Insulin Resistance Research Articles

Triglyceride glucose index is associated with vertebral fracture in older adults: a longitudinal study.

Diabetes is a risk factor for bone fractures. However, the association between insulin resistance and the risk of fracture has not been well studied. In the present study, we explored the association of the triglyceride glucose index as a measure of insulin resistance with the risk of vertebral fracture in older adults. A total of 1995 subjects aged 50 years or older who underwent computed tomography (CT) for lung cancer screening from 2016-2021 were included in this study. They were followed until July 2023. Demographic information and laboratory test data were collected from the electronic medical system. Vertebral fractures were evaluated on the basis of sagittal CT images of the spine. The triglyceride glucose (TYG) index was calculated via the following equation: Ln [fasting glucose (mg/dl)×fasting triglyceride (mg/dl)/2]. The association between the TYG index and vertebral fracture incidence was evaluated via a multivariable Cox proportional hazards model. Ninety-five cases of fracture were observed during the 60 months of follow-up. The incidence of fracture was lower for the fourth TYG index than for the first TYG index (3.26% vs. 6.00%, P = 0.04). The risk of vertebral fracture decreased with increasing TYG index (adjusted hazard ratio (aHR): 0.56, 95% confidence interval (CI): 0.35-0.90). Fracture risk was significantly lower in subjects with the highest TYG (the fourth quartile) than in those with the first quartile (aHR: 0.46, 95% CI: 0.22-0.96) according to the fully adjusted model. A similar association was observed in subjects without diabetes (aHR = 0.44, 95% CI: 0.21-0.95). Restricted cubic splines further revealed that the risk of vertebral fracture decreased with increasing TYG index. A greater TYG index was associated with a lower risk of vertebral fracture, independent of body mass index and bone mass.

Pediococcus acidilactici Y01 reduces HFD-induced obesity via altering gut microbiota and metabolomic profiles and modulating adipose tissue macrophage M1/M2 polarization.

Obesity-related metabolic syndrome is intimately associated with infiltrated adipose tissue macrophages (ATMs), gut microbiota, and metabolic disorders. Pediococcus acidilactici holds the potential to mitigate obesity; however, there exist strain-specific functionalities and diverse mechanisms, which deserve extensive exploration. This study aims to explore the potential of P. acidilactici Y01, isolated from traditional sour whey, in alleviating HFD-induced metabolic syndrome in mice and elucidating its underlying mechanism. The results showed that P. acidilactici Y01 could inhibit the increase of body weight gain, the deposition of fat, lipid disorders and chronic low-grade inflammation, improve glucose tolerance and insulin resistance, and could reduce adipose tissue inflammation by decreasing M1-type ATMs and increasing M2-type ATMs. Meanwhile, P. acidilactici Y01 significantly increased the abundance of potentially beneficial intestinal bacteria, such as Akkermansia, Alistipes, Bifidobacterium, Lachnospiraceae_NK4A136_group, Lactobacillus, norank_f__Muribaculaceae, and Parabacteroides, and partially restored the levels of metabolites, such as phosphatidylcholines, glycerophosphocholines, sphingolipids and unsaturated fatty acids. The fecal microbiota transplantation experiment demonstrated that P. acidilactici Y01 ameliorated obesity-related metabolic syndrome by modulating the polarization of M1/M2 ATMs mediated by gut microbiota. Overall, as a dietary supplement, P. acidilactici Y01 has good potential in the prevention and treatment of obesity.

Regulation of injury-induced skeletal myofiber regeneration by glucose transporter 4 (GLUT4)

BackgroundInsulin resistance and type 2 diabetes impair cellular regeneration in multiple tissues including skeletal muscle. The molecular basis for this impairment is largely unknown. Glucose uptake via glucose transporter GLUT4 is impaired in insulin resistance. In healthy muscle, acute injury stimulates glucose uptake. Whether decreased glucose uptake via GLUT4 impairs muscle regeneration is presently unknown. The goal of this study was to determine whether GLUT4 regulates muscle glucose uptake and/or regeneration following acute injury.MethodsTibialis anterior and extensor digitorum longus muscles from wild-type, control, or muscle-specific GLUT4 knockout (mG4KO) mice were injected with the myotoxin barium chloride to induce muscle injury. After 3, 5, 7, 10, 14, or 21 days (in wild-type mice), or after 7 or 14 days (in control & mG4KO) mice, muscles were isolated to examine [3H]-2-deoxyglucose uptake, GLUT4 levels, extracellular fluid space, fibrosis, myofiber cross-sectional area, and myofiber centralized nuclei.ResultsIn wild-type mice, muscle glucose uptake was increased 3, 5, 7, and 10 days post-injury. There was a rapid decrease in GLUT4 protein levels that were restored to baseline at 5–7 days post-injury, followed by a super-compensation at 10–21 days. In mG4KO mice, there were no differences in muscle glucose uptake, extracellular fluid space, muscle fibrosis, myofiber cross-sectional areas, or percentage of centrally nucleated myofibers at 7 days post-injury. In contrast, at 14 days injured muscles from mG4KO mice exhibited decreased glucose uptake, muscle weight, myofiber cross sectional areas, and centrally nucleated myofibers, with no change in extracellular fluid space or fibrosis.ConclusionsCollectively, these findings demonstrate that glucose uptake via GLUT4 regulates skeletal myofiber regeneration following acute injury.

