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We evaluated the impact of hepatic steatosis-insulin resistance (HS-IR) and liver fibrosis (LF) on type 2 diabetes mellitus (DM2) using triglyceride-glucose (TyG) and Fibrosis-4 (FIB-4). The incidence of DM2 was 12.9 [95% confidence interval (CI), 16.9-9.7] and 9.8 (95% CI, 6.9-13.6) per 1000 person-years in HS-IR and LF. The prevalence of HS-IR was significantly lower at 12 and 24 months with TDF + (3TC or FTC) + RPV [hazard ratio (HR) 0.5 [95% CI, 0.3-0.8], P < 0.01 at 12 months; 0.6 [0.4-0.9], P = 0.01 at 24 months]., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Aim: Insulin resistance (IR) is a pivotal metabolic disorder associated with type 2 diabetes and metabolic syndrome. This study investigated the potential of hypoxanthine (Hx), a purine metabolite and uric acid precursor, in ameliorating IR and regulating hepatic glucose and lipid metabolism., Methods: We utilized both in vitro IR-HepG2 cells and in vivo diet-induced IR mice to investigate the impact of Hx. The HepG2 cells were treated with Hx to evaluate its effects on glucose production and lipid deposition. Activity-based protein profiling (ABPP) was applied to identify Hx-target proteins and the underlying pathways. In vivo studies involved administration of Hx to IR mice, followed by assessments of IR-associated indices, with explores on the potential regulating mechanisms on hepatic glucose and lipid metabolism., Key Findings: Hx intervention significantly reduced glucose production and lipid deposition in a dose-dependent manner without affecting cell viability in IR-HepG2 cells. ABPP identified key Hx-target proteins engaged in fatty acid and pyruvate metabolism. In vivo, Hx treatment reduced IR severities, as evidenced by decreased HOMA-IR, fasting blood glucose, and serum lipid profiles. Histological assessments confirmed reduced liver lipid deposition. Mechanistic insights revealed that Hx suppresses hepatic gluconeogenesis and fatty acid synthesis, and promotes fatty acid oxidation via the AMPK/mTOR/PPARα pathway., Significance: This study delineates a novel role of Hx in regulating hepatic metabolism, offering a potential therapeutic strategy for IR and associated metabolic disorders. The findings provide a foundation for further investigation into the role of purine metabolites in metabolic regulation and their clinical implications., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Endogenous glucocorticoid levels display a strong circadian rhythm, which is often not considered when synthetic glucocorticoids are prescribed as anti-inflammatory drugs. In this study we evaluated the effect timing of glucocorticoid administration, i.e. in-phase (administered when endogenous glucocorticoid levels are high) versus out-of-phase (administered when endogenous glucocorticoid levels are low). We investigated the synthetic glucocorticoid betamethasone - which is extensively used in the clinic - and monitored the development of common metabolic side effects in mice upon prolonged treatment, with a particular focus on glucose metabolism., Methods: Male and female C57BL/6J mice were treated with the synthetic glucocorticoid betamethasone in-phase and out-of-phase, and the development of metabolic side effects was monitored., Results: We observed that, compared with in-phase treatment, out-of-phase treatment with betamethasone results in hyperinsulinemia in both male and female C57BL/6J mice. We additionally found that out-of-phase betamethasone treatment strongly reduced insulin sensitivity as compared to in-phase administration during morning measurements. Our study shows that the adverse effects of betamethasone are dependent on the time of treatment with generally less side effects on glucose metabolism with in-phase treatment., Conclusions: This study highlights differences in glucocorticoid outcome based on the time of measurement, advocating that potential circadian variation should be taken into account when studying glucocorticoid biology., Competing Interests: Declaration of competing interest OM received research funding from Corcept Therapeutics. JK is seconded to Corcept Therapeutics., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: One effective clinical strategy to combat obesity is intragastric botulinum toxin (BTX) injection, which increases gastric emptying time and regulates appetite. However, it remains unknown if and how BTX affects ghrelin levels., Materials and Methods: An obese animal model was established by feeding male mice with high-fat diet (HFD). BTX was administered by subserosal injection in the antrum via an upper midline laparotomy. The mice were monitored in terms of body weight and blood biochemical parameters. Glucose utility and insulin sensitivity were measured by intraperitoneal glucose and insulin tolerance tests. Additionally, stomach and liver were histologically examined after BTX treatment. AGS gastric adenocarcinoma cells were used to investigate the molecular mechanism by which BTX affects ghrelin expression., Key Findings: In HFD-fed mice, BTX injection significantly decreased both food intake and body weight over a 3-week monitoring period. Moreover, HFD-induced hyperglycemia, hyperinsulinemia, dyslipidemia and obesity readouts were improved after BTX injection. Importantly, mice also exhibited decreased plasma and gastric ghrelin levels after BTX injection. In cultured AGS cells, BTX significantly increased reactive oxygen species (ROS) levels and activated nuclear factor-κB (NF-κB), which led to decreased ghrelin expression. Pre-treatment with inhibitors of either ROS or NF-κB reversed the effects of BTX on ghrelin expression in the cultured cells., Significance: BTX decreases ghrelin expression in HFD-fed animals and in AGS cells through an ROS/NF-κB-dependent pathway. This mechanism may contribute to decreased food intake in obese subjects receiving intragastric BTX injection for weight control., Competing Interests: Declaration of competing interest We confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aim: Metabolic comorbidities such as obesity type 2 diabetes, insulin resistance, glucose intolerance, dyslipidemia are the major contributors for lower life expectancy and reduced patient compliance during antipsychotic therapy in patients with severe mental illnesses such as schizophrenia, bipolar disorder, and depression. TRPM8 activation by menthol is also reported to alleviate high fat diet-induced obesity in mice. Additionally, this TRPM8 activation leads to increase in gene expression of thermogenic genes in white adipocytes and dietary menthol was found to increase browning of WAT along with improved glucose utilization. Therefore, we aimed to evaluate the plausible role of TRPM8 channels in olanzapine-induced metabolic alterations in female balb/c mice., Methods: 6 weeks olanzapine (6 mg kg -1 , per oral) model was used in female balb/c mice. Pharmacological manipulation of TRPM8 channel was done using menthol and N-(3-aminopropyl)-2-[(3-methylphenyl)methoxy]-N-(2-thienylmethyl)-benzamide (AMTB), the agonist and antagonist respectively., Key Results: Menthol co-treatment for six weeks prevented olanzapine-induced metabolic alterations such as weight gain, increased food intake, decreased energy expenditure, adiposity, liver lipid accumulation, systemic inflammation and insulin resistance. Although no significant change in TRPM8 mRNA expression was found in the hypothalamus, however, some of the protective effects of menthol were absent in presence of AMTB indicating possible involvement of TRPM8 channels., Conclusion: Our results suggest possible therapeutic implications of menthol in the management of antipsychotic-induced weight gain and other metabolic alterations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Objective: To extract exosomes from obese and non-obese mice, screen specifically expressed microRNAs by high-throughput sequencing and explore their roles., Methods: An animal obesity model was constructed, and the successful construction of the obesity model was verified by HE staining, Western Blot and RT-qPCR. In addition, exosomes were extracted and verified by Western Blot. High-throughput sequencing was performed on the extracted serum exosomes to screen for differentially expressed microRNAs. fluorescence quantitative RT-PCR (RT-qPCR) was used to validate the differentially expressed miRNAs and explore their functions., Results: 8 microRNAs were up-regulated and 11 microRNAs were down-regulated. mmu-miR-674-5p and X&#95;28316 were significantly down-regulated and had the greatest impact on protein pathways. 8&#95;13258 was significantly up-regulated and affected multiple protein pathways. GO enrichment analysis suggested that the differentially expressed microRNAs were mainly involved in the cleavage of microtubule activity, transferase activity/transferase pentameric acid. GO enrichment analysis suggested that differentially expressed microRNAs were mainly involved in the processes of cleavage microtubule activity, transferase activity/transfer pentamer, and threonine phosphatase/threonine kinase activity.KEGG pathway enrichment analysis showed that differentially expressed microRNAs were mainly involved in the processes of regulating the phosphorylation of TP53 activity, the G2/M DNA damage checkpoint, and the processing of the ends of DNA double-strand breaks. Protein interaction networks were enriched for Stat3, Fgr, Camk2b, Rac1, Asb6, and Ankfy1. Suggesting that they may be mediated by differential genes to participate in the process of insulin resistance. qRT-PCR results showed that the expression trend of mmu-miR-674-5p was consistent with the sequencing results. It suggests that it may be able to participate in the regulation of insulin resistance as a target gene., Conclusion: microRNAs were differentially expressed in serum exosomes of obese and non-obese mice and might be involved in the specific regulation of insulin resistance. mmu-miR-674-5p was differentially expressed significantly and the validation trend was consistent with it, suggesting that it might be able to participate in the regulation of insulin resistance as a target gene., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Down syndrome (DS) is the most common genetic cause of intellectual impairment, characterised by an extra copy of chromosome 21. After the age of 40, DS individuals are highly susceptible to accelerated ageing and the development of early-onset Alzheimer-like neuropathology. In the context of DS, the brain presents a spectrum of neuropathological mechanisms and metabolic anomalies. These include heightened desensitisation of brain insulin and insulin-like growth factor-1 (IGF-1) reactions, compromised mitochondrial functionality, escalated oxidative stress, reduced autophagy, and the accumulation of amyloid beta and tau phosphorylation. These multifaceted factors intertwine to shape the intricate landscape of DS-related brain pathology. Altered brain insulin signalling is linked to Alzheimer's disease (AD). This disruption may stem from anomalies in the extracellular aspect (insulin receptor) or the intracellular facet, involving the inhibition of insulin receptor substrate 1 (IRS1). Both domains contribute to the intricate mechanism underlying this dysregulation. The PI3K-Akt/mammalian target of the rapamycin (mTOR) axis is a crucial intracellular element of the insulin signalling pathway that connects numerous physiological processes in the cell cycle. In age-related neurodegenerative disorders like AD, aberrant modulation of the PI3K-Akt signalling cascade is a key factor contributing to their onset. Aberrant and sustained hyperactivation of the PI3K/Akt-mTOR axis in the DS brain is implicated in early symptoms of AD development. Targeting the PI3K-Akt/mTOR pathway may help delay the onset of early-onset AD in individuals with DS, offering a potential way to slow disease progression and enhance their quality of life., Competing Interests: Declaration of competing interest The authors report no conflict of interest concerning the material or methods used in this study or the findings specified in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

