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Purpose: We investigated the effects of a 16-wk combined exercise training on body composition, and metabolic and inflammatory markers in sedentary middle-aged workers. We also assessed whether alterations in metabolic markers were associated with changes in health-related outcomes. Methods: This randomized controlled trial involved 46 participants randomly allocated into control and exercise groups. The exercise group performed 16-wk combined aerobic and resistance training for 75 min per session, 3 times a week. Fasting blood samples were collected at baseline and after 16-wk intervention to determine lipid profile, and metabolic and inflammatory markers as primary outcomes. Results: A total of 36 participants completed the intervention (53.70 ± 6.92 yr old; n = 18 in each group). Waist circumference (interaction effect: F = 7.423, P = 0.002), fat mass (interaction effect: F = 5.070, P = 0.011), and muscle mass (interaction effect: F = 5.420, P = 0.007) were improved in the exercise group compared with the control group. Fasting glucose increased after the 16-wk follow-up (time effect: F = 73.253, P < 0.001), without an intergroup difference. Insulin levels were greater in the control compared with exercise group (group effect: F = 6.509, P = 0.015). The control group tended to increase the homeostatic model assessment of insulin resistance index (interaction effect: F = 3.493, P = 0.070) and to decrease the QUICKI index (interaction effect: F = 3.364, P = 0.075) to a greater extent compared with the exercise group. Exercise group reduced leptin (interaction effect: F = 11.175, P = 0.002) and adiponectin (interaction effect: F = 4.437, P = 0.043) concentrations in a greater magnitude than the control group. Interleukin (IL)-6 (time effect: F = 17.767, P < 0.001) and tumor necrosis factor α (time effect: F = 9.781, P = 0.004) concentrations decreased after the intervention, without an intergroup difference. IL-17A levels increased in the control compared with exercise group (interaction effect: F = 5.010, P = 0.033). Effects on adiponectin, IL-6, and IL-17A levels seem to depend on baseline body mass index, age, and sex. Percentage changes in leptin correlated positively with changes in homeostatic model assessment of insulin resistance index in the exercise (r = 0.565, P = 0.015) and control (r = 0.670, P = 0.002) groups. Conclusions: A combined training program can be an effective strategy to improve body composition and inflammatory markers and prevent marked reductions in insulin sensitivity among middle-aged workers. [ABSTRACT FROM AUTHOR]

Summary: 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. [ABSTRACT FROM AUTHOR]

Functional impairments in the brain's insulin and insulin-like growth factor (IGF) signal transduction networks are recognized mediators of dysregulated energy metabolism, a major driver of the Alzheimer's disease (AD) neurodegeneration cascade. AD-associated insulin-deficient and insulin-resistant states mimic those of diabetes mellitus and affect all cell types in the brain. Besides accounting for abundant amyloid-β and hyperphosphorylated tau lesions in AD, insulin/IGF pathway dysfunctions cause cortical atrophy, loss of synaptic plasticity, white matter myelin/oligodendrocyte degeneration, astrocyte and microglial neuroinflammation and oxidative stress, deficits in energy metabolism, mitochondrial dysfunction, and microvascular disease. These same neuropathological processes have been linked to cognitive impairment in type 2 diabetes mellitus, Parkinson's disease, and vascular dementia. Strategies to address metabolic mediators of cognitive impairment have been borrowed from diabetes and other insulin-resistant diseases and leveraged on preclinical AD model data. The repurposing of diabetes drugs led to clinical trials with intranasal insulin, followed by insulin sensitizers including metformin and peroxisome-proliferator-activated receptor agonists, and then incretin mimetics primarily targeting GLP-1 receptors. In addition, other glucose-lowering agents have been tested for their efficacy in preventing cognitive declines. The strengths and limitations of these approaches are discussed. The main conclusion of this review is that we have now arrived at a stage in which it is time to address long-term deficits in trophic factor availability and receptor responsiveness, signaling abnormalities that extend beyond insulin and include IGFs and interconnected pathways, and the need for multi-pronged rather than single-pronged therapeutic targeting to remediate AD and other forms of neurodegeneration. [ABSTRACT FROM AUTHOR]

There are currently no effective treatments to prevent, halt, or reverse Alzheimer's disease (AD), the most common cause of dementia in older adults. Melatonin, a relatively harmless over-the-counter supplement, may offer some benefits to patients with AD. Melatonin is known for its sleep-enhancing properties, but research shows that it may provide other advantages as well, such as antioxidant and anti-amyloidogenic properties. Clinical trials for melatonin use in AD have mixed results but, overall, show modest benefits. However, it is difficult to interpret clinical research in this area as there is little standardization to guide the administration and study of melatonin. This review covers basic biology and clinical research on melatonin in AD focusing on prominent hypotheses of pathophysiology of neurodegeneration and cognitive decline in AD (i.e., amyloid and tau hypotheses, antioxidant and anti-inflammation, insulin resistance and glucose homeostasis, the cholinergic hypothesis, sleep regulation, and the hypothalamic-pituitary-adrenal axis and cortisol). This is followed by a discussion on pending clinical trials, considerations for future research protocols, and open questions in the field. [ABSTRACT FROM AUTHOR]

Background: No effective drugs currently exist to cure Alzheimer's disease (AD) due to its complexity and the lack of understanding of the involved molecular signaling and pathways. The relationship between liver health and AD is now widely recognized. Still, molecular links and shared pathways between the liver and brain remain unclear, making the liver-brain axis in AD therapies a new area for exploration. However, bibliometric studies on this topic are lacking. Objective: This study aims to review the liver-brain axis in AD and identify future research hotspots and trends through bibliometric analysis. Methods: Articles and reviews related to AD and liver and its related diseases were searched in the Web of Science Core Collection (WoSCC) database up to 2024. Data were processed and visually analyzed using VOSviewer, CiteSpace, and Pajek. Results: We collected 1,777 articles on AD and liver and its related diseases from 2,517 institutions across 80 countries. Keyword cluster analysis identified 11 clusters, with 'insulin resistance,' 'amyloid-beta,' 'apolipoprotein-E,' 'oxidative stress,' and 'inflammation' appearing most frequently, and exhibiting strong total link strength. These results indicate that these topics have been the primary focus of research on the liver-brain axis in AD. Conclusions: This study is the first to comprehensively analyze the liver-brain axis in AD using bibliometric methods. The research results identify recent research frontiers and hotspots, aiding scholars in gaining a deeper understanding of the correlation between AD and the liver. [ABSTRACT FROM AUTHOR]

The translocon-associated protein-δ (TRAPδ) plays a role in insulin biosynthesis within pancreatic β-cells. However, its pathophysiological significance in maintaining islet β-cell function and glucose homeostasis remains unclear. In this study, we generated a mouse model featuring pancreatic β-cell–specific deletion of TRAPδ (TRAPδ βKO). Our findings revealed that TRAPδ βKO resulted in decreased circulating insulin levels in mice fed either a normal chow diet or a high-fat diet. Multiple independent experiments established that although TRAPδ deletion reduced insulin content in the islets, it had no discernible effect on insulin gene expression, the insulin to proinsulin ratio, or the expression and glycosylation of the prohormone enzymes involved in proinsulin processing. These data suggest that TRAPδ does not play a pivotal role in the transcription of the insulin gene or proinsulin processing. However, untranslocated preproinsulin levels were significantly increased when islets were treated with a proteasomal inhibitor, suggesting that TRAPδ deficiency may hinder preproinsulin translocation, resulting in a rapid degradation of untranslocated preproinsulin that accounts for the decreased insulin production. Remarkably, despite the moderate decrease in circulating insulin levels in TRAPδ βKO mice, their glucose levels remained unaffected, indicating the presence of compensatory mechanisms that help maintain glucose homeostasis. Insulin tolerance tests further revealed improved insulin sensitivity, accompanied by upregulation of phosphorylated AKT in the peripheral tissues of TRAPδ βKO mice. Collectively, these data highlight the important role of TRAPδ in insulin biosynthesis and β-cell function. The moderate reduction in circulating insulin appears to promote insulin sensitivity in insulin target tissues. Article Highlights: Translocon-associated protein-δ (TRAPδ) plays a pivotal role in insulin biosynthesis and potentially contributes to β-cell survival in type 2 diabetes mellitus. Nevertheless, its specific function in preserving islet β-cell function in vivo has yet to be fully explored and elucidated. Specific knockout of TRAPδ in pancreatic β-cells leads to a decrease in proinsulin and insulin content within the islets, subsequently resulting in a slight reduction of serum insulin levels. Remarkably, despite this insulin decrease, euglycemia is preserved. The moderate decrease in circulating insulin levels may potentially enhance insulin sensitivity in target tissues. [ABSTRACT FROM AUTHOR]