Self-Nanoemulsifying Formulation Improves Oral Bioavailability and Insulin Sensitizing Potency of Formononetin-Vitamin E Conjugate in Type 2 Diabetic Mice.

The escalating incidence of obesity, diabetes, and insulin resistance has become a significant global health concern. In this study, we have developed a self-nanoemulsifying delivery system (SNEDS) of formononetin-vitamin E conjugate (VESylated-FMN) for improving its oral bioavailability and improving insulin sensitivity and glycemic control. The developed SNEDS were characterized using dynamic light scattering and transmission electron microscopy. Thereafter, the loading capacity, in vitro release, thermodynamic, and gastrointestinal stability of the developed formulation were evaluated. The safety and oral bioavailability of VESylated-FMN-SNEDS were assessed in Sprague-Dawley rats, whereas insulin-sensitizing potency was assessed in high-fat diet-induced type 2 diabetic mice. The VESylated-FMN-SNEDS quickly emulsified on dilution (droplet size ∼79.17 nm) and showed remarkable thermodynamic and gastrointestinal stability. The developed formulation demonstrated enhanced oral bioavailability (∼1.3-fold higher AUC0-t) of VESylated-FMN without liver and kidney injury. Consequently, VESylated-FMN-SNEDS significantly improves insulin sensitivity and glycemic control in HFD-fed mice compared to VESylated-FMN by upregulating the transcript level of insulin-sensitizing genes. Therefore, the SNEDS formulation could be an effective strategy to augment the oral bioavailability and insulin-sensitizing potency of VESylated-FMN.

Association of remnant cholesterol with insulin resistance and type 2 diabetes: mediation analyses from NHANES 1999–2020

BackgroundPrevious studies have established a correlation between elevated levels of remnant cholesterol (RC) and the occurrence of type 2 diabetes mellitus (T2D) as well as insulin resistance (IR); however, the precise nature of these associations remains incompletely elucidated. This study aimed to evaluate the relationships between RC and IR, as well as RC and T2D, and to determine the extent to which IR mediated the relationship between RC and T2D.MethodsThis was an observational study that utilized cross-sectional methods to examine the general population in the National Health and Nutrition Examination Survey (NHANES) 1999–2020. The participants were divided into 4 groups according to the RC quartiles. The outcome was the prevalence of IR and T2D. Survey-weighted binary logistic regression analysis was used to analyze the associations, and the restricted cubic spline (RCS) curve was used to further analyze the nonlinear relationship. Receiver operating characteristic (ROC) curves were generated to evaluate the diagnostic performance, and the areas under the curves (AUC) of RC, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) were compared using the DeLong test. The mediating effect of IR on the relationship between RC and T2D was evaluated through mediation analysis.ResultsA total of 23,755 participants (46.02 ± 18.48 years, 48.8% male) were included in our study. Higher RC levels were significantly associated with increased prevalence of both IR and T2D. After adjusting for potential confounders, logistic regression analysis showed that higher RC quartiles were associated with the increased prevalence of IR [Quartile 4 vs. Quartile 1: odds ratio (OR) (95% confidence interval, CI): 1.65 (1.41–1.94), p < 0.001] and T2D [Quartile 4 vs. Quartile 1: OR (95% CI): 1.24 (1.03–1.50), p = 0.024]. RCS analysis revealed two distinct nonlinear relationships: one between RC levels and the prevalence of IR (nonlinear p < 0.001), and another between RC levels and the prevalence of T2D (nonlinear p < 0.001). ROC curve analysis demonstrated that RC had the highest discriminative ability, significantly outperforming LDL-C, HDL-C, and TG in predicting both IR and T2D risk (all P < 0.001 by DeLong test). Mediation analysis revealed that IR significantly mediated the relationship between RC and T2D, with approximately 54.1% of the effect of RC on T2D being indirect through IR.ConclusionsHigher RC level was associated with increased prevalence of IR and T2D. IR mediated 54.1% of the association between RC and T2D, suggesting that managing IR could be crucial in reducing the risk of T2D in individuals with elevated RC levels.

