Heterocyclic amines (HCAs) are mutagens and carcinogens primarily generated when cooking meat at high temperatures or until well-done, and their major metabolic pathway includes hepatic N -hydroxylation via CYP1A2 followed by O -acetylation via N -acetyltransferase 2 (NAT2). NAT2 expresses a well-defined genetic polymorphism in humans resulting in rapid and slow acetylators. Recent epidemiological studies reported significant associations between dietary HCA exposure and insulin resistance and type II diabetes.

We assessed the effect of some of the most common HCAs found in cooked meat, 2-amino-3,4-dimethylimidazo[4,5-f]quinoline, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, on insulin signaling and gluconeogenic gene expression in cryopreserved human hepatocytes characterized by their NAT2 genotype and phenotype to investigate the role of NAT2 genetic polymorphism in HCA-induced metabolic dysregulation.

HCA treatment significantly reduced insulin-induced protein kinase B phosphorylation and significantly increased expression of genes involved in gluconeogenesis ( G6PC , PCK1 , FOXO1 , and PPARA ) in cryopreserved human hepatocytes from rapid but not from slow acetylators.

The findings suggest that NAT2 genetic polymorphism modifies HCA-induced insulin resistance and gluconeogenic gene expression, implying that individuals with rapid acetylator phenotype may be at greater risk of dysregulated glucose homeostasis following exposure to HCAs.

Interactions between the liver and pancreas are key features of the carbohydrate and lipid homeostasis in healthy and pathological patients. To investigate the crosstalk between the two organs, we have developed an organ-on-chip coculture model derived from human induced pluripotent stem cells. The presence of pancreatic-derived tissue in the culture environment contributed to increase the CYP3A4 activity, the glycogen storage, and the expression of genes related to lipids, bile acids and sterol metabolism in the liver derived tissue. Concomitantly, the presence of liver cells led to increase the C-peptide secretion in pancreas. The coculture with liver modulated the pancreatic differentiation by increasing the activity of important transcription factors (REST, MAFB, PBX1) and by downregulating several hormone encoding genes (INS, GCG, TTR). The liver also stimulated the expression of genes involved in the response to inflammation in pancreas (via TGFβ/SMAD pathway). In parallel we observed a pancreatic cell reorganization coupled with the activation of the cell proliferation related transcription factor (SCRT1) and the upregulation of cellular remodeling genes (FLNA, FLNB, FN1, COL4A5). Finally, the pancreatic lipid genes were also upregulated in presence of the liver tissue. Overall, our results reflect a complex synergy between both tissues. We believe that those results are an encouraging step toward the development of relevant human model using advanced organ-on-chip technology and stem cells sources.

This meta-analysis aimed to evaluate the efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) when compared to metformin and placebo in the management of body weight, glucose homeostasis and hormone levels in women polycystic ovary syndrome (PCOS). A systematic search of "PubMed", "EMBASE", "Cochrane Library", "Web of Science" and "Google Scholar" was conducted up to October 2024 for randomized controlled trials involving adult women with PCOS treated with GLP-1RAs compared to metformin or placebo. The primary outcomes were changes in body mass index (BMI), body weight, waist circumference (WC), waist-to-hip ratio (WHR) and abdominal girth (AG). Secondary outcomes included glucose homeostasis (fasting glucose, fasting insulin, OGTT results and HOMA-IR), hormone levels (DHEAS, SHBG, total and free testosterone and FAI), lipid profiles (total cholesterol, HDL, LDL and triglycerides) and safety. GLP-1RAs significantly reduced BMI, body weight, WC, WHR and AG (P < 0.0001 in all cases). For glucose homeostasis, GLP-1RAs significantly reduced fasting insulin, glucose level at 2 h after OGTT, and HOMA-IR. There was also a reduction in HDL. All the other parameters measured were unchanged. In addition, GLP-1RAs increased nausea (P = 0.02), vomiting (0.04) and dizziness (0.03). GLP-1RAs effectively reduced body weight, BMI and insulin resistance in patients with PCOS, although they were accompanied by nausea, vomiting and dizziness. Further studies are needed to explore their long-term effects on glucose homeostasis and lipid profiles.

In vitro human liver models are critical to mitigate species-specific differences observed for toxicology, disease modeling, and regenerative medicine. Interactions with mesenchyme (i.e., fibroblasts) can promote phenotypic functions of primary human hepatocytes (PHHs) in culture; however, using liver-derived fibroblasts remains elusive. Portal fibroblasts (PFs) around the portal triad influence bile duct formation during development, but their role in regulating homeostatic hepatic functions remains unknown. Here, we show that human liver PFs induce long-term phenotypic functions in PHHs at higher levels than activated hepatic stellate cells across 2-dimensional and 3-dimensional culture formats. While PF-conditioned media induces some hepatic functions, partly via insulin-like growth factor binding protein-5 signaling, direct contact is necessary to induce optimal functional levels. Inhibiting Notch signaling reduces progenitor-like characteristics of PHHs and further enhances functionality. Overall, this work demonstrates a unique role for PFs in modulating hepatic functions and provides all-human and all-liver coculture strategies for downstream applications.

Insulin resistance, a hallmark feature of type 2 diabetes and cardiovascular diseases, is critically influenced by liver-adipose tissue crosstalk, offering a novel therapeutic strategy for its management. Emerging evidence indicates that extracellular vesicles (EVs) secreted from adipose tissue serve as essential carriers of miRNA-mediated interorgan communication. This study aimed to investigate the regulatory effects of adipose tissue-derived EVs on obesity-induced hepatic insulin resistance and to elucidate the underlying molecular mechanisms by which EV-mediated signaling contributes to metabolic dysfunction.

EVs with miR-141-3p knockout or overexpression were constructed and administered to both in vitro cell models and in vivo mouse models to investigate the regulatory role and underlying mechanisms of miR-141-3p-mediated adipose tissue-derived EVs in obesity-induced hepatic insulin resistance.

miR-141-3p is significantly upregulated in adipose tissue-derived EVs from high-fat diet (HFD)-fed mice, as well as in other obesity-related conditions. Furthermore, the knockdown of miR-141-3p in EVs from chow diet (CD-EVs) counteracted the effect in improving obesity-induced hepatic insulin resistance, whereas the overexpression of miR-141-3p in HFD-EVs improved hepatic insulin resistance. Mechanistically, EVs-derived miR-141-3p directly targets PTEN to promote PI3K/AKT signaling, thereby mediating hepatic glucose homeostasis through the regulation of hepatic gluconeogenesis and glycogen synthesis.