Summary: Objective: To summarize the literature on pharmacotherapy for managing paediatric obesity. Methods: A systematic review and meta‐analysis were conducted of randomized controlled trials (RCTs) with <18‐year‐olds of pharmacotherapeutic agents published up to November 2022. Estimates of effect for outcomes were presented relative to minimal important differences and GRADE certainty of evidence. We examined data on patient/proxy‐reported outcome measures (PROMs), cardiometabolic risk factors, anthropometry and adverse events (AEs). Results: Overall, 35 RCTs were included. Trials examined metformin (n = 26), glucagon‐like peptide‐1 receptor agonists (GLP1RAs) (n = 7) and a lipase inhibitor (orlistat; n = 2). Intervention duration varied (3−24 months). Metformin had little to no benefit on PROMs (e.g., health‐related quality of life [HRQoL]; 6 RCTs), moderate reductions in triglycerides, a moderate decline in insulin resistance, a small to moderate decline in BMI z‐score (BMIz) and a moderate increase in mild to moderate gastrointestinal AEs. Response to GLP1RAs was heterogeneous and results of subgroup analysis demonstrated variability of impact. Liraglutide (2 RCTs) resulted in a small reduction in HOMA‐IR and BMIz, but little to no benefit on other outcomes. Exenatide (4 RCTs) had a moderate reduction on blood pressure and a small decrease in BMIz with little to no benefit on other outcomes. Semaglutide (1 RCT) had a small benefit on HRQoL, a small reduction on SBP, a moderate reduction on total cholesterol and LDL‐cholesterol, a large reduction on triglyceride, and a very large decline in BMIz accompanied by a small increase in mild to moderate gastrointestinal AEs. Orlistat had a moderate reduction in DBP and little to no benefit in other outcomes measured, but had a very large increased risk of mild to moderate gastrointestinal AEs. Serious AEs were rare and for interventions with sufficent AE reporting, were considered not likely attributable to the interventions. Conclusion: Few studies examined the impact of pharmacotherapy on PROMs. There is evidence that metformin and GLP1RAs lead to important improvements in cardiometabolic and anthropometric outcomes while accompanied by mild to moderate AEs. Long‐term effectiveness and safety of GLP1RAs remain to be evaluated. [ABSTRACT FROM AUTHOR]

• In pregnant women with GDM, Fetal subcutaneous fat thickness was found to be thicker compared to pregnant women without GDM. • Measuring a fetus' subcutaneous fat thickness predicts neonates' insulin resistance. • Glucose and insulin levels in the cord blood were significantly elevated in the GDM. 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. 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). 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). 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. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatohepatitis (MASH) is one of the most common liver diseases worldwide and is characterized by multi-tissue insulin resistance. The effects of a 10-month energy restriction and exercise intervention on liver histology, anthropometrics, plasma biochemistries, and insulin sensitivity were compared to standard of care (control) to understand mechanisms that support liver health improvements. Following medical diagnosis of MASH, individuals were randomized to treatment (n = 16) or control (n = 8). Liver fat (magnetic resonance spectroscopy), 18-hour plasma biochemical measurements, and isotopically labeled hyperinsulinemic-euglycemic clamps were completed pre- and post-intervention. Body composition and cardiorespiratory fitness (VO 2 peak) were also measured mid-intervention. Those in the treatment group were counseled to reduce energy intake and completed supervised, high-intensity interval training (3x/week) for 10 months. Controls continued physician-directed care. Treatment induced significant (p < 0.05) reductions in body weight, fat mass, and liver injury, while VO 2 peak (p < 0.05) and non-esterified fatty acid suppression (p = 0.06) were improved. Both groups exhibited reductions in total energy intake, hemoglobin A1c, hepatic insulin resistance, and liver fat (p < 0.05). Compared to control, treatment induced a two-fold increase in peripheral insulin sensitivity which was significantly related to higher VO 2 peak and resolution of liver disease. Exercise and energy restriction elicited significant and clinically meaningful treatment effects on liver health, potentially driven by a redistribution of excess nutrients to skeletal muscle, thereby reducing hepatic nutrient toxicity. Clinical guidelines should emphasize the addition of aerobic exercise in lifestyle treatments for the greatest histologic benefit in individuals with advanced MASH. The mechanisms that underpin histologic improvement in individuals with metabolic dysfunction-associated steatohepatitis (MASH) are not well understood. This study evaluated the relationship between liver and metabolic health, testing how changes in one may affect the other. We investigated the effects of energy restriction and exercise on the association between multi-tissue insulin sensitivity and histologic improvements in participants with biopsy-proven MASH. For the first time, these results show that an improvement in peripheral (but not hepatic) insulin sensitivity and systemic markers of muscle function (i.e. cardiorespiratory fitness) were strongly related to resolution of liver disease. Extrahepatic disposal of substrates and improved fitness levels supported histologic improvement, confirming the addition of exercise as crucial to lifestyle interventions in MASH. NCT03151798. [Display omitted] • Diet and exercise improved liver histology in metabolic-dysfunction associated steatohepatitis. • Standard of care improved metabolic health with minimal effects on histology. • Peripheral, not hepatic, insulin sensitivity was related to histologic resolution. • Improved substrate use at the muscle may relieve the liver of excess nutrients. [ABSTRACT FROM AUTHOR]

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/m2, 18.5–25 kg/m2, or ≥ 25 kg/m2). 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/m2. 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/m2 ≤ BMI < 25 kg/m2 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/m2, 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/m2 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/m2 ≤ BMI < 25 kg/m2. 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. [ABSTRACT FROM AUTHOR]

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. In this prospective study of hormone‐naive men who were eugonadal and did not have diabetes, 24 weeks of androgen deprivation therapy (ADT) for prostate cancer (PCa) was not associated with worsening of hepatic or skeletal muscle insulin resistance despite a substantial increase in fat mass. These findings have relevance for both physicians and patients when determining treatment for PCa and suggest that a short course of ADT may not worsen metabolic risk in patients without pre‐existing diabetes. [ABSTRACT FROM AUTHOR]

Summary: 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. DM is one of the most common chronic metabolic diseases caused by β‐cells β‐cell dysfunction and insulin resistance. IL‐18 contributes to the progression of DM and its complications by inducing β‐cells failure and death, insulin resistance, and pancreatitis. IL‐18 orchestrates β‐cell failure and death, insulin resistance, and pancreatitis through modulation of IL‐18‐related signaling pathway, inflammatory responses, NO production, and immune cells infiltration. [ABSTRACT FROM AUTHOR]

Summary: Adipose tissue is a large endocrine organ that serves numerous physiological functions. As we age, adipose tissue remodels and can develop functional changes that alters its phenotype, potentially contributing to metabolic and cardiovascular disorders. Aging adipose tissue is characterized by regional redistribution of fat, accumulation of senescent cells, fibrosis, and decline in adipocyte differentiation capacities, which collectively impact adipose tissue function and whole body health. A notable transformation involves increased accumulation of intra‐abdominal visceral adipose tissue and ectopic fat around internal organs such as the heart, blood vessels, liver, and kidneys that alter their functions. Other changes associated with aging include alterations in adipokine secretion and changes in adipocyte size and numbers. Aging adipocytes play a role in mediating chronic inflammation, metabolic dysfunction, and insulin resistance. Visceral adipose tissue, which increases in volume with aging, is in particular associated with inflammation, angiogenic dysfunction, and microvascular abnormalities, and mediators released by visceral fat may have adverse consequences systemically in multiple target organs, including the cardiovascular system. Understanding mechanisms underlying adipose tissue aging and its impact on cardiovascular health are important for developing interventions and treatments to promote healthy aging and reduce cardiometabolic disease risk. [ABSTRACT FROM AUTHOR]

Aim: To thoroughly investigate the impact of sustained neuropeptide Y4 receptor (NPY4R) activation in obesity‐associated diabetes. Methods: Initially, the prolonged pharmacodynamic profile of the enzymatically stable pancreatic polypeptide (PP) analogue, [P3]PP, was confirmed in normal mice up to 24 h after injection. Subsequent to this, [P3]PP was administered twice daily (25 nmol/kg) for 28 days to high‐fat‐fed mice with streptozotocin‐induced insulin deficiency, known as HFF/STZ mice. Results: Treatment with [P3]PP for 28 days reduced energy intake and was associated with notable weight loss. In addition, circulating glucose was returned to values of approximately 8 mmol/L in [P3]PP‐treated mice, with significantly increased plasma insulin and decreased glucagon concentrations. Glucose tolerance and glucose‐stimulated insulin secretion were improved in [P3]PP‐treated HFF/STZ mice, with no obvious effect on peripheral insulin sensitivity. Benefits on insulin secretion were associated with elevated pancreatic insulin content as well as islet and beta‐cell areas. Positive effects on islet architecture were linked to increased beta‐cell proliferation and decreased apoptosis. Treatment intervention also decreased islet alpha‐cell area, but pancreatic glucagon content remained unaffected. In addition, [P3]PP‐treated HFF/STZ mice presented with reduced plasma alanine transaminase and aspartate transaminase levels, with no change in circulating amylase concentrations. In terms of plasma lipid profile, triglyceride and cholesterol levels were significantly decreased by [P3]PP treatment, when compared to saline controls. Conclusion: Collectively, these data highlight for the first time the potential of enzymatically stable PP analogues for the treatment of obesity and related diabetes. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the efficacy and safety of dapagliflozin versus placebo as an add‐on in patients with type 2 diabetes who did not achieve adequate glycaemic control with evogliptin and metformin combination. Patients and Methods: In this multicentre, randomized, double‐blind, placebo‐controlled Phase 3 trial, patients with glycated haemoglobin (HbA1c) levels ≥7.0% (≥53 mmol/mol) and ≤10.5% (≤91 mmol/mol) who had received stable‐dose metformin (≥1000 mg) and evogliptin (5 mg) for at least 8 weeks were randomized to receive dapagliflozin 10 mg or placebo once daily for 24 weeks. Participants continued treatment with metformin and evogliptin. The primary endpoint was change in HbA1c level after 24 weeks of treatment from baseline level. Results: In total, 198 patients were randomized, and 195 patients were included in the efficacy analyses (dapagliflozin: 96, placebo: 99). At Week 24, dapagliflozin significantly reduced HbA1c levels. The least squares mean difference in HbA1c level change from baseline after 24 weeks of treatment was −0.70% (−7.7 mmol/mol) (p < 0.0001). The proportion of participants achieving HbA1c <7.0% (≥53 mmol/mol) was higher in the dapagliflozin group than in the placebo group. Compared to placebo, dapagliflozin significantly reduced fasting plasma glucose, mean daily glucose, 2‐h postprandial plasma glucose, fasting insulin, uric acid and gamma‐glutamyl transferase levels, homeostatic model assessment for insulin resistance index, body weight, hepatic steatosis index, and albuminuria. Adiponectin level significantly increased from baseline level after 24 weeks of dapagliflozin treatment. Adverse event rates were similar in the two groups. Conclusion: Dapagliflozin add‐on to evogliptin plus metformin improved glycaemic control and was well tolerated by the target patients. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Metabolic disorders are common in patients with psoriasis and contribute significantly to an increased cardiovascular risk. While biologic therapy is very successful in clearing skin lesions, its impact on metabolic parameters is uncertain. Our aim was to investigate the residual metabolic burden in psoriasis patients successfully treated with biologic therapy. We conducted a cross-sectional study of 80 young patients (54 men, 26 women, aged 30–45 years) successfully treated with either adalimumab, secukinumab or guselkumab and topical therapy or methotrexate, and 20 healthy controls. Anthropometric parameters, lipid levels and metabolic indices (HOMA-IR, TyG index and FIB-4 index) were measured. Patients did not receive any other treatments to exclude confounding effects. After analysis, we found that patients treated with three different biologics had similar metabolic status, only the FIB-4 index was higher in the adalimumab group than in the secukinumab and guselkumab treatment groups. There were no significant differences between the patients treated with biologics and the control group. The comparison with patients treated topically or with methotrexate showed that only triglyceride levels, HOMA-IR, TyG index, and FIB-4 index were elevated in patients treated with adalimumab compared to patients treated with topical therapy. Finally, metabolic status was also similar in patients treated with methotrexate or topical therapy. In conclusion, this study suggests that psoriasis patients successfully treated with biologics have similar metabolic parameters to the control group and patients treated with topical therapy or methotrexate. This indicates that there is no significant residual metabolic burden in young patients successfully treated with biologics. These results are clinically relevant and should be considered in the treatment of psoriasis patients. The study is registered at (identifier: NCT05957120). Date of registration: 24th of July 2023. [ABSTRACT FROM AUTHOR]

