2 ± 4.3years, 8 females) performed an eyes-open/finger tapping task (constant infusion). Task-specific changes in metabolism were assessed with the general linear model (GLM) and cerebral metabolic rate of glucose (CMRGlu) was quantified with the Patlak plot as reference. We then estimated simplified outcome parameters, including GLM beta values and percent signal change (%SC), and compared them, region and whole-brain-wise. We observed higher agreement with the reference for DS1 than DS2. Both DS resulted in strong correlations between regional task-specific beta estimates and CMRGlu (r = 0.763…0.912). %SC of beta values exhibited strong agreement with %SC of CMRGlu (r = 0.909…0.999). Average activation maps showed a high spatial similarity between CMRGlu and beta estimates (Dice = 0.870…0.979) as well as %SC (Dice = 0.932…0.997), respectively. The non-invasive method reliably estimates task-specific changes in glucose metabolism without blood sampling. This streamlines fPET, albeit with the trade-off of being unable to quantify baseline metabolism. The simplification enhances its applicability in research and clinical settings.

Serum adropin level in wet-type age-related macular degeneration

PurposeOur objective was to compare the serum Adropin levels between patients with wet-type Age-Related Macular Degeneration (AMD) and otherwise healthy individuals.MethodThe study included 45 patients with wet-type AMD and 45 individuals without age-related macular degeneration. Patients with co-morbidities such as diabetes, hypertension, autoimmune diseases, and a previous history of visual impairment; were excluded. FBS, Hemoglobin A1C (HbA1C), lipid profile, and serum Adropin level were checked.ResultsThe mean serum Adropin level of patients with wet-type AMD was significantly lower than the control group (P-value < 0.001). Also, the mean High-sensitivity C-reactive protein ( hsCRP) level and High Density Lipoprotein (HDL) were significantly higher in wet-type AMD patients (P-value = 0.031 and < 0.001 respectively).ConclusionsIn our study, wet-type AMD was associated with a lower level of serum Adropin. Because of Adropin involvement in glucose metabolism and age-related changes, it may have a role in the pathogenesis of AMD, but it requires more investigations at the molecular level to elucidate its function.

Assessment of a one-week ketogenic diet on brain glycolytic metabolism and on the status epilepticus stage of a lithium–pilocarpine rat model

The ketogenic diet (KD) has been shown to be effective in refractory epilepsy after long-term administration. However, its interference with short-term brain metabolism and its involvement in the early process leading to epilepsy remain poorly understood. This study aimed to assess the effect of a short-term ketogenic diet on cerebral glucose metabolic changes, before and after status epilepticus (SE) in rats, by using [18F]-FDG PET. Thirty-nine rats were subjected to a one-week KD (KD-rats, n = 24) or to a standard diet (SD-rats, n = 15) before the induction of a status epilepticus (SE) by lithium-pilocarpine administrations. Brain [18F]-FDG PET scans were performed before and 4 h after this induction. Morphological MRIs were acquired and used to spatially normalize the PET images which were then analyzed voxel-wisely using a statistical parametric-based method. Twenty-six rats were analyzed (KD-rats, n = 15; SD-rats, n = 11). The 7 days of the KD were associated with significant increases in the plasma β-hydroxybutyrate level, but with an unchanged glycemia. The PET images, recorded after the KD and before SE induction, showed an increased metabolism within sites involved in the appetitive behaviors: hypothalamic areas and periaqueductal gray, whereas no area of decreased metabolism was observed. At the 4th hour following the SE induction, large metabolism increases were observed in the KD- and SD-rats in areas known to be involved in the epileptogenesis process late—i.e., the hippocampus, parahippocampic, thalamic and hypothalamic areas, the periaqueductal gray, and the limbic structures (and in the motor cortex for the KD-rats only). However, no statistically significant difference was observed when comparing SD and KD groups at the 4th hour following the SE induction. A one-week ketogenic diet does not prevent the status epilepticus (SE) and associated metabolic brain abnormalities in the lithium-pilocarpine rat model. Further explorations are needed to determine whether a significant prevention could be achieved by more prolonged ketogenic diets and by testing this diet in less severe experimental models, and moreover, to analyze the diet effects on the later and chronic stages leading to epileptogenesis.

Metabolic Effects of Brown Adipose Tissue Activity Due to Cold Exposure in Humans: A Systematic Review and Meta-Analysis of RCTs and Non-RCTs.

Brown adipose tissue (BAT), specialized in thermoregulation in mammals, has been linked to improved glucose and lipid homeostasis when activated by cold exposure (CE). This systematic review and meta-analysis assessed the metabolic effects of CE-induced BAT activation in healthy humans, examining changes in glucose and lipid metabolism compared to thermoneutrality (TN). A literature search was conducted, identifying relevant human studies, including randomized controlled trials (RCTs) and non-RCTs, based on predefined inclusion criteria. Seven studies (a total of 85 participants) fully met the criteria. Data on plasma glucose, insulin, triglycerides (TGs), and free fatty acids (FFAs) were extracted for meta-analysis. When comparing TN and CE under fasting conditions, there were no significant changes in glucose, insulin, or TG concentrations (all p > 0.36). In contrast, CE significantly increased FFA concentrations (p = 0.002; n = 38). Bias was absent for all parameters, but heterogeneity was observed for insulin (I2 = 74.8%). CE primarily affects FFA concentration, likely reflecting cold-induced BAT activity. This suggests that circulating FFAs, serving as the primary fuel for thermogenesis, could indicate BAT activation. However, understanding the effects of BAT activation on overall metabolism requires a broader approach beyond fasting glucose and lipid concentration measurements.

