Insulin dysregulation (ID) is a common metabolic disorder in horses, characterized by hyperinsulinemia and/or peripheral insulin resistance. The critical role of hyperinsulinemia in endocrinopathic laminitis has driven research into the insulinotropic effects of dietary nutrients and the reciprocal impact of ID on nutrient metabolism. The relationship between ID and carbohydrate metabolism has been extensively studied; however, the effects of ID on protein metabolism in horses remain largely unexplored. This review begins with an overview of the importance of insulin in the regulation of muscle protein synthesis and degradation and then examines the current understanding of the interplay between ID and protein and carbohydrate metabolism in horses. Horses with ID exhibit altered resting plasma amino acid concentrations and shifts in postprandial amino acid dynamics. Recent work illustrated that ID horses had higher levels of plasma amino acids following a protein meal and delayed postprandial clearance from the blood compared to non-ID horses. The postprandial muscle synthetic response does not seem to be diminished in ID horses, but alterations in key cellular signaling molecules have been reported. ID horses display a pronounced hyperinsulinemic response following the consumption of feeds providing a range of protein, non-structural carbohydrate, starch and water-soluble carbohydrate intakes. Recent studies have shown that ID horses have an increased postprandial incretin response, contributing to the observed hyperinsulinemia. To minimize the postprandial insulin response, thresholds for carbohydrate consumption have recently been proposed. Similar thresholds should be established for protein to aid in the refinement of nutritional strategies to manage ID horses.

To identify hub metabolic biomarkers that constructively shape the type 2 diabetes mellitus (T2DM) risk network.

We analysed data from 98 831 UK Biobank participants, confirming T2DM diagnoses via medical records and International Classification of Diseases codes. Totally 168 circulating metabolites were quantified by nuclear magnetic resonance at baseline. Metabolome-wide association studies with Cox proportional hazards models were performed to identify statistically significant metabolites. Network analysis was applied to compute topological attributes (degree, betweenness, closeness and eigencentrality) and to detect small-world features (high clustering, short path lengths). Identified metabolites were used with XGBoost models to assess risk prediction performance.

Over a median 12-year follow-up, 114 metabolites were significantly associated with T2DM risk and clustered into three distinct small-world modules. Total triglycerides and large high-density lipoprotein (HDL) cholesterol emerged as the pivotal biomarkers in the 'risk' and 'protective' modules, respectively, as evidenced by their high eigencentrality. Moreover, total branched-chain amino acids (BCAAs) exhibited small-world network characteristics exclusively in pre-T2DM individuals, suggesting them as a potent early indicators. GlycA demonstrated high closeness centrality in females, implying a female-specific risk biomarker.

By constructing a metabolic network that captures the complex interrelationships among circulating metabolites, our study identified total triglycerides and large HDL cholesterol as central hubs in the T2DM risk metabolome network. BCAA and GlycA emerged as alarm indicators for pre-T2DM individuals and females, respectively. Network analysis not only elucidates the topological functional roles of biomarkers but also addresses the limitations of false positives and collinearity in single-metabolite studies, offering insights for metabolic pathway research and precision interventions.

Background: Muscle loss during sarcopenia and atrophy is also commonly associated with age-related insulin resistance. Interestingly, branched-chain amino acids (BCAA) which are known for stimulating muscle protein synthesis are commonly elevated during insulin resistance and sarcopenic obesity. Objectives: This study investigated the effects of the interplay between atrophy and insulin resistance on insulin sensitivity, mitochondrial metabolism, and BCAA catabolic capacity in a myotube model of skeletal muscle insulin resistance. Methods: C2C12 myotubes were treated with dexamethasone to induce atrophy. Insulin resistance was induced via hyperinsulinemia. Gene and expression were measured using qRT-PCR and Western blot, while mitochondrial and lipid content were assessed using fluorescent staining. Cell metabolism was analyzed via Seahorse metabolic assays. Results: Both dexamethasone-induced atrophy and insulin resistance independently reduced insulin-stimulated pAkt levels, as well as mitochondrial function and content. However, neither treatment affected gene or protein expression associated with mitochondrial biogenesis or content. Although dexamethasone independently reduced insulin sensitivity in otherwise previously insulin-sensitive cells, dexamethasone had no significant effect on extracellular BCAA content. Conclusions: Our findings indicate the metabolic interplay between atrophy and insulin resistance and demonstrate that both can reduce mitochondrial function, though only limited effects were observed on indicators of BCAA catabolism and utilization. This emphasizes the need for future studies to investigate the mechanisms that underlie atrophy and other metabolic disorders to develop new interventions.

We previously identified tetraspanin 7 (Tspan7) as a candidate gene influencing body weight in an obesity-related gene screening study. However, the mechanisms underlying its involvement in body weight regulation remained unclear. This study aims to investigate the role of TSPAN7 from a metabolic perspective.

We utilized genetically modified mice, including adipose tissue-specific Tspan7-knockout and Tspan7-overexpressing models, as well as human adipose-derived stem cells with TSPAN7 knockdown and overexpression. Morphological, molecular, and omics analyses, including proteomics and transcriptomics, were performed to investigate TSPAN7 function. Physiological effects were assessed by measuring blood markers associated with lipid regulation under metabolic challenges, such as high-fat feeding and aging.

We show that TSPAN7 is involved in regulating lipid droplet formation and stabilization. Tspan7-knockout mice exhibited an increased proportion of small-sized adipocytes and a reduced visceral-to-subcutaneous fat ratio. This shift in fat distribution was associated with improved insulin sensitivity and altered branched-chain amino acid metabolism, as evidenced by increased expression of the branched-chain α-keto acid dehydrogenase complex subunit B in Tspan7-modified mice. Mechanistically, TSPAN7 deficiency promoted subcutaneous fat expansion, alleviating metabolic stress on visceral fat, a major contributor to insulin resistance.

TSPAN7 influences lipid metabolism by modulating adipose tissue remodeling, particularly under metabolic challenges, such as high-fat diet exposure and aging. Its modulation enhances subcutaneous fat storage capacity while mitigating visceral fat accumulation, leading to improved insulin sensitivity. These findings position TSPAN7 as a potential target for therapeutic interventions aimed at improving metabolic health and preventing obesity-related diseases.