Evidence from observational and Mendelian randomization (MR) studies suggested that insulin resistance (IR) was associated with Alzheimer's disease (AD). However, the causal effects of different indicators of IR on AD remain inconsistent. Here, we aim to assess the causal association between the insulin sensitivity index (ISI), a measure of post‐prandial IR, and the risk of AD. We first conducted primary and secondary univariable MR analyses. We selected 8 independent genome‐wide significant (p < 5E‐08, primary analyses) and 61 suggestive (p < 1E‐05, secondary analyses) ISI genetic variants from large‐scale genome‐wide association studies (GWAS; N = 53 657), respectively, and extracted their corresponding GWAS summary statistics from AD GWAS, including IGAP2019 (N = 63 926) and FinnGen_G6_AD_WIDE (N = 412 181). We selected five univariable MR methods and used heterogeneity, horizontal pleiotropy test, and leave‐one‐out sensitivity analysis to confirm the stability of MR estimates. Finally, we conducted a meta‐analysis to combine MR estimates from two non‐overlapping AD GWAS datasets. We further performed multivariable MR (MVMR) to assess the potential mediating role of type 2 diabetes (T2D) on the association between ISI and AD using two MVMR methods. In univariable MR, utilizing 8 genetic variants in primary analyses, we found a significant causal association of genetically increased ISI with decreased risk of AD (OR = 0.79, 95% CI: 0.68–0.92, p = 0.003). Utilizing 61 genetic variants in secondary analyses, we found consistent findings of a causal effect of genetically increased ISI on the decreased risk of AD (OR = 0.89, 95% CI: 0.82–0.96, p = 0.003). Heterogeneity, horizontal pleiotropy test, and leave‐one‐out sensitivity analysis ensured the reliability of the MR estimates. In MVMR, we found no causal relationship between ISI and AD after adjusting for T2D (p > 0.05). We provide genetic evidence that increased ISI is significantly and causally associated with reduced risk of AD, which is mediated by T2D. These findings may inform prevention strategies directed toward IR‐associated T2D and AD. [ABSTRACT FROM AUTHOR]

Background: Non-alcoholic fatty liver disease (NAFLD) is one of the most universal liver diseases with complicated pathogenesis throughout the world. Insulin resistance is a leading risk factor that contributes to the development of NAFLD. Vascular endothelial growth factor B (VEGFB) was described by researchers as contributing to regulating lipid metabolic disorders. Here, we investigated VEGFB as a main target to regulate insulin resistance and metabolic syndrome. Methods: In this study, bioinformatics, transcriptomics, morphological experiments, and molecular biology were used to explore the role of VEGFB in regulating insulin resistance in NAFLD and its molecular mechanism based on human samples, animal models, and cell models. RNA-seq was performed to analyze the signal pathways associated with VEGFB and NAFLD; Palmitic acid and High-fat diet were used to induce insulin-resistant HepG2 cells model and NAFLD animal model. Intracellular glucolipid contents, glucose uptake, hepatic and serum glucose and lipid levels were examined by Microassay and Elisa. Hematoxylin-eosin staining, Oil Red O staining, and Periodic acid-schiff staining were used to analyze the hepatic steatosis, lipid droplet, and glycogen content in the liver. Western blot and quantitative real-time fluorescent PCR were used to verify the expression levels of the VEGFB and insulin resistance-related signals PI3K/AKT pathway. Results: We observed that VEGFB is genetically associated with NAFLD and the PI3K/AKT signal pathway. After VEGFB knockout, glucolipids levels were increased, and glucose uptake ability was decreased in insulin-resistant HepG2 cells. Meanwhile, body weight, blood glucose, blood lipids, and hepatic glucose of NAFLD mice were increased, and hepatic glycogen, glucose tolerance, and insulin sensitivity were decreased. Moreover, VEGFB overexpression reduced glucolipids and insulin resistance levels in HepG2 cells. Specifically, VEGFB/VEGFR1 activates the PI3K/AKT signals by activating p-IRS1Ser307 expression, inhibiting p-FOXO1pS256 and p-GSK3Ser9 expressions to reduce gluconeogenesis and glycogen synthesis in the liver. Moreover, VEGFB could also enhance the expression level of GLUT2 to accelerate glucose transport and reduce blood glucose levels, maintaining glucose homeostasis. Conclusions: Our studies suggest that VEGFB could present a novel strategy for treating NAFLD as a positive factor. [ABSTRACT FROM AUTHOR]

Metabolic syndrome (MetS) is a collection of metabolic abnormalities including insulin resistance, atherogenic dyslipidemia, central obesity, and hypertension. Recently, long noncoding RNAs (lncRNAs) have emerged as pivotal regulators of metabolic balance, influencing the genes associated with MetS. Although the prevalence of insulin resistance is rising, leading to an increased risk of type 2 diabetes mellitus (T2DM) and its vascular complications, there is still a notable gap in understanding the role of lncRNAs in the context of clinical diabetes. Among lncRNAs, lung adenocarcinoma metastasis‐associated transcript 1 (MALAT1) has been identified as a significant regulator of metabolism‐related disorders, including T2DM and cardiovascular disease (CVD). This review explores the mechanism of lncRNA MALAT1 and suggests that targeting it could offer a promising strategy to combat MetS, thereby enhancing the prognosis of MetS. [ABSTRACT FROM AUTHOR]

As the pathophysiological basis of type 2 diabetes mellitus (T2DM), insulin resistance (IR) is closely related to oxidative stress (OS) and inflammation, while nanozymes have a good therapeutic effect on inflammation and OS by scavenging reactive oxygen species (ROS). Hence, AuCePt porous hollow cascade nanozymes (AuCePt PHNs) are designed by integrating the dominant enzymatic activities of three metallic materials, which exhibit superior superoxide dismutase/catalase-like activities, and high drug loading capacity. In vitro experiments proved that AuCePt PHNs can ultra-efficiently scavenge endogenous and exogenous ROS. Moreover, AuCePt PHNs modified with lactobionic acid (LA) and loaded with disulfiram (DSF), named as AuCePt PHNs-LA@DSF, can significantly improve glucose uptake and glycogen synthesis in IR hepatocytes by regulating the insulin signaling pathways (IRS-1/AKT) and gluconeogenesis signaling pathways (FOXO-1/PEPCK). Intravenous administration of AuCePt PHNs-LA@DSF not only showed high liver targeting efficiency, but also reduced body weight and blood glucose and improved IR and lipid accumulation in high-fat diet-induced obese mice and diabetic ob/ob mice. This research elucidates the intrinsic activity of AuCePt PHNs for cascade scavenging of ROS, and reveals the potential effect of AuCePt PHNs-LA@DSF in T2DM treatment. [ABSTRACT FROM AUTHOR]

