Lactate Utilization Research Articles

Emerging Mechanisms of Lactate Regulation of Biological Processes

Lactate, once considered an inert byproduct of glycolysis, is now increasingly appreciated as a metabolite with diverse roles in cellular metabolism and physiologic regulation. Our understanding of the role of lactate in biological systems can be considered in two categories: metabolic substrate and metabolic signal. These shared roles of lactate can be reconciled through the lens of a metabolite that is suited to regulate cellular function to license adaptation in line with the bioenergetic state of the cell. The mechanisms through which lactate production, transport, and consumption occur within cells and organisms are an area of longstanding and still active research. Here, we focus on how lactate production and utilization as a metabolic substrate feed into its role as a metabolic signal and the emerging mechanisms through which it regulates biological processes.

A leucine responsive small RNA AbcR200 regulates expression of the lactate utilization (lut) operon in Acinetobacter baumannii DS002.

Noncoding small RNAs are essential for modulating bacterial gene expression, especially under carbon and nutrient-limited conditions. In this study, by employing both in silico and molecular hybridization tools, we identified a carbon source responsive small RNA in A. baumannii DS002. Expression of corresponding gene, abcR200, located at the intergenic region of omt (O-methyltransferase) and orf72 genes, is under the transcriptional control of a global transcriptional factor, Leucine Responsive Regulatory Protein (Lrp). A sequence motif that serves as a target for Lrp was found overlapping the abcR200 promoter (PabcR200). Chromatin immunoprecipitation (ChIP) demonstrated that Lrp oligomers, formed under low leucine conditions, strongly interacted to the PabcR200. However, the observed interactions were disrupted in the presence of leucine, as leucine promoted dissociation of Lrp to monomers and dimers, the conformation unfavourable to interact with PabcR200. The abcR200 promoter activity increased with increase of exogenous leucine concentrations, and at 2 mM maximum promoter activity was observed. The AbcR200 target mRNAs were identified by analysing the transcriptome of abcR200 negative strain of A. baumannii. Intriguingly, in abcR200 negative background, expression of lut (lactate utilization) mRNA has increased, suggesting that lut mRNA as one of the mRNA targets for AbcR200. Consistent of this observation, there existed extensive sequence complementarity between AbcR200 and lut mRNA, especially in the regions coding LutP, LutE and LutR. In support of the observed sequence complementarity, the levels of lut mRNA encoded proteins got elevated in abcR200 negative HS002 strains suggesting a role for AbcR200 in translational inhibition of lut mRNA.

Effects of Threshold Pressure Loading Exercises Applied to Inspiratory Muscles in Taekwondo Athletes on the Concentration and Utilization of Lactate

Effects of Threshold Pressure Loading Exercises Applied to Inspiratory Muscles in Taekwondo Athletes on the Concentration and Utilization of Lactate

Diminished lactate utilization in LDHB-deficient neurons leads to impaired long-term memory retention

Neurons' high energy demands for processing, transmitting, and storing information in the brain necessitate efficient energy metabolism to maintain normal neuronal function. The astrocyte-neuron lactate shuttle (ANLS) hypothesis suggests neurons preferentially use lactate from astrocytes over glucose for energy. This study investigated lactate dehydrogenase B (LDHB), which preferentially converts lactate to pyruvate, in neuronal energy metabolism and cognitive function. LDHB-deficient neurons showed reduced lactate-driven energy metabolism in culture, while LDHB-deficient brains accumulated lactate, both indicating decreased lactate utilization. This reduced lactate utilization was correlated with impaired long-term memory in LDHB-deficient mice, while short-term memory remained unaffected and overall neuropathology was only mildly disturbed. Unexpectedly, LDHB-deficient neurons maintain stable energy metabolism under physiological glucose conditions, indicating the presence of lactate dehydrogenase (LDH) activity in LDHB-deficient neurons. The observation of lactate dehydrogenase A (LDHA), which preferentially converts pyruvate to lactate but can also catalyze the reverse reaction less efficiently, in LDHB-deficient neurons may explain their stable energy metabolism and reduced lactate utilization. This study challenges the established concept of strict LDH isoform compartmentalization in brain cells, questioning the exclusive presence of LDHB in neurons and suggesting a more flexible neuronal metabolic profile than previously assumed by the ANSL hypothesis.