It raises questions about the impact of lard on the health and the differences in individual responses. Therefore, we developed a model of mice fed with high fat (HF) from lard in 130 days. The weight of the mice was measured every two days. Glucose tolerance test and insulin tolerance tests were performed at 70 days and 130 days of experiment. At the end of the study, the fat tissue was collected to check the weight, and a blood sample was collected to check the blood lipids and liver enzymes. Surprisingly, mice responded variously to the HF by being classified into two groups, one group had significantly high gained weight (HG&#95;HF) versus the mice fed a standard diet (STD) (p < 0.001), and another group (LG&#95;HF) has not difference in body weight compared to the STD groups. This phenomenon in body weight is directly reflected by the white fat accumulation, but not by brown fat. Eating HF from lard for a long time can disrupt glucose tolerance and cause dyslipidemia in mice, even in the LG&#95;HF group, but can not disrupt insulin tolerance and cause liver enzyme disorders. In summary, our findings are a wake-up call for many cases where eating HF from lard does not gain weight and not increase the white fat storage, but still has the potential to cause adverse health effects. Further studies are encouraged to understand the molecular mechanisms that causes the body to regulate its weight and responses when eating HF from lard, especially in the LG&#95;HF group., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The avermectin derivative doramectin is widely used clinically as an antiparasitic drug and, in addition, doramectin may have a modulatory role in obesity. Adipose tissue macrophage recruitment and polarization play an important role in obesity-induced inflammation and insulin resistance. The aim of this study was to investigate the effects of doramectin on high-fat diet-induced inflammation and macrophage polarization in white adipose tissue of epididymis of obese mice. We found that compared with high-fat diet-fed obese mice, doramectin treatment resulted in a significant decrease in body weight and lipid levels, improved insulin resistance, an increase in the proportion of M2-type macrophages and a decrease in the proportion of M1-type macrophages in the epididymal white adipose tissues, as well as a decrease in the infiltration of inflammatory cells in the adipose tissues. Thus, doramectin can ameliorate high-fat diet-induced obesity and adipose inflammation by affecting macrophage polarization in white adipose tissue., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Context: Polycystic ovary syndrome (PCOS) is a common, heritable endocrinopathy that is a common cause of anovulatory infertility in reproductive age women. Variants in LMNA cause partial lipodystrophy, a syndrome with overlapping features to PCOS., Objective: We tested the hypothesis that rare variation in LMNA contributes to PCOS pathogenesis and selects a lipodystrophy-like subtype of PCOS., Design, Setting, and Participants: We sequenced LMNA by targeted sequencing a discovery cohort of 811 PCOS patients and 164 healthy controls. We then analyzed LMNA from whole-exome sequencing (WES) of a replication cohort of 718 PCOS patients and 281 healthy controls., Main Outcome Measures: Variation in the LMNA gene, hormone and lipid profiles of participants., Results: In the discovery cohort, we identified 8 missense variants in 15/811 cases, and 1 variant in 1/172 reproductively healthy controls. There is strong evidence for association between the variants and PCOS compared to gnomAD non-Finnish European population controls (χ2=17, p=3.7x10-5, OR=2.9). In the replication cohort, we identified 11 unique variants in 15/718 cases, and 1 variant in 281 reproductively healthy controls. Again, there is strong evidence for association with population controls (χ2=30.5, p=3.4x10-8, OR= 4.0). In both the discovery and replication cohorts, variants in LMNA identify women with PCOS with high triglycerides and extreme insulin resistance., Conclusions: Rare missense variation in LMNA is reproducibly associated with PCOS and identifies some individuals with lipodystrophy-like features. The overlap between this PCOS phenotype and genetic partial lipodystrophy syndromes warrants further investigation into additional lipodystrophy genes and their potential in PCOS etiology., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Preclinical models suggest mitochondria-derived oxidative stress as an underlying cause of insulin resistance. However, it remains unknown whether this pathophysiological mechanism is conserved in humans. Here, we used an invasive in vivo mechanistic approach to interrogate muscle insulin action while selectively manipulating the mitochondrial redox state in humans. To this end, we conducted insulin clamp studies combining intravenous infusion of a lipid overload with intake of a mitochondria-targeted antioxidant (mitoquinone). Under lipid overload, selective modulation of mitochondrial redox state by mitoquinone enhanced insulin-stimulated glucose uptake in skeletal muscle. Mechanistically, mitoquinone did not affect canonical insulin signaling but augmented insulin-stimulated glucose transporter type 4 (GLUT4) translocation while reducing the mitochondrial oxidative burden under lipid oversupply. Complementary ex vivo studies in human muscle fibers exposed to high intracellular lipid levels revealed that mitoquinone improves features of mitochondrial bioenergetics, including diminished mitochondrial H 2 O 2 emission. These findings provide translational and mechanistic evidence implicating mitochondrial oxidants in the development of lipid-induced muscle insulin resistance in humans.

Background: Sarcopenic obesity (SO) and osteoarthritis (OA) are highly prevalent musculoskeletal conditions that significantly impair health-related quality of life., Aim: This study investigated the association between SO and OA, and explored the potential mediating role of insulin resistance in this relationship. We utilized data from the National Health and Nutrition Examination Survey (NHANES) 1999-2018., Methods: This cross-sectional analysis employs NHANES data collected from 1999 to 2018, including participants aged 18 years and older. SO was assessed using dual-energy X-ray absorptiometry (DXA) measurements. Insulin resistance was estimated using the triglyceride-glucose (TyG) index. OA status was based on self-reported physician diagnosis. Statistical analyses included weighted logistic regression, restricted cubic spline (RCS) interaction analysis, mediation analysis using structural equation modeling (SEM), and receiver operating characteristic (ROC) curve analysis. Subgroup analyses were conducted based on age, sex, and diabetes status., Results: The sarcopenic obese group demonstrated the highest prevalence of OA (23.4 %), hypertension (47.8 %), and diabetes (12.0 %). Additionally, they exhibited elevated levels of triglycerides, cholesterol, glucose, blood urea nitrogen (BUN), creatinine, and uric acid. Logistic regression revealed significant positive associations between sarcopenic obesity, the TyG index, and OA risk. RCS analysis identified significant non-linear relationships and interactions of the TyG index with age, sex, and diabetes status on OA risk. Mediation analysis indicated that the TyG index mediated approximately 4.9 % of the effect of sarcopenic obesity on OA risk. ROC curve analysis demonstrated moderate diagnostic accuracy for the TyG index (AUC = 0.65), which improved when incorporated into the multivariate model (AUC = 0.78). Subgroup analyses confirmed significant associations between the TyG index and sarcopenic obesity with OA risk across different age, sex, and diabetes status categories., Conclusion: Our findings suggest a significant correlation between insulin resistance, as measured by the TyG index, and elevated OA risk in individuals with sarcopenic obesity. Targeting insulin resistance through future research may be a promising avenue to lower OA risk in this population., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Metabolic dysfunction-associated steatotic liver disease (MASLD), which encompasses a spectrum of conditions ranging from simple steatosis to hepatocellular carcinoma, is a growing global health concern associated with insulin resistance. Since there are limited treatment options for MASLD, this study investigated the therapeutic potential of Atractylodes lancea , a traditional herbal remedy for digestive disorders in East Asia, and its principal component, atractylodin, in treating MASLD. Following 8 weeks of high-fat diet (HFD) feeding, mice received oral doses of 30, 60, or 120 mg/kg of Atractylodes lancea . In HFD-fed mice, Atractylodes lancea treatment reduced the body weight; serum triglyceride, total cholesterol, and alanine aminotransferase levels; and hepatic lipid content. Furthermore, Atractylodes lancea significantly ameliorated fasting serum glucose, fasting serum insulin, and homeostatic model assessment of insulin resistance levels in response to HFD. Additionally, a glucose tolerance test demonstrated improved glucose homeostasis. Treatment with 5 or 10 mg/kg atractylodin also resulted in anti-obesity, anti-steatosis, and glucose-lowering effects. Atractylodin treatment resulted in the downregulation of key lipogenic genes ( Srebf1 , Fasn , Scd2 , and Dgat2 ) and the upregulation of genes regulated by peroxisome proliferator-activated receptor-α. Notably, the molecular docking model suggested a robust binding affinity between atractylodin and AMP-activated protein kinase (AMPK). Atractylodin activated AMPK, which contributed to SREBP1c regulation. In conclusion, our results revealed that Atractylodes lancea and atractylodin activated the AMPK signaling pathway, leading to improvements in HFD-induced obesity, fatty liver, and glucose intolerance. This study suggests that the phytochemical, atractylodin, can be a treatment option for MASLD.

Identifying biomarkers can help in the early detection of muscle loss and drive the development of new therapies. Research suggests a potential link between retinol-binding protein 4 (RBP4) and muscle mass, particularly in postmenopausal women. This study aimed to examine the association between baseline RBP4 levels and changes in appendicular lean mass (ALM), an indicator of muscle mass, in postmenopausal women. A 12-month follow-up period ( n =  153) included baseline and 12-month ALM assessments using DXA. ALM was normalized to squared height (ALMI). Baseline evaluations encompassed insulin resistance via HOMA-IR and immunoassay magnetic bead panel measurements of RPB4, IL-6, TNF-α, and IL-10. Postmenopausal women were categorized into higher ( n =  77) and lower ( n =  76) RPB4 groups based on baseline RPB4 values. Their changes in ALMI were compared using Mann-Whitney tests. General linear model was employed to evaluate the predictive power of baseline RBP4 for ALMI changes, adjusting for confounding variables: age, physical activity, smoking status, body fat, HOMA-IR, inflammatory markers (TNF-α and IL-6), and anti-inflammatory factor (IL-10). The higher RBP4 group exhibited a more pronounced reduction in ALMI compared to the lower RBP4 group (Higher RBP4 = -0.39 kg/m 2 , 95% CI: -0.48 to -0.31 kg/m 2 vs. Lower RBP4 = -0.24 kg/m 2 , 95% CI: -0.32 to -0.15 kg/m 2 , P =  0.011). After adjusting for confounding factors, the association between baseline RBP4 changes and ALMI remained ( b = -0.008, SE = 0.002, P <  0.001), indicating higher baseline RBP4 values linked to greater ALMI reduction. Our findings support RBP4 as a potential biomarker for changes in muscle mass in postmenopausal women.