Summary C‐reactive protein (CRP) appears to improve the ability to detect cardiometabolic risk in young and middle‐aged adults with mild‐to‐moderate obstructive sleep apnea (mmOSA). The aim of this study is to assess utility of CRP in identifying the risk of hypertension and insulin resistance across a wide age range including older patients with mmOSA. Adults (n = 216) of a wide age range (28–90 years old, mean age 52.64 ± 12.74) with mmOSA (5 ≤ AHI < 30) completed in‐lab polysomnography or home sleep apnea testing, physical examination including blood pressure (BP) measures, structured medical history questionnaire, and blood draw for CRP and fasting glucose and insulin levels. In adults < 60 years, lnCRP but not the apnea–hypopnea index (AHI) was associated with greater odds for hypertension (odds ratio [OR] = 2.40, 95% CI = 1.20–4.84, p = 0.01; OR = 1.00, 95% CI = 0.92–1.08, p = 0.92, respectively) and with higher average systolic and diastolic BP. Also, in adults < 60 years lnCRP but not AHI, was associated with higher lnHOMA values. In contrast, in adults > 60 years neither lnCRP nor AHI were associated with greater odds for hypertension, average systolic and diastolic BP, and lnHOMA. Receiver‐operating characteristics curves revealed that adding CRP to standard clinical factors (age, sex, and BMI) yielded moderately good risk models for hypertension in patients < 60 years (AUC = 0.721). In conclusion, CRP improves the ability to detect cardiometabolic risk in young and middle‐aged, but not older adults with mmOSA, suggesting that inflammation may be a primary pathogenetic mechanism in younger patients with OSA. [ABSTRACT FROM AUTHOR]

Backgroud: Pregnancy is a state of increased metabolic demand, and poor maternal nutrition can exacerbate these changes, potentially increasing the risk of cardiometabolic disorders.This study is significant as it investigates the effect of high energy nutritional supplements on cardio metabolic risk markers in underweight primigravidas. Methodology: A single blinded randomized controlled trial was conducted from April 2018- August 2019 among the Pakistani tertiary care facilities of Khyber Pakhtunkhwa. A total of thirty six participants were randomized into two groups receiving either high energy nutritional supplement 'MAAMTA' or Placebo. They were instructed to take Placebo/Supplement alongside to their regular prenatal care and food from their first antenatal visit till a week postnatally. Anthropometric measurements and blood samples for biochemical parameters insulinlevels, fasting blood glucose & lipid profile were taken at baseline visit, between 16 and 20 weeks gestation and a post natal visit. Results: The two-way repeated measures ANOVA showed that there was a highly significant time effect on participant's Insulin level (F (1.8, 53.6) = 10.64, P < 0 0.000, ηp2 = 0.269). A highly significant time effect on participant's insulin resistance (F (2, 68) = 8.116,P < 0 0.001, ηp2 = 0.193) was also observed. There was a highly significant time effect on participant's LDL level as well (F (2, 68) = 11.82, P < 0 0.000, ηp2 = 0.258). Conclusion: Supplementation with high energy nutritional supplements may improve insulin levels and insulin sensitivity in underweight primigravidas. Trial registration: https://www.ClinicalTrials.govClinicalTrials.gov Identifier: ISRCTN 10088578. Registered on 27 March 2018. https://www.isrctn.com/ISRCTN10088578. [ABSTRACT FROM AUTHOR]

AbstractContext:Objectives:Materials and Methods:Results:Conclusion:Insulin resistance and a disturbed lipid profile are common associations with type 2 diabetes mellitus (T2DM) and different skin diseases, particularly psoriasis (PsO).We investigated potential therapeutic mechanisms of metformin in a murine animal model of psoriasiform lesions in T2DM.Forty-two rats were randomly divided into control, PsO, and type II DM (T2DM) groups. After confirmation of DM, the type II diabetic rats were allocated into T2DM+ PsO, T2DM+ PsO+ systemic metformin (S. met), T2DM+ PsO+ topical metformin (T. met)), and T2DM+ PsO + combined metformin (C. met). PsO was induced by topical imiquimod.Systemic administration of the cornerstone antidiabetic drug, metformin, was able to improve insulin resistance and lipid profile. At molecular levels, both topical and systemic metformin significantly increased AMP-activated protein kinase (AMPK), and lowered keratinocyte growth factor (KGF) / “Signal transducer and activator of transcription” (STAT)3 protein levels, and the IL-17RA and IL-17RC gene expression.Although its glucose-controlling effect was not optimum, T.met gel served anti-psoriatic and anti-inflammatory effects. [ABSTRACT FROM AUTHOR]

Objective: To determine the associations between triglyceride‐glucose (TyG) index and mortality from all causes and cardiovascular causes in diabetic population. Methods: 3349 participants with diabetes mellitus (DM) from the 1999–2014 National Health and Nutrition Examination Surveys (NHANES), aged 18–85 years were included and grouped based on the TyG index in quintiles. Mortality was followed up through December 31th, 2015. Cox proportional hazards models were used to assess the hazard ratios (HRs) and 95% confidence intervals (CIs). We clarified the shape of association between TyG index and mortality using restricted cubic splines and piecewise linear regression. Results: After a median follow‐up period of 82 months, 800 (23.9%) deaths occurred, of which 190 (5.7%) were due to cardiovascular causes. Participants in the top quintile had higher risks of all‐cause mortality (HR, 1.38; 95% CI, 1.04–1.48) and cardiovascular mortality (HR, 2.43; 95% CI, 1.32–4.45) than those in the lowest quintile. TyG index and all‐cause mortality had a J‐shaped relationship with a threshold value of 9.32, while TyG index and cardiovascular mortality had a reversed L‐shaped relationship with a threshold value of 9.37. Higher TyG index was associated with increased risks of all‐cause mortality (per SD increment, HR, 1.52; 95% CI, 1.27–1.82) and cardiovascular mortality (per SD increment, HR, 2.17; 95% CI, 1.54–3.04) when above the threshold values. The sensitivity analyses demonstrated similar findings. Conclusions: TyG index in diabetic patients was nonlinearly correlated with mortality risks, potentially predicting all‐cause and cardiovascular mortality. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is a highly heterogeneous and aggressive malignant tumor that seriously affects the life safety of people all over the world. Its early manifestations are subtle. The present study aimed to investigate the clinical significance of serum lipid profiles, insulin resistance markers including the triglyceride-glucose (TyG) index and the atherosclerotic index (AI), in GC patients. A retrospective analysis encompassed 215 GC patients and 827 healthy individuals. The study results show that the total cholesterol, triglycerides, low-density lipoprotein, high-density lipoprotein levels, and the TyG index of GC patients were significantly lower than those of the control group before and after propensity score matching analysis. In the GC group, the levels of CEA, CA199, CA125, and CA724 tumor markers were higher than those in the healthy control group. Patients in advanced stages exhibited lower serum levels of serum lipids and TyG index compared to those in early stages. ROC analysis revealed that the TyG index, CA125, and CA199 combination yielded the highest positive prediction rate for GC at 98.6%. TyG index is significantly associated with the risk of adverse reactions after chemotherapy (OR = 1.104, 95% CI 1.028–1.186, P < 0.01). Multiple tumor markers and the TyG index combined detection showed correlations with five adverse reactions caused by chemotherapy (r < 0.6, P < 0.05). Preoperative lipid profiles in the serum show a strong correlation with patients diagnosed with GC. Evaluating a combination of various serum lipids and cancer markers significantly improves diagnostic precision for GC and the ability to predict chemotherapy side effects. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes mellitus (T2DM) was one of the most prevalent comorbidities among patients with coronavirus disease 2019 (COVID-19). Interactions between different metabolic parameters contribute to the susceptibility to the virus; thereby, this study aimed to rank the importance of clinical and laboratory variables as risk factors for COVID-19 or as protective factors against it by applying machine learning methods. Method: This study is a retrospective cohort conducted at a single center, focusing on a population with T2DM. The patients attended the Yazd Diabetes Research Center in Yazd, Iran, from February 20, 2020, to October 21, 2020. Clinical and laboratory data were collected within three months before the onset of the COVID-19 pandemic in Iran. 59 patients were infected with COVID-19, while 59 were not. The dataset was split into 70% training and 30% test sets. Principal Component Analysis (PCA) was applied to the data. The most important components were selected using a 'sequential feature selector' and scored by a Linear Discriminant Analysis model. PCA loadings were then multiplied by the PCs' scores to determine the importance of the original variables in contracting COVID-19. Results: HDL-C, followed by eGFR, showed a strong negative correlation with the risk of contracting the virus. Higher levels of HDL-C and eGFR offer protection against COVID-19 in the T2DM population. But, the ratio of BUN to creatinine did not show any correlation. Conversely, the AIP, TyG index and TG showed the most positive correlation with susceptibility to COVID-19 in such a way that higher levels of these factors increase the risk of contracting the virus. The positive correlation of diastolic BP, TyG-BMI index, MAP, BMI, weight, TC, FPG, HbA1C, Cr, systolic BP, BUN, and LDL-C with the risk of COVID-19 decreased, respectively. Conclusion: The atherogenic index of plasma, triglyceride glucose index, and triglyceride levels are the most significant risk factors for COVID-19 contracting in individuals with T2DM. Meanwhile, high-density lipoprotein cholesterol is the most protective factor. [ABSTRACT FROM AUTHOR]

Background: Diabetes mellitus is characterized by insulin resistance (IR) and dysfunctional insulin secretion from pancreatic β-cells. However, little research has been conducted on the relationship between IR and β-cell function in relation to diabetic complications among Korean diabetic patients. This study aimed to examine the differential associations between IR and β-cell function and various diabetic complications among Korean diabetic patients. Methods: The analysis employed a common data model (CDM). IR and β-cell function were quantified using the homeostasis model assessment for insulin resistance (HOMA-IR) and β-cell function (HOMA-β), respectively. Hazard ratios for diabetic nephropathy, diabetic retinopathy, and cardiovascular disease (CVD) events were calculated. Results: The study cohort consisted of 2,034 diabetic patients aged over 20 years who visited EUMC between January 2001 and December 2019. Among diabetic patients in the highest quartile of HOMA-IR, the adjusted hazard ratio for total CVD events was 1.76 (95% confidence interval [CI], 1.20–2.57) compared with those in the lowest quartile of HOMA-IR (P = 0.004). In contrast, diabetic patients in the lowest quartile of HOMA-β exhibited an adjusted hazard ratio of 3.91 (95% CI, 1.80–8.49) for diabetic retinopathy compared to those in the highest quartile of HOMA-β (P = 0.001). Conclusion: Insulin resistance and β-cell function exhibited different associations with diabetic complications among Korean diabetic patients. Specifically, lower β-cell function was associated with an increased risk of diabetic retinopathy, whereas higher IR was associated with an increased risk of CVD events. Individuals with pronounced IR should prioritize CVD prevention measures, and those with significant β-cell dysfunction may benefit from early, intensive surveillance for diabetic retinopathy. [ABSTRACT FROM AUTHOR]

