BACKGROUND Insulin resistance (IR) plays a pivotal role in the pathogenesis of metabolic dysfunction-associated steatotic liver disease. While non-invasive imaging methods are increasingly used in pediatrics, the extent to which hepatic elastography reflects IR in children remains unclear. AIM To evaluate the association between ultrasound-based hepatic elastography parameters and clinical indices of IR in the pediatric population. METHODS A systematic search of PubMed, Scopus, and Web of Science databases was conducted through October 2025. Studies assessing correlations between elastography parameters - controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) - and IR indices were included. Data were pooled using random-effects meta-analysis with correlation coefficients (r ) as the primary effect size. Subgroup and sensitivity analyses examined differences by IR index, cohort characteristics, and elastography modality. RESULTS Sixteen studies, encompassing 2,032 children and adolescents, were included. The pooled correlation between hepatic elastography (CAP/LSM) and IR indices was r = 0.44 (95% confidence interval: 0.38-0.50; I 2 = 72%), indicating a moderate positive association. The strongest correlations were observed for adipose tissue IR (r = 0.65) and the metabolic score for IR (r = 0.49), surpassing simpler indices such as homeostatic model assessment of IR. CAP correlated moderately with early steatosis (r = 0.30-0.40), whereas LSM showed stronger associations with advanced fibrosis and systemic IR (r = 0.50-0.65). Heterogeneity was mainly attributed to differences in disease severity and measurement methods. CONCLUSION Ultrasound-based hepatic elastography provides a reliable, non-invasive surrogate for systemic metabolic dysfunction in pediatric metabolic dysfunction-associated steatotic liver disease. CAP reflects early, reversible hepatic fat accumulation, while LSM reflects more advanced fibrosis and systemic IR, and identifies fibrotic progression driven by chronic IR. The strongest associations with adipose tissue-IR and metabolic score-IR highlight the systemic, multisite nature of pediatric IR. Elastography thus holds promise as an integrated biomarker for IR severity, early risk stratification, and therapeutic monitoring in children and adolescents with metabolic risk factors.

An emerging body of evidence has highlighted the complex interplay among obesity, insulin resistance, and the gut microbiota. This observational study aimed to evaluate differences in intestinal microbiome profiles between individuals with obesity, with and without insulin resistance. Twenty individuals with obesity aged 20-50 years were enrolled and categorized according to insulin resistance status (N = 10 per group), as determined using the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). Fasting blood samples were collected and analyzed for glucose, lipid profiles, insulin, free fatty acids, and high-sensitivity C-reactive protein (hsCRP). Fecal DNA was extracted, and its quantity and quality were assessed.The V3-V4 region of 16s rRNA was amplified using specific primers, purified, and sequenced on the MiSeq Illumina platform with paired-end reads. The two groups showed notable disparities in fasting glucose (p=0.002), insulin (p<0.001), and HOMA-IR indices (p<0.001). While Alpha diversity remained comparable between groups when assessed using Shannon’s and Simpson’s indexes (but was significant for the Chao1 index), beta diversity was lower in the insulin-resistant group (p<0.05). Short-chain fatty acid-producing bacteria such as members of Lachnospiraceae family, Oscillospirales , and Faecalibacterium prausnitzii , were significantly enriched in insulin-sensitive individuals. In contrast, Alistipes putredenis was more abundant in those with insulin resistance. KEGG Orthology (KO) analysis revealed distinct functional enrichment: the Insulin Resistance group was enriched in carbohydrate metabolism pathways (e.g., glycolysis/gluconeogenesis, TCA cycle), while the Insulin Sensitive group showed more diverse metabolic activity, including amino acid and fatty acid metabolism, butyrate metabolism, and select carbohydrate pathways. These findings contribute to understanding the role of gut microbiota in metabolic heterogeneity associated with insulin resistance in obesity. • Beta diversity was significantly different between the groups, being lower in the Insulin- Resistance (IR) group, which indicates a distinct microbial community structure. • The study found two dominant enterotypes: the Prevotella genus and the Bacteroides genus. • The Insulin-Sensitive (IS) group was enriched in beneficial, short-chain fatty acid-producing bacteria, specifically members of the Lachnospiraceae family and species such as Faecalibacterium prausnitzii. • The Insulin-Resistant (IR) group had a higher abundance of proinflammatory bacteria, including Alistipes putredinis (also called Alistipes obesi ) and Escherichia–Shigella. • Predicted Functions: The microbiota in the IR group was enriched in carbohydrate metabolism pathways, whereas the IS group's microbiota showed greater activity in amino acid, fatty acid, and butyrate metabolism.

