miR-302 protects the liver from glucolipotoxicity-induced lipid accumulation through activating AMPK and suppressing Elovl6 in HepG2 cells and also in mice.

Size-dependent lipidomics and fatty acid profiles of fat globules in buffalo milk.

Acute kidney injury (AKI) and chronic kidney disease (CKD) are the two primary forms of kidney disease that significantly contribute to increased mortality and progression to end-stage renal disease. To effectively treat AKI and CKD, elucidating the detailed mechanisms underlying their onset and progression is essential for the development of novel therapeutic strategies. Impaired cellular function resulting from the altered metabolism of energy-producing nutrients, such as fatty acids, glucose, and amino acids, is closely involved in the pathogenesis of both AKI and CKD. Among these nutrients, branched-chain amino acids (BCAAs), such as leucine, isoleucine, and valine, are essential amino acids in humans and animals because they cannot be synthesized de novo. BCAAs play a crucial role in protein synthesis and energy production in various metabolic tissues, including skeletal muscle, liver, brown adipose tissue, pancreas, heart, and the kidney. Maintaining an appropriate balance between BCAA catabolism and anabolism is vital for optimal cellular function. Alterations in BCAA homeostasis have emerged as key contributors to the pathophysiology of several metabolic disorders, including obesity-related insulin resistance, type 2 diabetes, heart failure, kidney disease, and sarcopenia. In the present review, we provide a comprehensive overview of BCAA metabolism, with a particular focus on the molecular mechanisms linking disrupted BCAA homeostasis in proximal tubular cells to kidney disease. We also discuss the potential of targeting BCAA metabolism as a novel therapeutic strategy to suppress kidney disease progression.

Tonic activation of central nervous system (CNS) leptin receptors (LepRs) and melanocortin 4 receptors (MC4Rs) is critical for maintaining normal cardiometabolic function. Deficiency of CNS LepR or MC4R signaling causes severe obesity and is accompanied by multiple metabolic abnormalities including insulin resistance, glucose intolerance, and hyperlipidemia that are only partially explained by obesity. Defective LepR and MC4R signaling also causes dysfunction of the sympathetic nervous system (SNS) and blood pressure (BP) regulation. Hyperleptinemia and activation of the CNS melanocortin system in obesity are important compensatory mechanisms that attenuate abnormalities of glucose and lipid metabolism but may also contribute to SNS activation and increased BP. Despite potentially adverse effects of increases in SNS activity and BP, pharmacological activation of brain LepRs and MC4Rs may provide an important therapeutic approach for protecting target organs, such as the heart, kidneys, and brain, from ischemic injury by improving mitochondrial function and ATP production. However, additional preclinical studies are needed to address mechanistic questions before clinical studies are begun to test the effectiveness of leptin and MC4R agonists for treating people with ischemic injury of target organs.

Hepatic steatosis (HS) represents one of the most frequent metabolic complications of pediatric obesity and is closely linked with insulin resistance (IR). Although the homeostatic model assessment for insulin resistance (HOMA-IR) is widely used, lipid-derived indices such as the triglyceride-glucose (TyG) index and triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) ratio have recently emerged as simple IR surrogates. Data comparing these indices with HS severity in children remain limited. This single-center retrospective study included 462 children aged 6-18years with overweight or obesity who were evaluated between October 2023 and December 2024. Anthropometry, biochemical data, and ultrasonographic HS grading were obtained from medical records. HOMA-IR, TyG, and TG/HDL-C indices were calculated, and their associations with HS presence and severity were analyzed using correlation and multivariable regression models. HS was identified in 53.5 % of participants (grade 1: 29.9 %, grade 2: 16.6 %, grade 3: 6.0 %). Children with HS demonstrated significantly higher HOMA-IR, TyG index, and TG/HDL-C ratio compared with those without HS (all p<0.001). HOMA-IR increased progressively with HS grade (p<0.05), whereas TyG and TG/HDL-C did not display a significant gradient. Logistic regression confirmed that HOMA-IR was independently associated with HS severity (β=0.261; 95 % CI: 0.030-0.078; p<0.001), while TyG and TG/HDL-C were not. ALT levels rose significantly with HS grade, whereas AST showed no severity-related pattern. HOMA-IR remains the strongest metabolic predictor of hepatic steatosis severity in pediatric obesity. Although TyG and TG/HDL-C reliably differentiate HS presence, they do not independently estimate HS progression. Lipid-derived markers may support non-insulin-based screening; however, HOMA-IR should be prioritized when stratifying steatosisrisk.

Distinct Interplay Between β-Cell Function and Insulin Resistance in Latent Autoimmune Diabetes in Adults Versus Type 2 Diabetes.

Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disease caused by dystrophin deficiency and characterized by progressive muscle wasting. DMD is frequently accompanied by obesity and insulin resistance (IR); however, their influence on disease progression remains unknown. Moreover, the extent to which these comorbidities may interact with glucocorticoids, a commonly used intervention, is also unknown. We hypothesized that a high-fat, high-sucrose diet (HFHSD) would cause IR and accelerate disease progression, and treatment with prednisolone (Pred) would mitigate these effects. To test this hypothesis, 6-week-old C57 and mdx mice were fed a control diet (CD) or a HFHSD for 19weeks, with or without Pred. In C57 and mdx mice, the HFHSD increased body fat percentage and caused hyperglycaemia, glucose intolerance and IR, and, in mdx mice, Pred exacerbated HFHSD-mediated hyperglycaemia, glucose intolerance and IR. The HFHSD augmented diaphragm fatigue and blunted the beneficial effects of Pred on specific tension in mdx mice. In C57 and mdx mice, the HFHSD increased fatty infiltration in diaphragm, but trichrome staining revealed the HFHSD and/or Pred decreased disease-related fibrosis in mdx mice. Additionally, the HFHSD altered disease and/or Pred-mediated changes to proteins associated with lipid storage, inflammatory signalling, mitochondrial/metabolic regulation, and Sestrin signalling. These data indicate that in mdx mice, 19weeks of a HFHSD independently impaired muscle function, altered muscle composition, and further compromised muscle cell health, and that its interaction with Pred prevented functional recovery and further exacerbated glycaemic dysregulation and cellular dysfunction. KEY POINTS: Obesity and insulin resistance (IR) are common comorbidities of Duchenne muscular dystrophy (DMD), yet their influence on dystrophic pathology remains unknown. Additionally, the extent that obesity/IR interact with glucocorticoids in dystrophic progression is unclear. To address this, mdx mice were fed a high-fat, high-sucrose diet (HFHSD) for 6months, with and without glucocorticoid treatment, and outcomes related to muscle function, composition, and cell health were evaluated. A HFHSD decreased fatigue resistance, reduced fibrosis, increased fatty infiltration, and impaired cell health in dystrophic diaphragms. The addition of glucocorticoids to the HFHSD did not considerably improve most outcomes, suggesting that the diet may blunt some glucocorticoid-mediated benefits, but did increase specific tension, reduce fibrosis, and attenuate inflammatory signalling. These results demonstrate that a HFHSD impacts some parameters of dystrophic physiology and highlight the importance of considering systematic and muscle metabolism when implementing therapeutic strategies.

Rethinking insulin resistance in aging: A reserve-oriented clinical framework.

Down syndrome (DS) is the most common chromosomal abnormality associated with intellectual disabilities. Many metabolic issues begin in childhood, and children without DS are reported to have a high prevalence of metabolic syndrome (MS) according to various studies. However, our understanding of the risk of MS in children with DS is limited. A cross-sectional study assessed the prevalence of MS in DS children aged 10-18 during 2022-2024. Demographic details and anthropometric measurements were recorded for all participants. Fasting blood samples were collected for blood glucose, insulin, and lipid profile analysis. The modified NCEP-ATP III criteria were used to classify the MS. We also evaluated insulin resistance (IR) using HOMA-IR and body adiposity patterns with a DEXA scan in DS children aged 6-18. Seventy-six children aged 10-18 and 38 aged 6-9 were enrolled. The prevalence of MS was 18% in our cohort. Dyslipidemia (high triglycerides and low HDL) was observed in 21% and 15.8% of children aged 6-9 and 10-18, respectively. IR was observed in 27.6% and 7.8% of children aged 10-18 and 6-9, respectively. IR was positively correlated with BMI, whereas no correlation was observed with MS or dyslipidemia. Total body fat mass was positively correlated with MS. Our study observed a higher prevalence (18.0%) of MS than age-matched general population studies (pooled prevalence: 5.0%). Additionally, we observed a high prevalence of dyslipidemia and IR from 6 years of age. The results indicate the need to review the management guidelines and consider incorporating metabolic workups.

Exploratory analysis of insulin resistance and pro-inflammatory cytokines in dogs with chronic kidney disease.