Steady Laminar Flow Decreases Endothelial Glycolytic Flux While Enhancing Proteoglycan Synthesis and Antioxidant Pathways.

Endothelial cells in steady laminar flow assume a healthy, quiescent phenotype, while endothelial cells in oscillating disturbed flow become dysfunctional. Since endothelial dysfunction leads to atherosclerosis and cardiovascular disease, it is important to understand the mechanisms by which endothelial cells change their function in varied flow environments. Endothelial metabolism has recently been proven a powerful tool to regulate vascular function. Endothelial cells generate most of their energy from glycolysis, and steady laminar flow may reduce endothelial glycolytic flux. We hypothesized that steady laminar but not oscillating disturbed flow would reduce glycolytic flux and alter glycolytic side branch pathways. In this study, we exposed human umbilical vein endothelial cells to static culture, steady laminar flow (20 dynes/cm2 shear stress), or oscillating disturbed flow (4 ± 6 dynes/cm2 shear stress) for 24 h using a cone-and-plate device. We then measured glucose and lactate uptake and secretion, respectively, and glycolytic metabolites. Finally, we explored changes in the expression and protein levels of endothelial glycolytic enzymes. Our data show that endothelial cells in steady laminar flow had decreased glucose uptake and 13C labeling of glycolytic metabolites while cells in oscillating disturbed flow did not. Steady laminar flow did not significantly change glycolytic enzyme gene or protein expression, suggesting that glycolysis may be altered through enzyme activity. Flow also modulated glycolytic side branch pathways involved in proteoglycan and glycosaminoglycan synthesis, as well as oxidative stress. These flow-induced changes in endothelial glucose metabolism may impact the atheroprone endothelial phenotype in oscillating disturbed flow.

Sex-Specific Effects of Long-Term Antipsychotic Drug Treatment on Adipocyte Tissue and the Crosstalk to Liver and Brain in Rats.

Antipsychotic drug (APD) medication can lead to metabolic dysfunctions and weight gain, which together increase morbidity and mortality. Metabolically active visceral adipose tissue (VAT) in particular plays a crucial role in the etiopathology of these metabolic dysregulations. Here, we studied the effect of 12 weeks of drug medication by daily oral feeding of clozapine and haloperidol on the perirenal fat tissue as part of VAT of male and female Sprague Dawley rats in the context of complex former investigations on brain, liver, and blood. Adipocyte area values were determined, as well as triglycerides, non-esterified fatty acids (NEFAs), glucose, glycogen, lactate, malondialdehyde equivalents, ferric iron and protein levels of Perilipin-A, hormone-sensitive-lipase (HSL), hepcidin, glucose transporter-4 (Glut-4) and insulin receptor-ß (IR-ß). We found increased adipocyte mass in males, with slightly higher adipocyte area values in both males and females under clozapine treatment. Triglycerides, NEFAs, glucose and oxidative stress in the medicated groups were unchanged or slightly decreased. In contrast to controls and haloperidol-medicated rats, perirenal adipocyte mass and serum leptin levels were not correlated under clozapine. Protein expressions of perilipin-A, Glut-4 and HSL were decreased under clozapine treatment. IR-ß expression changed sex-specifically in the clozapine-medicated groups associated with higher hepcidin levels in the perirenal adipose tissue of clozapine-treated females. Taken together, clozapine and haloperidol had a smaller effect than expected on perirenal adipose tissue. The perirenal adipose tissue shows only weak changes in lipid and glucose metabolism. The main changes can be seen in the proteins examined, and probably in their effect on liver metabolism.

Lipidomics based on UHPLC/Q-TOF-MS to characterize lipid metabolic profiling in patients with newly diagnosed type 2 diabetes mellitus with dyslipidemia

Dyslipidemia often accompanies type 2 diabetes mellitus (T2DM). Elevated blood glucose in patients commonly leads to high levels of lipids. Lipid molecules can play a crucial role in early detection, treatment, and prognosis of T2DM with dyslipidemia. Previous lipid studies on T2DM mainly focused on Western diabetic populations with elevated blood glucose. In this research, we investigate both high blood sugar and high lipid levels to better understand changes in plasma lipid metabolism in newly diagnosed Chinese T2DM patients with dyslipidemia (NDDD). We used a plasma lipid analysis method based on ultra-high performance liquid chromatography coupled with mass spectrometry technology (UHPLC-MS) and statistical analysis to characterize lipid profiles and identify potential biomarkers in NDDD patients compared to healthy control (HC) subjects. Additionally, we examined the differences in lipid profiles between hyperlipidemia (HL) patients and HC subjects. We found significant changes in 15 and 23 lipid molecules, including lysophosphatidylcholine (LysoPC), phosphatidylcholine (PC), phosphatidylethanolamine (PE), sphingomyelin (SM), and ceramide (Cer), in the NDDD and HL groups compared to the HC group. These altered lipid molecules are associated with five metabolic pathways, with sphingolipid metabolism and glycerophospholipid metabolism being the most relevant to glucose and lipid metabolism changes. These lipid biomarkers are strongly correlated with traditional markers of glucose and lipid metabolism. Notably, Cer(d18:1/24:0), SM(d18:1/24:0), SM(d18:1/16:1), SM(d18:1/24:1), and SM(d18:2/24:1) were identified as essential potential biomarkers closely linked to clinical parameters through synthetic analysis of receiver operating characteristic curves, random forest analysis, and Pearson matrix correlation. These lipid biomarkers can enhance the risk prediction for the development of T2DM in individuals with dyslipidemia but no clinical signs of high blood sugar. Furthermore, they offer insights into the pathological mechanisms of T2DM with dyslipidemia.