Aims: Insulin resistance (IR) is an important risk factor for obesity and cardiometabolic diseases, and our previous findings have demonstrated that visceral fat area to skeletal muscle mass ratio (VSR) is significantly and positively associated with the risk of cardiometabolic diseases. Hence, this study aimed to investigate the relationship between VSR and multiorgan IR, provide a new approach to improve body composition, and set the basis for VSR to increase the incidence of cardiometabolic diseases. Materials and Methods: The study included 398 patients who underwent anthropometric and biochemical measurements, and body composition assessment. Spearman correlation analysis was used to investigate the correlation between VSR and homeostatic model assessment for insulin resistance (HOMA‐IR) as well as multiorgan IR, including homeostasis model assessment adiponectin (HOMA‐AD), adipose tissue insulin resistance (ADIPO‐IR), and hepatic insulin sensitivity (HISI). The new model that incorporated into the present study is made up of easily measured biochemical indicators and is used to predict IR. Logistic regression was used to analyze the odds ratio (OR) of VSR on the risk of multiorgan IR. The predictive value of VSR for HOMA‐IR and new model was evaluated using the receiver operating characteristic (ROC) curve. Results: VSR was significantly associated with HOMA‐IR, HOMA‐AD, ADIPO‐IR, 1/HISI, and new model (p < 0.001). With the increase of VSR, the OR increased significantly for HOMA‐IR and new model (p < 0.001). Then, multiorgan IR indicators were quantified, compared to the lowest quartile group, and increased VSR exacerbated the risk of IR in the highest quartile (ptrend < 0.001). The area under the curve for predicting IR using VSR for HOMA‐IR and new model was 0.88 for men, 0.85 for women and 0.73 for men, 0.76 for women, respectively. Conclusions: There was significant correlation between VSR and multiorgan IR, and the risk of multiorgan IR increased with increasing VSR. Trial Registration: Clinical Trial Registry identifier: ChiCTR2100044305. [ABSTRACT FROM AUTHOR]

Non‐alcoholic fatty liver disease (NAFLD) is a liver pathology concomitant with metabolic disarrangement. This study assessed the therapeutic impacts of delphinidin, an anthocyanin, or α‐amyrin, a pentacyclic triterpenoid, on NAFLD in rats and the underlying mechanisms involved. NAFLD was established by feeding a high‐fat diet (HFD) for 10 weeks, either alone or in combination with delphinidin (40 mg/kg, oral) or α‐amyrin (20 mg/kg, oral). Delphinidin or α‐amyrin ameliorated the metabolic and histopathological perturbations induced by HFD. These compounds markedly attenuated NAFLD‐induced hepatic steatosis, as evidenced by a substantial decrease in body weight, insulin resistance, and liver and adipose tissue indices. Alongside normalization of the atherogenic index, both improved HFD‐mediated abnormalities in serum lipids, liver enzymes, leptin, and ghrelin levels. Moreover, their intervention activated the NFE2 like bZIP transcription factor 2 and heme oxygenase 1 pathways and abrogated HFD‐triggered activation of mitogen‐activated protein kinase 1 signaling. These remedies inhibited hepatic apoptosis and modulated the gene expression of lipogenic enzymes. Furthermore, histological analysis corroborated the suppression of lipid accumulation and amelioration of hepatic architecture in the treated rats. Our findings highlight the hepatoprotective value of delphinidin or α‐amyrin against NAFLD and related metabolic diseases through their insulin‐sensitizing, anti‐inflammatory, antioxidant, and antiapoptotic effects. [ABSTRACT FROM AUTHOR]

Summary To evaluate the relationship between serum gamma‐glutamyl transferase (GGT) levels and fatty pancreas in subjects with concurrent obesity, insulin resistance and metabolic dysfunction‐associated steatotic liver disease (MASLD) without a history of pancreatitis. From March 2019 to September 2021, 31 adult subjects with concurrent obesity and MASLD were recruited as part of the study investigating the biological impact of bariatric surgery and lifestyle modification on obesity. Chemical shift encoded MRI of the abdomen, LiverMultiScan, anthropometric, clinical and blood biochemistry analyses were performed prior to any intervention at baseline. GGT (p <.001) was significantly different between those ‘with fatty pancreas’ and ‘without fatty pancreas’ groups. GGT (p <.001) was significantly different between those ‘with both metabolic syndrome and fatty pancreas’ and those ‘with metabolic syndrome but without fatty pancreas.’ GGT (p <.001) was also significantly different between those ‘with both diabetes and fatty pancreas’ and those ‘with diabetes but without fatty pancreas’. Logistic regression analysis showed that abnormal GGT levels (p = .010) and Hypertension (p = .045) were significant independent predictors of fatty pancreas. GGT was associated with fatty pancreas by an odds ratio 7.333 (95% [CI]: 1.467–36.664), while the AUROC of GGT in determining fatty pancreas was 0.849. Elevation in serum GGT might be a potential marker to identify fatty pancreas. [ABSTRACT FROM AUTHOR]

Advanced glycation end products (AGEs), the products of non-enzymatic browning reactions between the active carbonyl groups of reducing sugars and the free amines of amino acids, are largely considered oxidative derivatives resulting from diabetic hyperglycemia, which are further recognized as a potential risk for insulin resistance (IR) and type 2 diabetes (T2D). The accumulation of AGEs can trigger numerous negative effects such as oxidative stress, carbonyl stress, inflammation, autophagy dysfunction and imbalance of gut microbiota. Recently, studies have shown that cereal polyphenols have the ability to inhibit the formation of AGEs, thereby preventing and alleviating T2D. In the meanwhile, phenolics compounds could produce different biological effects due to the quantitative structure activity-relationship. This review highlights the effects of cereal polyphenols as a nonpharmacologic intervention in anti-AGEs and alleviating T2D based on the effects of oxidative stress, carbonyl stress, inflammation, autophagy, and gut microbiota, which also provides a new perspective on the etiology and treatment of diabetes. [ABSTRACT FROM AUTHOR]

Background: Air pollution may exacerbate diabetes-related indicators; however, the longitudinal associations between air pollutant concentrations and glycemic markers remain unclear. In this prospective cohort study, we examined the longitudinal associations between air pollution and glycemic indicators among older individuals with normoglycemia at baseline and determined whether these associations differed according to changes in physical activity levels. Methods: Overall, 1,856 participants (mean age, 70.9 years) underwent baseline and 4-year follow-up surveys. We used linear mixed-effect models to examine the associations between previous 1-year exposures to air pollutants and glycemic indicators. We further investigated associations between previous 5-year exposures to air pollutants and glycemic indicators after the inverse probability of treatment weighting (IPTW). We explored effect modifications by the level of physical activity maintenance and changes in metabolic equivalent of task (METs) for physical activity. Results: Levels of particulate matter with aerodynamic diameters ≤ 10 μm (PM10) and ≤ 2.5 μm, and nitrogen dioxide (NO2) were significantly associated with increased fasting blood glucose, Hemoglobin A1c, insulin, and homeostatic model assessment for insulin resistance (HOMA-IR) values. After IPTW, the associations remained significant for PM10 and NO2. The positive associations of NO2 with insulin and HOMA-IR remained significant in the maintained inactive group, but not in the maintained moderate-to-vigorous active group. The positive associations of PM10 or NO2 with insulin and HOMA-IR remained significant in the group with increased METs, but not in those with decreased METs. In the post-hoc analysis of non-linear relationships between an increase in METs and glycemic indicators, insulin and HOMA-IR remarkably increased in the higher PM10 and NO2 exposure group from the point of 12,000 and 13,500 METs-min/week increase, respectively. Conclusions: We demonstrated longitudinal associations between air pollution exposures and increased insulin resistance in older individuals. Maintaining moderate-to-vigorous physical activity may mitigate the adverse effects of air pollution on insulin resistance. In older individuals dwelling in highly polluted areas, an increase of less than 12,000 METs-min/week may be beneficial for insulin resistance. Highlights: Why did we undertake this study? Air pollution exposures may increase the risk of diabetes mellitus; however, the impacts of changes in physical activity on the associations between air pollution exposures and glycemic indicators remained unclear. What is the specific question(s) we wanted to answer? We investigated the associations of previous 1-year and 5-year air pollution exposures with glycemic indicators in older individuals with normoglycemia and explored the potential impacts of changes in physical activity levels on the associations. What did we find? Previous 1-year exposures to PM10 and NO2 were associated with elevated fasting blood glucose, Hemoglobin A1c, insulin, and insulin resistance. Previous 5-year exposures to PM10 and NO2 were associated with increased insulin resistance. The adverse effects of NO2 existed in those who maintained inactive but not in those with maintained moderate-to-vigorous activity. What are the implications of our findings? Our findings underscore the detrimental impact of air pollution on glycemic health and emphasize that maintaining moderate to vigorous physical activity may mitigate the adverse effects of air pollution on insulin resistance in older individuals. [ABSTRACT FROM AUTHOR]