The number of colorectal cancer (CRC) patients is steadily growing worldwide, particularly in developing nations. Nonetheless, recent advances in early detection studies and therapy alternatives have reduced CRC mortality in affluent countries, despite rising incidence. Gut microbiota and their metabolites may contribute to tumor growth and reduced therapeutic efficacy. This preliminary study sought to uncover metabolic fingerprints in colorectal cancer patients. It also emphasizes the correlation between the gut microbiome, microbial metabolism, and altered metabolites in CRC. In this study, stool samples from 20 CRC patients and matched healthy controls were enrolled. Untargeted metabolomics approach based on an ultra-high-performance liquid chromatography high-resolution mass spectrometry (UHPLC-MS/MS) were applied. Statistical approaches, pathway enrichment analysis, and network analysis were employed to unleash CRC perturbed metabolic pathways and putative biomarkers. The study identified a distinct manually curated metabolite profile that is substantially linked to CRC. The steroidogenesis, aspartate, tryptophan (Trp), and urea cycle were the most significant pathways that concurrently contributed to CRC.Prominently, among other pathways, Trp metabolism was identified as a critical pathway, indicating a possible connection between the development of CRC and gut microbiota. In a nutshell the notable resulted metabolites reveal auspicious biomarkers for the initial diagnosis as well as surveilling of CRC progression. This preliminary study highlights the potential involvement that gut bacteria may contribute in CRC patients. Further investigation into the composition of the gut microbiome associated with this metabolic profile may lead to the identification of novel biomarkers for early detection and possible targets for treatment.

Diabetes-associated cognitive impairment (DACI) is a common complication of Type 2 diabetes mellitus (T2DM), with its mechanisms and treatments for DACI remaining incompletely clarified. This study investigated the protective efficacy of the novel lipid S-enantiomer of 9-palmitic acid esters of hydroxy stearic acids (S-9-PAHSA, S9P) in a high-fat diet-induced DACI mouse model.

Mice were randomly assigned to three groups: normal diet (ND), high-fat diet (HFD), and HFD + 30 mg/kg/day S9P (HFD + S9P). Fasting blood glucose (FBG), intraperitoneal glucose tolerance test (IPGTT), and insulin tolerance test (ITT) were conducted to assess blood glucose homeostasis. Morris Water Maze and Y maze tests evaluated cognitive function, and neuronal status was examined through pathological analysis, Golgi staining, and transmission electron microscopy (TEM). Colonic barrier integrity was assessed using periodic acid-Schiff and Alcian blue staining (AB-PAS) and immunohistochemistry (IHC) staining. Intestinal microbiota composition was analyzed by 16S rDNA sequencing, and serum metabolic characteristics were determined by metabolomics sequencing.

S9P improved glucose homeostasis and alleviated cognitive decline in DACI mice. It also mitigated neuronal damage, dendritic degeneration, and synaptic damage, while restoring colonic barrier integrity and ameliorating gut microbiome imbalances, insulin resistance, and lipid imbalance. Additionally, S9P regulated metabolite profiles and the PI3K/AKT/mTOR signaling pathways, and reduced astrocyte activation and neuroinflammatory responses in the hippocampus of HFD-induced DACI mice.

S9P had a protective effect against HFD-induced diabetic cognitive impairment closely related to the modulation of the gut-brain axis, suggesting that S9P has the potential to become a new therapeutic approach for DACI.

The sleep-wake cycle stands as an integrative process essential for sustaining optimal brain function and, either directly or indirectly, overall body health, encompassing metabolic and cardiovascular well-being. Given the heightened metabolic activity of the brain, there exists a considerable demand for nutrients in comparison to other organs. Among these, the branched-chain amino acids, comprising leucine, isoleucine, and valine, display distinctive significance, from their contribution to protein structure to their involvement in overall metabolism, especially in cerebral processes. Among the first amino acids that are released into circulation post-food intake, branched-chain amino acids assume a pivotal role in the regulation of protein synthesis, modulating insulin secretion and the amino acid sensing pathway of target of rapamycin. Branched-chain amino acids are key players in influencing the brain's uptake of monoamine precursors, competing for a shared transporter. Beyond their involvement in protein synthesis, these amino acids contribute to the metabolic cycles of γ-aminobutyric acid and glutamate, as well as energy metabolism. Notably, they impact GABAergic neurons and the excitation/inhibition balance. The rhythmicity of branched-chain amino acids in plasma concentrations, observed over a 24-hour cycle and conserved in rodent models, is under circadian clock control. The mechanisms underlying those rhythms and the physiological consequences of their disruption are not fully understood. Disturbed sleep, obesity, diabetes, and cardiovascular diseases can elevate branched-chain amino acid concentrations or modify their oscillatory dynamics. The mechanisms driving these effects are currently the focal point of ongoing research efforts, since normalizing branched-chain amino acid levels has the ability to alleviate the severity of these pathologies. In this context, the Drosophila model, though underutilized, holds promise in shedding new light on these mechanisms. Initial findings indicate its potential to introduce novel concepts, particularly in elucidating the intricate connections between the circadian clock, sleep/wake, and metabolism. Consequently, the use and transport of branched-chain amino acids emerge as critical components and orchestrators in the web of interactions across multiple organs throughout the sleep/wake cycle. They could represent one of the so far elusive mechanisms connecting sleep patterns to metabolic and cardiovascular health, paving the way for potential therapeutic interventions.

Pecan consumption consistently improves lipoproteins, but less research has investigated the effect of pecans on lipoprotein subfractions.

The aim was to investigate the effect of substitution of usual snack foods with 57 g/d of pecans on lipoprotein particle subfractions and apolipoproteins compared with continuing usual intake after 12 wk. Exploratory analyses evaluated effects on early markers of insulin resistance including the Lipoprotein Insulin Resistance Index (LP-IR), Diabetes Risk Index, and GlycA.

A 12-wk, randomized, 2-armed parallel trial in adults at risk of cardiometabolic disease was conducted. Participants were instructed to either consume 57 g/d of pecans in place of usual snacks or to continue their usual intake. Plasma samples collected at baseline and 12 wk were analyzed for lipoproteins, apolipoproteins, and GlycA by proton nuclear magnetic resonance spectroscopy. Between-group differences in the change from baseline were evaluated with linear regression.

In total, 138 participants were randomly assigned (n = 69 per group) and 130 participants (pecan group n = 62; usual diet group n = 68) completed the trial. The pecan group had a greater reduction from baseline in the concentrations of apolipoprotein B (apoB) [-4.38 mg/dL; 95% confidence interval (CI): -8.02, -0.73], total low-density lipoprotein particles (-75.3 nmol/L; 95% CI: -144, -6.93), total triglyceride-rich lipoprotein particles (TRL-P) (-20.4 nmol/L; 95% CI: -33.8, -7.03), large (-1.47 nmol/L; 95% CI: -2.69, -0.26) and small (-11.3 nmol/L; 95% CI: -22.4, -0.27) TRL-P and the LP-IR (-4.42 points; 95% CI: -8.14, -0.69), and greater increases from baseline in the concentration of large high-density lipoprotein particles (0.35 μmol/L; 95% CI: 0.07, 0.63) compared with the usual diet group.