In summary, our results highlight the emerging role of miR-141-3p in mediating adipose tissue-derived EVs to alleviate obesity-induced hepatic insulin resistance, providing potential therapeutic targets for type 2 diabetes.

Hepatocytes are organized along a spatial axis between the portal triad and the central vein to form functionally repetitive units known as lobules. The hepatocytes perform distinct metabolic functions depending on their location within the lobule. Single-cell analysis of hepatocytes across the liver lobule demonstrates that gluconeogenic gene expression is relatively low in the fed state and gradually increases in the periportal hepatocytes during the initial fasting period. As fasting progresses, pericentral hepatocyte gluconeogenic gene expression and gluconeogenic activity also increase and, following entry into a starvation state, the pericentral hepatocytes show similar gluconeogenic gene expression and activity to the periportal hepatocytes. In parallel, starvation suppresses canonical β-catenin signalling and modulates the expression of pericentral and periportal glutamine synthetase and glutaminase, respectively, resulting in enhanced incorporation of glutamine into glucose. Thus, hepatocyte gluconeogenic gene expression and glucose production are spatially and temporally plastic across the liver lobule, underscoring the complexity of defining hepatic insulin resistance and glucose production on a whole-organ level, as well as for a particular fasted or fed condition.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is emerging as the leading cause of chronic liver disease worldwide, reflecting the global epidemics of obesity, metabolic syndrome, and type 2 diabetes. Beyond its strong association with excess adiposity, MASLD encompasses a heterogeneous population that includes individuals with normal body weight ("lean MASLD") highlighting the complexity of its pathogenesis. This disease results from a complex interplay between genetic susceptibility, epigenetic modifications, and environmental factors, which converge to disrupt metabolic homeostasis. Adipose tissue dysfunction and insulin resistance trigger an overflow of lipids to the liver, leading to mitochondrial dysfunction, oxidative stress, and hepatocellular injury. These processes promote hepatic inflammation and fibrogenesis, driven by cross talk among hepatocytes, immune cells, and hepatic stellate cells, with key contributions from gut-liver axis perturbations. Recent advances have unraveled pivotal molecular pathways, such as transforming growth factor-β signaling, Notch-induced osteopontin, and sphingosine kinase 1-mediated responses, that orchestrate fibrogenic activation. Understanding these interconnected mechanisms is crucial for developing targeted therapies. This review integrates current knowledge on the pathophysiology of MASLD, emphasizing emerging concepts such as lean metabolic dysfunction-associated steatohepatitis (MASH), epigenetic alterations, hepatic extracellular vesicles, and the relevance of extrahepatic signals. It also discusses novel therapeutic strategies under investigation, aiming to provide a comprehensive and structured overview of the evolving MASLD landscape for both basic scientists and clinicians.

Silent Information Regulator 5 (SIRT5) has been established as a crucial regulator of cellular alanylation modification. Furthermore, accumulating evidence suggests that SIRT5 plays a significant regulatory role in key metabolic pathways, including glycolysis, the tricarboxylic acid (TCA) cycle, and fatty acid oxidation, all of which are closely associated with cellular lipid metabolism. Despite these advancements, the specific role of SIRT5 in regulating intramuscular fat (IMF) deposition in goats, as well as the underlying molecular mechanisms, remains largely unexplored. In this study, we cloned the complete coding sequence of the goat SIRT5 gene and, through amino acid sequence alignment, demonstrated its closest phylogenetic relationship with sheep. Additionally, we characterized the higher expression of SIRT5 during the differentiation of goat intramuscular precursor adipocytes. The silencing of SIRT5 by siRNA-mediated knockdown significantly upregulated the expression of lipogenesis-related genes and enhanced lipid deposition in goat intramuscular preadipocytes. Concurrently, SIRT5 deficiency led to the inhibition of cell proliferation and a marked reduction in apoptosis. Interestingly, although overexpression of SIRT5 promoted cell proliferation, it did not significantly alter lipid deposition in goat intramuscular precursor adipocytes. RNA sequencing (RNA-seq) analysis identified a total of 106 differentially expressed genes (DEGs) following SIRT5 silencing in goat preadipocytes, predominantly involved in the Focal adhesion, HIF-1, PI3K-Akt, and MAPK signaling pathways by KEGG pathway enrichment analysis. Notably, we successfully reversed the phenotypic effects observed in SIRT5 knockdown goat precursor adipocytes by inhibiting the PI3K-Akt and MAPK signaling pathways using the AKT inhibitor LY294002 and the p38 MAPK pathway inhibitor PD169316, respectively. In conclusion, our findings demonstrated that SIRT5 may modulate intramuscular fat deposition in goats through PI3k-Akt and MAPK signaling pathways. These results expand the gene regulatory network associated with IMF formation and provide a theoretical foundation for improving meat quality by targeting IMF deposition.

The interaction between metabolic dysfunction and inflammation is central to the development of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Obesity-related conditions like type 2 diabetes and non-alcoholic fatty liver disease exacerbate this relationship. Peripheral lipid accumulation, particularly in the liver, initiates a cascade of inflammatory processes that extend to the brain, influencing critical metabolic regulatory regions. Ceramide and palmitate, key lipid components, along with lipid transporters lipocalin-2 and apolipoprotein E, contribute to neuroinflammation by disrupting blood-brain barrier integrity and promoting gliosis. Peripheral insulin resistance further exacerbates brain insulin resistance and neuroinflammation. Preclinical interventions targeting peripheral lipid metabolism and insulin signaling pathways have shown promise in reducing neuroinflammation in animal models. However, translating these findings to clinical practice requires further investigation into human subjects. In conclusion, metabolic dysfunction, peripheral inflammation, and insulin resistance are integral to neuroinflammation and neurodegeneration. Understanding these complex mechanisms holds potential for identifying novel therapeutic targets and improving outcomes for neurodegenerative diseases.