2D: 4D digit ratio, bilateral asymmetry, and insulin resistance in women with obesity.

Growing evidence indicates that both exogenous lactate administration and physical exercise improve insulin resistance (IR). This study investigates, from a novel perspective, whether exercise-induced lactate serves as a signaling molecule to ameliorate adipose tissue IR and explores the underlying mechanisms. Using diet-induced obese and insulin-resistant (DIO-IR) mice subjected to high-lactate exercise training, insulin-resistant 3T3-L1 (IR-3T3-L1) adipocytes treated with lactate, and a G protein-coupled receptor 81 (GPR81)-overexpressing cell line, we demonstrate three key findings: first, high-lactate exercise training markedly alleviated adipose tissue and systemic IR in DIO-IR mice. Second, acute high-lactate exercise mirrored the effects of l-lactate injection by elevating circulating and epididymal white adipose tissue (eWAT) lactate concentrations, concomitantly upregulating GPR81 and glucose uptake signaling expression while modulating adipokine secretion. Mechanistically, lactate/GPR81 signaling potentiated glucose uptake in IR-3T3-L1 adipocytes via the insulin receptor substrate 1 (IRS1)-AKT-glucose transporter 4 (GLUT4) pathway. Collectively, these results demonstrate that exercise-induced lactate enhances glucose uptake signaling and rebalances adipokine secretion. It may act as a signaling molecule that upregulates the specific receptor GPR81, thereby alleviating adipose tissue and systemic insulin resistance in DIO-IR mice. Our findings uncover a previously unrecognized link between exercise metabolism and adipose tissue homeostasis, highlighting lactate as a potential therapeutic target for IR-related metabolic disorders.NEW & NOTEWORTHY Exercise-induced lactate as a critical signaling molecule that ameliorates insulin resistance in obesity. Lactate enhances adipose tissue glucose uptake and rebalances adipokine secretion by upregulating the receptor G protein-coupled receptor 81 (GPR81). The findings establish lactate as an essential exercise metabolite with therapeutic potential for metabolic disorders.

Insulin resistance is an endocrine disorder associated with various diseases, including diabetes, metabolic syndrome, cardiovascular diseases, and cancer. However, severe insulin resistance differs significantly from common insulin resistance regarding the causes and treatment approaches. Severe insulin resistance is a group of rare disorders characterized by hyperglycemia and hyperinsulinemia, with or without hypoglycemia, along with various metabolic abnormalities and diverse clinical manifestations. Owing to their rarity and complexity, these conditions can be easily misdiagnosed as common diabetes and are often overlooked. Severe insulin resistance is typically reported in individual case studies, lacking comprehensive summaries. This article provides a detailed overview of the different types of severe insulin resistance based on the specific sites of insulin signaling defects. It includes pre-receptor signaling defects, such as insulin autoimmune syndrome, which results from insulin autoantibodies; receptor-level insulin resistance syndromes, including type A and type B insulin resistance syndromes; and post-receptor signaling defects, such as lipodystrophy syndrome. We describe the causes, clinical symptoms, diagnosis, and treatment of extreme insulin resistance and differentiate between these diseases. In this review, we aim to assist physicians in identifying the causes of severe insulin resistance early and in providing individualized treatment for patients, ultimately improving clinical outcomes.