The American Heart Association (AHA) recently proposed the concept of Cardiovascular-Kidney-Metabolic (CKM) syndrome, highlighting the strong pathophysiological links among metabolic disorders, chronic kidney disease, and cardiovascular disease (CVD). Insulin resistance (IR) is regarded as a central mechanism underlying CKM syndrome. However, studies comparing the predictive value of different IR surrogate markers for incident CVD are still limited. This study aimed to evaluate the associations between multiple IR surrogate markers and incident cardiovascular disease and to further assess their predictive performance using machine learning approaches. Using data from the China Health and Retirement Longitudinal Study (CHARLS), this prospective cohort study included 5,528 participants. Twelve IR surrogate indices were assessed, including TyG-related indices, TG/HDL-C, METS-IR, CTI, CHG, and eGDR. Incident CVD was defined as self-reported physician-diagnosed heart disease or stroke during follow-up. Cox proportional hazards models were used to estimate associations between standardized IR indices and incident CVD. Restricted cubic splines, weighted quantile sum regression, and quantile g-computation were used to examine dose-response patterns and the relative contribution of correlated IR indices. Predictive performance was evaluated using ROC analysis, calibration, Brier score, decision curve analysis, NRI, IDI, and machine-learning models. During a median follow-up of 7.0 years, 741 participants developed incident CVD. In fully adjusted Cox models, several IR surrogate indices were associated with incident CVD. TyG-related composite indices incorporating adiposity-related information, particularly TyG-WC, TyG-CVAI, TyG-WHtR, and TyG-BMI, showed stronger positive associations with CVD risk, whereas eGDR showed an inverse association. Restricted cubic spline analyses showed significant overall associations for most indices, with nonlinear patterns observed for METS-IR, CTI, and eGDR. Mixture-based analyses suggested relatively larger contributions of CTI, TyG-BMI, and TyG-WC. Among individual indices, eGDR showed the highest discrimination for incident CVD, followed by TyG-CVAI and TyG-WC. Adding selected IR indices, particularly eGDR, to the covariate-based model modestly improved discrimination and reclassification. Among adults with CKM syndrome stages 0-3, several IR surrogate indices were prospectively associated with incident CVD, with stronger and more consistent associations observed for TyG-based indices incorporating adiposity-related measures and for eGDR. These results suggest that the combined assessment of metabolic dysfunction, adiposity, and insulin sensitivity may provide useful information for identifying individuals at higher cardiovascular risk in early-stage CKM syndrome.

Chronic mifepristone administration induces obese sarcopenia, hepatic steatosis and insulin resistance in androgen-deprived male mice.

SIK1 drives lipid-induced insulin resistance in skeletal muscle by linking TGFβ1-Smad2/3 activation to PDE4-cAMP dysregulation.

Exposure to heavy metals has been implicated in insulin resistance (IR), yet the mechanisms remain unclear. Systemic inflammation may link metal exposure to metabolic outcomes. We analyzed 3042 U.S. adults from NHANES 2021-2023. Blood lead, cadmium, mercury, selenium, and manganese were examined in relation to IR (HOMA-IR), with high-sensitivity C-reactive protein (hs-CRP) as the inflammatory mediator. We used survey-weighted regression, Baron-Kenny mediation, and weighted quantile sum (WQS) regression for the mixture, stratified by sex; sensitivity analyses additionally adjusted for body mass index (BMI) and smoking. In primary models, lead, cadmium, and mercury were inversely associated with HOMA-IR (lead β = -0.259), as was a WQS mixture dominated by these metals, and hs-CRP significantly mediated several associations. After additional adjustment for BMI and smoking, the inverse single-metal and mixture associations remained significant but were attenuated by roughly half, indicating substantial adiposity confounding. hs-CRP continued to mediate a smaller but significant share (roughly 10% to 30%, vs. 25% to 43% before adjustment). The positive manganese association did not survive BMI adjustment and is not robust. Mediation was larger in females and younger adults. In a nationally representative sample, blood lead, cadmium, and mercury, individually and as a mixture, were inversely associated with insulin resistance, with hs-CRP mediating a smaller but significant share after adjustment for adiposity. Because the associations are substantially attenuated by BMI and the design is cross-sectional, reverse causation is plausible. These findings are hypothesis-generating and motivate prospective studies.