Waist-to-height ratio and body roundness index: superior predictors of insulin resistance in Chinese adults and take gender and age into consideration

Background and objectivesMetabolic disease has become a global health concern, and insulin resistance (IR) is a crucial underlying mechanism in various metabolic diseases. This study aims to compare the ability of seven anthropometric indicators in predicting IR in the Chinese population, and to find more sensitive and simple anthropometric indicator for early identification of IR.MethodsThis prospective cross-sectional study obtained participants’ medical history, anthropometric indicators, and serum samples from three hospitals in China. Various anthropometric indicators were calculated, including body mass index (BMI), Waist-to-hip ratio (WHR), waist-to-height ratio (WtHR), conicity index (CI), A Body Shape Index (ABSI), body roundness index (BRI), abdominal volume index (AVI). The evaluation of IR is performed using the homeostasis model assessment-insulin resistance (HOMA-IR). Logistic regression analysis examined the relationship between indicators and HOMA-IR. The ability of the anthropometric indicators to predict IR was analyzed using the receiver operating characteristic (ROC) curve. Additionally, a stratified analysis was performed to evaluate the ability of the indicators in different age and gender groups.ResultsThe study included 1,592 adult subjects, with 531 in the non-IR group and 1,061 in the IR group. After adjusting for confounding factors, the anthropometric indicators showed a positive correlation with IR in the general population and across different genders and age groups (OR &amp;gt; 1, p &amp;lt; 0.05), except for ABSI. In the ROC curve analysis, WtHR and BRI had the highest AUC values of 0.711 for detecting IR. The optimal cut-off value for WtHR to diagnose IR was 0.53, while for BRI, it was 4.00. In the gender-stratified and age-stratified analysis, BMI, WtHR, BRI, and AVI all had AUC values &amp;gt;0.700 in females and individuals below 60.ConclusionWtHR and BRI demonstrated a better ability to predict IR in the overall study population, making them preferred indicators for screening IR, and gender and age are important considerations. In the stratified analysis of different genders or age, BMI, WtHR, BRI, and AVI are also suitable for detecting IR in women or individuals under 60 years old in this study.Clinical trial registrationwww.chictr.org.cn, ChiCTR2100054654.

Exploring the Potential of Epigallocatechin Gallate in Combating Insulin Resistance and Diabetes

Background/Objectives: In this study, the potential effects are evaluated of epigallocatechin gallate (EGCG) on the prognosis of diabetes and insulin resistance. Methods: In an experiment, 35 male Wistar albino rats were used and in the streptozotocin (STZ)-induced diabetic rats, the effects were examined of different doses (50 mg/kg, 100 mg/kg, 200 mg/kg) of EGCG on metabolic parameters associated with diabetes and insulin resistance. Results: The findings show favorable effects of EGCG on fasting blood glucose levels, insulin secretion, insulin resistance, and beta cell function. In this study, it was observed that EGCG was able to significantly lower fasting blood glucose levels, especially at high doses (200 mg/kg), providing the most significant improvement. Furthermore, EGCG has been found to reduce insulin resistance and improve insulin sensitivity by increasing insulin secretion. When the biochemical parameters of increased insulin secretion are evaluated, it is also observed that it creates clinically significant changes. At doses of 100 mg/kg and 200 mg/kg, EGCG has the potential to help control diabetes by most effectively improving insulin resistance and beta cell function. The study results suggest that EGCG, especially at high doses, is an effective component in the treatment of diabetes and the management of insulin resistance. Conclusions: The inclusion of EGCG as a natural flavonoid in medical nutrition therapy may contribute to glycemic control and improve insulin sensitivity in individuals with diabetes. These findings suggest that EGCG may be used as an alternative option in the treatment of diabetes and future studies may further clarify the potential benefits in this area.