Incorporating 57 g/d of pecans into the diet in place of usual snacks for 12 wk improved apoB, atherogenic lipoprotein subfractions, and the LP-IR in adults at risk of cardiometabolic diseases. This trial was registered at clinicaltrials.gov as NCT05071807.

How different is the global proteomic and metabolic profile of mouse blastocysts generated by IVF, cultured in optimal (5% O2) or stressful (20% O2) conditions, compared to in vivo generated blastocysts?

We found that in IVF-generated embryos: (i) the proteome was more sensitive to high oxygen levels than the global metabolomic profile; (ii) enzymes involved in splicing and the spliceosome are altered; (iii) numerous metabolic pathways, particularly amino acids metabolism, are altered (iv) there is activation of the integrated stress response (ISR) and downregulation of mTOR pathways.

IVF culture conditions are known to affect the gene expression of embryos. However, comprehensive data on the global metabolic and proteomic changes that occur in IVF-generated embryos are unknown.

Mouse embryos were generated by natural mating (in vivo control or flushed blastocyst-FB-group) or by IVF using KSOM medium and two distinct oxygen concentrations: 5% O2 (optimal) and 20% O2 (stressful). Proteomic and metabolomic analyses were performed using state-of-the-art mass spectrometry techniques in triplicate (n = 100 blastocysts per replicate), allowing for detailed profiling of protein and metabolite alterations in each group.

Mouse blastocysts were collected from CD-1 and B6D2F1 strains as specified above. High-resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used for proteomics, while high-performance liquid chromatography coupled with mass spectrometry (HILIC-MS) was used for metabolomics. In addition, Immunofluorescence was used to assess the activation of stress response pathways, including the ISR.

Proteomic analysis revealed significant changes in protein expression in embryos cultured under 20% O2 compared to 5% O2 and in vivo embryos. Compared to in vivo embryos, IVF embryos cultured under 20% O2 exhibited 599 differentially expressed proteins, with an increase in proteins involved in oxidative stress responses, aminoacyl-tRNA synthesis, and spliceosome pathways. In contrast, IVF embryos cultured under 5% O2 showed fewer changes, with 426 differentially expressed proteins, though still reflecting significant alterations compared to in vivo embryos. These results indicate that embryos in stressful conditions (20% O2) exhibit a stronger stress response and alterations in critical pathways for protein synthesis and DNA repair. Metabolomic analysis revealed that embryos cultured under 20% O2 showed changes in branch-chained amino acid levels, and decreased levels of key metabolites of the TCA cycle and pentose phosphate pathway. Embryos cultured under 5% O2 had increased pyruvate levels, suggesting altered glycolysis. Immunofluorescence confirmed that oxidative stress markers such as GCN2, EIF2α, and ATF4 were upregulated in IVF embryos, indicating ISR activation. Overall, IVF and embryo culture have a direct impact on embryo proteomes and metabolomes affecting amino acid metabolism and stress-related pathways.

N/A.

Results in a murine model should be extrapolated with caution to human embryos.

These findings offer valuable insights into how different IVF culture conditions, specifically oxygen levels, impact the global metabolic and proteomic profiles of embryos. These findings provide critical insights into the profound impact of IVF culture conditions, particularly oxygen levels, on the global metabolic and proteomic landscapes of embryos. By identifying key metabolic pathways disrupted by oxidative stress, we highlight the potential clinical importance of proteomic and metabolomic analyses in understanding embryo quality, improving ART, and ultimately enhancing pregnancy outcomes. The integration of metabolomic and proteomic data offers a comprehensive understanding of how oxidative stress influences cellular function. These insights have direct clinical relevance, providing a foundation for optimizing ART protocols to mitigate oxidative stress.

This work was supported by grant R01 HD108166-01A1 from the National Institute of Child Health and Human Development (NICHD) to P.F.R. The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Plasma amino acids (AAs) have emerged as promising biomarkers for metabolic disorders, yet their causality remains unclear. We aimed to investigate the genetic determinants of AA levels in a cohort of 10,333 individuals and their causal effects on cardiometabolic traits using Mendelian randomization (MR). Plasma levels of 20 AAs were quantified using capillary electrophoresis mass spectrometry. Genome-wide association studies were conducted using BOLT-LMM and heritability estimation via LDSC analysis. Causal effects of AAs on 11 cardiometabolic traits were examined using two-sample MR analyses. We identified 85 locus-metabolite associations across 43 genes for 18 AAs, including 44 novel loci linked to metabolic genes. Heritability for AAs was estimated at 16%. MR analysis demonstrated cystine to positively associate with systolic blood pressure (SBP) (β = 0.056, SE = 0.010), while serine indicated protective effects on SBP (β = - 0.040, SE = 0.011), diastolic BP (β = - 0.044, SE = 0.010), and coronary artery disease (odds ratio 0.888, SE = 0.028). We identified potentially novel genetic loci associated with AA levels and demonstrated robust causal associations between several AAs and cardiometabolic traits. These findings reinforce the importance of AAs as potential biomarkers and therapeutic targets in cardiometabolic health.

The gut microbiota, shaped by factors such as diet, lifestyle, and genetics, plays a pivotal role in regulating host metabolism, immune function, and overall health. The diversity and balance of the gut microbiota are closely linked to the onset and progression of various chronic diseases. A growing body of evidence has demonstrated that alterations in the composition, function, and metabolites of the gut microbiota are significantly associated with cardiovascular diseases, including hypertension, atherosclerosis, and heart failure; metabolic disorders such as obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease; and gastrointestinal conditions like inflammatory bowel disease and colorectal cancer. Despite substantial advances in microbiome research, challenges remain in fully elucidating the causal relationships between the gut microbiota and disease, as well as in translating these insights into clinical applications. This review aims to investigate the regulatory pathways via which the gut microbiota affects cardiovascular health, metabolic function, and gastrointestinal disease. Additionally, it highlights emerging strategies for the prevention and treatment of these chronic conditions, focusing on microbiota-targeted therapies and personalized dietary interventions as promising approaches for improving health outcomes.