Background: Hyperuricaemia is common among obese children and adolescents, and is closely related to insulin resistance. The aim of this study was to explore the relationships between youth insulin resistance and hyperuricaemia, as well as their relationships with lifestyle factors in youths, to provide early guidance on the risk factors for hyperuricaemia in adolescents. Methods: This study included 233 adolescents aged 10 to 20 years. Insulin resistance was evaluated via the homeostasis model assessment-insulin resistance (HOMA-IR) method. Binary logistic regression analysis was used to assess the associations of HOMA-IR with hyperuricaemia status and serum uric acid (UA) levels. The participants were subsequently divided into two groups, the noninsulin resistant group (HOMA-IR ≤ 3.2) and the insulin resistant group (HOMA-IR > 3.2), to further explore the factors that may affect the serum UA level. Finally, the predictive ability of different indicators of hyperuricaemia was evaluated via the ROC curve. Results: Binary logistic regression analysis revealed a significant increase in the risk of developing hyperuricaemia for individuals with elevated HOMA-IR (p < 0.001) and insulin resistance (p < 0.01). Spearman's correlation analysis revealed a significant positive linear correlation between HOMA-IR and serum UA levels (r = 0.4652, p < 0.001). Among insulin-resistant adolescents, UA levels were positively correlated with weight ratings, frequency of staying up late, and sugary beverages intake. Notably, individuals who engaged in 1–3 h of weekly exercise had the lowest UA levels. The area under the ROC curve for HOMA-IR was 0.847 (cut-off value = 2.165, p < 0.001), and the optimal prediction model included HOMA-IR, BMI z-score, and other lifestyle factors (AUC: 0.870, p < 0.001)). Conclusion: HOMA-IR was identified as an independent risk factor for the development of hyperuricaemia and could be used as a sensitive indicator for the prediction its development in adolescents. In insulin-resistant adolescents with hyperuricaemia, maintaining normal weight, engaging in physical exercise for 1–3 h per week, avoiding staying up late and limiting sugary beverages intake are recommended to reduce the prevalence of hyperuricaemia among adolescents. [ABSTRACT FROM AUTHOR]

Polycystic ovarian syndrome (PCOS) is one of the most common endocrinopathies among reproductive women worldwide, contributing greatly on the incidence of female infertility and gynecological cancers. It is a complex health condition combining of multiple symptoms like androgen excess, uncontrolled weight gain, alopecia, hirsutism, etc. Conventionally PCOS was associated with obesity while it is often found among lean women nowadays, making the disease more critical to diagnose as well treatment. The disorder has an impact on several signal transduction pathways, including steroidogenesis, steroid hormone activity, gonadotrophin regulation, insulin secretion, energy balance, and chronic inflammation. Understanding the aetiology and pathophysiology of PCOS is difficult due to its multiple causes, which include environmental factors, intricate genetic predisposition, and epigenetic modifications. Despite research supporting the role of familial aggregations in PCOS outcomes, the inheritance pattern remains unknown. Henceforth, to reduce the burden of PCOS, it is inevitably important to diagnose at early ages as well as intervene through personalized medicine. With this brief background, it was imperative to elucidate the genetic architecture of PCOS considering BMI as an controlling factor. This study aims to investigate the genetic basis behind obesity-mediated PCOS, focusing on both obese and lean individuals. It uses a comprehensive bioinformatics methodology to depict pathways and functionality enrichment, allowing for cost-effective risk prediction and management. In the present research, the representative study participants (N = 2) were chosen from a cross-sectional epidemiological survey, based on their anthropometric parameters and confirmation of PCOS. Upon voluntary participation and written consent, biological fluids (whole blood and buccal swab) were taken from where DNA was extracted. The clinical-exome sequencing was performed by the Next-generation Illumina platform using the Twist Human Comprehensive Exome Kit. A comprehensive bioinformatics methodology was employed to identify the most important, unique, and common genes. A total of 26,550 variants were identified in clinically important exomes from two samples, with 5170 common and 2232 and 2322 unique among PCOS lean and obese phenotypes, respectively. Only 262 and 94 variants were PCOS-specific in lean and obese PCOS. Three filters were applied to shortlist the most potent variants, with 4 unique variants in lean PCOS, 2 unique variants in obese PCOS, and 5 common variants in both. The study found that leptin signalling impairment and insulin resistance, as well as mutations in CYP1A1, CYP19A1, ESR1, AR, AMH, AdipoR1, NAMPT, NPY, PTEN, EGFR, and Akt, all play significant roles in PCOS in the studied group. Young women in West Bengal, India, are more likely to have co-occurring PCOS, which includes estrogen resistance, leptin receptor insufficiency, folate deficiency, T2DM, and acanthosis nigricans, with obesity being a common phenotypic expression. [ABSTRACT FROM AUTHOR]

AbstractHelicobacter pylori infection has been associated with the development of insulin resistance (IR). This study aimed to examine the effect of H. pylori-derived extracellular vesicles (EVs) on IR induction. EVs were derived from two H. pylori strains, and characterised by transmission electron microscopy and dynamic light scattering. Different concentrations of insulin were added to HepG2 cells to induce IR model. HepG2 cells were exposed to various concentrations of H. pylori-derived EVs to assess IR development. The gene expression of IRS1, AKT2, GLUT2, IL-6, SOCS3, c-Jun and miR-140 was examined using RT-qPCR. Glucose uptake analysis revealed insulin at 5 × 10 −7 mol/l and EVs at 50 µg/ml induced IR model in HepG2 cells. H. pylori-derived EVs downregulated the expression level of IRS1, AKT2, and GLUT2, and upregulated IL-6, SOCS3, c-Jun, and miR-140 expression in HepG2 cells. In conclusion, our findings propose a novel mechanism by which H. pylori-derived EVs could potentially induce IR. [ABSTRACT FROM AUTHOR]

Given that the extracellular matrix polymer hyaluronan (HA) has been implicated in longevity, we asked whether 4-methylumbelliferone (4-MU), an inhibitor of HA synthesis, impacts lifespan in mice. We designed a prospective study of long-term administration of 4-MU with conventional C57BL/6J mice. We find that 4-MU extends median survival from 122 weeks (control) to 154 weeks (4-MU), an increase of 32 weeks (p < 0.0001 by Log-rank Mantel Cox test). The maximum lifespan of 4-MU treated mice increased from 159 to 194 weeks. In tandem with these effects, 4-MU enhances insulin sensitivity, a metabolic parameter known to regulate lifespan, as measured by insulin tolerance testing (ITT) as well as frequent sampling intra venous glucose tolerance tests (FSIVGTTs). We further observed that 4-MU treated mice weigh less while consuming the same amount of food, indicating that 4-MU treatment alters energy expenditure. However, we do not observe changes in tissue HA content in this model. We conclude that 4-MU promotes insulin sensitivity and longevity but that the underlying mechanism, and the contribution of HA is unclear. 4-MU, already approved in various countries for hepatobiliary conditions, is currently under investigation and clinical development as a therapy for several chronic inflammatory conditions. These data suggest that the beneficial effects of 4-MU on tissue metabolism may include effects on longevity. [ABSTRACT FROM AUTHOR]

Background: Metabolic-dysfunction-associated steatotic liver disease (MASLD) represents a major clinical complication of obesity. Methods: In this study, we used magnetic resonance (MR) methods to determine the effect of obesity treatment with semaglutide, a GLP-1 receptor agonist, on the liver fat content and selected metabolic variables. We investigated whether treatment would affect the acute response of liver fat to glucose and fructose administration and whether it would affect the fatty acid profile of VLDL-triglycerides. Sixteen obese non-diabetic men underwent a 16-week dietary intervention and 16-week treatment with subcutaneous semaglutide in a crossover design without a washout period. The order of the interventions was randomized. Results: After treatment, body weight of the subjects decreased by 5% and liver fat by a third, whereas dietary intervention had no impact on these parameters. The decrease in liver fat with semaglutide did not correlate with changes in body weight and other measures of adiposity and was unrelated to improved insulin sensitivity. Conclusions: The proportion of palmitic and palmitoleic acids in VLDL-triglycerides decreased after treatment, suggesting that the beneficial effects of semaglutide on liver fat are mediated by the suppression of de novo lipogenesis. [ABSTRACT FROM AUTHOR]

Obesity and type 2 diabetes (T2D) are widespread metabolic disorders that significantly impact global health today, affecting approximately 17% of adults worldwide with obesity and 9.3% with T2D. Both conditions are closely linked to disruptions in lipid metabolism, where peroxisomes play a pivotal role. Mitochondria and peroxisomes are vital organelles responsible for lipid and energy regulation, including the β-oxidation and oxidation of very long-chain fatty acids (VLCFAs), cholesterol biosynthesis, and bile acid metabolism. These processes are significantly influenced by estrogens, highlighting the interplay between these organelles' function and hormonal regulation in the development and progression of metabolic diseases, such as obesity, metabolic dysfunction-associated fatty liver disease (MAFLD), and T2D. Estrogens modulate lipid metabolism through interactions with nuclear receptors, like peroxisome proliferator-activated receptors (PPARs), which are crucial for maintaining metabolic balance. Estrogen deficiency, such as in postmenopausal women, impairs PPAR regulation, leading to lipid accumulation and increased risk of metabolic disorders. The disruption of peroxisomal–mitochondrial function and estrogen regulation exacerbates lipid imbalances, contributing to insulin resistance and ROS accumulation. This review emphasizes the critical role of these organelles and estrogens in lipid metabolism and their implications for metabolic health, suggesting that therapeutic strategies, including hormone replacement therapy, may offer potential benefits in treating and preventing metabolic diseases. [ABSTRACT FROM AUTHOR]