Lactate utilization in Lace1 knockout mice promotes browning of inguinal white adipose tissue

Recent studies have focused on identifying novel genes involved in the browning process of inguinal white adipose tissue (iWAT). In this context, we propose that the mitochondrial ATPase gene lactation elevated 1 (Lace1) utilizes lactate to regulate the browning capacity of iWAT, specifically in response to challenge with CL-316,243 (CL), a beta3-adrenergic receptor (β3-AR) agonist. The mice were injected with CL over a span of 3 days and exposed to cold temperatures (4–6 °C) for 1 week. The results revealed a significant increase in Lace1 expression levels during beige adipogenesis. Additionally, a strong positive correlation was observed between Lace1 and Ucp1 mRNA expression in iWAT under browning stimulation. To further explore this phenomenon, we subjected engineered Lace1 KO mice to CL and cold challenges to validate their browning potential. Surprisingly, Lace1 KO mice presented increased oxygen consumption and heat generation upon CL challenge and cold exposure, along with increased expression of genes related to brown adipogenesis. Notably, deletion of Lace1 led to increased lactate uptake and browning in iWAT under CL challenge compared with those of the controls. These unique phenomena stem from increased lactate release due to the inactivation of pyruvate dehydrogenase (PDH) in the hearts of Lace1 KO mice.

A reproducible extended ex-vivo normothermic machine liver perfusion protocol utilising improved nutrition and targeted vascular flows

BackgroundNormothermic machine perfusion of donor livers has become standard practice in the field of transplantation, allowing the assessment of organs and safe extension of preservation times. Alongside its clinical uses, there has been expanding interest in extended normothermic machine perfusion (eNMP) of livers as a potential vehicle for medical research. Reproducible extended normothermic machine perfusion has remained elusive due to its increased complexity and monitoring requirements. We set out to develop a reproducible protocol for the extended normothermic machine perfusion of whole human livers.MethodsHuman livers declined for transplantation were perfused using a blood-based perfusate at 36 °C using the Liver Assist device (XVIVO, Sweden), with continuous veno-venous haemofiltration in-parallel. We developed the protocol in a stepwise fashion.ResultsPerfusion techniques utilised included: targeted physiological vascular flows, phosphate replacement (to prevent hypophosphataemia), N-acetylcysteine (to prevent methaemoglobin accumulation), and the utilisation of sodium lactate as both a nutritional source and real-time measure of hepatocyte function. All five human livers perfused with the developed protocol showed preserved function with a median perfusion time of 168 h (range 120–184 h), with preserved viability throughout.ConclusionsLivers can be reproducibly perfused in excess of 120 (range 121–184) hours with evidence of preserved hepatocyte and cholangiocyte function.

Thermodynamics-driven metabolic and microbial preference for lactate methanization at different operational temperatures

Lactate-dominant organic acids released from acidified feedstocks inhibit anaerobic digestion processes, which can result in decreased biomethane (CH4) yield or even complete process failure. Herein, this study focus on exploring the effects of temperature (35 °C, 38 °C, 41 °C, 44 °C, 47 °C, 50 °C, and 55 °C) on the thermodynamics of microbial communities to assess the thermodynamics or microbial flora in driving the concurrent bioreactions involved in organic acid degradation. The findings revealed a prevalence of species such as Syntrophaceticus schinkii, DTU014, and Methanosarcina at 38 °C-44 °C. These species are known for their abilities in propionate and butyrate degradations, acetate oxidation, and methanation, respectively. Conversely, at thermophilic temperatures (47 °C, 50 °C, and 55 °C), this study observed higher abundance of thermophilic microorganisms like Defluviitoga and Methanoculleus, although these organisms are adapted to higher temperatures, their lactate utilization and methane production were less efficient than mesophilic species. Despite higher ΔG values for lactate, propionate, and butyrate degradation at 38 °C–44 °C compared with thermophilic temperatures, the relative abundance of functional enzymes (specifically, propionate and butyrate degrading enzymes) was found to be marginally higher than 47 °C–55 °C. As a result, 41 °C–44 °C induced remarkable thermodynamic effects that not only facilitated organic acid degradation but also promoted subsequent methanation, indicating the suitability of these temperatures for the methanation of biowaste acidified by lactate. Overall, this study provides insight into the temperature-dependent response of organic acid degradation, specifically focusing on the mechanisms involved in overcoming energy barriers, shaping the microbial flora, and ultimately improving the efficiency and stability of anaerobic digestion, especially for lactate-acidified feedstock.