Interpreting genetic associations with complex traits can be greatly improved by detailed understanding of the molecular consequences of these variants. However, although genome-wide association studies (GWAS) for common complex diseases routinely profile 1M+ individuals, studies of molecular phenotypes have lagged behind. We performed a GWAS meta-analysis for 249 circulating metabolic traits in the Estonian Biobank and the UK Biobank in up to 619,372 individuals, identifying 88,604 significant locus-metabolite associations and 8,774 independent lead variants, including 987 lead variants with a minor allele frequency less than 1%. We demonstrate how common and low-frequency associations converge on shared genes and pathways, bridging the gap between rare-variant burden testing and common-variant GWAS. We used Mendelian randomisation (MR) to explore putative causal links between metabolic traits, coronary artery disease and type 2 diabetes (T2D). Surprisingly, up to 85% of the tested metabolite-disease pairs had statistically significant genome-wide MR estimates, likely reflecting complex indirect effects driven by horisontal pleiotropy. To avoid these pleiotropic effects, we used cis-MR to test the phenotypic impact of inhibiting specific drug targets. We found that although plasma levels of branched-chain amino acids (BCAAs) have been associated with T2D in both observational and genome-wide MR studies, inhibiting the BCAA catabolism pathway to lower BCAA levels is unlikely to reduce T2D risk. Our publicly available results provide a valuable novel resource for GWAS interpretation and drug target prioritisation.

Branched- chain fatty acids (BCFAs) are a category of saturated fatty acids that are commonly present in various organisms and play a crucial role in a variety of metabolic reactions, including anticancer, lipid-lowering, anti-inflammatory, and neuroprotective actions. Currently, there is growing interest in the relationship between BCFAs and obesity. Branched- chain fatty acids regulate the gene expression of related enzymes by activating PPARα and sterol regulatory element-binding protein-1c, thereby reducing triglyceride synthesis in the body. Additionally, BCFAs reduce inflammation by decreasing the expression of pro-inflammatory factors in obesity such as cyclooxygenase-2, interleukin-6, and lipoxygenase-15 genes. Branched- chain fatty acids can also expedite the conversion of branched chain amino acids to BCFAs to regulate obesity-induced insulin resistance. In this article we provide a comprehensive review of research progress on how BCFAs affect obesity from the perspectives of lipid metabolism, inflammation, and insulin resistance.

Metabolic reprogramming enables tumour cells to sustain their continuous proliferation and adapt to the ever-changing microenvironment. Branched-chain amino acids (BCAAs) and their metabolites are involved in intracellular protein synthesis and catabolism, signal transduction, epigenetic modifications, and the maintenance of oxidative homeostasis. Alterations in BCAA metabolism can influence the progression of various tumours. However, how BCAA metabolism is dysregulated differs among depending on tumour type; for example, it can manifest as decreased BCAA metabolism leading to BCAA accumulation, or as enhanced BCAA uptake and increased catabolism. In this review, we describe the role of BCAA metabolism in the progression of different tumours. As well as discuss how BCAA metabolic reprogramming drives tumour therapy resistance and evasion of the antitumour immune response, and how these pro-cancer effects are achieved in part by activating the mTORC signalling pathway. In-depth investigations into the potential mechanisms by which BCAA metabolic reprogramming affects tumorigenesis and tumour progression can enhance our understanding of the relationship between metabolism and cancer and provide new strategies for cancer therapy.

With the global population expected to reach 10 billion by the 2050s, the demand for protein will surge, intensifying the need for high protein utilization efficiency. This study investigates the use of protease-enhanced Streptomyces sp. SCUT-3-3940 to degrade soybean meal (SBM) via solid-state fermentation (SSF). Optimized conditions resulted in anti-nutritional factors elimination and high soluble protein recovery (41.1 g/100 g), including bioactive oligopeptides (17.3 g/100 g) with antihypertensive and antioxidant properties. The degradation also produced free amino acids rich in essential amino acids, and other nutrient enhancing compounds. The fermented SBM (FSBM) exhibited superior digestibility, making it a valuable protein source. In a 60-day largemouth bass trial, replacing 10 % SBM with FSBM in feed significantly improved feed intake and weight gain. This method offers an efficient, eco-friendly, and cost-effective solution to address global protein shortages.

Pyridoxal 5'-phosphate (PLP), the biologically active form of vitamin B6 is involved in 4% of cellular enzymatic activities and its deficiency is responsible for or contributes to several human diseases. The study of underlying mechanisms is still in its infancy and requires suitable model organisms. In Drosophila the deficiency of vitamin B6 produces chromosome aberrations and hallmarks of human diseases including diabetes and cancer. However, the effects of vitamin B6 deficiency have never been examined at a metabolic level.

This study evaluates the metabolic changes in vitamin B6 deficient Drosophila larvae with the aim of validating flies as a suitable model for diseases associated to vitamin B6 deficiency.

To induce vitamin B6 deficiency we fed Drosophila wild type larvae with 4-deoxypyridoxine (4DP), a PLP antagonist. By HPLC analysis we verified that the 4DP treatment was effective in inducing vitamin B6 deficiency. Using an NMR-based metabolomic approach we compared the metabolites in larval extracts from untreated and 4DP-fed larvae.

The NMR spectra analysis identified quantitative differences for sixteen metabolites out of forty, including branched chain and aromatic amino acids, glucose, and lipids, thus revealing interesting possible associations with the phenotypes showed by vitamin B6 deficient flies.

Our results validate Drosophila as a suitable model to study in depth the molecular mechanisms underlying human diseases associated with vitamin B6 deficiency and confirmed that 4DP treatment is effective in inducing vitamin B6 deficiency.

To investigate the efficacy of Sarcomeal® sachet, as a protein supplement, plus vitamin D3 on muscle parameters, metabolic factors, and quality of life (QoL) in individuals with diabetes and sarcopenia.

Sixty individuals were randomized into the control or intervention group. The intervention group received a daily dose of one Sarcomeal sachet and 1000 IU of vitamin D and both groups were recommended to consume protein-rich food, be educated about the disease, and perform physical activity for 12 weeks. Various assessments including muscle parameters, blood tests, and QoL were conducted at the beginning and the end of the trial.

Over 12 weeks, although the intervention group had significant improvements in mean skeletal muscle mass index (SMI) (change: 0.17[0.016, 0.329] kg/m²; p < 0.05) and handgrip strength (change: 1.33[0.256, 2.410] kg; p < 0.05), differences between groups were not statistically significant. However, significant improvements were observed in lean mass (1.70 [0.749, 2.665] kg; P < 0.01) and lean mass index (0.62[0.287, 0.954] kg/m2; P < 0.01) between groups. Weight was maintained in the intervention arm, whereas the control arm experienced significant weight loss (1.87 [0.654, 3.109] kg; P < 0.01). Participants in the intervention arm did not show significant changes in blood parameters. The most reported side effects were loss of appetite (50%) and stomach heaviness (20.8%).