Insulin resistance in childhood obesity: The role of dietary habits and their association with novel markers of cardiovascular disease

Background Childhood obesity presents numerous comorbidities such as insulin resistance (IR) and dyslipidemia, and could be associated with alterations in novel markers of cardiovascular (CV) risk like: (1) the activities of associated enzymes such as lipoprotein associated phospholipase A2 (Lp-PLA2) and paraoxonase 1 (PON 1), (2) reverse cholesterol transport (RCT), which comprises cellular cholesterol efflux (CCE), in addition to lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) activities, and (3) high density lipoprotein (HDL) antioxidant capacity. Moreover, IR could worsen these cardiometabolic alterations. The objective of the present study was to characterize the effect of IR on novel CV markers in a pediatric population with obesity. Methods Twenty-five obese children and adolescents with IR, and 25 without IR took part in the study. Anthropometric parameters, Tanner stage and dietary habits were registered. Glucose, insulin, non-esterified fatty acid (NEFA), lipid, and high sensitivity C reactive protein (hsCRP) levels, plus Lp-PLA2, LCAT, CETP and PON 1 activities, as well as CCE and HDL antioxidant capacity were measured. A cutoff point of 3.16 in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) determined the presence of IR. Results No differences were observed in age, sex and Tanner stage. Expectedly, the group with IR displayed higher insulin and NEFA levels (p &lt; 0.05). They also presented increased Lp-PLA2 and decreased PON activities (p &lt; 0.05). Importantly, these differences were associated with dietary habits (p &lt; 0.05). Conclusion IR present in pediatric obesity associated with vascular specific inflammation and reduced PON 1 activity, in addition to alterations in glucose metabolism, thus increasing CV risk in adulthood. These proatherogenic disturbances were conditioned by dietary habits.

The association between thyroid function and insulin resistance as measured by the metabolic score for insulin resistance (METS-IR): insights from NHANES 2007–2012

BackgroundAltered thyroid function has been linked to insulin resistance (IR), but its relationship with the Metabolic Score for Insulin Resistance (METS-IR), a novel non-insulin-based index of IR, remains unclear. This study aimed to investigate the association between thyroid function status and METS-IR in a U.S. population.MethodsThis cross-sectional study utilized data from 6,507 adults (aged ≥ 20 years) participating in the National Health and Nutrition Examination Survey from 2007 to 2012. Thyroid function status was categorized into five groups based on thyroid-stimulating hormone and free thyroxine levels. METS-IR was calculated from measures of fasting glucose, triglycerides, high-density lipoprotein cholesterol (HDL-C), and body mass index (BMI). Multivariate regression analyzed the relationship between thyroid status and METS-IR after adjusting for potential confounders.ResultsHigher thyroid-stimulating hormone levels were positively associated with METS-IR (β = 0.003, 95% CI 0.001–0.004, p = 0.021). Subclinical hypothyroidism in males and subclinical hyperthyroidism in females showed significant correlations with higher METS-IR. Thyroid peroxidase antibodies (TPO Ab) positivity strengthened the association between overt hypothyroidism and METS-IR.ConclusionsThis study demonstrates significant associations between thyroid function status, particularly subclinical thyroid dysfunction, and insulin resistance as measured by METS-IR in a U.S. population. Thyroid status may serve as an early marker of insulin resistance risk.

A systematic review of the association between insulin resistance surrogate indices and bone mineral density

BackgroundThe relationship of insulin resistance with bone mineral density (BMD) remains unclear, offering an opportunity for novel indices to shed light on the matter. The aim of this review was to evaluate the association between surrogate indices of insulin resistance and BMD.MethodsA systematic review was conducted to evaluate observational studies that examined the relationship between insulin resistance surrogate indices and BMD in adults. Databases including PubMed, Web of Science, Scopus, and Embase were searched. Quality assessment was performed using Joanna Briggs Institute (JBI) critical appraisal tools.ResultsThis systematic review included 27 cohorts and cross-sectional studies with 71,525 participants to assess the potential link between insulin resistance surrogate indices like HOMA-IR, HOMA-β, TyG, TyG-BMI, TyG-WtHR, and TyG-WC, along with METS-IR, and VAI, and BMD at various sites. There seems to be no link between BMD and the HOMA index, despite being extensively studied in various studies (adjusted β ranging from -0.49 to 0.103). Most literature suggests that a higher TyG index is associated with decreased BMD levels (adjusted β ranging from -0.085 to 0.0124). Despite limited evidence, other insulin resistance indices such as VAI (adjusted β ranging from 0.007 to 0.016), TyG-BMI (adjusted β ranging from 0.002 to 0.415), METS-IR (adjusted β ranging from 0.005 to 0.060), TyG-WtHR (β = 0.012) and TyG-WC (β = 0.0001) have shown a positive association with BMD in a few studies.ConclusionThis systematic review emphasizes the intricate connection between insulin resistance and BMD. The lack of ability to perform a meta-analysis and the dependence on cross-sectional studies hinder the robustness of the findings, hence necessitating well-designed longitudinal studies.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42024512770.