Polyethylene glycol loxenatide (PEG-Loxe) is applied in treating type 2 diabetes mellitus. Nevertheless, the effect and mechanism of PEG-Loxe on lipid metabolism disorder and insulin resistance in type 2 diabetes mellitus are not fully understood.

Type 2 diabetes mellitus rats developed by high-fat diet/streptozotocin injection were treated with PEG-Loxe (0.3 or 1 mg/kg). Insulin resistance was evaluated by fasting blood glucose (FBG), oral glucose tolerance test, fasting insulin, homeostasis model of assessment for insulin resistance and for insulin sensitivity. Immunohistochemistry, hematoxylin and eosin staining, and biochemistry measurements were performed to assess lipid metabolism. Inflammatory response and oxidative stress were assessed by inflammatory cytokines and reactive oxygen species. Genes' expressions were tested using RT-qPCR, western blot, and in situ hybridization. Relationships of molecules were validated by pull-down assay and RNA immunoprecipitation. mRNA stability was examined by actinomycin D assay.

High-PEG-Loxe decreased FBG and ameliorated glucose tolerance, hyperinsulinemia, and insulin resistance. Low-PEG-Loxe partly while high-PEG-Loxe apparently relieved hepatocyte injury, reduced lipase I, triglyceride, total cholesterol and leptin, and increased adiponectin in type 2 diabetes mellitus rats. PEG-Loxe mitigated inflammatory response and oxidative stress. High-PEG-Loxe reduced RhoA and Rho-associated coiled-coil kinase 2 (ROCK2) in liver tissues of type 2 diabetes mellitus rats, while both doses of PEG-Loxe decreased steroid receptor RNA activator (SRA). SRA overexpression reversed the protective functions of high-PEG-Loxe. SRA cooperated with cellular nucleic acid binding protein (CNBP) to enhance ROCK2 mRNA stability.

High-PEG-Loxe relieves insulin resistance and lipid metabolism disorder in type 2 diabetes mellitus through SRA/CNBP/ROCK2 axis. This research provides a molecular mechanism of PEG-Loxe for treating type 2 diabetes mellitus.

This study mimics the metabolic environment of metabolic dysfunction-associated steatotic liver disease (MASLD) and diabetic mellitus (DM) to investigate the function of BRCA1 in regulating glucose and lipid metabolism in hepatocytes under high glucose (HG) settings.

MASLD and DM-related datasets (GSE89632, GSE95849) were screened for overlapping genes, Protein-Protein Interaction (PPI) network and enrichment analyses were performed. Then, quantitative real-time polymerase chain reaction (qRT-PCR), Western Blotting (WB), and enzymatic colorimetric assays to examine the expression changes of BRCA1 in mouse primary hepatocytes under HG conditions and the impact of the combined PI3K/Akt signaling pathway on key metabolic markers of gluconeogenesis and lipid metabolism.

Our study identified seven key overlapping genes (AURKA, BRCA1, ISG15, NUSAP1, OAS1, RSAD2, TLR7) between MASLD and DM. Experiments found that when BRCA1 was overexpressed in mouse primary hepatocytes, intracellular triglyceride content and lipid metabolism-related biomarkers (such as PEPCK, SREBP-1c, G6Pase, and FAS) were significantly increased in HG circumstances. However, the knockdown of BRCA1 reduced the expression of these indicators. Besides, we also observed that under HG conditions, the expression of proteins linked to the PI3K/Akt signaling pathway was negatively regulated by BRCA1 expression. Moreover, TG content and expression of lipid metabolism markers are also regulated by BRCA1 and PI3K/Akt pathway inhibitor Ly294002.

As a key regulator of hepatocyte metabolism under HG conditions, BRCA1 can participate in regulating glucose and lipid metabolism in mouse primary hepatocytes through the PI3K/AKT signaling pathway, which be able to become a possible remedy strategy for DM with MASLD.

The ketogenic diet has been successfully used in the last 100 years in the treatment of epilepsy and other neurological disorders. In recent decades, it gained wider application in the treatment of obesity, metabolic syndrome, and type 2 diabetes. However, there have been only a few studies on its use in children with obesity and associated metabolic disorders.

To determine the clinical and metabolic effects of a well-formulated low-carbohydrate (ketogenic) diet in children with obesity.

One hundred children with obesity and metabolic disorders underwent initial anthropometric, laboratory, and ultrasound examinations. They were placed on a well-formulated ketogenic diet and monitored for 4 months. The 58 patients who completed the study underwent follow-up examinations to assess the effects of the diet on anthropometric, clinical, and laboratory markers of metabolic syndrome and insulin resistance, cardiovascular risk factors, and certain hormone levels. Compliance with the diet, common difficulties in adhering to it, side effects, and positive changes in the patients' health were analyzed.

At the end of the study, the average weight loss for the entire group was 6.45 kg, with a reduction in BMI of 3.12 kg/m2. Significant improvements were also observed in insulin resistance indicators, including fasting insulin levels, HOMA-IR index, QUICKI (p < 0.0001), and adiponectin (p = 0.04). The cases of hepatosteatosis decreased twofold, the number of patients with arterial hypertension was significantly reduced, as well as the number of children receiving antihypertensive therapy. Additionally, the number of patients meeting the criteria for metabolic syndrome decreased threefold.

A well-formulated short-term ketogenic diet is effective in treating obesity, metabolic syndrome, and related comorbidities, and can be part of a comprehensive approach for these patients.

Current lifestyles bring about an increasing prevalence of unhealthy habits that can negatively affect male fertility. Cigarette smoking, alcohol intake, stress, inadequate physical activity, an unequilibrated diet leading to obesity, and use of mobile telephones and portable electronic devices can affect the male reproductive system through multiple mechanisms. Moreover, the modern man is often exposed to environmental factors independent of his will, such as air pollution, exposure to heat or toxicants in his workplace, or the presence of harmful chemicals in food, beverages, agricultural and industrial products, etc. The susceptibility to these factors depends on genetic and epigenetic predisposition, potentially present systemic disease and medication, and local affections of the genitourinary system. The multifaceted nature of both the causative factors and the susceptibility background makes the resulting fertility disturbance highly individual and variable among different men exposed to the same conditions. This paper critically reviews the current knowledge of different causative and susceptibility factors with a special attention to the molecular mechanisms of their action. Finally, strategies for the prevention of abnormalities due to lifestyle and environmental factors and available treatment modalities for already-present abnormalities are exposed.