This mixture of supplements significantly improved lean muscle mass, preserved physical function, and helped maintain weight, supporting its potential as a strategy to counter muscle loss and enhance the QoL in diabetic sarcopenia patients.

This trial is registered at the Iranian Registry of Clinical Trials (IRCT) with IRCT20230831059311N1 ID.

Mitochondrial homeostasis (MH) refers to the dynamic balance of mitochondrial number, function, and quality within cells. Maintaining MH is significant in the occurrence, development, and clinical treatment of Gastrointestinal (GI) tumors. Ubiquitination, as an important post-translational modification mechanism of proteins, plays a central role in the regulation of MH. Over the past decade, research on the regulation of MH by ubiquitination has focused on mitochondrial biogenesis, mitochondrial dynamics, Mitophagy, and mitochondrial metabolism during these processes. This review summarizes the mechanism and potential therapeutic targets of ubiquitin (Ub)-regulated MH intervention in GI tumors.

The metabolomic approach has recently been used in the assessment of semen quality and male fertility. Additionally, the crucial roles of branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs) in metabolic syndrome (MetS) were reported. However, little information exists about the association between BCAAs and AAAs with semen parameters, particularly in men with and without MetS. Our objective was to explore the association between BCAAs and AAAs in blood and seminal plasma and sperm parameters in men with MetS (MetS +) and without MetS (MetS-). In a cross-sectional study between January-July 2022, we investigated 98 men (age: 25-42 years; MetS + : n = 28 and MetS-: n = 70) at Royan Institute, Tehran, Iran. All participants underwent anthropometric indices measurements using standard protocols. From each participant, a single fasting blood sample was collected on the same day that the semen sample was collected. The BCAAs and AAAs in blood and seminal plasma were measured using high-performance liquid chromatography (HPLC). The aromatase activity (total testosterone/ estradiol ratio) was significantly lower in MetS + (0.16) than MetS- (0.35) (p = 0.016). Semen parameters were similar between the MetS + and the MetS- groups. All BCAA and AAA family members, except tryptophan, were higher in the blood plasma of men with metabolic syndrome. Meanwhile, the seminal plasma of BCAA and AAAs were similar. Intriguingly, Valine in blood (r = -0.329; p < 0.001) and seminal (r = -0.237; p < 0.05) plasma were correlated with abnormal sperm morphology in patients without metabolic syndrome (MetS-). Further research is necessary to validate these findings and to explore the underlying mechanisms and interactions between the plasma BCAAs and AAAs and sperm parameters.

Appetite, as the internal drive for food intake, is often dysregulated in a broad spectrum of conditions associated with over- and under-nutrition across the lifespan. Appetite regulation is a complex, integrative process comprising psychological and behavioral events, peripheral and metabolic inputs, and central neurotransmitter and metabolic interactions. The microbiota-gut-brain axis has emerged as a critical mediator of multiple physiological processes, including energy metabolism, brain function, and behavior. Therefore, the role of the microbiota-gut-brain axis in appetite and obesity is receiving increased attention. Omics approaches such as genomics, epigenomics, transcriptomics, proteomics, and metabolomics in appetite and weight regulation offer new opportunities for featuring obesity phenotypes. Furthermore, gut-microbiota-targeted approaches such as pre-, pro-, post-, and synbiotic, personalized nutrition, and fecal microbiota transplantation are novel avenues for precision treatments. The aim of this narrative review is 1) to provide an overview of the role of the microbiota-gut-brain axis in appetite regulation across the lifespan and 2) to discuss the potential of omics and gut microbiota-targeted approaches to deepen understanding of appetite regulation and obesity.

Plant-based diets emphasize higher intake of plant foods and are low in animal products. Individuals following plant-based diets have a lower risk of chronic conditions; however, the mechanisms underlying these associations are not completely understood. Omics data have opened opportunities to investigate the mechanistic effect of dietary intake on health outcomes. Here, we review omics analyses of plant-based diets in feeding and observational studies, showing that although metabolomics and proteomics identified candidate biomarkers and distinct pathways modifiable by plant-based diets, current evidence from transcriptomics and methylomics is limited. We also argue that future studies should examine how unhealthful plant-based diets are associated with a higher risk of health outcomes and integrate multiple omics data from feeding studies to provide further mechanistic insights.

Obesity is intricately linked with metabolic disturbances. The comprehensive exploration of metabolomes is important in unravelling the complexities of obesity development. This study was aimed to discern unique metabolite signatures in obese and lean individuals using liquid chromatography-mass spectrometry quadruple time-of-flight (LC-MS/Q-TOF), with the goal of elucidating their roles in obesity.

A total of 160 serum samples (Discovery, n = 60 and Validation, n = 100) of obese and lean individuals with stable Body Mass Index (BMI) values were retrieved from The Malaysian Cohort biobank. Metabolic profiles were obtained using LC-MS/Q-TOF in dual-polarity mode. Metabolites were identified using a molecular feature and chemical formula algorithm, followed by a differential analysis using MetaboAnalyst 5.0. Validation of potential metabolites was conducted by assessing their presence through collision-induced dissociation (CID) using a targeted tandem MS approach.

A total of 85 significantly differentially expressed metabolites (p-value <0.05; -1.5 < FC > 1.5) were identified between the lean and the obese individuals, with the lipid class being the most prominent. A stepwise logistic regression revealed three metabolites associated with increased risk of obesity (14-methylheptadecanoic acid, 4'-apo-beta,psi-caroten-4'al and 6E,9E-octadecadienoic acid), and three with lower risk of obesity (19:0(11Me), 7,8-Dihydro-3b,6a-dihydroxy-alpha-ionol 9-[apiosyl-(1->6)-glucoside] and 4Z-Decenyl acetate). The model exhibited outstanding performance with an AUC value of 0.95. The predictive model underwent evaluation across four machine learning algorithms consistently demonstrated the highest predictive accuracy of 0.821, aligning with the findings from the classical logistic regression statistical model. Notably, the presence of 4'-apo-beta,psi-caroten-4'-al showed a statistically significant difference between the lean and obese individuals among the metabolites included in the model.

Our findings highlight the significance of lipids in obesity-related metabolic alterations, providing insights into the pathophysiological mechanisms contributing to obesity. This underscores their potential as biomarkers for metabolic dysregulation associated with obesity.

Metabolic syndrome is a pressing public health issue and risk factor for the development of type 2 diabetes (T2D) and cardiovascular disease (CVD), yet clinical practice is lacking in biomarkers that represent pre-clinical perturbations of the heterogenous subtypes of risk. This study aimed to characterize the baseline metabolome in relation to known clinical characteristics of risk in a sample of obese adults.

