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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]