Insulin resistance (IR) is a significant factor in the development and progression of metabolic-related diseases like dyslipidemia, T2DM, hypertension, nonalcoholic fatty liver disease, cardiovascular and cerebrovascular disorders, and cancer. The pathogenesis of IR depends on multiple factors, including age, genetic predisposition, obesity, oxidative stress, among others. Abnormalities in the insulin-signaling cascade lead to IR in the host, including insulin receptor abnormalities, internal environment disturbances, and metabolic alterations in the muscle, liver, and cellular organelles. The complex and multifaceted characteristics of insulin signaling and insulin resistance envisage their thorough and comprehensive understanding at the cellular and molecular level. Therapeutic strategies for IR include exercise, dietary interventions, and pharmacotherapy. However, there are still gaps to be addressed, and more precise biomarkers for associated chronic diseases and lifestyle interventions are needed. Understanding these pathways is essential for developing effective treatments for IR, reducing healthcare costs, and improving quality of patient life.

Recent investigations suggest that the chemical compound F-53B (6:2 chlorinated polyfluorinated ether sulfonate) may pose risks of liver toxicity. Within environmental settings, F-53B attaches to microplastics and nanoplastics, which are capable of being consumed by diverse species. To investigate the synergistic effects on hepatotoxicity, adult male mice were subjected to F-53B at daily doses of 1, 10, and 100 μg/kg, NPs at 100 mg/kg per day, or a combination of both treatments for a duration of 2 months. The results indicated that NPs moderately increased the buildup of F-53B within both the liver and plasma. Co-exposure to F-53B (100 μg/kg/day) and NPs induced hepatocellular edema and elevated plasma ALT levels, which were rarely observed in groups exposed to F-53B or NPs alone. Additionally, we found that co-exposure decreased the concentrations of total cholesterol (TC) and triglycerides (TG) in both plasma and liver tissues, while increasing fasting plasma glucose and insulin levels. Transcriptomic analysis revealed that the PI3K-AKT signaling pathway is potentially involved in mediating hepatic metabolic disorders. Further experiments demonstrated that the combined treatment significantly suppressed the expression of FGF21, an upstream regulator of the PI3K-AKT pathway. This alteration resulted in the suppression of PI3K-regulated gene expression associated with glucose and lipid metabolism. The findings suggest that F-53B impairs hepatic glucolipid metabolism in mice by suppressing of the PI3K-AKT signaling cascade, with NPs amplifying its toxicity.

Serum insulin-like growth factor 1 (IGF-1), a hepatocyte-derived cytokine, has been suggested to reflect hepatic function reserve. The aim of this systematic review and meta-analysis was to investigate the association between serum IGF-1 levels on the admission and prognosis of patients with advanced liver diseases.

A thorough examination of the literature was conducted across various databases, namely PubMed, Embase, Web of Science, Wanfang, and CNKI, with the aim of identifying relevant cohort studies. The data were synthesized using the random-effects model, taking into account the potential impact of heterogeneity.

A total of 9 cohorts were included. Patients with a low serum level of IGF-1, as compared with those with a high IGF-1 at baseline, exhibited a significantly poorer transplant-free survival (risk ratio: 3.03, 95% confidence interval: 2.17 to 4.22, P < 0.001), with no significant heterogeneity observed ( P for Cochrane Q test = 0.92, I2 = 0%). A sensitivity analysis, which was conducted by excluding 1 study at a time, yielded consistent results (risk ratio: 2.94-3.24, P all < 0.05). In addition, consistent results were observed in further subgroup analyses based on various factors, including cutoffs of IGF-1, country of the study, patient diagnosis, methods for measuring serum IGF-1, follow-up duration, analytic model, and quality scores ( P for subgroup difference all > 0.05).

A diminished serum IGF-1 level on admission could potentially serve as an indicator for an unfavorable prognosis among patients afflicted with advanced liver disease, such as severe hepatitis and cirrhosis.

Humans are perhaps evolutionarily engineered to get deeply addicted to sugar, as it not only provides energy but also helps in storing fats, which helps in survival during starvation. Additionally, sugars (glucose and fructose) stimulate the feel-good factor, as they trigger the secretion of serotonin and dopamine in the brain, associated with the reward sensation, uplifting the mood in general. However, when consumed in excess, it contributes to energy imbalance, weight gain, and obesity, leading to the onset of a complex metabolic disorder, generally referred to as diabetes. Type 2 diabetes mellitus (T2DM) is one of the most prevalent forms of diabetes, nearly affecting all age groups. T2DM is clinically diagnosed with a cardinal sign of chronic hyperglycemia (excessive sugar in the blood). Chronic hyperglycemia, coupled with dysfunctions of pancreatic β-cells, insulin resistance, and immune inflammation, further exacerbate the pathology of T2DM. Uncontrolled T2DM, a major public health concern, also contributes significantly toward the onset and progression of several micro- and macrovascular diseases, such as diabetic retinopathy, nephropathy, neuropathy, atherosclerosis, and cardiovascular diseases, including cancer. The current review discusses the epidemiology, causative factors, pathophysiology, and associated comorbidities, including the existing and emerging therapies related to T2DM. It also provides a future roadmap for alternative drug discovery for the management of T2DM.