Introduction: There has been a surge in interest in identifying the factors that impact cognitive impairment (CI) in patients with multiple sclerosis (MS). The purpose of our study was to examine the correlation between fasting blood sugar (FBS), fasting insulin level, as well as insulin sensitivity and cognitive function in patients with MS., Material and Methods: A total of 85 patients with MS enrolled in this cross-sectional study. Insulin sensitivity (IS) was determined using the quantitative insulin sensitivity check index (Quicki) formula. Cognitive function was evaluated using the Persian version of the Brief International Cognitive Assessment for MS (BICAMS). Spearman correlation test was employed to examine the correlation between cognition and FBS, insulin and IS., Results: The mean ± SD age of the participants was 39.4 ± 10.2 years, and 62 (72.9%) were female. The participants had a FBS level of 87.05 ± 11.73 mg/dL, insulin level of 10.14 ± 7.57 μU/mL and a Quicki index of 0.36 ± 0.05. A higher score on the BVMT-R and BVMT-R-Delayed subtests showed a significant negative correlation with FBS (r: -0.32; p: 0.003 and r: -0.31; p: 0.004, respectively). Conversely, a significant negative correlation (r: -0.24; p: 0.031) was observed between higher fasting insulin levels and the CVLT&#95;II score. IS showed a positive correlation with the CVLT-II (r: 0.24; p: 0.027) and BVMT&#95;R (r: 0.21; p: 0.054) subtests., Conclusion: Our data indicate that elevated fasting glucose, developed fasting insulin levels and reduced insulin sensitivity may serve as potential predictors for CI in patients with MS., (© 2024 The Author(s). Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd.)

Objectives: This study aimed to determine whether fetal subcutaneous tissue (SCT) thickness, measured using ultrasound immediately before and after delivery, can reflect changes in glucose metabolism immediately after delivery. We also evaluated the impact of insulin resistance changes during pregnancy by comparing pregnant women with well-controlled gestational diabetes mellitus (GDM) and those with normal glucose metabolism., Study Design: The study participants were 117 pregnant women, including 97 controls and 20 patients with GDM who visited our obstetric clinic between February and December 2022. The participants were scheduled for cesarean delivery at a gestational age of ≥37 weeks. SCT thickness before delivery was measured using ultrasound and within 48 h after delivery using Holtain calipers. The glucose and insulin concentrations were quantified from cord blood collected immediately after delivery. Based on these results, a Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) was performed to assess insulin resistance. Independent t-test or Wilcoxon rank-sum test for continuous variables and Fisher's exact test for categorical variables were used to compare the various parameters. Correlations among the variables in each group were assessed by calculating the correlation coefficient (Pearson's correlation)., Results: SCT thickness measured using ultrasound and calipers demonstrated a strong correlation where pregnant women with GDM exhibited thicker fetal SCT and neonate skinfolds than in those without GDM. Glucose and insulin levels in the cord blood were significantly elevated (p < 0.05) in the gestational diabetic group, along with remarkable differences (p < 0.001) in HOMA-IR. These variables indicated a higher prevalence of glucose intolerance in the neonates of mothers with GDM. In pregnant women with GDM, there was a statistically significant correlation between fetal abdominal SCT thickness and glucose levels (r = 0.64, p < 0.01) and HOMA-IR (r = 0.48, p < 0.05)., Conclusions: Measuring the subcutaneous fat thickness of the fetus shortly before delivery is beneficial for predicting insulin resistance in neonates. This is considered particularly useful for women with effectively managed GDM, where the presence of conditions such as macrosomia may not be pronounced., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose of Review: The impact of vitamin D on improving insulin resistance in prediabetes remains controversial. The purpose of this review is to examine whether vitamin D supplementation improves insulin resistance in adults with prediabetes, and if so, to identify the mechanisms and the specific populations., Recent Findings: Global prevalence of prediabetes is increasing, and prevention is a critical issue because these people with prediabetes will develop type 2 diabetes soon, which will put pressure on healthcare costs. Recent evidence on the effectiveness of vitamin D administration in improving insulin resistance and preventing the onset of type 2 diabetes in adults with prediabetes has been accumulating. The 2024 updated clinical practice guideline of the American Diabetes Association states that vitamin D administration to patients with prediabetes potentially benefits type 2 diabetes incidence in specific populations. There are also reports that vitamin D administration improves insulin resistance via increased serum osteocalcin levels, a marker of bone turnover., Summary: Vitamin D is likely to improve insulin resistance, which is already present at the time of prediabetes. However, the effectiveness may vary depending on ethnic differences and blood vitamin D levels at the start of administration., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Aim: To identify the characteristics and pregnancy outcomes across different subgroups of gestational diabetes mellitus (GDM) categorized by insulin resistance index and body mass index (BMI) in early pregnancy., Methods: This retrospective study included 1804 women who underwent a 75 g-OGTT during 22-28 weeks of gestation, categorized into normal glucose tolerance (NGT) (1487) and GDM (317 [17.57%] of the total cohort). Metabolic parameters were assessed, and equation of homeostatic model assessment (HOMA) were utilized to compute indices of insulin resistance (HOMA-IR), β-cell secretory (HOMA-B), and insulin sensitivity (HOMA-%S) in early and mid-pregnancy. The cut-off value of HOMA-IR (1.61) in early pregnancy was determined via ROC curve analysis. This value, combined with pre-pregnancy BMI, further categorized NGT and GDM into six subgroups respectively, based on HOMA-IR levels (≥ 1.61 or < 1.61) and BMI categories (< 18.5 kg/m 2 , 18.5-25 kg/m 2 , or ≥ 25 kg/m 2 )., Results: In comparison to women with NGT, those with GDM were notably older, had higher pre-BMI, fasting plasma glucose (FPG), insulin, and lipid levels in early pregnancy. They also exhibited more pronounced insulin resistance in both early and mid-pregnancy, leading to poorer outcomes. Following an oral glucose load, the peaks of glucose and insulin were out of sync in GDM and its subgroups, accompanied by further increases in HOMA-IR, HOMA-B, and a decrease in HOMA-%S, except for the GDM subgroup with HOMA-IR < 1.61/BMI < 18.5 kg/m 2 . Conversely, glucose and insulin secretion in NGT and its subgroups peaked synchronously at 60 min. GDM women with HOMA-IR ≥ 1.61/18.5 kg/m 2  ≤ BMI < 25 kg/m 2 had higher rates of neonatal jaundice (34.5% vs 13.9%, p < 0.0001), LGA (28.9% vs 13.2%, p = 0.001), macrosomia (9.8% vs 3.7%, p = 0.025) compared to peers, while in GDM women with HOMA-IR ≥ 1.61/BMI ≥ 25 kg/m 2 , the rates of LGA and macrosomia were 26.6% and 8.4%, respectively. The GDM subgroup with HOMA-IR < 1.61/BMI < 18.5 kg/m 2 exhibited the highest rates of premature rupture of membrane (46.7%) and postpartum hemorrhage (20%), predominantly with vaginal delivery and a 1 min Apgar score of 4.5% in GDM women with HOMA-IR < 1.61/18.5 kg/m 2  ≤ BMI < 25 kg/m 2 ., Conclusion: GDM and its subgroups displayed severe insulin resistance and poorer insulin sensitivity, leading to an increased risk of adverse pregnancy outcomes. GDM women with higher IR and normal or over weight were more likely to experience LGA and macrosomia, while those with lower IR and underweight were prone to premature rupture of membrane and postpartum hemorrhage during vaginal delivery., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Medicinal and food homologous plants (MFHPs) which can improve Type 2 Diabetes Mellitus (T2DM) draw significant attention among the public due to their low toxicity and more safety. Polysaccharides, one of the various active components of MFHPs, are recognized as effective modulators of the intestinal flora. By altering the composition of intestinal flora and affecting their metabolic products, polysaccharides can improve T2DM, making them a central focus of anti-diabetic research., Purpose: The purpose of this study is to systematically review the mechanism by which polysaccharides from MFHPs (MFHPPs) regulate the composition of intestinal flora and its metabolic products to improve T2DM., Methods: This study follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and conducts a comprehensive search on the PubMed, Web of Science and Embase databases. All experimental articles published up to March 4, 2024, are included in the search., Results: Among the 5733 articles reviewed, 29 were selected, covering 22 different MFHPs. MFHPPs can improve T2DM, particularly in lowering blood glucose levels, with consistent results. MFHPPs can regulate the diversity of intestinal flora in T2DM animal models, primarily affecting four phyla: decreasing Firmicutes and Proteobacteria while increasing Bacteroidetes and Actinobacteriota. At the genus level, the improvement of T2DM by MFHPPs is associated with the modulation of 12 key genera: Allobaculum, Akkermansia, Bifidobacterium, Lactobacillus, Helicobacter, Halomonas, Olsenella, Oscillospira, Shigella, Escherichia-Shigella, Romboutsia and Bacteroides. At the molecular level, MFHPPs primarily act by modulating the intestinal flora to increase short-chain fatty acid levels, promote the secretion of glucagon-like peptide-1, influence the IGF1/PI3K/AKT signaling pathway, or the PI3K/AKT/GSK-3β pathway, to lower blood glucose levels. They may also improve T2DM by working in glucose metabolism through the "microbiota-gut-organ" axis. MFHPPs can also alleviate T2DM by mitigating inflammation and oxidative stress: MFHPPs regulate intestinal flora to reduce lipopolysaccharide "leakage" and enhance intestinal mucosal permeability to tackle the inflammation associated with T2DM; MFHPPs enhance the expression of oxidative stress-related enzymes to alleviate oxidative stress and improve T2DM. Lastly, from a metabolic pathway perspective, MFHPPs are primarily involved in the metabolism of amino acids and their derivatives, carbohydrate metabolism and glutathione metabolism., Conclusion: MFHPPs can improve T2DM by enhancing the composition of intestinal flora, regulating its metabolic products to promote insulin secretion, inhibiting glucagon-like peptide secretion, facilitating glycogen synthesis, reducing inflammation levels and alleviating oxidative stress. Furthermore, MFHPPs demonstrate potential protective effects on critical organs such as the pancreas, liver, kidneys and heart. Therefore, MFHPPs demonstrate significant clinical potential. However, most studies can only indicate the potential of MFHPPs intervention in improving T2DM through the intestinal flora. The causality between MFHPPs regulating the intestinal flora and T2DM requires further investigation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