Utility of Umbilical Arterial Blood Gas Lactate Levels in Predicting Short-term Neonatal Morbidity: A Retrospective Audit in a Tertiary Neonatal Unit

Background: Umbilical cord arterial lactate is a surrogate marker for fetal hypoxia. A poor cord lactate often portends poorer neurological outcomes. Currently, there is no universally accepted threshold for normal cord lactate. Methodology: A retrospective case–control study of 1978 neonates born in a tertiary women’s and children’s hospital with a neonatal intensive care unit was conducted from July 1, 2022, to December 31, 2022. The primary outcome was evaluating the utility of arterial lactate to predict neonatal outcomes. Secondary outcomes included comparing institution guidelines with that of the American College of Obstetricians and Gynecology (ACOG) to determine cutoff thresholds for arterial pH, base excess (BE), and lactate to aid in risk stratification. Results: Cord blood arterial lactate was not a statistically significant predictor of poor neonatal outcomes (odds ratio [OR]: 1.09, [95% confidence interval (CI): 0.84–1.41], P = 0.5320). Babies who are delivered by crash cesarean section (OR: 3.96, [95% CI: 1.11–14.23], P = 0.0343), needed urgent resuscitation at birth (OR: 4.79, [95% CI: 1.63–14.06], P = 0.0044), with poor 1-min Apgar score (OR: 0.62, [95% CI: 0.49–0.78], P < 0.0001) or 5-min Apgar score (OR: 0.12, [95% CI: 0.04–0.37], P = 0.0002), higher venous BE (OR: 0.77, [95% CI: 0.65–0.92], P = 0.0034), or higher venous lactate (OR: 1.43, [95% CI: 1.12–1.82], P = 0.0043) had poorer outcomes. An arterial pH < 7.024, an arterial BE ≥−11.6 mmol/L, and an arterial lactate ≥8.4 mmol/L were deemed optimal cutoffs to predict a poorer neonatal outcome. Both ACOG and our institutional guidelines shared a similar predictive ability to identify neonates with poor cord gases at risk of poor outcomes. Conclusion: Although umbilical cord arterial lactate was not a statistically significant predictor of short-term neonatal morbidity, its clinical utility in predicting poor outcomes alongside maternal, fetal risk factors, and other biochemical indices on the cord blood gas, should not be undervalued.

LDHB-deficient brain exhibits resistance to ischemic neuronal cell death due to increased vasodilation

Ischemic stroke triggers a cascade of metabolic and inflammatory events leading to neuronal death, particularly in the hippocampus. Here, we investigate the role of lactate metabolism in ischemic resistance using LDHB-deficient mice, which exhibit impaired lactate utilization. Contrary to expectations of severe neuronal damage due to metabolic defects, LDHB-deficient mice displayed significantly increased neuronal survival following ischemic insult. Magnetic resonance spectroscopy revealed elevated lactate levels in LDHB-deficient brains, which correlated with enhanced vasodilation of the posterior communicating artery (PComA) and increased extracellular PGE2 levels. These findings suggest that elevated lactate inhibits PGE2 reabsorption, promoting vasodilation and neuronal protection. Our results highlight lactate's potential role in neuroprotection and its therapeutic promise for ischemic stroke.