Untargeted metabolome data from N = 126 plasma samples with baseline data from a previously completed study including obese adults with metabolic syndrome. Metabolites were acquired using validated liquid chromatography mass spectrometry methods with 15-25 internal standards quantified by peak heights. Pearson's correlations were used to determine relationships between baseline metabolites, sample characteristics (e.g., age, body mass index (BMI)), and atherosclerotic clinical characteristics (e.g., high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), triglycerides), adjusting for multiple comparisons using the Benjamini-Hochberg False Discovery Rate (FDR) method. Differences in metabolite levels between clinical classifications of dysglycemia (e.g., normal, prediabetes, diabetes) at baseline were assessed using ANOVA and adjusted for multiple comparisons and adjusted for covariates.

The sample consisted primarily of female (74%) participants, predominantly white (70%), with an average age of 56 years. After FDR adjustment, two baseline metabolites were significantly associated with age (xylose, threitol), two with BMI (shikimic acid, propane-1,3-diol), one with LDL (tocopherol-alpha), and 42 with HDL cholesterol. Three metabolites were significantly associated with fasting blood glucose (FBG) levels at baseline (glucose, gluconic acid lactone, pelargonic acid).

This study identified novel metabolite associations with known markers of T2D and CVD risk. Specific metabolites, such as alpha-tocopherol, branched-chain amino acids (BCAAs), and sugar-derived metabolites like mannose and xylose, were significantly associated with age, BMI, lipid profiles, and glucose measures. Although most sample participants had normal HDL cholesterol at baseline, 42 metabolites including branched chain amino acids were significantly associated with HDL, suggesting pre-clinical perturbations in biological pathways associated with both diabetes and cardiovascular comorbidities. Metabolomic signatures Specific to prediabetes and metabolic syndrome can enhance risk stratification and enable targeted prevention strategies for T2D. Longitudinal studies are needed to understand how these associations change over time in at-risk individuals compared with controls.

The Cullin-3 E3 ligase adaptor protein SPOP targets proteins for ubiquitination and proteasomal degradation. We previously established the β-cell transcription factor (TF) and human diabetes gene PDX1 as an SPOP substrate, suggesting a functional role for SPOP in the β cell. Here, we generated a β-cell-specific Spop deletion mouse strain (Spop βKO) and found that Spop is necessary to prevent aberrant basal insulin secretion and for maintaining glucose-stimulated insulin secretion through impacts on glycolysis and glucose-stimulated calcium flux. Integration of proteomic, TF-regulatory gene network, and biochemical analyses identified XBP1 as a functionally important SPOP substrate in pancreatic β cells. Furthermore, loss of SPOP strengthened the IRE1α-XBP1 axis of unfolded protein response (UPR) signaling. ER stress promoted proteasomal degradation of SPOP, supporting a model whereby SPOP fine-tunes XBP1 activation during the UPR. These results position SPOP as a regulator of β-cell function and proper UPR activation.

Cancer cells frequently rewire their metabolism to support proliferation and evade immune surveillance, but little is known about metabolic targets that could increase immune surveillance. Here we show a specific means of mitochondrial respiratory complex I (CI) inhibition that improves tumor immunogenicity and sensitivity to immune checkpoint blockade (ICB). Targeted genetic deletion of either Ndufs4 or Ndufs6, but not other CI subunits, induces an immune-dependent growth attenuation in melanoma and breast cancer models. We show that deletion of Ndufs4 induces expression of the major histocompatibility complex (MHC) class I co-activator Nlrc5 and antigen presentation machinery components, most notably H2-K1. This induction of MHC-related genes is driven by a pyruvate dehydrogenase-dependent accumulation of mitochondrial acetyl-CoA, which leads to an increase in histone H3K27 acetylation within the Nlrc5 and H2-K1 promoters. Taken together, this work shows that selective CI inhibition restricts tumor growth and that specific targeting of Ndufs4 or Ndufs6 increases T cell surveillance and ICB responsiveness.

Gut microbiota has been extensively demonstrated to modulate host lipid metabolism. Higher intramuscular fat (IMF) accumulation in Chinese indigenous breed pigs is associated with their special gut microbiota structure. However, the specific microbes and metabolic pathways responsible for lipid deposition are still poorly understood.

In the present study, a comparative analysis of the gut microbiota and metabolome in obese Ningxiang (NX) pigs and lean Duroc × Landrace × Yorkshire (DLY) pigs was conducted. The results revealed a higher abundance of gut lactobacilli and a correlation of branched-chain amino acid (BCAA) metabolism pathway in NX pigs. We proceeded to verify the roles of various lactobacilli strains originating from NX pigs in BCAA metabolism and lipids deposition in SD rats. We demonstrated that L. reuteri is a fundamental species responsible for modulating lipid deposition in NX pigs and that increased circulating levels of BCAA are positively linked to greater lipid deposition. Additionally, it has been verified that L. reuteri originating from NX pigs has the ability to improve BCAA synthesis in the gut and enhance IMF content in lean DLY pigs. The expression of genes related to lipid synthesis was also significantly upregulated.

Taken together, our results imply that NX pig-derived L. reuteri regulates BCAA metabolism and plays a potential role in improving the meat quality of lean pig breeds through modulation of host intramuscular lipid deposition. The results provide a new strategy for improving the meat quality of commercial pigs by influencing host metabolism through supplementing dietary additives. Video Abstract.

Background: Incidence of cardiometabolic disease among U.S. Hispanics/Latinos is higher than in non-Hispanic Whites. Prolonged sitting duration is prevalent in older adults, and compounded with menopause, greatly increases cardiometabolic risk in postmenopausal women. Metabolomic analyses of interventions to reduce sitting are lacking and mechanistic understanding of health-promoting behavior change in postmenopausal Latinas is needed. Methods: To address this knowledge gap, an exploratory analysis investigated the plasma metabolome impact of a 12-week increased standing intervention among sedentary postmenopausal Latinas with overweight or obesity. From a parent-randomized controlled trial, a subset of Best Responders (n = 43) was selected using parameters of highest mean change in sitting bout duration and total sitting time; baseline variable-Matched Controls (n = 43) were selected using random forest modeling. Targeted LC-MS/MS analysis of archived baseline and 12-week plasma samples was conducted. Metabolite change was determined using a covariate-controlled general linear model and multivariate testing was performed. A false discovery rate correction was applied to all analyses. Results: Best Responders significantly changed time sitting (-110.0 ± 11.0 min; -21%), standing (104.6 ± 10.1 min; 40%), and sitting in bouts >30 min (-102.3 ± 13.9 min; -35%) compared to Matched Controls (7.1 ± 9.8 min, -7.8 ± 9.0 min, and -4.6 ± 12.7 min, respectively; all p < 0.001). Twelve-week metabolite change was significantly different between the two groups for 24 metabolites (FDR < 0.05). These were primarily related to amino acid metabolism, improved blood flow, and ATP production. Enzyme enrichment analysis predicted significant changes regulating glutamate, histidine, phenylalanine, and mitochondrial short-chain fatty acid catabolism. Pathway analysis showed significant intervention effects on glutamate metabolism and phenylalanine, tyrosine, and tryptophan biosynthesis, potentially indicating reduced cardiometabolic disease risk. Conclusions: Replacing nearly two hours of daily sitting time with standing and reduced prolonged sitting bouts significantly improved metabolomic profiles associated with cardiometabolic risk among postmenopausal Latinas.