Polycystic ovary yndrome (PCOS) is a common metabolic disorder in women, which is usually associated with insulin resistance (IR) and chronic inflammation. Loureirin B (LrB) can effectively improve insulin resistance and alleviate chronic inflammation, and in order to investigate the therapeutic effect of LrB on polycystic ovary syndrome with insulin resistance (PCOS-IR), we conducted animal experiments. A PCOS-IR rat model was established by feeding a high-fat diet combined with letrozole (1 mg/kg·d for 21 days). The rats were treated with the GPR120 agonists TUG-891 and LrB for 4 weeks. Biochemical parameters (fasting blood glucose, total cholesterol, triglycerides, high- and low-density lipoprotein), hormone levels (serum insulin, E2, T, LH, and FSH), and inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-18) were analyzed. Histopathological analyses of ovaries were performed using hematoxylin/eosin (H&E) staining. Real-time PCR and western blotting were used to assess GPR120, NLRP3, and caspase-1 expression in ovaries, and immunohistochemistry was used to evaluate LKB1 and AMPK protein expression. LrB reduced body weight, Lee's index, ovarian index, ovarian area, and volume in PCOS-IR rats. It lowered fasting blood glucose, serum insulin, and HOMA-IR. LrB decreased total serum cholesterol, triglyceride, and LDL levels and increased HDL levels. It reduced serum T, LH, and LH/FSH and raised serum E2 and FSH levels. LrB downregulated the mRNA and protein expression levels of NLRP3 and Caspase-1, increased the protein and mRNA expression levels of GPR120 in rat ovaries, and increased LKB1 and AMPK protein expression in ovaries, ameliorating ovarian histopathological changes in PCOS-IR rats. Taken together, LrB upregulated GPR120, LKB1, and AMPK protein expression, downregulated NLRP3 and Caspase-1 protein expression, reduced insulin resistance and chronic inflammation, and ameliorated histopathological changes in ovarian tissues in PCOS rats, suggesting its potential as a treatment for PCOS. [ABSTRACT FROM AUTHOR]

There is no literature available about the growth differentiation factor-15 (GDF-15) biomarker in combination with mitochondrial DNA (mtDNA) deletions in insulin resistance (IR), and polycystic ovary syndrome (PCOS); however, it would be useful to achieve optimal metabolic status and improve pregnancy success. In this study, the role of GDF-15 and mtDNA deletions as biomarkers in the pathogenesis of IR and PCOS was investigated. In our study, 81 female patients who were treated for IR and/or PCOS and 41 healthy controls were included. GDF-15 levels in patients showed a marked increase compared to controls. Elevated GDF-15 levels were found in 12 patients; all of them had a BMI > 25 kg/m2, which is associated with reactive hyperinsulinemia. The presence of mitochondrial dysfunction was mainly observed in the IR-only subgroup. The increase in plasma levels of GDF-15 and the prevalence of mtDNA deletions is directly proportional to body mass index. The more marked metabolic abnormalities required more intensive drug therapy with a parallel increase in plasma GDF-15 levels. Elevated levels of GDF-15 and the presence of mitochondrial DNA deletions may be a consequence of carbohydrate metabolism disorders in patients and thus a predictor of the process of accelerated aging. [ABSTRACT FROM AUTHOR]

Among all nephropathies, diabetic kidney disease (DKD) is the most common cause of kidney impairment advancement to end-stage renal disease (ESRD). Although DKD has no cure, the disease is commonly managed by strict control of blood glucose and blood pressure, and in most of these cases, kidney function often deteriorates, resulting in dialysis, kidney replacement therapy, and high mortality. The difficulties in finding a cure for DKD are mainly due to a poor understanding of the underpinning complex cellular mechanisms that could be identified as druggable targets for the treatment of this disease. The review is thus aimed at giving insight into the interconnection between chronic hyperglycaemia and cellular mechanistic perturbations of nephropathy in diabetes. A comprehensive literature review of observational studies on DKD published within the past ten years, with 57 percent published within the past three years was carried out. The article search focused on original research studies and reviews published in English. The articles were explored using Google Scholar, Medline, Web of Science, and PubMed databases based on keywords, titles, and abstracts related to the topic. This article provides a detailed relationship between hyperglycaemia, oxidative stress, and various cellular mechanisms that underlie the onset and progression of the disease. Moreover, it also shows how these mechanisms affect organelle dysfunction, resulting in fibrosis and podocyte impairment. The advances in understanding the complexity of DKD mechanisms discussed in this review will expedite opportunities to develop new interventions for treating the disease. [ABSTRACT FROM AUTHOR]

Background: The triglyceride glucose (TyG) index, defined as Ln [fasting triglyceride (mg/dL) × fasting glucose (mg/dL)/2], provides insights into overall metabolic status. However, the association between the TyG index and gout has not been investigated. Therefore, this study explored the correlation between the TyG index and gout. Methods: Using data from the National Health and Nutrition Examination Survey, which was conducted from 2007 to 2018, this study investigated the relationship between the TyG index and gout. Demographic data and potential risk factors were analyzed and compared using t tests for continuous data and chi-square tests for categorical data. Logistic regression and subgroup analysis were performed to examine the association between the TyG index and gout. Results: A total of 14,924 participants were enrolled, among whom 726 (4.86%) were diagnosed with gout. Without controlling for any covariates, a significant positive correlation was observed between an elevated TyG index and increased risk of gout, with an odds ratio (OR) of 2.07 and a 95% confidence interval (CI) ranging from 1.76 to 2.43. After full adjustment, this association remained statistically significant, with an adjusted OR of 1.43 and a 95% CI from 1.14 to 1.80. Subgroup analyses revealed significant interactions, particularly for females (OR = 2.55; 95% CI: 2.00-3.26), individuals with no military service history (OR = 2.15; 95% CI: 1.66–2.43), and those without diabetes (OR = 2.00; 95% CI: 1.64–2.43). Conclusion: A positive correlation was observed between the TyG index and gout. Consequently, further large-scale prospective studies are warranted for a comprehensive analysis of the role of the TyG index in gout. [ABSTRACT FROM AUTHOR]

Background: Polycystic ovary syndrome (PCOS) affects 6–20% of women worldwide, with insulin resistance and hyperinsulinemia occurring in 50-70% of patients. Hyperinsulinemia exacerbates oxidative stress, contributing to PCOS pathogenesis. N-acetylcysteine (NAC) is an antioxidant and insulin sensitizer that shows promise as a therapeutic for PCOS. Our current study aimed to investigate the effects of NAC supplementation on endocrine-metabolic parameters in PCOS mice and its effect on ovulation induction (OI) efficacy in women with PCOS. Methods: Female C57BL/6 mice were orally administered letrozole (LE) to induce PCOS and then randomly divided into groups receiving daily oral administration of 160 mg/kg NAC (PCOS + NAC group), 200 mg/kg metformin (PCOS + Met group), or 0.5% carboxymethyl cellulose (drug solvent) (pure PCOS group) for 12 days. Healthy female mice served as pure controls. Estrous cycles were monitored during the intervention. Metabolic and hormone levels, ovarian phenotypes, antioxidant activity in ovarian tissues, and oxidative stress levels in oocytes were assessed post-intervention. Furthermore, a pragmatic, randomized, controlled clinical study was conducted with 230 PCOS women, randomly assigned to the NAC group (1.8 g/day oral NAC, n = 115) or the control group (n = 115). Patients in both groups underwent ≤ 3 cycles of OI with sequential LE and urinary follicle-stimulating hormone (uFSH). Cycle characteristics and pregnancy outcomes were compared between groups. Results: Similar to metformin, NAC supplementation significantly improved the estrous cycles and ovarian phenotypes of PCOS mice; reduced the LH concentration, LH/FSH ratio, and T level; and increased glucose clearance and insulin sensitivity. Notably, NAC significantly reduced oocyte ROS levels and increased the mitochondrial membrane potential in PCOS mice. Additionally, NAC significantly enhanced enzymatic and nonenzymatic antioxidant activities in PCOS mouse ovaries, whereas metformin had no such effect. In the clinical trial, compared to women in the control group, women receiving NAC had significantly lower average uFSH dosage and duration (p < 0.005) and significantly greater clinical pregnancy rates per OI cycle and cumulative clinical pregnancy rates per patient (p < 0.005). Conclusion: NAC supplementation improved endocrine-metabolic parameters in PCOS mice and significantly enhanced OI efficacy with sequential LE and uFSH in women with PCOS. Therefore, NAC could be a valuable adjuvant in OI for women with PCOS. [ABSTRACT FROM AUTHOR]

The triglyceride glucose (TyG) related index, a metric used to evaluate assessing insulin resistance (IR), has received limited attention in its association with sarcopenia. Our study aims to explore the predictive potential of the TyG index for sarcopenia. This study utilized data from the China Health and Retirement Longitudinal Study, a nationally representative, community-based cohort study, including a sample size of 10,537 participants aged 45 years and older. Associations between TyG related index and sacopenia was explored using multivariate logistic regression. Analysis of the predictive value of TyG related index for sarcopenia using receiver-operating characteristic curve (ROC). We evaluated the correlation between the TyG related index and the risk of sarcopenia using Cox proportional hazards models. Additionally, we utilized restricted cubic spline (RCS) regression analyses to explore the connections between the TyG-related index and sarcopenia. Logistic regression analysis showed an association between TyG (OR 0.961[0.955,0.968], P < 0.001), TyG-body mass index (TyG-BMI) (OR 0.872[0.867,0.878], P < 0.001), TyG- waist circumference (TyG-WC) (OR 0.896[0.890,0.902], P < 0.001) and sarcopenia. The results of the ROC analysis indicated that the area under the curve values for TyG, TyG-BMI, and TyG-WC were 0.659, 0.903, and 0.819, respectively. Compared to those without sarcopenia, patients with sarcopenia had a 37.7% (HR 0.623[0.502,0.774], P < 0.001), 4.8% (HR 0.952[0.947,0.958], P < 0.001), and 0.4% (HR 0.996[0.995,0.996], P < 0.001) lower risk with increasing TyG, TyG-BMI, and TyG-WC, respectively. RCS results show nonlinear relationship between TyG-BMI (P < 0.001) and TyG-WC (P < 0.001) and risk of sarcopenia. We observed a correlation between the TyG-related index and sarcopenia, with the TyG-BMI index demonstrating strong predictive capability for sarcopenia. [ABSTRACT FROM AUTHOR]