Predicting metabolic pathways and microbial interactions in dark fermentation systems treating real cheese whey effluents

Dark fermentation of agro-industrial effluents is a promising way for waste valorization. However, understanding the complex microbial dynamics and metabolic interactions within the microbial communities remains challenging. This study investigates the microbial communities involved in continuous hydrogen production from cheese whey and fermented cheese whey using functional profiling with PICRUSt2. The analysis reveals the primary roles of key microbial genera. Lactobacillus dominates carbohydrate consumption and lactate production, while Clostridium sensu stricto 12 and Caproiciproducens are engaged in a competitive dynamic for lactate utilization. Clostridium sensu stricto 12 drives hydrogen production via electron bifurcation reactions, whereas Caproiciproducens may utilize alternative energy conservation mechanisms. The interaction between these genera is influenced by substrate availability and process conditions. This study highlights the utility of functional profiling in elucidating microbial interactions and metabolic pathways in dark fermentation. The findings emphasize the importance of understanding microbial interactions to optimize biohydrogen production processes.

Defining metabolic flexibility in hair follicle stem cell induced squamous cell carcinoma.

We previously showed that inhibition of glycolysis in cutaneous squamous cell carcinoma (SCC)-initiating cells had no effect on tumorigenesis, despite the perceived requirement of the Warburg effect, which was thought to drive carcinogenesis. Instead, these SCCs were metabolically flexible and sustained growth through glutaminolysis, another metabolic process frequently implicated to fuel tumorigenesis in various cancers. Here, we focused on glutaminolysis and genetically blocked this process through glutaminase (GLS) deletion in SCC cells of origin. Genetic deletion of GLS had little effect on tumorigenesis due to the up-regulated lactate consumption and utilization for the TCA cycle, providing further evidence of metabolic flexibility. We went on to show that posttranscriptional regulation of nutrient transporters appears to mediate metabolic flexibility in this SCC model. To define the limits of this flexibility, we genetically blocked both glycolysis and glutaminolysis simultaneously and found the abrogation of both of these carbon utilization pathways was enough to prevent both papilloma and frank carcinoma.

A novel PDHK inhibitor restored cognitive dysfunction and limited neurodegeneration without affecting amyloid pathology in 5xFAD mouse, a model of Alzheimer’s disease

BackgroundAlzheimer’s disease (AD) is the most common form of dementia. Although drugs focusing on reducing amyloid β slow progression, they fail to improve cognitive function. Deficits in glucose metabolism are reflected in FDG-PET and parallel the neurodegeneration and synaptic marker loss closely preceding cognitive decline, but the role of metabolic deficits as a cause or consequence of neurodegeneration is unclear. Pyruvate dehydrogenase (PDH) is lost in AD and an important enzyme connecting glycolysis and the tricarboxylic acid (TCA) cycle by converting pyruvate into acetyl-CoA. It is negatively regulated by pyruvate dehydrogenase kinase (PDHK) through phosphorylation.MethodsIn the present study, we assessed the in vitro/ in vivo pharmacological profile of the novel PDHK inhibitor that we discovered, Compound A. We also assessed the effects of Compound A on AD-related phenotypes including neuron loss and cognitive impairment using 5xFAD model mice.ResultsCompound A inhibited human PDHK1, 2 and 3 but had no inhibitory activity on PDHK4. In primary neurons, Compound A enhanced pyruvate and lactate utilization, but did not change glucose levels. In contrast, in primary astrocytes, Compound A enhanced pyruvate and glucose utilization and enhanced lactate production. In an efficacy study using 5xFAD mice, Compound A ameliorated the cognitive dysfunction in the novel object recognition test and Morris water maze. Moreover, Compound A prevented neuron loss in the hippocampus and cerebral cortex of 5xFAD without affecting amyloid β deposits.ConclusionsThese results suggest ameliorating metabolic deficits by activating PDH by Compound A can limit neurodegeneration and is a promising therapeutic strategy for treating AD.