NAA25 as a regulator of insulin signaling: Integration of FOXO1 imaging CRISPRi screen and Mendelian randomization.

Elevated lactate aggravates insulin resistance by downregulating the PI3K/AKT/GLUT2 pathway in type 2 diabetes mellitus.

Insulin resistance (IR) manifesting as a result of muscle unloading is often accompanied by an altered amino acid (AA) profile. The aim of this study was to assess the potential impact of AAs on IR during inactivity. Plasmatic AA, glucose, and insulin were retrospectively analyzed from three different bed rest studies (BR1, BR2, BR3) involving 26 young healthy males. Since AAs were analyzed on different days, we imputed all missing values with multivariate imputation by chained equations, which allowed us to evaluate trends of plasmatic AAs in relation to IR (HOMA IR) during 9 d of inactivity. A generalized linear mixed model (GLMM) was fitted to examine the effect of selected plasmatic AAs (predictors) on HOMA IR (outcome). Results of GLMM were further validated with data from BR1 and BR2 (19 subjects), in which AAs were analyzed on days 1, 5, and 9. Serine exhibited a sig. negative fixed effect on HOMA IR [-0,015] (P = 0.006), while HOMA-IR had no sig. effect on serine (P = 0.507), suggesting a unidirectional relationship. Furthermore, data from BR1 and BR2 confirmed the inverse effect: serine levels sig. increased during the initial days (+13%), followed by a sig. drop from fifth to the ninth d (-6.5%). When serine was available, HOMA IR was not sig. affected. When serine availability dropped, HOMA IR continued to rise, reaching a sig. difference from baseline values to ninth d of BR (+27%). Our findings indicate that serine can have an inverse impact on IR and not vice versa. Upholding serine levels during short-term BR could have a protective role against IR.

Type 2 diabetes mellitus (T2DM), sarcopenia, and gut microbiota dysbiosis are increasingly recognized as interrelated conditions. T2DM accelerates muscle wasting through insulin resistance, inflammation, and oxidative stress, while sarcopenia worsens metabolic dysfunction. This review explores the interconnected conditions of Type 2 Diabetes, sarcopenia, and gut microbiota dysbiosis, highlighting their therapeutic potential and the need for interventions targeting these conditions for metabolic and musculoskeletal health. An extensive literature search was performed in PubMed, EMBASE, Scopus, and Web of Science up to July 2025 using terms related to gut microbiota, sarcopenia, and T2DM. Both preclinical and human studies were included if they addressed microbial composition, metabolites, inflammation, insulin resistance, or muscle protein turnover. Evidence indicates bidirectional relationships: T2DM patients show higher prevalence of sarcopenia, while reduced muscle mass increases T2DM risk. Gut dysbiosis in T2DM is characterized by depletion of SCFA-producing taxa (e.g., Faecalibacterium prausnitzii) and enrichment of endotoxin-producing bacteria, leading to systemic inflammation and impaired insulin signaling. Germ-free and antibiotic-treated rodent models demonstrate muscle atrophy, whereas probiotic or prebiotic supplementation restores muscle mass and improves glucose metabolism. Limited clinical trials suggest dietary fibre, probiotics, and fecal microbiota transplantation improve glycemic control and inflammatory markers, with potential secondary benefits on muscle function. T2DM, sarcopenia, and gut microbiota are linked through insulin resistance, inflammation, and altered signaling. Targeting gut-muscle-metabolism axis through diet, microbiota modulation, and exercise is promising. Future longitudinal and interventional studies are needed to establish causality and develop precision microbiome-based therapies. Type 2 diabetes mellitus (T2DM), sarcopenia, and gut microbiota dysbiosis are interconnected in a triangular pathophysiological network. T2DM accelerates muscle loss through insulin resistance, inflammation, and oxidative stress, while sarcopenia worsens glycaemic control. Gut dysbiosis reduces beneficial short-chain fatty acid (SCFA) production and increases pro-inflammatory metabolites such as lipopolysaccharides, further impairing muscle metabolism and glucose regulation. Preclinical and emerging clinical evidence shows that dietary fibre, probiotics, and fecal microbiota transplantation can modulate this axis. Targeting the gut-muscle-metabolism triad offers promising integrative strategies for preventing and managing diabetic sarcopenia.