Background: The association between changes in insulin resistance, reflected by the triglyceride-glucose (TyG) index, and mortality remains unclear. This study investigated whether longitudinal trajectories of TyG index changes are associated with all-cause and cardiovascular disease (CVD) mortality. Methods: This retrospective cohort study analyzed data from 233,546 adults aged ≥ 19 years from the Korea National Health Insurance Service-National Sample Cohort. Participants were categorized as having increasing, stable, or decreasing TyG index changes during a 4-year exposure period (2009–2014). Mortality outcomes were assessed during an 8.13-year follow-up period (2015–2021). Cox proportional hazards regression and competing risk analysis were used to evaluate all-cause and CVD mortality. Results: A total of 7918 mortality events, including 651 CVD deaths, were recorded. Compared with the stable group, adjusted hazard ratios for all-cause mortality were 1.09 (95% CI 1.03–1.15) in the increasing group and 1.23 (95% CI 1.01–1.50) for CVD mortality. An increased TyG index was significantly associated with all-cause mortality in individuals aged < 50 years; men; and individuals with obesity, hypertension, diabetes, and/or dyslipidemia. For CVD mortality, significant associations were found in individuals aged 50–69 years, with obesity, with diabetes, or without dyslipidemia. Conclusion: An increasing TyG index from baseline during follow-up was independently associated with higher risks of all-cause and CVD mortality. Serial monitoring of TyG index changes could enhance risk stratification and inform targeted interventions to reduce insulin resistance, and ultimately lower mortality risk. [ABSTRACT FROM AUTHOR]

Background: The cardiometabolic index (CMI) is a novel metric for assessing cardiometabolic health and type 2 diabetes mellitus (DM), yet its relationship with insulin resistance (IR) and prediabetes (preDM) is not well-studied. There is also a gap in understanding the nonlinear associations between CMI and these conditions. Our study aimed to elucidate these associations. Methods: We included 13,142 adults from the National Health and Nutrition Examination Survey (NHANES) 2007–2020. CMI was calculated by multiplying the triglyceride-to-high density lipoprotein cholesterol (TG/HDL-C) by waist-to-height ratio (WHtR). Using weighted multivariable linear and logistic regression explored the relationships of CMI with glucose metabolism markers, IR, preDM, and DM. Nonlinear associations were assessed using generalized additive models (GAM), smooth curve fittings, and two-piecewise logistic regression. Results: Multivariate regression revealed positive correlations between CMI and glucose metabolic biomarkers, including FBG (β = 0.08, 95% CI: 0.06–0.10), HbA1c (β = 0.26, 95% CI: 0.22–0.31), FSI (β = 4.88, 95% CI: 4.23–5.54), and HOMA-IR (β = 1.85, 95% CI: 1.56–2.14). There were also significant correlations between CMI and increased risk of IR (OR = 3.51, 95% CI: 2.94–4.20), preDM (OR = 1.49, 95% CI: 1.29–1.71), and DM (OR = 2.22, 95% CI: 2.00-2.47). Inverse nonlinear L-shaped associations were found between CMI and IR, preDM, and DM, with saturation inflection points at 1.1, 1.45, and 1.6, respectively. Below these thresholds, increments in CMI significantly correlated with heightened risks of IR, preDM, and DM. Conclusions: CMI exhibited inverse L-shaped nonlinear relationships with IR, preDM, and DM, suggesting that reducing CMI to a certain level might significantly prevent these conditions. [ABSTRACT FROM AUTHOR]

Background: No effective drugs currently exist to cure Alzheimer's disease (AD) due to its complexity and the lack of understanding of the involved molecular signaling and pathways. The relationship between liver health and AD is now widely recognized. Still, molecular links and shared pathways between the liver and brain remain unclear, making the liver-brain axis in AD therapies a new area for exploration. However, bibliometric studies on this topic are lacking. Objective: This study aims to review the liver-brain axis in AD and identify future research hotspots and trends through bibliometric analysis. Methods: Articles and reviews related to AD and liver and its related diseases were searched in the Web of Science Core Collection (WoSCC) database up to 2024. Data were processed and visually analyzed using VOSviewer, CiteSpace, and Pajek. Results: We collected 1,777 articles on AD and liver and its related diseases from 2,517 institutions across 80 countries. Keyword cluster analysis identified 11 clusters, with 'insulin resistance,' 'amyloid-beta,' 'apolipoprotein-E,' 'oxidative stress,' and 'inflammation' appearing most frequently, and exhibiting strong total link strength. These results indicate that these topics have been the primary focus of research on the liver-brain axis in AD. Conclusions: This study is the first to comprehensively analyze the liver-brain axis in AD using bibliometric methods. The research results identify recent research frontiers and hotspots, aiding scholars in gaining a deeper understanding of the correlation between AD and the liver. [ABSTRACT FROM AUTHOR]

Triglyceride-glucose (TyG) index has emerged as a novel biomarker for detecting insulin resistance (IR) and has been proven to be associated with various diseases. However, its correlation with the prognosis of severe sepsis remains unraveled. This retrospective cohort study utilized patient records from the Medical Information Mart for Intensive Care (MIMIC-IV, version 2.2) to examine the outcomes of patients with sepsis. The primary outcomes were hospital mortality and intensive care unit (ICU) mortality. The correlation between the TyG index and outcomes was evaluated through the Kaplan-Meier method, the Log-rank test, and univariate and multivariate Cox regression analyses. Additionally, restricted cubic spline (RCS) regression analysis was employed to delve into the nonlinear relationship between baseline TyG index and outcomes, with trend significance assessed through quartile levels. Subgroup analyses were conducted to evaluate the consistency of the TyG index's prognostic value across various influencing factors. The study included 1,742 patients with sepsis requiring intensive care. The in-hospital mortality rate was 19.75% (344/1,742), and the ICU mortality rate was 14.75% (257/1,742). Cox regression analysis revealed that, in comparison to the first quartile (Q1), patients in the fourth quartile (Q4) had a 63% higher risk of in-hospital mortality (HR 1.63 [95% CI 1.22 to 2.18], P < 0.01) and a 79% higher risk of ICU mortality (HR 1.79 [95% CI 1.28 to 2.51], P < 0.001). Model 3 showed that ICU mortality risks for Q4, Q3, and Q2 were 240%, 75%, and 33% higher, respectively (HR 3.40 [95% CI 2.24 to 5.16], P < 0.001; HR 1.75 [95% CI 1.16 to 2.63], P = 0.007; HR 1.33 [95% CI 1.20 to 1.53], P < 0.001). RCS regression analysis identified a nonlinear association between the TyG index and mortality (overall P < 0.001; P for nonlinearity < 0.001, with an inflection point at 8.9). Subgroup analysis showed that the effect size and direction were consistent across different subgroups, suggesting the stability of the results. This study demonstrates that a higher TyG index is significantly associated with increased in-hospital and ICU mortality risk in critically ill sepsis patients, with evidence of non-linear correlation. Therefore, the TyG index helps identify the mortality prognosis of sepsis patients in the ICU. [ABSTRACT FROM AUTHOR]

Preclinical and clinical studies suggest that lipid-induced hepatic insulin resistance is a primary defect that predisposes to dysfunction in islets, implicating a perturbed liver-pancreas axis underlying the comorbidity of T2DM and MASLD. To investigate this hypothesis, we developed a human biomimetic microphysiological system (MPS) coupling our vascularized liver acinus MPS (vLAMPS) with pancreatic islet MPS (PANIS) enabling MASLD progression and islet dysfunction to be assessed. The modular design of this system (vLAMPS-PANIS) allows intra-organ and inter-organ dysregulation to be deconvoluted. When compared to normal fasting (NF) conditions, under early metabolic syndrome (EMS) conditions, the standalone vLAMPS exhibited characteristics of early stage MASLD, while no significant differences were observed in the standalone PANIS. In contrast, with EMS, the coupled vLAMPS-PANIS exhibited a perturbed islet-specific secretome and a significantly dysregulated glucose stimulated insulin secretion response implicating direct signaling from the dysregulated liver acinus to the islets. Correlations between several pairs of a vLAMPS-derived and a PANIS-derived factors were significantly altered under EMS, as compared to NF conditions, mechanistically connecting MASLD and T2DM associated hepatic-factors with islet-derived GLP-1 synthesis and regulation. Since vLAMPS-PANIS is compatible with patient-specific iPSCs, this platform represents an important step towards addressing patient heterogeneity, identifying disease mechanisms, and advancing precision medicine. A coupled liver-islet MPS was used to investigate the comorbidity between MASLD and T2DM. This study demonstrated that secreted factors from the MASLD liver disrupt islet function and suggest potential underlying mechanisms of disease progression along the liver-islet axis. [ABSTRACT FROM AUTHOR]