Adult-based genetic risk scores for insulin resistance associate with cardiometabolic traits in children and adolescents.

Insulin resistance (IR) is a key factor in the development of cardiometabolic diseases. While genetic risk scores (GRSs) for IR have been developed and validated in adult population, it is unclear if they can be used for risk assessment in youth. Our objective was to investigate whether adult-derived genetic risk scores (GRSs) for insulin resistance (IR) associate with cardiometabolic traits in children and adolescents. We studied a group of children and adolescents with obesity (n= 1,680) and a group without obesity (n=1,804). We constructed three GRSs based on fasting (IR-GRS27), oral glucose tolerance test (IR-GRS8), and IR-related phenotypes (IR-GRS51) from previous genome-wide association studies. Using an additive genetic model, we calculated weighted GRSs and analysed their associations with cardiometabolic traits using linear and logistic regression models. The IR-GRS27 was associated with higher serum concentrations of fasting insulin, C-peptide, triglyceride (TG), gamma-glutamyl transferase and alanine aminotransferase (ALT), and homeostatic model assessment of insulin resistance. The IR-GRS27 was furthermore associated with higher prevalence of IR and ALT. IR-GRS51 was associated with higher TG and lower high-density lipoprotein cholesterol, while IR-GRS8 associated with lower total cholesterol, low-density lipoprotein cholesterol, and increased ALT. IR-GRS27 and IR-GRS8 were additionally associated with higher prevalence of IR and steatotic liver disease respectively. Adult-derived GRSs for IR are significantly associated with cardiometabolic traits in children and adolescents. If validated in independent study samples, our findings suggest the contribution of adult-based GRSs in assessing IR-related cardiometabolic risk in youth.

Relationship of adiponectin, leptin and reproductive endocrine hormones with insulin resistance in polycystic ovary syndrome patients with normal BMI

Objective This study aimed to analyze the correlation of adiponectin (APN) and leptin (LEP), reproductive endocrine hormones with insulin resistance (IR) in polycystic ovary syndrome (PCOS) patients with normal body mass index (BMI). Methods Totally 160 PCOS patients were categorized into the Normal BMI (BMI: 18.5–25 kg/m2, n = 62) and High BMI (BMI > 25 kg/m2, n = 98) groups. Glucose indicators [fasting plasma glucose, fasting insulin and Homeostasis Model Assessment of Insulin Resistance (HOMA-IR)], lipid indicators [total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C)], adipokines [APN and LEP] and reproductive endocrine hormones [luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin (PRL), total testosterone (TT), dehy-droepiandrosterone sulfate (DHEAS) and estradiol (E2)] were collected, and their correlations were analyzed. The relationship of HOMA-IR with APN, LEP and reproductive endocrine hormones was subjected to multiple linear regression analysis. Results Correlation analysis revealed positive correlations of HOMA-IR with TC, TG, LDL-C, LEP, PRL, DHEAS and TT and negative correlations with HDL-C, APN, LH, FSH and E2 in PCOS patients with normal BMI. Multiple linear regression analysis showed that LH, FSH and E2 negatively affected HOMA-IR, while PRL positively affected HOMA-IR. Conclusion There were strong correlations of HOMA-IR in PCOS patients with normal BMI with APN, LEP, and reproductive endocrine hormones. Besides, LH, FSH, E2 and PRL expression had an important effect on IR in normal BMI PCOS patients, which provided a theoretical basis for the exploration of pathogenic mechanisms in normal BMI PCOS patients.

Sphingolipid profiling as a biomarker of type 2 diabetes risk: evidence from the MIDUS and PREDIMED studies