Farrerol ameliorates hepatic insulin resistance via AMPKα1/mTOR/SREBP-1 pathway: A study in T2DM rat models and palmitic acid-induced BRL 3 A hepatocytes.

To examine the cross-sectional relationship between dietary intake and epigenetic age acceleration, as well as the prospective relationship between epigenetic age acceleration and cardiometabolic parameters measured two years later. In 526 adolescents aged 7-18 years (average age 14.50) residing in Mexico City, dietary intake was assessed using a semi-quantitative food frequency questionnaire. Adherence to three dietary patterns was derived from principal component analysis. Blood leukocyte DNA methylation was measured with the Illumina Infinium MethylationEPIC BeadChip, from which epigenetic age acceleration was calculated for six epigenetic clocks: Horvath, Skin-Blood, PhenoAge, GrimAge, Pediatric-Buccal-Epigenetic (PedBE), and Wu. Nine cardiometabolic parameters were assessed two years after assessment of diet and epigenetic age acceleration. Linear regression models for sex-stratified associations were examined. Among males, the Meat & Starchy foods pattern was positively associated with Wu epigenetic age acceleration, showing a 0.096-year increase, while folate intake in females was associated with a 0.004-year decelerated GrimAge. Prospective analysis showed positive associations between epigenetic age acceleration and fat distribution and insulin resistance, particularly in males. In females, only GrimAge acceleration was associated in the expected manner with increased waist circumference (β=0.62cm), BMI (β=0.25kg/m2), fasting insulin (β=0.86 μIU/mL), and insulin resistance (β=0.21). Skin-Blood acceleration was associated with decreased HDL in males, and PedBE acceleration was associated with triglycerides in both sexes, though in opposing directions. Adolescent diet was not strongly associated with baseline epigenetic age acceleration. However, epigenetic age acceleration was associated prospectively with fat distribution and insulin resistance.

Metabolomics profiles of type 2 diabetes and insulin resistance and their associations with total mortality.

Insulin resistance plays a key role in the development of type 2 diabetes and predates the development of frank hyperglycemia. Thyroid hormone (TH) signaling plays a critical role in glucose homeostasis, as both hyperthyroidism and hypothyroidism have been linked to the development of insulin resistance and diabetes. The mechanism behind the effects of TH action on insulin sensitivity is incompletely understood, but the liver is thought to play a key role. Indeed, resmetirom, a selective thyroid hormone receptor beta (THRβ) agonist, has recently been approved for treatment of liver fibrosis, and more THRβ agonists are currently in phase 2-3 clinical trials for use in metabolic dysfunction-associated fatty liver disease. As insulin resistance is closely associated with this disease, it is crucial that we understand the role of hepatic THRβ in glucose homeostasis. Thus, we hypothesized that TH, acting via the THRβ, is a key regulator of hepatic glucose metabolism. In wild-type (WT) and liver-specific THRβ knock-out (L-TRBKO) mice we analyzed the effect of changes in thyroid status and diet on glucose homeostasis and insulin signaling. Mice were assessed under basal conditions on a chow fed diet, under hypothyroid conditions using a propylthiouracil/low iodine diet with and without T3 treatment and following a high-fat diet. We measured glucose tolerance, hepatic insulin signaling, liver histology, energy expenditure and skeletal muscle metabolism. In high-fat diet fed WT and L-TRBKO mice we addidionally analyzed the effect of a single i.p. injection of T3. Finally we studied insulin signaling in human induced pluripotent stem cells differentiated to hepatocytes (iHeps) both with and without THRβ expression. In contrast to our hypothesis, we found that insulin signaling in mice was not impacted by the selective deletion of THRβ only in hepatocytes. Both WT and L-TRBKO mice have similar glucose homeostasis under basal conditions and developed hyperglycemia on a high-fat diet. Further, a single dose of T3 administered to high-fat diet fed insulin-resistant mice improves insulin sensitivity to the levels of control chow-fed mice in both WT and L-TRBKO male mice. This single dose of T3 also increased glucose transporter expression in skeletal muscle. In iHeps, THRβ1 was not required to activate insulin signaling, and T3 treatment did not affect insulin signaling. T3 signaling impacts glucose homeostasis independently of its actions through the THRβ1 in hepatocytes in both a murine and human model.