In aging and metabolic syndrome oxidative stress is a causative factor in the cardiovascular pathology. Upregulation of 5-⍺ reductase is associated with cardiac hypertrophy but how inhibition of 5-⍺ reductase affects cardiometabolic function during oxidative damage under those conditions is unclear. Our hypothesis was that Finasteride (Fin), a 5-⍺ reductase inhibitor, promotes an antioxidant response, leading to an improvement in cardiac function in obese and aging rats. Male rats were divided into 3 groups including normal diet (ND) fed rats, ND-fed rats treated with d-galactose (D-gal) to induce aging, and high-fat diet (HFD) fed rats to induce obesity. Rats received their assigned diet or D-gal for 18 weeks. At week 13, rats in each group were divided into 2 subgroups and received either a vehicle or Fin (5 mg/kg/day, oral gavage). Cardiometabolic and molecular parameters were subsequently investigated. Both D-gal and HFD successfully induced cardiometabolic dysfunction, oxidative stress, mitochondrial dysfunction, and DNA fragmentation. Fin treatment did not affect metabolic disturbances; however, it reduced cardiac sympathovagal imbalance, cardiac dysfunction through the inhibition of oxidative stress and promoted antioxidants, resulting in reduced p53 protein levels and DNA fragmentation. Surprisingly, Fin induced insulin resistance in ND-fed rats. Fin effectively improved cardiac function in both models by enhancing antioxidant levels, suppressing oxidative stress and DNA fragmentation. However, Fin treatment did not confer any beneficial effects on metabolic status. Fin administration effectively improved cardiac sympathovagal balance and cardiac function in rats with oxidative damage induced by either D-gal or HFD., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Targeting white adipose tissue (WAT) browning to increase systemic energy expenditure is a promising therapeutic strategy to combat obesity. Actein from Actaea cimicifuga L. has recently been reported to ameliorate high fat-induced hepatic steatosis. However, the effect of actein on diet-induced obesity merits more and further investigation., Purpose: We aimed to examine the anti-obesity potential of actein and unravel its actions on WAT browning., Methods: The effect of actein on diet-induced obesity was evaluated using a high-fat diet model in C57BL/6 mice. Systemic energy expenditure of mice was measured with a combined indirect calorimetry system. Quantitative real-time PCR analyses were performed to investigate the mRNA levels of genes involved in thermogenesis, browning, and lipolysis. The protein levels were assessed by Western blot. Moreover, WAT explants and a transwell co-culture system consisting of SVFs and adipocytes were constructed to study the mechanisms of actein on promoting WAT browning and lipolysis., Results: At a dosage of 5 mg/kg/d, actein not only protected mice against diet-induced obesity and insulin resistance, but also reversed pre-established obesity and glucose intolerance in mice. Meanwhile, actein facilitated systemic energy expenditure by activating WAT lipolysis and browning. Further, mechanistic studies revealed that actein indirectly induced epididymal adipocyte lipolysis and directly promoted a white-to-beige conversion of subcutaneous adipocytes by activating the AMPK signaling., Conclusion: Actein ameliorated diet-induced obesity and was discovered as a natural lead compound directly targeting white-to-beige conversion of subcutaneous adipocytes, suggesting the potential of developing new therapies for obesity and associated metabolic disorders., Competing Interests: Declaration of competing interest We have no competing financial interests., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Insulin resistance, defined as an impaired biological response to insulin stimulation in target tissues, arises most frequently in the presence of central obesity. Although obesity is generally associated with increased bone mass, recent data challenge this view and, if complicated by T2DM, obese patients are at high risk for fragility fractures. IR may play a key role in this increased fracture risk through effects on bone quality rather than bone quantity. Further understanding of the mechanisms and approaches to prevent osteoporotic fractures in IR-related diseases is needed., Clinical Relevance: The dramatic increase in obesity and metabolic syndrome (MetS) over the last half-century has led to a worldwide epidemic of type 2 diabetes mellitus (T2DM) as well as in the incidence of insulin resistance (IR). IR is defined as an impaired biological response to insulin stimulation in target tissues and is primarily related to the liver, muscle, and adipose tissue. The most frequent underlying cause is central obesity, and it is known that excess abdominal adipose tissue secretes increased amounts of free fatty acids, which directly affects insulin signalling, reduces glucose uptake in muscle, and triggers excessive triglyceride synthesis and gluconeogenesis in the liver. When pancreatic β cells are unable to secrete the higher levels of insulin needed, T2DM, the main complication of IR, occurs., Observations: Although obesity is generally associated with increased bone mass, recent data challenge this view and highlight the multifaceted nature of the obesity-bone relationship. Patients with T2DM are at significant risk for well-known complications of diabetes, including retinopathy, nephropathy, macrovascular disease, and neuropathy, but it is clear that they are also at high risk for fragility fractures. Moreover, recent data provide strong evidence that IR may key role in the increased fracture risk observed in both obesity and T2DM., Conclusions: In this concise review article, the role of IR in increased risk of osteoporotic fractures in MetS, obesity, and T2DM is discussed and summarised, including consideration of the need for fracture risk assessment as a 'preventive measure', especially in patients with T2DM and chronic MetS with abdominal obesity. Personalised and targeted diagnostic and therapeutic approaches to prevent osteoporotic fractures in IR-related diseases are needed and could make significant contributions to health outcomes., (© 2024. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

The liver plays a major role in glucose and lipid homeostasis and acts as a key organ in the pathophysiology of metabolic diseases. Intriguingly, increased sympathetic nervous system (SNS) activity to the liver has been associated with the development and progression of type 2 diabetes and obesity. However, the precise mechanisms by which the SNS regulates hepatic metabolism remain to be defined. Although liver α1-adrenoceptors were suggested to play a role in glucose homeostasis, the specific subtypes involved are unknown mainly because of the limitations of pharmacological tools. Here, we generated and validated a novel mouse model allowing tissue-specific deletion of α-1b adrenoceptor ( Adra1b ) in hepatocytes to investigate the role of liver ADRA1B in energy and glucose metabolism. We found that selective deletion of Adra1b in mouse liver has limited metabolic impact in lean mice. However, loss of Adra1b in hepatocytes exacerbated diet-induced obesity, insulin resistance, and glucose intolerance in female, but not in male mice. In obese females, this was accompanied by reduced hepatic gluconeogenic capacity and reprogramming of gonadal adipose tissue with hyperleptinemia. Our data highlight sex-dependent mechanisms by which the SNS regulates energy and glucose homeostasis through liver ADRA1B. NEW & NOTEWORTHY The sympathetic nervous system plays an important role in regulating hepatic physiology and metabolism. However, the identity of the adrenoceptors involved in these effects is still elusive. Using CRISPR-Cas9, we developed a novel transgenic tool to study the role of liver α-1b adrenoceptor (ADRA1B). We show that ADRA1B plays a key role in mediating the effects of the sympathetic nervous system on hepatic metabolism, particularly in female mice.

Skeletal muscle is one of the predominant sites involved in glucose disposal, accounting for ∼80% of postprandial glucose uptake, and plays a critical role in maintaining glycemic homeostasis. Dysregulation of energy metabolism in skeletal muscle is involved in developing insulin resistance and type 2 diabetes (T2D). Transcriptomic responses of skeletal muscle to exercise found that the expression of Klf3 was increased in T2D Goto-Kakizaki (GK) rats and decreased after exercise with improved hyperglycemia and insulin resistance, implying that Klf3 might be associated with insulin sensitivity and glucose metabolism. We also found that knockdown of Klf3 promoted basal and insulin-stimulated glucose uptake in L6 myotubes, whereas overexpression of Klf3 resulted in the opposite. Through pairwise comparisons of L6 myotubes transcriptome, we identified 2,256 and 1,988 differentially expressed genes in Klf3 knockdown and overexpression groups, respectively. In insulin signaling, the expression of Slc2a4 , Akt2 , Insr , and Sorbs1 was significantly increased by Klf3 knockdown and decreased with Klf3 overexpression; Ptprf and Fasn were markedly downregulated in Klf3 reduced group and upregulated in Klf3 overexpressed group. Moreover, downregulation of Klf3 promoted the expression of glucose transporter 4 (GLUT4) and protein kinase B (AKT) proteins, as well as the translocation of GLUT4 to the cell membrane in the basal situation, and enhanced insulin sensitivity, characterized by increased insulin-stimulated GLUT4 translocation and AKT, TBC1 domain family member 1 (TBC1D1) and TBC1 domain family member 4 (TBC1D4) phosphorylation, whereas overexpression of Klf3 showed contrary results. These results suggest that Klf3 affects glucose uptake and insulin sensitivity via insulin signal transduction and intracellular metabolism, offering a novel potential treatment strategy for T2D. NEW & NOTEWORTHY The knockdown of Klf3 increased glucose uptake and improved insulin sensitivity in L6 myotubes, whereas its overexpression had the opposite effect. To explore the underlying mechanisms, we evaluated the transcriptional profiles of L6 myotubes after Klf3 knockdown and overexpression and revealed that metabolism and insulin-related pathways were significantly impacted. Klf3 also influenced the expression or modification of glucose transporter 4 (GLUT4), protein kinase B (AKT), TBC1 domain family member 1 (TBC1D1), and TBC1 domain family member 4 (TBC1D4) in the insulin signaling pathway, affecting insulin sensitivity and glucose uptake.