BackgroundType 2 diabetes (T2D) has become a worldwide pandemic. While ceramides may serve as intermediary between obesity-related lipotoxicity and T2D, the relationship with simple glycosphingolipids remains uncertain. The aim of this study was to characterize the associations between blood glycosphingolipid and ceramide species with T2D and to identify a circulating sphingolipid profile that could serve as novel biomarker for T2D risk.MethodsCross-sectional relationship between sphingolipid levels, insulin resistance, and T2D prevalence were evaluated in 2,072 American adults from MIDUS cohort. Prospectively, the association between sphingolipid species and the incidence of T2D was analyzed using a case-cohort design nested within the PREDIMED trial (250 cases and a random sample of 692 participants, with 3.8 years of median follow-up). Circulating levels of sphingolipid species in both populations were measured using LC/MS. Hazard ratios were estimated with weighted Cox regression models using Barlow weights.ResultsIn American adults, only CER18:0 and CER22:0 were linked to insulin resistance and a higher prevalence of T2D. Conversely, three lactosylceramides (LCER 14:0, 16:0, and 24:1) showed a strong inverse relationship with both insulin resistance and T2D. These findings led to development of two sphingolipid scores. In the prospective analysis, these scores consistently predicted a reduced risk of T2D incidence in PREDIMED (HR: 0.64, 95% CI 0.44 to 0.94 and 0.58, 0.40 to 0.85 respectively) between extreme quartiles, with 5-year absolute risk differences of 9.6% (95% CI: 0.3–20.5%) and 11.4% (1.0–21.6%). They were validated in the same trial with samples obtained after 1 year of follow-up.ConclusionsOur findings support the potential usefulness of circulating sphingolipid profiles as novel biomarkers for T2D risk. Moreover, this study opens the door for future research on the predictive value and possible protective roles of lactosylceramides in T2D.Graphical abstract

Gender differences in the association between the uric acid to high-density lipoprotein cholesterol ratio and diabetes risk: a mediation analysis of c-reactive protein, triglycerides, and insulin resistance

BackgroundThe uric acid to high-density lipoprotein cholesterol ratio (UHR) has emerged as a novel metabolic marker and is proven to be associated with diabetes risk. However, there is still a lack of systematic research regarding its role in gender differences and underlying mechanisms. This study aims to assess the association of UHR with diabetes risk in the context of gender differences and to investigate its mediation effects through metabolic and inflammatory pathways.MethodsThis study utilized data from NHANES 2005–2010 and included 6,843 adult participants. Multivariate logistic regression was employed to assess the association between UHR and diabetes risk, and restricted cubic spline (RCS) along with correlation analysis was applied to explore its relationship with metabolic risk factors. Multiple mediation analysis was conducted to evaluate the mediating effects of homeostasis model assessment of insulin resistance (HOMA-IR), triglycerides (TG), and C-reactive protein (CRP) on the association between UHR and diabetes risk.ResultsIn the overall population, UHR was significantly positively associated with diabetes risk, but gender-stratified analysis revealed a stronger predictive effect in women. In the unadjusted model, every unit increase in UHR was linked to an 18.6% increase in diabetes risk in women (p < 0.001). In the quartile analysis, women in the highest quartile showed an 8.49-fold increased risk of diabetes (OR = 8.494, 95% CI: 5.542–13.019, p < 0.001), whereas no significant association was observed in men (p > 0.05). Mediation analysis revealed that HOMA-IR was the main mediator of the relationship between UHR and diabetes risk, with mediation effects of 64.55%, 118.38%, and 39.09% in the overall population, men, and women, respectively. Additionally, the mediation effect of TG was stronger in men (36.78%) and weaker in women (17.31%). The mediation effect of CRP was relatively minimal across all groups, accounting for 7.62% in men and 2.67% in women.ConclusionThis study demonstrates that the association between UHR and diabetes risk exhibits gender differences, with higher diabetes risk observed in women, while men show stronger mediation effects in insulin resistance, lipid metabolism, and inflammatory response.

Chain splitting of insulin: an underlying mechanism of insulin resistance?

Despite decades of intense research, the mechanisms underlying insulin resistance are still poorly understood. What if one of the major causes of insulin resistance is not related to defects in the target tissues and/or insulin receptor signaling, but rather to a reduced survival of endogenously secreted insulin on its way to activating the receptor on the cell surface of the target tissues? Here, we present data and lay out arguments in support of this novel hypothesis, which is fundamentally different from the common view that insulin resistance is caused by the body’s cells becoming less sensitive to insulin.