Origin of biogeographically distinct ecotypes during laboratory evolution

Resource partitioning is central to the incredible productivity of microbial communities, including gigatons in annual methane emissions through syntrophic interactions. Previous work revealed how a sulfate reducer (Desulfovibrio vulgaris, Dv) and a methanogen (Methanococcus maripaludis, Mm) underwent evolutionary diversification in a planktonic context, improving stability, cooperativity, and productivity within 300–1000 generations. Here, we show that mutations in just 15 Dv and 7 Mm genes within a minimal assemblage of this evolved community gave rise to co-existing ecotypes that were spatially enriched within a few days of culturing in a fluidized bed reactor. The spatially segregated communities partitioned resources in the simulated subsurface environment, with greater lactate utilization by attached Dv but partial utilization of resulting H2 by low affinity hydrogenases of Mm in the same phase. The unutilized H2 was scavenged by high affinity hydrogenases of planktonic Mm, producing copious amounts of methane. Our findings show how a few mutations can drive resource partitioning amongst niche-differentiated ecotypes, whose interplay synergistically improves productivity of the entire mutualistic community.

Evaluating Lactate and D-Dimer as Mortality Predictors of Paediatric Multiple Organ Dysfunction Syndrome: A Prospective Study in a Low-Middle Income Country.

Multiple Organ Dysfunction Syndrome (MODS) is a complex medical condition characterised by dysfunction across multiple organs. With limited information available on mortality prediction in the paediatric population, particularly in low-middle income countries, this study evaluates the mortality predicting capabilities of lactate, D-dimer, and their combination. This prospective study involved paediatric patients admitted to the paediatric intensive care unit (PICU) of the largest central children's hospital in the Mekong Delta region, Vietnam, from 2019 to 2021. The discriminative ability and calibration of both individual and combined tests were assessed using the receiver operating characteristic (ROC) curves and the Hosmer-Lemeshow goodness-of-fit test. Among the patients studied, 63.1% did not survive. Lactate and D-dimer concentrations were significantly higher in the non-survivor group (P < 0.001). The area under the curve (AUC) values for lactate, D-dimer and the combined lactate-D-dimer test were 0.742, 0.775 and 0.804, respectively, with the combination showing the highest AUC value, though without statistical significance. Specific thresholds for lactate, D-dimer and the combination yielded sensitivities of 75.5%, 71.7%, and 66.0%, respectively. All three tests showed no statistically significant differences between observed and predicted mortality in the Hosmer-Lemeshow test (all P-values > 0.05). Lactate and D-dimer levels showed a significant association with mortality, along with good discrimination and calibration abilities. These results highlight the utility of lactate and D-dimer as effective predictors in paediatric MODS, particularly in resource-limited settings, and their role in improving patient outcomes.

Determining lactate concentrations in Korean indigenous calves and evaluating its role as a predictor for acidemia in calf diarrhea

BackgroundCalf diarrhea leads to high mortality rates and decreases in growth and productivity, causing negative effects on the livestock industry. Lactate is closely associated with metabolic acidosis in diarrheic calves. However, there have been no reports on lactate concentrations in Korean indigenous (Hanwoo) calves, especially those with diarrhea. This study aimed to determine the reference range of L-lactate and D-lactate concentrations in Hanwoo calves and to better understand the utility of lactate as predictive factors for acidemia in diarrheic calves.ResultsL-lactate and D-lactate concentrations were measured in healthy (n = 44) and diarrheic (n = 93) calves, and blood gas analysis was performed on diarrheic calves. The reference range in healthy calves was 0.2–2.25 mmol/L for L-lactate and 0.42–1.38 mmol/L for D-lactate. Diarrheic calves had higher concentrations of L-lactate and D-lactate than healthy calves. In diarrheic calves, L-lactate and D-lactate each had weak negative correlation with pH (r = − 0.31 and r = − 0.35). In diarrheic calves with hyper-L-lactatemia, the combined concentrations of L-lactate and D-lactate had moderate correlation with pH (r = − 0.51) and anion gap (r = 0.55). Receiver operating characteristic analysis showed D-lactate had fair predictive performance (AUC = 0.74) for severe acidemia, with an optimal cut-off value of > 1.43 mmol/L. The combined concentrations of L-lactate and D-lactate showed fair predictive performance for predicting acidemia (AUC = 0.74) and severe acidemia (AUC = 0.72), with cut-off values of > 6.05 mmol/L and > 5.95 mmol/L.ConclusionsThe determined reference ranges for L-lactate and D-lactate in Hanwoo calves enable the identification of hyper-L-lactatemia and hyper-D-lactatemia. Diarrheic calves exhibited increased lactate concentrations correlated with acid-base parameters. While the concentrations of L-lactate and D-lactate have limitations as single diagnostic biomarkers for predicting acidemia or severe acidemia, their measurement remains important, and L-lactate has the advantage of being measurable at the point-of-care. Assessing lactate concentrations should be considered by clinicians, especially when used alongside other clinical indicators and diagnostic tests. This approach can improve calf diarrhea management, contributing positively to animal welfare and providing economic benefits to farms.