Diabetes mellitus (DM) is a chronic metabolic disease characterized by hyperglycemia. Type 2 diabetes mellitus (T2DM) represents approximately 90 % of all DM cases and is primarily caused by an imbalance in blood glucose homeostasis due to inadequate insulin secretion or insulin resistance. This study explores the potential therapeutic effects of chitosan guanidine (CSG) on a T2DM mouse model. The findings reveal that CSG significantly enhances oral glucose tolerance (OGTT) and insulin sensitivity (ITT), reduces fasting blood glucose (FBG) levels, and suppresses the expression of proinflammatory cytokines in T2DM mice. These changes improve insulin resistance and diminish inflammation. Additionally, CSG markedly ameliorates lipid metabolism disorders, lowers total cholesterol (TC) and triglyceride (TG) levels, and inhibits hepatic fat accumulation. 16S rRNA and Spearman correlation analyses indicate that CSG promotes the relative abundance of probiotic genera such as Bacteroidota, Patescibacteria, Actinobacteria, and Cyanobacteria. These bacteria are positively correlated with short-chain fatty acids (SCFAs) and high-density lipoprotein cholesterol (HDLC) levels. Conversely, CSG reduces the relative abundance of pathogenic bacteria, including Proteobacteria and Ralstonia, leading to an improved intestinal microbial community composition in T2DM mice and alleviating T2DM symptoms. These results suggest that CSG holds significant potential as a non-insulin therapeutic agent for diabetes management., Competing Interests: Declaration of competing interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled. We confirm that the mentioned received grants in the “Acknowledgement” section, did not lead to any conflicts of interest regarding the publication of this manuscript., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Salt-sensitive hypertension is associated with insulin resistance in nonobese individuals. However, no data have been reported for normotensive offspring of hypertensive salt-sensitive parents., Aims: To evaluate in normotensive salt-sensitive or salt-resistant offspring of hypertensive parents (offSS-HT and offSR-HT, respectively): the possible association between insulin resistance and endothelial dysfunction, and the risk of developing hypertension in a 10-year follow-up., Design and Methods: Forty-one offSS-HT (29 ± 2 years; 20 female) and 36 offSR-HT (25 ± 3 years; 16 female) were followed up for 10 years. Both groups were considered lean. At baseline, creatinine clearance (CrCl), 24 h urinary albumin excretion (UAE), glycemia, and insulinemia were measured before and after 60 and 120 min of glucose overload (75 g). HOMA Index and the area under the curve (AUC) were calculated. Blood pressure (BP) and 24 h urine sodium excretion was measured annually. Postischemic minimum vascular resistance (forearm plethysmography) was assessed at baseline., Results: In offSS-HT, UAE (53 ± 3 mg/min) and CrCl (136 ± 8 ml/min) were higher in offSS-HT than in offSR-HT. (UAE: 12 ± 4 mg.min; p,0.01 and CrCl 107 ± 6 ml.min; P  < 0.01). An impaired vasodilatory postischemic response was observed in offSS-HT compared with offSR-HT ( P  < 0.01). In offSS-HT glycemia, insulin, AUC at 69 and 120 min post OTG were greater than in offSR-HT, p  < 0.02. In offSS-HT, blood pressure rose ( P  < 0.01) the 10 years follow-up compared with offSR-HT., Conclusion: Salt sensitivity in the offspring of hypertensive salt-sensitive individuals is associated with insulin resistance and endothelial dysfunction and is prone to hypertension over a short period of time., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Insulin Resistance (IR) is associated with stroke. This study aimed to investigate the correlation between metabolic score for insulin resistance (METS-IR) level, a new biomarker for assessing IR, and stroke., Methods: This is a cross-sectional study based on data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2020 and included participants aged ≥ 20 years. All participants provided complete stroke and METS-IR related data. The study employed statistical techniques, including multivariate logistic regression analysis, restricted cubic splines (RCS), and stratified analyses to evaluate the relationship between the amounts of METS-IR and the risk of stroke., Results: The study included 14,029 participants aged 20 years or older. The fully adjusted model revealed a statistically significant correlation between METS-IR and stroke (OR=1.21, 95% CI: 1.00, 1.46; P<0.05). Specifically, for every 10-unit increase in METS-IR, there was a 21% increase in the prevalence of stroke. The prevalence of stroke was 60% higher in the Q4 group compared to the Q1 group, as indicated by a significant association with METS-IR (OR=1.60, 95% CI: 1.01, 2.54; P<0.05). The RCS analysis revealed a strong linear correlation between METS-IR and the incidence of stroke (P<0.05). Subgroup analyses showed that gender, age, race, alcohol consumption, smoking, diabetes, and hypertension exhibited correlation with this positive association, and a significant interaction was observed in age (P for interaction < 0.05)., Conclusions: The findings of this study indicate that elevated METS-IR levels are strongly linked to a greater risk of stroke in adults., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Numerous studies have shown that the triglyceride-glucose (TyG) index is a reliable substitute marker for insulin resistance. Nevertheless, its correlation with carotid artery plaques (CAPs) among patients with ischemic stroke (IS) remains to be elucidated., Methods: 9248 IS patients hospitalized at the First Teaching Hospital of Tianjin University of Traditional Chinese Medicine were grouped according to the quartiles of TyG index. Patients were further stratified by blood pressure status, sex, age and hypertension control status. Employing logistic regression to examine the connection between the TyG index and CAPs.Additionally, analyzing the receiver operating characteristic (ROC) curve to evaluate the predictive value of the TyG index for CAPs., Results: Participants with an elevated TyG index had an increased prevalence of CAPs. The TyG index was positively correlated with CAPs (OR: 1.26, CI: 1.14-1.40, P<0.001). Compared with normal blood pressure and prehypertensive patients, the TyG index was markedly correlated with CAPs among hypertensive patients (OR: 1.29, 95% CI: 1.15-1.44, P<0.001). Females had a higher OR value than males(OR: 1.31, 95% CI: 1.11-1.54, P=0.001 versus OR: 1.24, 95% CI: 1.09-1.41, P=0.001). Older patients (>60 years) had a higher OR value than their middle-aged counterparts (≤60 years) (OR: 1.35; 95% CI: 1.16-1.58, P<0.001 versus OR: 1.20; 95% CI: 1.05-1.37, P=0.007). Patients with poorly-controlled hypertension had a higher OR value than patients with well-controlled hypertension(OR: 1.36; 95% CI: 1.14-1.63, P=0.001 versus OR: 1.24; 95% CI: 1.07-1.44, P=0.003). After adjusting for potential confounding factors, the area under the ROC curve (AUC) value in the overall population, sex-stratified group, hypertensive patients and hypertension control status-stratified group were all above 0.7 (P<0.01), demonstrating good forecasting capability., Conclusions: In IS patients, the TyG index was significantly associated with CAPs. Additionally, this correlation was more pronounced in hypertensive patients, females, older individuals and patients with poorly-controlled hypertension., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Objective: The aim was to investigate the mediating role of inflammatory biomarkers in the causal effect of body composition on glycaemic traits and type 2 diabetes., Methods: A retrospective observational study and a Mendelian randomization (MR) study were used. Observational analyses were performed using data from 4717 Chinese children and adolescents aged 6-18 years who underwent dual-energy X-ray absorptiometry for body composition. MR analyses were based on summary statistics from UK Biobank, deCODE2021, Meta-Analysis of Glucose and Insulin-Related Traits Consortium (MAGIC) and other large consortiums. Inflammatory biomarkers included leptin, adiponectin, osteocalcin, fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH)., Results: In a retrospective observational study, increased fat mass had a positive effect on homeostasis model assessment of insulin resistance (HOMA-IR) and homeostasis model assessment of pancreatic beta cell function (HOMA-β) through FGF23, whereas fat-free mass produced the opposite effects. PTH and osteocalcin played significant roles in the association of fat mass and fat-free mass with fasting glucose, fasting insulin and HOMA-IR (all p < 0.05). Mediation MR results indicated that childhood body mass index affected glycaemic traits through leptin and adiponectin. There existed a causal effect of fat-free mass on type 2 diabetes via FGF23 (indirect effect: OR [odds ratio]: 1.14 [95% CI, confidence interval: 1.01-1.28]) and adiponectin (OR: 0.85 [95% CI: 0.77-0.93]). Leptin mediated the causal association of fat mass (indirect effect: β: -0.05 [95% CI: -0.07, -0.02]) and fat-free mass (β: 0.03 [95% CI: 0.01, 0.04]) with fasting glucose., Conclusions: Our findings suggest that different body compositions have differential influences on glycaemic traits and type 2 diabetes through distinct inflammatory biomarkers. The findings may be helpful in tailoring management of body composition based on inflammatory biomarkers with different glycaemic statuses., (© 2024 John Wiley & Sons Ltd.)