Genetics is a significant risk factor for developing type 2 diabetes, with a family history conferring a 1.5-3-fold increased risk. Intriguingly, this heritable risk is higher when the affected parent is the mother, suggesting a potential role of mitochondrial genetics -maternally inherited DNA - in diabetes pathogenesis, a hypothesis this chapter will explore. While obesity mediates some of the genetic risk of type 2 diabetes, the chapter and will focus on genetic influences on diabetes independent of obesity. Mechanistically, genetic variants directly or indirectly contribute to insulin resistance across key tissues, including liver, muscle and adipose tissue. This insulin resistance prevents the liver from efficiently suppressing glucose production in response to insulin and impairs glucose uptake in muscle during postprandial states. Insulin resistance is driven by complex interactions between the genome and environmental, which can, in turn, influence gene expression and contribute to worsening of metabolic dysfunction. This chapter examines how tissue-specific genetic changes drive insulin resistance in individual organs and how these localized dysfunctions contribute to the broader, multi-organ metabolic dysfunction that characterize type 2 diabetes.

Metabolic and insulin-resistant diseases, such as type 2 diabetes mellitus (T2DM), have become major health issues worldwide. The prevalence of insulin resistance in the general population ranges from 15.5% to 44.6%. Shockingly, the global T2DM population is anticipated to double by 2050 compared with 2021. Prior studies indicate that oxidative stress and inflammation are instrumental in causing insulin resistance and instigating metabolic diseases. Numerous methods and drugs have been designed to combat insulin resistance, including metformin, thiazolidinediones (TZDs), sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide 1 receptor agonists (GLP1RA), and dipeptidyl peptidase 4 inhibitors (DPP4i). Bilirubin is an antioxidant with fat-burning actions by binding to the PPARα nuclear receptor transcription factor, improving insulin sensitivity, reducing inflammation, and reversing metabolic dysfunction. Potential treatment with antioxidants like bilirubin and increasing the enzyme that produces it, heme oxygenase (HMOX), has also gained attention. This review discusses the relationships between bilirubin, HMOX, and insulin sensitivity, how T2DM medications affect HMOX levels and activity, and potentially using bilirubin nanoparticles to treat insulin resistance. We explore the sex differences between these treatments in the HMOX system and how bilirubin levels are affected. We discuss the emerging concept that bilirubin bioconversion to urobilin may have a role in metabolic diseases. This comprehensive review summarizes our understanding of bilirubin functioning as a hormone, discusses the HMOX isoforms and their beneficial mechanisms, analyzes the sex differences that might cause a dichotomy in responses, and examines the potential use of HMOX and bilirubin nanoparticle therapies in treating metabolic diseases.

Mitochondrial function is crucial for hepatic lipid metabolism. Current research identifies two types of mitochondria based on their contact with lipid droplets: peridroplet mitochondria (PDM) and cytoplasmic mitochondria (CM). This work aimed to investigate the alterations of CM and PDM in metabolic dysfunction-associated steatotic liver disease (MASLD) induced by spontaneous type-2 diabetes mellitus (T2DM) in db/db mice. It was found that insulin resistance increased both the number and size of lipid droplets in the liver by enhancing the accumulation of free fatty acids, which is accompanied by an increase in contacts with mitochondria. We described the different patterns of tight contacts between small lipid droplets and mitochondria in purified CM and PDM by examining their oxidation states and morphological characteristics. In CM, enhanced fatty acid oxidation resulted in elongated mitochondria that surrounded single small lipid droplets and were responsible for lipid droplet consumption, while in PDM, increased substrates for lipid synthesis promoted lipid droplet expansion with the assistance of the endoplasmic reticulum. These data show the different ways in which mitochondrial contact with lipid droplets could provide new insights for future research on liver lipid metabolism.

Nuclear factor erythroid 2-related factor 2 (NRF2) is a master regulator of cellular homeostasis, overseeing the expression of a wide array of genes involved in cytoprotective processes such as antioxidant and proteostasis control, mitochondrial function, inflammation, and the metabolism of lipids and glucose. The accumulation of misfolded proteins triggers the release, stabilization, and nuclear translocation of NRF2, which in turn enhances the expression of critical components of both the proteasomal and lysosomal degradation pathways. This process facilitates the clearance of toxic protein aggregates, thereby actively maintaining cellular proteostasis. As we age, the efficiency of the NRF2 pathway declines due to several factors including increased activity of its repressors, impaired NRF2-mediated antioxidant and cytoprotective gene expression, and potential epigenetic changes, though the precise mechanisms remain unclear. This leads to diminished antioxidant defenses, increased oxidative damage, and exacerbated metabolic dysregulation and inflammation-key contributors to age-related diseases. Given NRF2's role in mitigating proteotoxic stress, the pharmacological modulation of NRF2 has emerged as a promising therapeutic strategy, even in aged preclinical models. By inducing NRF2, it is possible to mitigate the damaging effects of oxidative stress, metabolic dysfunction, and inflammation, thus reducing protein misfolding. The review highlights NRF2's therapeutic implications for neurodegenerative diseases and cardiovascular conditions, emphasizing its role in improving proteostasis and redox homeostasis Additionally, it summarizes current research into NRF2 as a therapeutic target, offering hope for innovative treatments to counteract the effects of aging and associated diseases.

Introduction: The aim of present study was to evaluate the impact of perimenopause on insulin resistance. Specifically, insulin sensitivity was assessed in a perimenopausal mouse model treated with 4-vinylcyclohexene diepoxide (VCD), together with the changes in exosomal miRNA and hepatic mRNA expression profiles. Methods: Homeostasis model assessment of insulin resistance (HOMA-IR) was utilized to assess the status of insulin resistance, and insulin action was evaluated during menopausal transition. RNA sequencing (RNA-seq) analysis was used to identify altered expression profiles of exosomal miRNAs and hepatic mRNAs. Differentially expressed miRNA (DEM)-differentially expressed gene (DEG) network analyses were also conducted. Furthermore, altered expression levels of these exosomal miRNAs and genes were validated in plasma exosomes and liver tissue of perimenopausal mice. Results: HOMA-IR in VCD-treated mice was significantly increased, and hepatic glycogen was significantly decreased. Key exosomal miRNAs (miR-17-3p, miR-134-5p, miR-700-5p, and miR-6899-3p) and hepatic genes (G6pdx, Ptpn2, Lepr, Kras, and Braf) may be associated with impaired insulin signaling during perimenopause. Conclusion: The perimenopausal period acts as a potential factor in introducing insulin resistance as evidenced by impaired insulin action and altered expression profiles of exosomal miRNAs and hepatic genes. The present study contributes to the understanding that abnormal cargos carried by plasma exosomes, such as miRNAs, may be related to altered expression of the corresponding genes in the liver and abnormal insulin response.