The disrupted homeostasis of branched-chain amino acids (BCAAs, including leucine, isoleucine, and valine) has been strongly correlated with diabetes with a potential causal role. However, the relationship between BCAAs and diabetic kidney disease (DKD) remains to be established. Here, we show that the elevated BCAAs from BCAAs homeostatic disruption promote DKD progression unexpectedly as an independent risk factor.

Similar to other tissues, the suppressed BCAAs catabolic gene expression and elevated BCAAs abundance were detected in the kidneys of type 2 diabetic mice and individuals with DKD. Genetic and nutritional studies demonstrated that the elevated BCAAs from systemic disruption of BCAAs homeostasis promoted the progression of DKD. Of note, the elevated BCAAs promoted DKD progression without exacerbating diabetes in the animal models of type 2 DKD. Mechanistic studies demonstrated that the elevated BCAAs promoted fibrosis-associated epithelial-mesenchymal transition (EMT) by enhancing the activation of proinflammatory macrophages through mTOR signaling. Furthermore, pharmacological enhancement of systemic BCAAs catabolism using small molecule inhibitor attenuated type 2 DKD. Finally, the elevated BCAAs also promoted DKD progression in type 1 diabetic mice without exacerbating diabetes.

BCAA homeostatic disruption serves as an independent risk factor for DKD and restoring BCAA homeostasis pharmacologically or dietarily represents a promising therapeutic strategy to ameliorate the progression of DKD.

Southern Schisandra is the dried and matured fruit of Schisandra sphenanthera Rehd. et Wils. in the family of Magnoliaceae; Traditional medicine reports that Schisandra sphenanthera has astringent and astringent properties, benefiting qi and promoting the production of body fluid, tranquilising the heart and calming the mind; it is clinically utilized for prolonged cough, thirst due to injury of the body fluid, internal heat and thirst, palpitation and insomnia, etc., and thirst belongs to the category of diabetes mellitus; the literature reports and the preliminary study of our team showed that Schisandra sphenanthera can be used to prevent and control diabetes mellitus.

In the research, we investigated the mechanism of action of SDP against T2DM by integrating pharmacodynamics, endogenous metabolite assays and signalling pathways.

UPLC-MS/MS was used to identify the chemical constituents. HPLC was utilized to determine the content of eight lignan-like components in SDP. A T2DM rat model was established by the combined induction of high-fat and high-sugar feed and STZ, and the mechanism of action of SDP on T2DM was investigated by using biochemical indices, Western blot analysis of protein expression, mRNA expression, immunohistochemistry and endogenous metabolites.

The chemical components in SDP were determined by UPLC-MS/MS and HPLC, and biochemical indicators determined that SDP has the effects of lowering blood glucose, anti-glycolipid metabolism, and anti-oxidative stress, and is able to restore pathological damage in the liver and pancreas, activate the PI3K/AKT, AMPK/mTOR, and sweetness receptor signalling pathways, restore the sweetness receptor mRNAs, and modulate the urinary compounds such as malic acid, γ-aminobutyric acid, leucine, N-acetylaspartic acid and other compounds thereby achieving the therapeutic effect of T2DM.

SDP can ameliorate diabetes-induced symptoms related to elevated blood glucose, dyslipidaemia, elevated fasting insulin levels and impaired glucose tolerance in rats; the anti-T2DM of SDP may be through the regulation of the sweet taste receptor pathway, the PI3K/AKT/mTOR and the AMPK/mTOR signalling pathway, which leads to the development of a normal level and exerts an antidiabetic effect.

Fecal microbiota transplantation (FMT) has emerged as a promising therapeutic approach for various health conditions, particularly obesity and metabolic disorders. This review examines the mechanisms underlying FMT, including its role in restoring gut microbiota diversity and enhancing immunomodulatory functions, which are essential for maintaining overall health. Recent studies indicate that FMT can significantly improve body weight and metabolic parameters, suggesting its potential as an alternative or complementary treatment to current obesity therapies. However, the effectiveness of FMT depends on several factors, including the composition of the donor microbiota, recipient characteristics, and concomitant medications or dietary interventions. Despite its great promise, challenges such as standardized protocols, donor screening, and the need for a deeper understanding of gut microbiota dynamics remain key hurdles. Future research should focus on elucidating the specific microbial compositions necessary for optimal therapeutic outcomes and exploring personalized FMT approaches tailored to individual patient profiles. This evolving field presents exciting opportunities for innovative strategies in obesity treatment, warranting further investigation and clinical application.

Heart failure (HF) is a complex syndrome and a leading cause of mortality worldwide. While current medical treatment is based on known pathophysiology and is effective for many patients, the underlying cellular mechanisms are poorly understood. Energy deficiency is a characteristic of HF, marked by complex alterations in metabolism. Within the tricarboxylic acid cycle, anaplerosis emerges as an essential metabolic process responsible for replenishing lost intermediates, thereby playing a crucial role in sustaining energy metabolism and consequently cardiac function. Alterations in cardiac anaplerosis are commonly observed in HF, demonstrating potential for therapeutic intervention. This review discusses recent advances in understanding the anaplerotic adaptations that occur in HF. We also explore therapeutics that can directly modulate anaplerosis or are likely to confer cardioprotective effects through anaplerosis, which could potentially be implemented to rescue the failing heart.

Epistasis, the phenomenon where the effect of one gene (or variant) is masked or modified by one or more other genes, significantly contributes to the phenotypic variance of complex traits. Traditionally, epistasis has been modeled using the Cartesian epistatic model, a multiplicative approach based on standard statistical regression. However, a recent study investigating epistasis in obesity-related traits has identified potential limitations of the Cartesian epistatic model, revealing that it likely only detects a fraction of the genetic interactions occurring in natural systems. In contrast, the exclusive-or (XOR) epistatic model has shown promise in detecting a broader range of epistatic interactions and revealing more biologically relevant functions associated with interacting variants. To investigate whether the XOR epistatic model also forms distinct network structures compared to the Cartesian model, we applied network science to examine genetic interactions underlying body mass index (BMI) in rats (Rattus norvegicus).