Ex-Vivo 13C NMR Spectroscopy of Rodent Brain: TNF Restricts Neuronal Utilization of Astrocyte-Derived Metabolites.

Tumor necrosis factor (TNF) has well-established roles in neuroinflammatory disorders, but the effect of TNF on the biochemistry of brain cells remains poorly understood. Here, we microinjected TNF into the brain to study its impact on glial and neuronal metabolism (glycolysis, pentose phosphate pathway, citric acid cycle, pyruvate dehydrogenase, and pyruvate carboxylase pathways) using 13C NMR spectroscopy on brain extracts following intravenous [1,2-13C]-glucose (to probe glia and neuron metabolism), [2-13C]-acetate (probing astrocyte-specific metabolites), or [3-13C]-lactate. An increase in [4,5-13C]-glutamine and [2,3-13C]-lactate coupled with a decrease in [4,5-13C]-glutamate was observed in the [1,2-13C]-glucose-infused animals treated with TNF. As glutamine is produced from glutamate by astrocyte-specific glutamine synthetase the increase in [4,5-13C]-glutamine reflects increased production of glutamine by astrocytes. This was confirmed by infusion with astrocyte substrate [2-13C]-acetate. As lactate is metabolized in the brain to produce glutamate, the simultaneous increase in [2,3-13C]-lactate and decrease in [4,5-13C]-glutamate suggests decreased lactate utilization, which was confirmed using [3-13C]-lactate as a metabolic precursor. These results suggest that TNF rearranges the metabolic network, disrupting the energy supply chain perturbing the glutamine-glutamate shuttle between astrocytes and the neurons. These insights pave the way for developing astrocyte-targeted therapeutic strategies aimed at modulating effects of TNF to restore metabolic homeostasis in neuroinflammatory disorders.

MCT1-dependent lactate recycling is a metabolic vulnerability in colorectal cancer cells upon acquired resistance to anti-EGFR targeted therapy

Despite the implementation of personalized medicine, patients with metastatic CRC (mCRC) still have a dismal overall survival due to the frequent occurrence of acquired resistance mechanisms thereby leading to clinical relapse. Understanding molecular mechanisms that support acquired resistance to anti-EGFR targeted therapy in mCRC is therefore clinically relevant and key to improving patient outcomes. Here, we observe distinct metabolic changes between cetuximab-resistant CRC cell populations, with in particular an increased glycolytic activity in KRAS-mutant cetuximab-resistant CRC cells (LIM1215 and OXCO2) but not in KRAS-amplified resistant DiFi cells. We show that cetuximab-resistant LIM1215 and OXCO2 cells have the capacity to recycle glycolysis-derived lactate to sustain their growth capacity. This is associated with an upregulation of the lactate importer MCT1 at both transcript and protein levels. Pharmacological inhibition of MCT1, with AR-C155858, reduces the uptake and oxidation of lactate and impairs growth capacity in cetuximab-resistant LIM1215 cells both in vitro and in vivo. This study identifies MCT1-dependent lactate utilization as a clinically actionable, metabolic vulnerability to overcome KRAS-mutant-mediated acquired resistance to anti-EGFR therapy in CRC.