Metabolic disorders such as Type 2 diabetes mellitus (T2DM) imposes a significant global health burden. Plant-derived exosome like nanoparticles (P-ELNs) have emerged as a promising therapeutic alternate for various diseases. Present data demonstrates that treatment with Ginger-derived exosome like nanoparticles (G-ELNs) enhance insulin dependent glucose uptake, downregulate gluconeogenesis and oxidative stress in insulin resistant HepG2 cells. Furthermore, oral administration of G-ELNs in T2DM mice decreases fasting blood glucose levels and improves glucose tolerance as effectively as metformin. These improvements are attributed to the enhanced phosphorylation of Protein kinase B (Akt-2), the phosphatidylinositol 3-kinase at serine 474 which consequently leads to increase in hepatic insulin sensitivity, improvement in glucose homeostasis and decrease in ectopic fat deposition. Oral administration of G-ELNs also exerts protective effect on Streptozotocin (STZ)-induced pancreatic β-cells damage, contributing to systemic amelioration of T2DM. Further, as per computational tools, miRNAs present in G-ELNs modulate the phosphatidylinositol 3-kinase (PI3K)/Akt-2 pathway and exhibit strong interactions with various target mRNAs responsible for hepatic gluconeogenesis, ectopic fat deposition and oxidative stress. Furthermore, synthetic mimic of G-ELNs miRNA effectively downregulates its target mRNA in insulin resistant HepG2 cells. Overall, the results indicate that the miRNAs present in G-ELNs target hepatic metabolism thus, exerting therapeutic effects in T2DM.

Non-alcoholic fatty liver disease is a globally prevalent disorder that can rapidly progress if not detected early. Currently, no accepted markers exist for early diagnosis and prognosis of NAFLD. This review describes derangement in major metabolic pathways of lipid, carbohydrate, and amino acids in NAFLD. It suggests that measuring levels of thrombospondin, TyG index, asymmetric dimethylarginine, LAL-A, GLP-1, FGF-21, and GSG index are potential markers for early diagnosis of NAFLD. A single marker may not indicate early NAFLD, and further large-scale studies on correlating levels of Thrombospondin-2, triglyceride-glucose index, and FGF-21 with NAFLD are warranted.

UpToDate, no drugs have been approved to treat nonalcoholic steatohepatitis, the advanced stage of the most prevalent liver disease, non-alcoholic fatty liver disease. The present study was conducted to explore the potential influences of L-carnitine on the pathomechanisms of hepatic injury that mediate progression to non-alcoholic steatohepatitis in dexamethasone-toxified rats.

Male Wistar rats were allocated as follows: dexamethasone group, rats received dexamethasone (8 mg/kg/day, intraperitoneally) for 6 days; DEXA-LCAR300, DEXA-LCAR500, and DEXA-MET groups, rats administered L-carnitine (300 or 500 mg/kg/day, IP) or metformin (500 mg/kg/day, orally) one week prior to dexamethasone injection (8 mg/kg/day, IP) and other six days alongside dexamethasone administration. Two groups of age-matched normal rats received either the drug vehicle (the control group) or the higher dose of L-carnitine (the drug-control group). At the end of the experiment, sets of biochemical, histological, and immunohistochemical examinations were performed.

L-carnitine (mainly at the dose of 500 mg/kg/day) markedly abolished dexamethasone-induced alterations in glucose tolerance, hepatic histological features, and serum parameters of hepatic function and lipid profile. Moreover, it significantly ameliorated dexamethasone-induced elevations of hepatic oxidative stress, SREBP-1 and p-MLKL protein levels, and nuclear FOXO1, LC3, P62, and caspase-3 immunohistochemical expression. Furthermore, it markedly diminished dexamethasone-induced suppression of hepatic Akt phosphorylation and Bcl2 immunohistochemical expression. The effects of L-carnitine (500 mg/kg/day) were comparable to those of metformin in most assessments and better than its corresponding lower dose.

These findings introduce L-carnitine as a potential protective drug that may mitigate the rate of disease progression in non-alcoholic fatty liver disease patients with early stages or those at the highest risks.

We aimed to investigate the association of the triglyceride glucose-body mass index(TyG-BMI), metabolic score for insulin resistance (METS-IR) with regression to normoglycaemia, and further to compare the value of the four insulin resistance(IR) related indices(TyG-BMI, METS-IR, TyG and triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio) in identifying regressions to normoglycaemia from prediabetes.

A total of 15,025 patients with prediabetes from the DATA-DRYAD database were included. Cox proportional hazards regression models and restricted cubic spline functions were performed to explore the association and nonlinearity between the indices with the incidence rate of normoglycaemia. Sensitivity and subgroup analyses evaluated the robustness of our findings.

Compared with the first quintile, TyG-BMI and METS-IR was negatively linked with the probability of regression to normoglycaemia from prediabetes, the adjusted effect size of the highest quintiles of METS-IR were the most obvious (HR:0.456,95% CI:0.4-0.519), followed by TG/HDL (HR:0.792, 95% CI:0.733-0.856), TyG-BMI (HR:0.816, 95% CI:0.73-0.911) and TyG (HR:0.841, 95% CI: 0.754-0.937) (all p for trend <0.001). A 1.0 SD increase in METS-IR induced a 43% decrease in the probability of regression to normoglycaemia, with 9.8% for TyG-BMI. There were nonlinear associations between TyG-BMI and METS-IR and outcomes, with the inflection point of the TyG-BMI being 218.2 and that of the METS-IR being 37.

The METS-IR might be the most superior indicator among the four non-insulin indices in identifying regressions to normoglycaemia from prediabetes in clinical application. The inflection points of the METS-IR and TyG-BMI may be instructive therapeutic points for assessing the status of prediabetes in advance and making more appropriate management and health care decisions.