We previously found that higher insulin resistance (IR) was associated with larger prostate size and greater risk of benign prostatic hyperplasia (BPH). Since BPH is the most common cause of lower urinary tract symptoms (LUTS), we investigated whether IR is also linked to incidence and progression of LUTS in the REDUCE study, a 4-year randomized trial of dutasteride vs. placebo for prostate cancer prevention. Participants were required to complete the International Prostate Symptom Score (IPSS) questionnaire at recruitment and every subsequent 6 months. Fasting insulin and glucose levels were measured at study baseline, and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) was calculated based on these values. Multivariable Cox regression was used to assess associations between HOMA-IR and (1) LUTS incidence among asymptomatic patients (baseline IPSS < 8); or (2) LUTS progression among symptomatic patients (baseline IPSS ≥ 8) respectively. As previously reported within this cohort, at baseline, higher HOMA-IR quartiles were correlated with larger prostate volumes among both asymptomatic (N = 2745; p < 0.001) and symptomatic patients (N = 1942; p = 0.007). However, among asymptomatic patients, HOMA-IR whether analyzed as a continuous (p = 0.74) or categorized variable (all p ≥ 0.60) was not associated with LUTS incidence in multivariable analysis. Similarly, in symptomatic participants, no associations were found between HOMA-IR and LUTS progression in multivariable analyses, whether HOMA-IR was assessed as a categorical (all p ≥ 0.46) or continuous variable (p = 0.83). Although IR was linked to larger prostate volumes, it was not an independent risk factor of LUTS development or progression despite the known associations between BPH and LUTS.

Pathophysiology and pharmacotherapy of cardiovascular complications in metabolic syndrome.

Type 2 diabetes mellitus (T2DM) is a progressive, multi-organ disorder that often requires intensive combination therapy. This Phase III, randomised, double-blind, placebo-controlled study evaluated the efficacy and safety of two fixed-dose combinations (FDCs) of sitagliptin 100 mg with empagliflozin 10 mg (DW1026C1) or empagliflozin 25 mg (DW1026C2) as add-on therapy for patients with inadequately controlled T2DM. Two hundred thirty adults with T2DM inadequately controlled by metformin (≥ 1000 mg/day) and sitagliptin (100 mg) were 1:1:1 randomised to receive DW1026C1 (E10 group, n = 77), DW1026C2 (E25 group, n = 76), or a placebo (n = 77). Treatment was administered for 24 weeks, followed by a 28-week extension period. The primary endpoint was the change in HbA1c from baseline to Week 24. Baseline characteristics were similar among groups. At Week 24, both active treatments demonstrated statistically significant HbA1c reductions versus the placebo. The least square mean differences [95% CI] versus the placebo were -0.54% [-0.78, -0.29] for E10 group and -0.61% [-0.85, -0.36] for E25 group (both p < 0.0001). Fasting plasma glucose (FPG), insulin resistance, body weight, systolic blood pressure, albumin-creatinine ratio and high-density lipoprotein cholesterol also improved in the active groups. Reductions in HbA1c, FPG and insulin resistance were sustained in Week 52. Safety profiles were favourable with adverse events similar in frequency and no increased hypoglycaemia risk. Sitagliptin/empagliflozin FDC doses achieved improvements in glycaemic control at 24 weeks, which was maintained through 52 weeks. These benefits were accompanied by a favourable safety profile, including a very low risk of hypoglycaemia. NCT07076056.