The association between the metabolic score for insulin resistance and mortality in patients with cardiovascular disease: a national cohort study

BackgroundThe metabolic score for insulin resistance (METS-IR) is a novel index for evaluating insulin resistance and identifying high-risk cardiovascular disease (CVD) patients. This study aims to assess the prognostic value of METS-IR in predicting mortality risk in CVD patients.MethodsWe analyzed data from 2,515 CVD patients in the National Health and Nutrition Examination Survey (NHANES). Associations between METS-IR and all-cause mortality and cardiovascular mortality were evaluated using multivariable Cox proportional hazards models and restricted cubic splines (RCS). Threshold effects and sensitivity analyses were conducted to ensure robustness.ResultsOver a median follow-up of 91.4 months, 1,090 patients died, including 447 from cardiovascular causes. A U-shaped relationship was identified between lnMETS-IR and all-cause and cardiovascular mortality, with thresholds at 3.70 and 3.67. Below thresholds, an increase of lnMETS-IR was associated with a 75% reduction in the risk of all-cause mortality (HR: 0.25, 95% CI: 0.14–0.46) and a 79% reduction in the risk of cardiovascular mortality (HR: 0.21, 95% CI: 0.07–0.56). While above thresholds, an increase of lnMETS-IR was associated with a 180% increase in the risk of all-cause mortality (HR: 2.80, 95% CI: 1.61–4.88) and a 233% increase in the risk of cardiovascular mortality (HR: 3.33, 95% CI: 1.43–7.75).ConclusionsThis study identified a U-shaped association between lnMETS-IR and mortality among CVD patients, underscoring the potential of METS-IR as a valuable prognostic marker for mortality risk in patients with CVD.

Exploring the prognostic impact of triglyceride-glucose index in critically ill patients with first-ever stroke: insights from traditional methods and machine learning-based mortality prediction

BackgroundThe incidence and mortality of first-ever strokes have risen sharply, especially in the intensive care unit (ICU). Emerging surrogate for insulin resistance, triglyceride-glucose index (TyG), has been linked to stroke prognosis. We aims to explore the relationships between TyG with ICU all-cause mortality and other prognosis, and to develop machine learning (ML) models in predicting ICU all-cause mortality in the first-ever strokes.MethodsWe included first-ever stroke patients from the eICU Collaborative Research Database in 2014–2015 as the primary analysis cohort (then divided into training and internal validation cohorts) and from local hospital’s ICUs as the external validation cohort. Multivariate Cox proportional hazards models and restricted cubic spline analyses were used to evaluate the association between TyG and ICU/hospital all-cause mortality. Linear regression and correlation analyses were performed to examine the relationships between TyG with length of ICU/hospital stay and Glasgow Coma Score.ResultsThe primary analysis cohort included 3173 first-ever strokes (median age 68.0 [55.0–68.0] years; 63.0% male), while the external validation cohort included 201 first-ever strokes (median age 71.0 [63.0–77.0] years; 62.3% male). Multivariate Cox proportional hazards models revealed that the high TyG group (TyG ≥ 9.265) was associated with higher ICU (HR 1.92, 95% CI 1.38–2.66) and hospital (HR 1.69, 95% CI 1.32–2.16) all-cause mortality, compared with low TyG group (TyG < 9.265). TyG was also correlated with ICU length of stay (r = 0.077), hospital length of stay (r = 0.042), and Glasgow Coma Score (r = -0.132). TyG and other six features were used to construct ML models. The random forest model performed best in internal validation with AUC (0.900) and G-mean (0.443), and in external validation with AUC (0.776) and G-mean (0.399).ConclusionTyG (optimal cut-off: 9.265) was identified as an independent risk factor for ICU and hospital all-cause mortality in first-ever strokes. The ML model incorporating TyG demonstrated strong predictive performance. This emphasises the importance of insulin resistance (with TyG as a surrogate measure) in the prognostic assessment and early risk stratification of first-time stroke patients.

PPARβ/δ upregulates the insulin receptor β subunit in skeletal muscle by reducing lysosomal activity and EphB4 levels

BackgroundThe increased degradation of the insulin receptor β subunit (InsRβ) in lysosomes contributes to the development of insulin resistance and type 2 diabetes mellitus. Endoplasmic reticulum (ER) stress contributes to insulin resistance through several mechanisms, including the reduction of InsRβ levels. Here, we examined how peroxisome proliferator-activated receptor (PPAR)β/δ regulates InsRβ levels in mouse skeletal muscle and C2C12 myotubes exposed to the ER stressor tunicamycin.MethodsWild-type (WT) and Ppard−/− mice, WT mice treated with vehicle or the PPARβ/δ agonist GW501516, and C2C12 myotubes treated with the ER stressor tunicamycin or different activators or inhibitors were used.ResultsPpard−/− mice displayed reduced InsRβ protein levels in their skeletal muscle compared to wild-type (WT) mice, while the PPARβ/δ agonist GW501516 increased its levels in WT mice. Co-incubation of tunicamycin-exposed C2C12 myotubes with GW501516 partially reversed the decrease in InsRβ protein levels, attenuating both ER stress and the increase in lysosomal activity. In addition, the protein levels of the tyrosine kinase ephrin receptor B4 (EphB4), which binds to the InsRβ and facilitates its endocytosis and degradation in lysosomes, were increased in the skeletal muscle of Ppard−/− mice, with GW501516 reducing its levels in the skeletal muscle of WT mice.ConclusionsOverall, these findings reveal that PPARβ/δ activation increases InsRβ levels by alleviating ER stress and lysosomal degradation.