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by high blood sugar levels (hyperglycemia). Poorly managed diabetes can lead to complications affecting multiple organ systems. Antioxidants play a crucial role in reducing oxidative stress caused by reactive oxygen species (ROS), primarily triggered by uncontrolled high blood sugar levels in diabetes. Antioxidants like vitamin C, E, selenium, and alpha-lipoic acid, when used as supplements, have shown promise in reducing oxidative stress markers and improving antioxidant status in laboratory and animal studies and diabetic patients. Antioxidant supplementation may help reduce the risk of diabetic complications such as neuropathy, nephropathy, retinopathy, and cardiovascular disease. Additionally, antioxidants also have anti-inflammatory properties, which could be beneficial in reducing inflammation associated with diabetes. Antioxidant supplementation has been shown to enhance endothelial function, insulin sensitivity, and glucose metabolism, thereby aiding in glycemic control and overall diabetic management. Combining antioxidants with certain medications may have therapeutic benefits, such as effectively neutralizing free radicals and enhancing the regulation of antioxidant defense systems. This review presents an update on diabetes, the sources of free radical generation, the body's natural defense mechanisms, the clinical evidence regarding using antioxidants in managing diabetic complications, and the potential new therapeutic approaches. Overall, antioxidant supplementation may offer some benefits in managing diabetic complications. However, further studies are needed to understand the mechanisms of action, determine the optimal supplementation, explore potential interactions with other medications, and conduct long-term studies to establish the possible use of antioxidants for optimal benefits in diabetes care.

Insulin resistance impairs the cellular insulin response, and often precedes metabolic disorders, like type 2 diabetes, impacting an increasing number of people globally. Understanding the molecular mechanisms in hepatic insulin resistance is essential for early preventive treatments. To elucidate changes in insulin signal transduction associated with hepatocellular resistance, we employed a multi-layered mass spectrometry-based proteomics approach focused on insulin receptor (IR) signaling at the interactome, phosphoproteome, and proteome levels in a long-term hyperinsulinemia-induced insulin-resistant HepG2 cell line with a knockout of the insulin-like growth factor 1 receptor (IGF1R KO). The analysis revealed insulin-stimulated recruitment of the PI3K complex in both insulin-sensitive and -resistant cells. Phosphoproteomics showed attenuated signaling via the metabolic PI3K-AKT pathway but sustained extracellular signal-regulated kinase (ERK) activity in insulin-resistant cells. At the proteome level, the ephrin type-A receptor 2 (EphA2) showed an insulin-induced increase in expression, which occurred through the ERK signaling pathway and was concordantly independent of insulin resistance. Induction of EphA2 by insulin was confirmed in additional cell lines and observed uniquely in cells with high IR-to-IGF1R ratio. The multi-layered proteomics dataset provided insights into insulin signaling, serving as a resource to generate and test hypotheses, leading to an improved understanding of insulin resistance.

This study investigates the impact of maternal nutrition during lactation on inflammation and oxidative stress in the offspring of diet-induced obese rats, along with the potential benefits of leptin supplementation during suckling. Dams were fed either a standard diet (SD), a western diet (WD) before and during gestation and lactation (WD-dams), or a WD switched to an SD during lactation (Rev-dams). Offspring were supplemented with leptin or vehicle during suckling and then fed an SD or WD until four months. Offspring of the Rev-dams exhibited improved metabolic indicators, including lower body weight, reduced plasma levels of TNF-alpha, a higher adiponectin/leptin (A/L) ratio, enhanced liver antioxidant defenses, and decreased inflammation markers in white adipose tissue (WAT) compared to WD-dams, with sex differences. Leptin supplementation further modulated these markers, reducing oxidative stress in liver and inflammation in WAT and liver (e.g., hepatic Tnfa expression decreased by 45% (males) and 41% (females) in the WD group on an SD), and improving the A/L ratio, with effects varying by maternal conditions and sex. In conclusion, this study underscores the importance of maternal nutrition and leptin intake during suckling in shaping long-term metabolic and inflammatory health in offspring, offering strategies to mitigate the adverse effects of maternal obesity on future generations.

Type 2 diabetes and nonalcoholic fatty liver diseases (NAFLDs) are promoted by insulin resistance (IR), which alters lipid homeostasis in the liver. This study aims to investigate the effect of N-methylpyridinium (NMP), a bioactive alkaloid of coffee brew, on lipid metabolism in hepatocytes.

The effect of NMP in modulating lipid metabolism is evaluated at physiological concentrations in a diabetes cell model represented by HepG2 cells cultured in a high-glucose medium. Hyperglycemia triggers lipid droplet accumulation in cells and enhances the lipogenic gene expression, which is transactivated by sterol regulatory element binding protein-1 (SREBP-1). Lipid droplet accumulation alters the redox status and endoplasmic reticulum (ER) stress, leading to the activation of the unfolded protein response and antioxidative pathways by X-Box Binding Protein 1(XBP-1)/eukaryotic Initiation Factor 2 alpha (eIF2α) Protein Kinase RNA-Like ER Kinase and nuclear factor erythroid 2-related factor 2 (NRF2), respectively. NMP induces the phosphorylation of AMP-dependent protein kinase (AMPK) and acetyl-CoA carboxylase α (ACACA), and improves the redox status and ER homeostasis, essential steps to reduce lipogenesis and lipid droplet accumulation.

These results suggest that NMP may be beneficial for the management of T2D and NAFLD by ameliorating the cell oxidative and ER homeostasis and lipid metabolism.

BACKGROUND The relationship between different subgroups of type 2 diabetes (T2D) and the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) and liver fibrosis has not been thoroughly studied. This study aims to determine the association between T2D subgroups and the risk of developing advanced liver fibrosis using the Fibrosis-4 (FIB-4) index, a non-invasive marker for assessing liver fibrosis risk. MATERIAL AND METHODS A total of 1205 patients with T2D were categorized into 4 distinct subgroups: severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes (MARD). The FIB-4 index was calculated for each patient to estimate the degree of liver fibrosis, with the following cutoff points: <1.3 indicating no or mild fibrosis, 1.3-2.67 suggesting moderate fibrosis, and >2.67 indicating advanced fibrosis (F3-F4). Logistic regression was used to compare the odds of advanced fibrosis across these subgroups. RESULTS The SIRD subgroup exhibited significantly higher odds of advanced liver fibrosis (F3-F4), compared with the other subgroups, as indicated by elevated FIB-4 scores (P<0.05). In contrast, the SIDD and MOD subgroups had lower odds of advanced fibrosis, while the MARD subgroup showed an intermediate association. CONCLUSIONS The findings suggest that the FIB-4 index, as a noninvasive assessment tool, effectively stratifies liver fibrosis risk among different T2D subgroups. This stratification can inform more personalized management strategies for patients with MASLD, underscoring the importance of accounting for the heterogeneity within T2D in clinical assessments of liver fibrosis risk.