Aims: Obesity is a global public health issue, and some studies have linked it to an increased risk of prostatic diseases. This study aimed to evaluate the effects of a high-fat diet on metabolic parameters and prostate morphology in wild-type (WT) and adiponectin knockout (KO) mice., Main Methods: Male WT and KO mice were fed a control diet (CD) or high-fat diet (HFD) for 6 months. Serum metabolic parameters, inflammatory cytokines in epididymal fat tissue, dorsal prostatic lobe morphometry and histopathology were analyzed., Key Findings: CD WT and CD KO mice did not exhibit altered metabolic or prostatic parameters. However, HFD WT mice showed altered glucose and insulin tolerance even without excessive weight gain. On the other hand, HFD KO mice developed obesity, with an increase in low-density lipoprotein (11.8 ± 5.1 vs. 31.4 ± 3.6 mg/dL), high-density lipoprotein (73.4 ± 7.4 vs. 103.4 ± 2.5 mg/dL), and total cholesterol levels (126.2 ± 16.1 vs. 294.6 ± 23.2 mg/dL), a decrease in insulin levels (28.7 ± 12.2 vs. 4.6 ± 2.3 μIU/mL), and glucose and insulin resistance. We also observed that HFD KO animals display an increase in inflammatory cytokines, such as IL6, IL1β, and IL1RA. The dorsal prostate from HFD KO animals also presented significant increases in the mast cells (1.9 ± 0,7 vs. 5,3 ± 1.5 cells/field) and Ki67 index (2.91 ± 0.6 vs. 4.7 ± 0.4 %)., Significance: The above findings highlight the complex interactions between adiponectin, metabolism, malnutrition, and prostate health. Metabolic deregulation combined with adipose inflammation potentially induces a proliferative and inflammatory microenvironment in the prostate gland under conditions of low adiponectin production, potentially impairing prostate morphophysiology in the context of obesity and aging., Competing Interests: Declaration of competing interest All authors report no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cardiovascular diseases (CVD), primarily ischemic heart disease and stroke, remain leading global health burdens. Environmental risk factors have a major role in the development of CVD, particularly exposure to heavy metals. The Triglyceride Glucose Index (TyG), a measure of insulin resistance and CVD risk, is the primary focus of this study, which summarizes the most recent findings on the effects of lead (Pb), arsenic (As), and cadmium (Cd) on CVD risk. A higher risk of CVD is correlated with an elevated TyG index, which has been linked to insulin resistance. Exposure to Cd is associated with disturbance of lipid metabolism and oxidative stress, which increases the risk of CVD and TyG. Exposure reduces insulin secretion and signaling, which raises the TyG index and causes dyslipidemia. Pb exposure increases the risk of CVD and TyG index via causing oxidative stress and pancreatic β-cell destruction. These results highlight the need of reducing heavy metal exposure by lifestyle and environmental modifications in order to lower the risk of CVD. To comprehend the mechanisms and create practical management plans for health hazards associated with heavy metals, more study is required., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: The cumulative impact of metabolic syndrome (MetS) components on micro- and macrovascular disease in metabolic dysfunction-associated steatotic liver disease (MASLD) is unclear. We aimed to determine whether the number of the MetS components increases the risk of micro- and macrovascular disease in patients with MASLD., Methods: We performed a retrospective cohort study of electronic medical records using the TriNetX network, a global federated database. The exposure arm was patients with hepatic steatosis (defined via International Classification of Diseases, 10th Revision coding, or modified hepatic steatosis index), and ≥1 MetS components (obesity/central adiposity, insulin resistance, hypertension, or dyslipidaemia), compared with a reference arm of adults without any MetS components or hepatic steatosis. Our propensity score matched (1:1) for confounders with 5 years of follow-up. Primary outcomes included microvascular (peripheral neuropathy, retinopathy, and nephropathy) and macrovascular (cardiovascular events, cerebrovascular accidents, and peripheral vascular disease) disease. Secondary analyses assessed the impact of additional MetS components on these outcomes, as well as the impact of sex., Results: MASLD, defined by hepatic steatosis and insulin resistance (n = 15 937), carried the highest risk of microvascular disease (HR 13.93 (95% CI 8.55-22.68)), whilst MASLD, defined by hepatic steatosis and hypertension (n = 53 028), carried the highest risk of macrovascular disease (7.23 (6.45-8.13)). MASLD with all MetS components carried greatest risk of both micro- (31.20 (28.88-33.70) (n = 462 789)) and macrovascular (8.04 (7.33-8.82) (n = 336 010)) disease., Conclusion: We demonstrate a differential effect of MetS components on micro- and macrovascular disease risk in patients with MASLD, with a cumulative impact of multiple MetS on overall risk. The impact of MetS components was most pronounced in women. Aggressive metabolic risk factor management is critical for prevention of micro- and macrovascular complications., (© 2024 The Author(s). Liver International published by John Wiley & Sons Ltd.)

Aims/hypothesis: It is not known whether the early-pregnancy metabolome differs in patients with early- vs late-onset gestational diabetes mellitus (GDM) stratified by maternal overweight. The aims of this study were to analyse correlations between early-pregnancy metabolites and maternal glycaemic and anthropometric characteristics, and to identify early-pregnancy metabolomic alterations that characterise lean women (BMI <25 kg/m 2 ) and women with overweight (BMI ≥25 kg/m 2 ) with early-onset GDM (E-GDM) or late-onset GDM (L-GDM)., Methods: We performed a nested case-control study within the population-based prospective Early Diagnosis of Diabetes in Pregnancy cohort, comprising 210 participants with GDM (126 early-onset, 84 late-onset) and 209 normoglycaemic control participants matched according to maternal age, BMI class and primiparity. Maternal weight, height and waist circumference were measured at 8-14 weeks' gestation. A 2 h 75 g OGTT was performed at 12-16 weeks' gestation (OGTT1), and women with normal results underwent repeat testing at 24-28 weeks' gestation (OGTT2). Comprehensive metabolomic profiling of fasting serum samples, collected at OGTT1, was performed by untargeted ultra-HPLC-MS. Linear models were applied to study correlations between early-pregnancy metabolites and maternal glucose concentrations during OGTT1, fasting insulin, HOMA-IR, BMI and waist circumference. Early-pregnancy metabolomic features for GDM subtypes (participants stratified by maternal overweight and gestational timepoint at GDM onset) were studied using linear and multivariate models. The false discovery rate was controlled using the Benjamini-Hochberg method., Results: In the total cohort (n=419), the clearest correlation patterns were observed between (1) maternal glucose concentrations and long-chain fatty acids and medium- and long-chain acylcarnitines; (2) maternal BMI and/or waist circumference and long-chain fatty acids, medium- and long-chain acylcarnitines, phospholipids, and aromatic and branched-chain amino acids; and (3) HOMA-IR and/or fasting insulin and L-tyrosine, certain long-chain fatty acids and phospholipids (q<0.001). Univariate analyses of GDM subtypes revealed significant differences (q<0.05) for seven non-glucose metabolites only in overweight women with E-GDM compared with control participants: linolenic acid, oleic acid, docosapentaenoic acid, docosatetraenoic acid and lysophosphatidylcholine 20:4/0:0 abundances were higher, whereas levels of specific phosphatidylcholines (P-16:0/18:2 and 15:0/18:2) were lower. However, multivariate analyses exploring the early-pregnancy metabolome of GDM subtypes showed differential clustering of acylcarnitines and long-chain fatty acids between normal-weight and overweight women with E- and L-GDM., Conclusions/interpretation: GDM subtypes show distinct early-pregnancy metabolomic features that correlate with maternal glycaemic and anthropometric characteristics. The patterns identified suggest early-pregnancy disturbances of maternal lipid metabolism, with most alterations observed in overweight women with E-GDM. Our findings highlight the importance of maternal adiposity as the primary target for prevention and treatment., (© 2024. The Author(s).)

Objectives: Insulin resistance is associated with increased levels of IGF-1. IGF-1 has been shown to increase the risk of laryngeal squamous cell carcinoma. The Triglyceride-glucose index (TyG index) is a marker of insulin resistance. Our study aimed to investigate the relationship between the TyG index and laryngeal squamous cell carcinoma., Design: Retrospective cohort study., Setting: Two tertiary care academic hospitals., Methods: The study included 53 patients with laryngeal squamous cell carcinoma (Group 1) and 48 healthy volunteers (Group 2). Laryngeal cancer patients were divided into two groups according to their stage. Stages I and II were named Group 1A, and Stages III and IV were called Group 1B. The TyG index was calculated as ln [fasting Triglycerides (mg/dL) × fasting plasma glucose (mg/dL)/2]. The effect of the TyG index on laryngeal cancer was investigated on the parameters of sex, age, body mass index, and stage of the disease., Results: There were no significant differences in age, sex, and BMI between the groups. The TyG index of group 1 (4.75 ± 0.33) was significantly higher than that of group 2 (4.59 ± 0.15). The TyG index value of group 1B (4.84 ± 0.31) was significantly higher than both group 1A (4.61 ± 0.32) and group 2 (4.59 ± 0.15). There was no significant difference between the TyG index values of group 1A (4.61 ± 0.32) and group 2 (4.59 ± 0.15)., Conclusion: The TyG index may be a promising laryngeal squamous cell carcinoma biomarker. People with a higher TyG index may have a higher incidence of laryngeal squamous cell carcinoma and a higher risk of progression., (© 2024 John Wiley & Sons Ltd.)

Phenanthrene (Phe) is a commonly occurring polycyclic aromatic hydrocarbon (PAH) found in various food sources and drinking water. Previous studies have shown that long-term exposure to Phe in male mice leads to insulin resistance in a dose-dependent manner. However, the effect of Phe on glucose homeostasis in female mice remains unknown. To address this knowledge gap, female Kunming mice were exposed to Phe through their drinking water at concentrations of 0.05, 0.5, and 5 ng/mL. After 270 d of exposure, we surprisingly discovered a low-dose effect of Phe on insulin resistance in female mice, which differed from the effect observed in male mice and showed sexual dimorphism. Specifically, insulin resistance was only observed in the 0.05 ng/mL treatment, and this low-dose effect was also reflected in the concentration of Phe in white adipose tissue (WAT). Differences in metabolic enzyme activities in the liver may potentially explain this effect. The observed sexual dimorphism in Phe exposure could be attributed to variations in estrogen (E2) level and estrogen receptor beta (ERβ) expression in WAT. These findings highlight the association between environmental factors and the development of insulin resistance, emphasizing the pathogenic effect of even low doses of Phe. Moreover, sex dependent-effect should be given more attention when studying the toxic effects of environmental pollutants., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Androgen deprivation therapy (ADT) in prostate cancer (PCa) has been associated with development of insulin resistance. However, the predominant site of insulin resistance remains unclear., Methods: The ADT & Metabolism Study was a single-center, 24-week, prospective observational study that enrolled ADT-naive men without diabetes who were starting ADT for at least 24 weeks (ADT group, n = 42). The control group comprised men without diabetes with prior history of PCa who were in remission after prostatectomy (non-ADT group, n = 23). Prevalent diabetes mellitus was excluded in both groups using all three laboratory criteria defined in the American Diabetes Association guidelines. All participants were eugonadal at enrollment. The primary outcome was to elucidate the predominant site of insulin resistance (liver or skeletal muscle). Secondary outcomes included assessments of body composition, and hepatic and intramyocellular fat. Outcomes were assessed at baseline, 12, and 24 weeks., Results: At 24 weeks, there was no change in hepatic (1.2; 95% confidence interval [CI], -2.10 to 4.43; p = .47) or skeletal muscle (-3.2; 95% CI, -7.07 to 0.66; p = .10) insulin resistance in the ADT group. No increase in hepatic or intramyocellular fat deposition or worsening of glucose was seen. These changes were mirrored by those observed in the non-ADT group. Men undergoing ADT gained 3.7 kg of fat mass., Conclusions: In men with PCa and no diabetes, 24 weeks of ADT did not change insulin resistance despite adverse body composition changes. These findings should be reassuring for treating physicians and for patients who are being considered for short-term ADT., (© 2024 American Cancer Society.)

Abnormal glucose metabolism is a common disease of the endocrine system. The effects of drugs on glucose metabolism have been reported frequently in recent years, and since abnormal glucose metabolism increases the risk of microvascular and macrovascular complications, metabolic disorders, and infection, clinicians need to pay close attention to these effects. A variety of common drugs can affect glucose metabolism and have different mechanisms of action. Hypertension is a common chronic cardiovascular disease that requires long-term medication. Studies have shown that various antihypertensive drugs also have an impact on glucose metabolism. Among them, α-receptor blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers can improve insulin resistance, while β-receptor blockers, thiazides and loop diuretics can impair glucose metabolism. The aim of this review was to discuss the mechanisms underlying the effects of various antihypertensive drugs on glucose metabolism in order to provide reference information for rational clinical drug use., (© 2024 John Wiley & Sons Ltd.)