Effects of the Interaction Between Oxidative Balance Score and Polygenic Risk Scores on Incidence of Metabolic Syndrome in Middle-Aged Korean Adults

Oxidative stress is implicated in insulin resistance, obesity, and metabolic syndromes (MetSs). However, the interplay between oxidative stress and genetic predisposition during the development of MetS remains unclear. In this study, we aimed to investigate the effects of the interaction between oxidative balance score (OBS) and polygenic risk score (PRS) on the incidence of MetS in middle-aged Korean adults. We analyzed data from 25,879 participants aged ≥40 years from the Health Examinees Cohort of the Korean Genome and Epidemiology Study. The OBS was calculated using 11 antioxidant and five pro-oxidant factors. A genome-wide association study and clumping analysis identified 16 independent single-nucleotide polymorphisms associated with MetS that were used to calculate individual PRSs. Multivariable Cox proportional hazard models adjusted for confounding variables were used to assess the impact of OBS and PRS on the incidence of MetS. During a mean follow-up period of 4.3 years, we recorded 3153 cases of MetS. In both men and women, the group with the lowest OBS and a high PRS had a 1.50-fold (hazard ratio [HR] 1.50, 95% confidence interval [CI] 1.07–2.11) and 1.89-fold (HR 1.89, 95% CI 1.40–2.56) higher incidence, respectively, of MetS compared to those with the highest OBS and a low PRS. Among women with a high PRS, the HRs decreased significantly across OBS quintiles 1 through 5 (p for trend = 0.009). These findings suggest that managing the oxidative balance may be particularly crucial for individuals with a high genetic risk for MetS.

Therapeutic potential of SGLT-2 inhibitors and DDP4 inhibitors in elderly patients with type 2 diabetes mellitus and benign prostatic hyperplasia

Background. Benign prostatic hyperplasia (BPH) has recently been linked to diabetes mellitus and insulin resistance. This study aims to explore whether the use of either sodium-glucose co-transporter-2 (SGLT-2) inhibitors or dipeptidyl peptidase-4 (DPP-4) inhibitors is associated with favorable outcomes in prostate volume and symptoms. Methods. This is a before-and-after study involving 57 elderly male patients with type 2 diabetes mellitus and BPH, who were recruited and followed up for one year. Twenty-seven patients were prescribed SGLT-2 inhibitors (Dapagliflozin 10 mg), and thirty patients were prescribed DPP-4 inhibitors (Sitagliptin 100 mg). Prostate volume, International Prostate Symptom Score (IPSS), and Pittsburgh Sleep Quality Index (PSQI) were assessed in all patients. Results. The use of either SGLT-2 inhibitors or DPP-4 inhibitors was associated with a statistically significant decrease in prostate volume after one year of treatment (p = 0.04 for SGLT-2 inhibitors and p = 0.02 for DPP-4 inhibitors). Statistically significant reductions were found in both groups regarding post-voiding urine volume after one year of treatment compared to baseline levels (p = 0.014 for SGLT-2 inhibitors and p = 0.017 for DPP-4 inhibitors). At the end of the follow-up period, there was a statistically significant reduction in IPSS scores (p = 0.02 for SGLT-2 inhibitors and p = 0.03 for DPP-4 inhibitors). Similarly, the use of either DPP-4 inhibitors or SGLT-2 inhibitors was associated with a statistically significant improvement in nocturia and sleep quality (PSQI score) (p = 0.012 for SGLT-2 inhibitors and p = 0.01 for DPP-4 inhibitors). Post-hoc analysis showed that DPP-4 inhibitors were superior to SGLT-2 inhibitors in reducing prostate volume and symptoms (p &lt; 0.05). Conclusion. Both SGLT-2 inhibitors and DPP-4 inhibitors improve prostate volume and symptoms in patients with diabetes mellitus and BPH. Notably, DPP-4 inhibitors exhibited superiority over SGLT-2 inhibitors in terms of reducing prostate volume and alleviating symptoms. Larger-scale studies are required to confirm these favorable effects.