Small molecules selectively inducing peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α acetylation and inhibiting glucagon-dependent gluconeogenesis causing anti-diabetic effects have been identified. However, how these small molecules selectively suppress the conversion of gluconeogenic metabolites into glucose without interfering with lipogenesis is unknown. Here, we show that a small molecule SR18292 inhibits hepatic glucose production by increasing lactate and glucose oxidation. SR18292 increases phosphoenolpyruvate carboxykinase 1 (PCK1) acetylation, which reverses its gluconeogenic reaction and favors oxaloacetate (OAA) synthesis from phosphoenolpyruvate. PCK1 reverse catalytic reaction induced by SR18292 supplies OAA to tricarboxylic acid (TCA) cycle and is required for increasing glucose and lactate oxidation and suppressing gluconeogenesis. Acetylation mimetic mutant PCK1 K91Q favors anaplerotic reaction and mimics the metabolic effects of SR18292 in hepatocytes. Liver-specific expression of PCK1 K91Q mutant ameliorates hyperglycemia in obese mice. Thus, SR18292 blocks gluconeogenesis by enhancing gluconeogenic substrate oxidation through PCK1 lysine acetylation, supporting the anti-diabetic effects of these small molecules.

Liver disease, including hepatocellular carcinoma (HCC), is a major global health concern, claiming approximately 2 million lives worldwide annually, yet curative treatments remain elusive. In this study, we aimed to investigate the role of microRNA-21-5p (miR-21) in metabolic dysfunction-associated steatotic liver disease (previously NAFLD), metabolic-associated steatohepatitis (previously NASH), and HCC within the context of a Western high-fat diet, without additional choline (HFD) and offering potential therapeutic insights. We found that reduced miR-21 levels correlated with liver disease progression in WT mice fed on HFD, while miR-21 knockout mice showed exacerbated metabolic dysfunction, including obesity, hepatomegaly, hyperglycemia, insulin resistance, steatosis, fibrosis, and HCC. Our study reveals that miR-21 plays a protective role in metabolic syndrome and in the progression of liver disease to cancer. MiR-21 directly targets Transforming growth factor beta-induced (Tgfbi), a gene also known to be significantly upregulated and a potential oncogene in HCC. Further, our study showed that intervention with the administration of a miR-21 mimic in WT livers effectively improves insulin sensitivity, steatosis, fibrosis, Tgfbi expression and tumor burden in HFD conditions. These findings indicate that miR-21 could serve as an effective strategy to delay or prevent liver disease in high-fat-diet environments.

Fatty Liver Index (FLI), Triglyceride-Glucose Index (TyG), Lipid Accumulation Product (LAP), Zhejiang University Index (ZJU), and Visceral Adiposity Index (VAI) are five classical predictive models for fatty liver disease. Our cross-sectional study aimed to identify the optimal predictors by comparing the predictive value of five models for metabolic dysfunction-associated steatotic liver disease (MASLD) risk.

Data on 2687 participants were collected from West China Hospital of Sichuan University. Controlled attenuation parameters assessed by transient elastography were used to effectively diagnose MASLD. Logistic regression analysis was used to estimate the odd ratios and 95% confidence intervals between indices and MASLD risk. Receiver operating characteristic curves were plotted to evaluate the predictive value of indices.

This study included 1337 normal and 1350 MASLD samples. The average age of MASLD patients is 47 years old, and the prevalence was higher in males (39.3%) than in females (10.9%). Five indices were positively correlated with MASLD risk, with the strongest correlation for TyG. Overall, the area under the curve of the indicators was: ZJU 0.988, FLI 0.987, LAP 0.982, TyG 0.942, and VAI 0.941. In the gender stratification, ZJU (0.989) performed best in males. FLI (0.988) and ZJU (0.987) had similar predictive ability in females. In the age stratification, FLI performed better in predicting the middle-aged group aged 30-40 years (0.991).

For Chinese Han adults, ZJU is the best predictive index for initial screening of MASLD. FLI can serve as an alternative tool for ZJU to predict females.

LDL receptor-related protein-1 (LRP1) is a cell-surface receptor that functions in diverse physiological pathways. We previously demonstrated that hepatocyte-specific LRP1 deficiency (hLRP1KO) promotes diet-induced insulin resistance and increases hepatic gluconeogenesis in mice. However, it remains unclear whether LRP1 regulates hepatic glycogenesis.

Insulin signaling, glycogenic gene expression, and glycogen content were assessed in mice and HepG2 cells. The pcDNA 3.1 plasmid and adeno-associated virus serotype 8 vector (AAV8) were used to overexpress the truncated β-chain (β∆) of LRP1 both in vitro and in vivo.

On a normal chow diet, hLRP1KO mice exhibited impaired insulin signaling and decreased glycogen content. Moreover, LRP1 expression in HepG2 cells was significantly repressed by palmitate in a dose- and time-dependent manner. Both LRP1 knockdown and palmitate treatment led to reduced phosphorylation of Akt and GSK3β, increased levels of phosphorylated glycogen synthase (GYS), and diminished glycogen synthesis in insulin-stimulated HepG2 cells, which was restored by exogenous expression of the β∆-chain. By contrast, AAV8-mediated hepatic β∆-chain overexpression significantly improved the insulin signaling pathway, thus activating glycogenesis and enhancing glycogen storage in the livers of high-fat diet (HFD)-fed mice.

Our data revealed that LRP1, especially its β-chain, facilitates hepatic glycogenesis by improving the insulin signaling pathway, suggesting a new therapeutic strategy for hepatic insulin resistance-related diseases.