Aim: To assess the effects of a small-molecule nicotinamide N-methyltransferase (NNMT) inhibitor, 5A1MQ, on body composition, metabolic variables, fatty liver pathologies, and circulating biomarkers in diet-induced obese (DIO) mice, and characterize its plasma pharmacokinetics (PK) and tissue distribution in vivo., Materials and Methods: DIO mice were administered vehicle or 5A1MQ once daily for 28 days. Longitudinal measures of body composition, blood glucose and plasma insulin levels, and terminal measures of liver histopathology and serum markers, were evaluated. Plasma and tissue PK were established in age- and strain-matched mice after intravenous, oral, and subcutaneous dosing of 5A1MQ., Results: 5A1MQ treatment dose-dependently limited body weight and fat mass gains, improved oral glucose tolerance and insulin sensitivity, and suppressed hyperinsulinaemia in DIO mice. Liver histology from 5A1MQ-treated DIO mice showed attenuated hepatic steatosis and macrophage infiltration, and correspondingly reduced liver weight, size, and triglyceride levels. 5A1MQ treatment normalized circulating levels of alanine transaminase, aspartate transaminase, and ketone bodies, supporting an overall improvement in liver and metabolic functions. The pharmacodynamic effects of 5A1MQ were further corroborated by its high systemic exposure and effective distribution to metabolically active tissues, including adipose, muscle and liver, following subcutaneous dosing of mice., Conclusions: This work validates NNMT inhibition as a viable pharmacological approach to ameliorate metabolic imbalances and improve liver pathologies that develop with obesity., (© 2024 John Wiley & Sons Ltd.)

Background and Aims: Triglyceride-glucose (TyG) index, a surrogate measure of insulin resistance, is associated with hypertension mediated organ damage (HMOD) and cardiovascular disease. This study investigated the association between TyG index and major adverse cardiovascular events (MACE) and its interaction with traditional risk factors and HMOD., Methods and Results: Healthy subjects recruited from the general population were thoroughly examined and followed for MACE using nation-wide registries. Cox proportional hazard models were used to calculate the association between TyG index and MACE occurrence. Models were adjusted for Systematic Coronary Risk Evaluation (SCORE) risk factors, pulse wave velocity, left ventricular mass index, carotid atherosclerotic plaque status, and microalbuminuria. Continuous net reclassification and Harrell's Concordance index (C-index) were used to assess the added prognostic value of TyG index. During a follow-up period of mean 15.4 ± 4.7 years, MACE were observed in 332 (17%) of 1970 included participants. TyG index was associated with MACE; HR = 1.44 [95%CI:1.30-1.59] per standard deviation. After adjustment for traditional cardiovascular (CV) risk factors, HR was 1.16 [95%CI:1.03-1.31]. The association between TyG index and MACE remained significant after further adjustment for each HMOD component. However, this finding was evident only in subjects aged 41 or 51 years (HR = 1.39; 95%CI:1.15-1.69). Including TyG index in a risk model based on traditional CV risk factors improved C-index with 0.005 (P = 0.042)., Conclusion: In this population-based study of healthy middle-aged subjects, TyG index was associated with MACE independently of traditional CV risk factors and HMOD. TyG index may have a potential role in future risk prediction systems., Competing Interests: Declaration of competing interest The authors received no financial support for the research, authorship, and / or publication of this article. Dr. Manan Pareek discloses the following relationships – Advisory Board: AstraZeneca, Janssen-Cilag, Novo Nordisk; Grant Support: Danish Cardiovascular Academy funded by the Novo Nordisk Foundation and the Danish Heart Foundation (grant number: CPD5Y-2022004-HF); Speaker Honorarium: AstraZeneca, Bayer, Boehringer Ingelheim, Janssen-Cilag. Prof. Michael Hecht Olsen discloses that he has received speaker fees from Novo Nordisk Foundation, Boehringer & Ingelheim, Astra Zeneca and Teva. The remaining authors have no disclosures to report., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims/hypothesis: The temporal suppression of insulin clearance after glucose ingestion is a key determinant of glucose tolerance for people without type 2 diabetes. Whether similar adaptations are observed after the ingestion of a mixed-macronutrient meal is unclear., Methods: In a secondary analysis of data derived from two randomised, controlled trials, we studied the temporal responses of insulin clearance after the ingestion of a standardised breakfast meal consisting of cereal and milk in lean normoglycaemic individuals (n=12; Lean-NGT), normoglycaemic individuals with central obesity (n=11; Obese-NGT) and in people with type 2 diabetes (n=19). Pre-hepatic insulin secretion rates were determined by the deconvolution of C-peptide, and insulin clearance was calculated using a single-pool model. Insulin sensitivity was measured by an oral minimal model., Results: There were divergent time course changes in insulin clearance between groups. In the Lean-NGT group, there was an immediate post-meal increase in insulin clearance compared with pre-meal values (p<0.05), whereas insulin clearance remained stable at baseline values in Obese-NGT or declined slightly in the type 2 diabetes group (p<0.05). The mean AUC for insulin clearance during the test was ~40% lower in the Obese-NGT (1.3 ± 0.4 l min -1 m -2 ) and type 2 diabetes (1.4 ± 0.7 l min -1 m -2 ) groups compared with Lean-NGT (1.9 ± 0.5 l min -1 m -2 ; p<0.01), with no difference between the Obese-NGT and type 2 diabetes groups. HOMA-IR and glucagon AUC emerged as predictors of insulin clearance AUC, independent of BMI, age or insulin sensitivity (adjusted R 2 =0.670). Individuals with increased glucagon AUC had a 40% reduction in insulin clearance AUC (~ -0.75 l min -1 m -2 ; p<0.001)., Conclusions/interpretation: The ingestion of a mixed-macronutrient meal augments differing temporal profiles in insulin clearance among individuals without type 2 diabetes, which is associated with HOMA-IR and the secretion of glucagon. Further research investigating the role of hepatic glucagon signalling in postprandial insulin kinetics is warranted., Trial Registration: ISRCTN17563146 and ISRCTN95281775., (© 2024. The Author(s).)

Interleukin-18 (IL-18), a potent and multifunctional pro-inflammatory cytokine, plays a critical role in regulating β-cell failure, β-cell death, insulin resistance, and various complications of diabetes mellitus (DM). It exerts its effects by triggering various signaling pathways, enhancing the production of pro-inflammatory cytokines and nitric oxide (NO), as well as promoting immune cells infiltration and β-cells death. Abnormal alterations in IL-18 levels have been revealed to be strongly associated with the onset and development of DM and its complications. Targeting IL-18 may present a novel and promising approach for DM therapy. An increasing number of IL-18 inhibitors, including chemical and natural inhibitors, have been developed and have been shown to protect against DM and diabetic complications. This review provides a comprehensive understanding of the production, biological functions, action mode, and activated signaling pathways of IL-18. Next, we shed light on how IL-18 contributes to the pathogenesis of DM and its associated complications with links to its roles in the modulation of β-cell failure and death, insulin resistance in various tissues, and pancreatitis. Furthermore, the therapeutic potential of targeting IL-18 for the diagnosis and treatment of DM is also highlighted. We hope that this review will help us better understand the functions of IL-18 in the pathogenesis of DM and its complications, providing novel strategies for DM diagnosis and treatment., (© 2024 World Obesity Federation.)