Our comparative analysis of XOR and Cartesian epistatic models in rats reveals distinct topological characteristics. The XOR model exhibits enhanced sensitivity to epistatic interactions between the network communities found in the Cartesian epistatic network, facilitating the identification of novel trait-related biological functions via community-based enrichment analysis. Additionally, the XOR network features triangle network motifs, indicative of higher-order epistatic interactions. This research also evaluates the impact of linkage disequilibrium (LD)-based edge pruning on network-based epistasis analysis, finding that LD-based edge pruning may lead to increased network fragmentation, which may hinder the effectiveness of network analysis for the investigation of epistasis. We confirmed through network permutation analysis that most XOR and Cartesian epistatic networks derived from the data display distinct structural properties compared to randomly shuffled networks.

Collectively, these findings highlight the XOR model's ability to uncover meaningful biological associations and higher-order epistasis derived from lower-order network topologies. The introduction of community-based enrichment analysis and motif-based epistatic discovery emphasize network science as a critical approach for advancing epistasis research and understanding complex genetic architectures.

Metabolomics has come to the fore as an efficient tool in the search for biomarkers that are critical for precision health approaches and improved diagnostics. This review will outline recent advances in biomarker discovery based on metabolomics, focusing on metabolomics biomarkers reported in cancer, neurodegenerative disorders, cardiovascular diseases, and metabolic health. In cancer, metabolomics provides evidence for unique oncometabolites that are important for early disease detection and monitoring of treatment responses. Metabolite profiling for conditions such as neurodegenerative and mental health disorders can offer early diagnosis and mechanisms into the disease especially in Alzheimer's and Parkinson's diseases. In addition to these, lipid biomarkers and other metabolites relating to cardiovascular and metabolic disorders are promising for patient stratification and personalized treatment. The gut microbiome and environmental exposure also feature among the influential factors in biomarker discovery because they sculpt individual metabolic profiles, impacting overall health. Further, we discuss technological advances in metabolomics, current clinical applications, and the challenges faced by metabolomics biomarker validation toward precision medicine. Finally, this review discusses future opportunities regarding the integration of metabolomics into routine healthcare to enable preventive and personalized approaches.

This comprehensive review explores the intricate relationship between gut microbiota, diet, and insulin resistance, emphasizing the novel roles of diet-induced microbial changes in influencing metabolic health. It highlights how diet significantly influences gut microbiota composition, with different dietary patterns fostering diverse microbial communities. These diet-induced changes in the microbiome impact human metabolism by affecting inflammation, energy balance, and insulin sensitivity, particularly through microbial metabolites like short-chain fatty acids (SCFAs). Focusing the key mediators like endotoxemia and systemic inflammation, and introduces personalized microbiome-based therapeutic strategies, it also investigates the effects of dietary components-fiber, polyphenols, and lipids-on microbiota and insulin sensitivity, along with the roles of protein intake and amino acid metabolism. The study compares the effects of Western and Mediterranean diets on the microbiota-insulin resistance axis. Therapeutic implications, including probiotics, fecal microbiota transplantation (FMT), and personalized diets, are discussed. Key findings reveal that high-fat diets, especially those rich in saturated fats, contribute to dysbiosis and increased intestinal permeability, while high-fiber diets promote beneficial bacteria and SCFAs. The review underscores the future potential of food and microbiota interventions for preventing or managing insulin resistance.

Sarcopenia, a disorder marked by muscle loss and dysfunction, is a global health concern, particularly in aging populations. Sarcopenia is intricately related to various health conditions, including obesity, dysphagia, and frailty, which underscores the complexity. Despite recent advances in metabolomics and other omics data for early detection and treatment, the precise characterization and diagnosis of sarcopenia remains challenging. In the present review we provide an overview of the complex metabolic mechanisms that underlie sarcopenia, with particular emphasis on protein, lipid, carbohydrate, and bone metabolism. The review highlights the importance of leucine and other amino acids in promoting muscle protein synthesis and clarifies the critical role played by amino acid metabolism in preserving muscular health. In addition, the review provides insights regarding lipid metabolism on sarcopenia, with an emphasis on the effects of inflammation and insulin resistance. The development of sarcopenia is largely influenced by insulin resistance, especially with regard to glucose metabolism. Overall, the review emphasizes the complex relationship between bone and muscle health by highlighting the interaction between sarcopenia and bone metabolism. Furthermore, the review outlines various therapeutic approaches and potential biomarkers for diagnosing sarcopenia. These include pharmacological strategies such as hormone replacement therapy and anabolic steroids as well as lifestyle modifications such as exercise, nutrition, and dietary changes.

Accumulation of circulating branched-chain amino acids (BCAA) is a hallmark feature of impaired insulin sensitivity. As intracellular BCAA catabolism is dependent on glycine availability, we hypothesised that the concurrent measurement of circulating glycine and BCAA may yield a stronger association with markers of insulin sensitivity than either BCAA or glycine alone. This study therefore examined the correlative relationships of BCAA, BCAA and glycine together, plus glycine alone on insulin sensitivity-related markers before and after an 8-week low energy diet (LED) intervention.

This is a secondary analysis of the PREVIEW (PREVention of diabetes through lifestyle Intervention and population studies in Europe and around the World) Study New Zealand sub-cohort. Eligible participants with pre-diabetes at baseline who achieved ≥8 % body weight loss following an LED intervention were included, of which 167 paired (Week 0 and Week 8) blood samples were available for amino acid analysis. Glycemic and other data were retrieved from the PREVIEW consortium database. Repeated measures linear mixed models were used to test the association between amino acids and insulin sensitivity-related markers (HOMA2-IR, glucose, insulin, and C-peptide).

Elevated BCAA was associated with impaired insulin sensitivity (p < 0.05), with strength of association (ηp2) almost doubled when glycine was added to the model. However, glycine in isolation was not associated with insulin sensitivity-related markers. The magnitude (β-estimates) of positive association between BCAA and HOMA2-IR, and inverse association between glycine and HOMA2-IR, increased when body weight was higher (Body weight∗BCAA, Body weight∗glycine, p < 0.05, both).

Low serum glycine strengthened the association between BCAA and impaired insulin sensitivity. Given that glycine is necessary to facilitate intracellular BCAA catabolism, measurement of glycine is necessary to complement BCAA analysis to comprehensively understand the contribution of amino acid metabolism in insulin sensitivity.

This study was registered with ClinicalTrials.gov (NCT01777893).