Thermophilic fermentation of sugarcane vinasse: Process flexibility explained through characterizing microbial community and predicting metabolic functions

This study unravels some of the complex microbial interactions established in the fermentation of sugarcane vinasse. The microbial communities of four thermophilic (55 °C) fixed-bed vinasse-fed reactors were analyzed by 16S rRNA gene amplicon sequencing and the marker gene data were aligned with reference genomes to predict metabolic functions of the microorganisms. The production (by Lactobacillus) and utilization (mainly by Thermoanaerobacterium and Caproiciproducens) of lactate explain the primary pathways associated with substrate fermentation towards biohydrogen, whilst only a single genus (Desulfotomaculum) and very low abundances of the enzymes involved in sulfate reduction were found. Although the abundant microbes in the inocula failed to grow during the continuous operation in all reactors, these fermentative consortia behave like microbial pantries containing bacteria that will grow according to the operating conditions, shaping lactate-accumulating (pH < 5.0) or lactate-consuming (pH > 5.0) and eventually sulfate-reducing (pH > 6.0) microbial communities in vinasse thermophilic fermentation.

Blocking the utilization of carbon sources via two pathways to induce tumor starvation for cancer treatment

Glucose oxidase (GOx) is often used to starvation therapy. However, only consuming glucose cannot completely block the energy metabolism of tumor cells. Lactate can support tumor cell survival in the absence of glucose. Here, we constructed a nanoplatform (Met@HMnO2-GOx/HA) that can deplete glucose while inhibiting the compensatory use of lactate by cells to enhance the effect of tumor starvation therapy. GOx can catalyze glucose into gluconic acid and H2O2, and then HMnO2 catalyzes H2O2 into O2 to compensate for the oxygen consumed by GOx, allowing the reaction to proceed sustainably. Furthermore, metformin (Met) can inhibit the conversion of lactate to pyruvate in a redox-dependent manner and reduce the utilization of lactate by tumor cells. Met@HMnO2-GOx/HA nanoparticles maximize the efficacy of tumor starvation therapy by simultaneously inhibiting cellular utilization of two carbon sources. Therefore, this platform is expected to provide new strategies for tumor treatment.

Modelling and assessment of glucose-lactate kinetics in youth withoverweight, obesityand metabolic dysfunction-associated steatotic liver disease: A pilot study.

In this study, we investigated glucose and lactate kinetics during a 75 g oral glucose tolerance test (OGTT) in 23 overweight and obese adolescents and assessed putative differences among participants with and without metabolic dysfunction-associated steatotic liver disease (MASLD). We enrolled 23 young people (six girls) with obesity [body mass index 33 (29-37)]. Glucose-lactate kinetics parameters (disposal glucose insulin sensitivity, SID; fraction of glucose converted into lactate, fr; fractional lactate clearance rate, kL) and lactate production rate (LPR) were estimated using the oral glucose-lactate minimal model. MASLD presence was assessed using the proton density fat fraction. We analysed glucose, lactate and LPR time to peak, peak values and area under the curve and evaluated differences using the Wilcoxon test. MASLD and no-MASLD participants were compared using the Mann-Whitney test. Correlations between parameters were assessed using the Spearman correlation coefficient (ρ). We also tested the performance of two (4 or 3 h OGTT) protocols in estimating oral glucose-lactate minimal model and LPR parameters. Glucose peaks 30 min earlier than lactate (p = .0019). This pattern was present in the no-MASLD group (p < .001). LPR peaks 30 min later in the MASLD group (p = .02). LPR and kL were higher in MASLD, suggesting higher glycolysis and lactate utilization. SID and fr correlate significantly (ρ = -0.55, p = .008). SID and fr were also correlated with the body mass index, (ρ = -0.45, p = .04; and ρ = 0.45; p = .03). The protocol duration did not influence the estimates of the parameters. Youth with MASLD showed a delayed glucose metabolism, possibly because of greater utilization of the underlying substrates. A 3-h OGTT may be used to assess lactate metabolism effectively.