Neuro-immune, metabolic, and oxidative pathways in depression due to hypothyroidism and Hashimoto's thyroiditis.

Diabetic cardiomyopathy is a clinical condition of ventricular dysfunction, with obesity and insulin resistance as the primary risk factors. Under this condition, the heart encounters lipotoxicity, which impairs cardiac insulin sensitivity and leads to cardiomyopathy. Angiotensin-(1-9) is a peptide of the counter-regulatory axis of the renin-angiotensin system with cardioprotective effects. However, its role in diabetic cardiomyopathy is unknown. To investigate the role of angiotensin-(1-9), we first induced lipotoxic stress in the heart by high-fat diet (HFD) feeding in mice. Angiotensin-(1-9) was then administered for 4weeks using osmotic mini-pumps. Cardiac function was assessed, and insulin sensitivity was evaluated in heart tissues after insulin bolus injection. Moreover, lipotoxic stress in vitro was modelled by high glucose medium plus palmitate in neonatal rat ventricular myocytes (NRVMs). Angiotensin-(1-9) improves myocardial function and reverts pathological cardiac remodelling under HFD feeding in mice. Moreover, angiotensin-(1-9) enhances whole-body glucose tolerance and reduces homeostatic model assessment of insulin resistance (HOMA-IR). We demonstrate that angiotensin-(1-9) increases insulin sensitivity in the heart and skeletal muscle but not in adipose tissue or the liver. Mechanistically, angiotensin-(1-9) does not affect insulin signalling in cardiomyocytes at baseline, whereas it significantly improves insulin action under lipotoxic stress through AT2 receptors and protein kinase A. These findings demonstrate that angiotensin-(1-9) improves cardiac function under metabolic challenge and promotes insulin signalling in cardiomyocytes under lipotoxicity, which may shed light on the therapeutic exploration against diabetic cardiomyopathy.

Visceral adiposity and insulin resistance in polycystic ovarian syndrome - A cross-sectional, observational study.

The prevalence of obstructive sleep apnea (OSA) increases during pregnancy and is associated with gestational diabetes mellitus (GDM), although its clinical impact on birth outcomes remains unclear. We aimed to assess the effect of several OSA criteria and intermittent hypoxia in the third trimester on perinatal outcomes in women with GDM. In this prospective study, polysomnography was performed on 89 women with GDM. Insulin resistance indices (HOMA-IR/QUICKI) were calculated, and biomarkers (insulin-like growth factor-1 (IGF-1), resistin, soluble endoglobulin, galectin-3, and free fatty acids) were analysed from women and some cord blood samples using enzyme-linked immunosorbent assay. Whereas OSA did not significantly affect overall perinatal outcomes, specific OSA features-including REM-OSA, supine-position OSA, and an oxygen desaturation index (ODI) ≥ 1 h-1-were linked to adverse effects on neonatal birthweight and length. Moreover, apnea duration was an independent predictor of birthweight, while insulin resistance was more impaired in women with OSA and showed an inverse relationship with sleep and REM time, respectively. IGF-1 was elevated and demonstrated a significant predictive value for OSA, as indicated by the AUC-ROC curve. In summary, although OSA did not adversely affect overall perinatal outcomes in women with GDM, specific OSA characteristics were associated with adverse neonatal growth metrics. Insulin resistance was higher in women with OSA, and IGF-1 may serve as a potential biomarker for OSA in this population. Further prospective studies with attention to REM-stage, supine-position OSA, apnea duration, and hypoxic burden are needed to elucidate the complex interactions between OSA, GDM, and fetal outcomes.