Alzheimer's disease (AD) associated with insulin resistance represents a major challenge in sporadic neurodegeneration, where impaired neuronal survival and synaptic plasticity are compounded by aberrant DNA methylation. Epigenetic silencing of Wnt pathway genes under insulin-resistant conditions exacerbates β-amyloid accumulation, tau hyperphosphorylation, and oxidative stress. The present study aimed to establish insulin-resistant AD models and evaluate the mechanistic potential of DNA methyltransferase (DNMT) inhibition, with a specific focus on canonical Wnt/β-catenin restoration. An in vitro AD model was generated by exposing SHSY-5Y cells to streptozotocin (STZ, 400 μM), resulting in elevated DNMT1, Aβ1-42, and sFRP1 levels, alongside reduced β-catenin and survivin expression. Treatment with the DNMT1 inhibitor 5-azacytidine (5-AZA), employed here as a mechanistic probe rather than a therapeutic candidate, reversed these changes, restoring Wnt signaling and attenuating amyloid burden. In vivo, intracerebroventricular administration of STZ (3 mg/kg) in rats induced an insulin-resistant AD-like pathology characterized by cognitive decline, increased pTau and acetylcholinesterase activity, and reduced neuroprotective markers. 5-AZA treatment improved memory and behavior, decreased pTau and AChE levels, and enhanced ADAM10, TREM2, BDNF, and antioxidant activity. Histological analysis further revealed preservation of neuronal layers and structural integrity. Collectively, these findings demonstrate that DNMT inhibition, exemplified by 5-AZA as a mechanistic tool, can mitigate STZ-induced molecular and behavioral alterations by relieving hypermethylation-mediated repression and supporting partial reactivation of canonical Wnt/β-catenin signaling. While 5-AZA itself is not a viable therapeutic option, the results highlight DNMT inhibition as a promising disease-modifying strategy in insulin resistance-associated AD.

Association between hemodynamic parameters, insulin resistance, and body composition in primary care

Diagnostic accuracy of fibroblast growth factor-21 (FGF-21) and growth differentiation factor-15 (GDF-15) for predicting insulin resistance using triglyceride-glucose Index, HOMA-C-Peptide, and C-peptide-to-glucose ratio in type 2 diabetes: A systematic review and bivariate diagnostic test accuracy meta-analysis.

Effectiveness and safety of preoperative carbohydrate loading in pediatric patients: A systematic review and meta-analysis of randomized controlled trials.

Obesity has reached epidemic proportions globally, with its prevalence nearly tripling since 1975. It is now recognized as a chronic, relapsing disease associated with increased morbidity and mortality due to its strong relationship with several cardio-renal-metabolic conditions. This narrative review aims to explore the major obesity-related complications - namely obstructive sleep apnea syndrome (OSAS), metabolic dysfunction-associated steatotic liver disease (MASLD), dyslipidemia, and chronic kidney disease (CKD) - highlighting their pathophysiological mechanisms, clinical consequences, and current therapeutic strategies. Obesity contributes to OSAS by increasing upper airway collapsibility and to MASLD through ectopic fat accumulation, insulin resistance, and inflammatory responses. Dyslipidemia in obesity is characterized by elevated triglycerides, small dense LDL particles, and low HDL-C, driven by chronic inflammation and insulin resistance. CKD progression, particularly obesity-related glomerulopathy (ORG), is also mediated by metabolic and hemodynamic derangements, including renin-angiotensin-aldosterone system activation and glomerular hyperfiltration. Therapeutic interventions such as lifestyle modification, pharmacological therapy - including glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT-2is) - and bariatric surgery have shown efficacy not only in promoting weight loss but also in improving the clinical course of these obesity-related conditions. In particular, Very Low Energy Ketogenic Therapy (VLEKT) is emerging as a promising approach in improving metabolic parameters, hepatic steatosis, and cardiovascular risk factors. A comprehensive and multidisciplinary approach to obesity is essential, focusing not only on weight loss but also on mitigating associated complications. Effective management can significantly improve patients' quality of life and reduce the long-term burden of obesity on healthcare systems.

[Purpose] Impaired insulin-mediated suppression of adipocyte lipolysis, adipose tissue insulin resistance (ATIR), may influence lipolysis and substrate utilization during exercise. This pilot study aimed to investigate the effects of ATIR on metabolic responses and substrate utilization during exercise in young men. [Participants and Methods] Twenty-four young men were divided into two groups based on their ATIR index (Adipo-IR): low Adipo-IR (LA) and high Adipo-IR (HA). The participants performed 40 min of aerobic exercise at an intensity corresponding to 40% peak oxygen uptake. Venous blood samples were collected at baseline and immediately after exercise to measure hormones and metabolite levels. Expired gas was collected during the exercise to estimate substrate oxidation. [Results] After adjusting for whole-body insulin resistance, circulating free fatty acid (FFA) levels at baseline and immediately after exercise were significantly higher in the HA group than in the LA group. The HA group demonstrated significantly lower carbohydrate oxidation and significantly higher fat oxidation than the LA group. Adipo-IR and FFA levels were significantly correlated with parameters of substrate utilization during exercise. [Conclusion] ATIR was associated with substrate utilization during exercise, independent of whole-body insulin resistance. ATIR may play a distinct role in the regulation of substrate utilization during exercise.