Purpose: No study has comprehensively assessed the relationship of metabolic factors including insulin resistance, hypertension, hyperuricemia, and hypercholesterolemia with the development of carotid plaque. Therefore, we constructed metabolic scores based on the above metabolic factors and examined its association with carotid plaque in young and older Chinese adults., Methods: This study included 17,396 participants who underwent carotid ultrasound examinations, including 14,173 young adults (<65 years) and 3,223 older adults (≥65 years). Individual metabolic score was calculated using triglyceride-glucose (TyG) index, mean arterial pressure (MAP), uric acid, and total cholesterol (TC). Logistic regression models were conducted to examine the role of metabolic score and its components in the prevalence of carotid plaque. The nonlinear relationship was examined using restricted cubic spline regression. Meanwhile, subgroup, interaction, and sensitivity analyses were conducted., Results: The multivariate logistic regression analysis showed that TyG (OR: 1.088; 95%CI: 1.046-1.132), MAP (OR: 1.121; 95%CI: 1.077-1.168), TC (OR: 1.137; 95%CI: 1.094-1.182) and metabolic score (OR: 1.064; 95%CI: 1.046-1.082) were associated with carotid plaque prevalence in young adults rather than older adults. The nonlinear association was not observed for metabolic scores and carotid plaque. Subgroup analyses showed significant associations between metabolic scores and carotid plaque prevalence in men, women, normal-weight, and overweight young adults. No interaction of metabolic score with sex and BMI were observed., Conclusions: The results support that control of TyG, MAP, TC, and metabolic scores is a key point in preventing the prevalence of carotid plaque in the young adults., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide; however, effective intervention strategies for NAFLD are still unavailable. The present study sought to investigate the efficacy of chiglitazar, a pan-PPAR agonist, in protecting against NAFLD in mice and its underlying molecular mechanism. Male C57BL/6 J mice were fed a high-fat diet (HFD) for 8 weeks to generate NAFLD and the HFD was continued for an additional 10 weeks in the absence or presence of 5 mg/kg/d or 10 mg/kg/d chiglitazar by gavage. Chiglitazar significantly improved dyslipidemia and insulin resistance, ameliorated hepatic steatosis and reduced liver inflammation and oxidative stress in NAFLD mice. RNA-seq revealed that chiglitazar alleviated HFD-induced NAFLD in mice through multiple pathways, including fatty acid metabolism regulation, insulin signaling pathway, and AMPK signaling pathway. This study demonstrated the potential therapeutic effect of chiglitazar on NAFLD. Chiglitazar ameliorated NAFLD by modulating multiple pathways., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Type 2 diabetes (T2DM) is one of the major metabolic diseases and poses a serious challenge to human life and global economic development. Jinqi Jiangtang Tablets (JQJT) is effective in ameliorating the effects of T2DM, but the mechanism of JQJT is unclear., Purpose: This study integrated metabolomics and transcriptomics to reveal the mechanism by which JQJT improves T2DM., Methods: The T2DM mouse model was established, and the effects of JQJT on improving T2DM were evaluated by determining the levels of blood lipids, fasting blood glucose (FBG), insulin metabolism and hepatic lipid accumulation in mice after JQJT administration for 8 weeks. Serum metabolites were detected using ultra-performance liquid chromatography/quadrupole time-of-flight-tandem mass spectrometry (UPLC-Q-TOF-MS) technology, and mouse liver differential genes were detected using transcriptomic technology. Correlation analysis was used to extract metabolites and RNA with correlations, and potential pathways were enriched and constructed using the common pathway analysis function of MetaboAnalyst 5.0. Finally, the expression of key target proteins and genes was verified by Western blot (WB) and Polymerase Chain Reaction (PCR) to further elucidate the mechanism by which JQJT improves T2DM., Results: JQJT reduced FBG and lipid levels, improved insulin resistance (IR) and hepatic lipoatrophy in mice. A total of 35 differentially abundant metabolites were identified by metabolomics, and 328 differential genes were detected by transcriptomics. The integrated metabolomics and transcriptomics results suggested that JQJT may ameliorate T2DM mainly by regulating glucose and lipid metabolic pathways. WB and PCR results showed that JQJT regulates the insulin signaling pathway, involved in fatty acid metabolism, glycogen synthesis and catabolism., Conclusions: JQJT improved IR in T2DM mice by regulating the insulin signaling pathway, improving glycogen synthesis and glycolysis, and increasing hepatic triglyceride and fatty acid metabolism., Competing Interests: Declaration of competing interest The authors declare that there have no conflicts of interest., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Background and Aims: Insulin resistance (IR) is a major risk factor for cardiovascular disease. Recently, a novel index (triglyceride-glucose index-TyG) has been proposed as a surrogate marker of IR and a better expression of IR than the Homeostatic Model Assessment of IR (HOMA-IR) index. Few and heterogeneous data are so far available on the relationship between vascular damage and this novel index. Therefore, we aimed to estimate the predictive role of TyG, in comparison with the HOMA-IR, on the development of arterial stiffening (AS), defined as a pulse pressure>60 mmHg, in an 8-year follow-up observation of a sample of non-diabetic adult men (the Olivetti Heart Study)., Methods and Results: The analysis included 527 non-diabetic men, with normal arterial elasticity at baseline and not on antihypertensive or hypolipidemic treatment. TyG was significantly greater in those who developed AS than those who did not (p = 0.006). On the contrary, the HOMA-IR index was not different between the two groups (p = 0.24). Similar trends were shown by logistic regression analysis adjusting for main confounders. After the stratification by the optimal cut-off point, values of TyG >4.70 were significantly associated with the development of AS, also after adjustment for main confounders. On the contrary, the HOMA-IR index >1.90 was not associated with the risk of AS development in multivariate models., Conclusion: The results of this study indicate a predictive role of TyG on AS, independently of the main potential confounders. Moreover, the predictive power of TyG seems to be greater than that of the HOMA-IR index., Competing Interests: Declaration of competing interest All the authors declare that they have no conflict of interest. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients to be included in the study. No animal studies were carried out by the authors for this article., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Aims: Recently, a new entity was introduced, MetALD, which includes patients with metabolic dysfunction-associated steatotic liver disease (MASLD), who consume moderate amounts of alcohol. However, little is known regarding the metabolic and clinical characteristics of these patients., Methods: Data from the National Health and Nutrition Examination Surveys 2017-2020 was used. Participants without valid transient elastography (TE) measurements, incomplete alcohol consumption report, or with alternative etiologies of liver steatosis were excluded., Results: A total of 6901 patients were included in the study, of which 106 (1.5%) had MetALD. Overall, MetALD patients showed a metabolic profile that was more similar to patients with alcohol related liver disease (ALD) than MASLD. Specifically, while patients with MetALD showed values in-between MASLD and ALD for body mass index (BMI), aspartate transaminase (AST), alanine transaminase (ALT), gamma glutamyltransferase (GGT) and haemoglobin A1c, they had similar high-density lipoprotein cholesterol (HDL-C), blood pressure, prevalence of diabetes and insulin resistance to ALD patients. Increasing alcohol consumption was associated with lower insulin resistance and A1c and higher triglycerides, HDL-C and blood pressure. Moreover, while AST, ALT and GGT increased with alcohol consumption, this did not translate into worse hepatic steatosis or liver fibrosis by TE., Conclusions: MetALD patients share some characteristics with MASLD, but they resemble ALD patients more, especially after adjusting for BMI. Alcohol consumption produces a dissociation between insulin resistance and some cardiometabolic risk factors (blood pressure and HDL-C), which may make the current classification of patients challenging., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Non-alcoholic fatty liver disease (NAFLD) has reached pandemic proportions globally, particularly affecting individuals with type 2 diabetes mellitus (T2DM)., Objective: Our study aims to elucidate the diagnostic value of fasting C-peptide in combination with insulin resistance for assessing hepatic fibrosis in patients with T2DM and comorbid NAFLD., Design: This was a retrospective study., Setting: The study was conducted at the Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine., Participants: The research involved 76 type 2 diabetes mellitus patients with nonalcoholic fatty liver disease, diagnosed at our hospital from April 2020 to October 2022. Patients were categorized into the non-progressive hepatic fibrosis group (n = 64) and progressive hepatic fibrosis group (n = 12) based on fibrosis-4 value., Interventions: General data, systolic/diastolic blood pressure, fasting plasma glucose, fasting C-peptide, fasting insulin, glycosylated hemoglobin, uric acid, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, aspartate transaminase, alanine transaminase, and γ-glutamyl transferase were collected. Insulin resistance was calculated using a designated formula., Primary Outcomes Measures: The predictive impact of fasting C-peptide in combination with insulin resistance was evaluated through receiver operating characteristic curves., Results: The age, body mass index, fasting C-peptide, fasting insulin, aspartate transaminase, and insulin resistance showed a significant increase in the progressive hepatic fibrosis group compared to the non-progressive group (P = .006, P = .014, P < .001, P < .001, P = .004, and P = .021). The combination's sensitivity demonstrated an elevation compared to fasting C-peptide or insulin resistance alone (P = .005)., Conclusions: Fasting C-peptide in combination with insulin resistance proves to have a substantial predictive impact on hepatic fibrosis in type 2 diabetes mellitus patients with nonalcoholic fatty liver disease, holding valuable clinical diagnostic potential.

Aim: Diminished hepatic insulin clearance (HIC) is observed in obese adults and is presumed to be mediated by fatty liver. However, few reports have examined HIC in Chinese children with metabolic (dysfunction)-associated fatty liver disease (MAFLD). This study aimed to investigate the correlation between HIC, insulin sensitivity and β-cell function in obese Chinese children with MAFLD., Methods: In total, 204 obese children (74 MAFLD) aged 4-17 years were enrolled into this study. HIC, insulin sensitivity and β-cell function were calculated using the oral glucose tolerance test (1.75 g/kg body weight). Correlation analyses between the HIC and clinical variables were performed using Pearson's product-moment correlation coefficients. HIC and glucose homeostasis were assessed in a high-fat diet mouse model, and liver samples were collected for molecular analysis., Results: Obese children with MAFLD exhibited significantly lower HIC (AUC C-peptide/insulin ratio , p = 0.0019), higher insulin resistance (homeostatic model assessment of insulin resistance, p = 0.002), and increased compensatory β-cell function (homeostatic model assessment-β, p = 0.046) than obese children without liver involvement. Notably, HIC was negatively correlated with insulin sensitivity (r = -0.5035, p < 0.0001) and β-cell function (r = -0.4576, p < 0.0001). However, pancreatic β-cell dysfunction (p = 0.046) was accompanied by future reduced HIC (p = 0.034) in children with MAFLD in prediabetes. In a high-fat diet mouse model, MAFLD mice showed a 50% reduction in insulin-degrading enzyme expression, consistent with the observed decrease in HIC., Conclusions: A lower HIC may offload pancreatic β-cells at an early stage. However, obese children with MAFLD are at risk of developing diabetes, and preventive efforts should be prioritized., (© 2024 John Wiley & Sons Ltd.)

Background: Protease-activated receptor-1 (PAR1) has emerged as an important link between coagulation and the complications of obesity including metabolic dysfunction-associated steatotic liver disease (MASLD). PAR1 is expressed by various cells and cleaved by different proteases to generate unique tethered agonists that activate distinct signaling pathways. Mice expressing PAR1 with an R41Q mutation have disabled canonical thrombin-mediated signaling, whereas R46Q mice express PAR1 resistant to noncanonical signaling by activated protein C., Methods: Mice with whole body and hepatocyte-selective PAR1 deficiency as well as PAR1 R41Q and R46Q mice were fed a high-fat diet (HFD) to induce MASLD., Results: HFD-fed R41Q mice displayed reduced hepatic steatosis and liver/body weight ratio. In contrast, HFD-fed R46Q mice displayed increased relative liver weight and hepatic steatosis alongside increased serum alanine aminotransferase activity. Surprisingly, despite the distinct impact of PAR1 mutations on steatosis, selective deletion of PAR1 in hepatocytes had no impact. To evaluate a viable PAR1-targeted approach, mice with HFD-induced obesity were treated with the allosteric PAR1 modulator NRD-21, which inhibits canonical PAR1 inflammatory signaling but promotes PAR1 protective, noncanonical anti-inflammatory signaling. NRD-21 treatment reduced plasma tumor necrosis factor-alpha, serum alanine aminotransferase activity, hepatic steatosis, and insulin resistance (Homeostatic Model Assessment for Insulin Resistance) but increased plasma active glucagon-like peptide-1., Conclusion: The results suggest that nonhepatocellular canonical PAR1 cleavage drives MASLD in obese mice and provide translational proof-of-concept that selective pharmacologic modulation of PAR1 yields multiple metabolic benefits in experimental obesity., Competing Interests: Declaration of competing interests C.D. is Chief Strategy Officer and Chief Executive Officer at Function Therapeutics, which provided NRD-21 for these studies. Function Therapeutics did not provide financial support. Beyond research support noted in acknowledgments, no other authors have relevant conflicts of interests to disclose., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)