Surrogate Measures Of Insulin Resistance Research Articles

Can adiposity measures enhance the predictive power of the triglyceride-glucose index for metabolic syndrome in adults in the United States?

BackgroundInsulin resistance is a hallmark feature of metabolic syndrome (MetSyn). The triglyceride-glucose (TyG) index is considered a reliable surrogate measure of insulin resistance. However, the efficacy of the TyG-index combined with adiposity measures for identifying MetSyn in U.S. adults is unknown. MethodsIn the present cross-sectional study, 2746 men and women from the 2017–2020 National Health and Nutrition Examination Survey (NHANES) with physical and laboratory characteristics were included. Predictive powers (estimated by the area under the curve of receiver operating characteristic [ROC-AUC]) of TyG-index combined with adiposity for MetSyn were compared with other traditional surrogate markers of insulin resistance including the TyG index, homeostatic assessment of insulin resistance (HOMA-IR), 1/fasting insulin, and quantitative insulin sensitivity check index (QUICKI). ResultsPredictive power of TyG-WHtR (ROC-AUC: 0.875) for MetSyn was highest, followed by TyG-WC (0.866), TyG-BMI (0.845), TyG index (0.832), HOMA-IR (0.820), QUICKI (0.820) and 1/fasting insulin (0.786). TyG-WHtR and TyG-WC showed significantly higher ROC-AUCs compared with TyG-index, HOMA-IR, 1/fasting insulin, and QUICKI (p ≤ 0.001). ConclusionsTyG index combined with adiposity metrics is more effective in predicting MetSyn when compared to insulin resistance surrogates (TyG index, HOMA-IR, 1/fasting insulin, and QUICKI) which has been widely used in large cohort observational studies.

Triglyceride-glucose index improves risk prediction beyond traditional risk factors and hypertension mediated organ damage in healthy adults

Background and aimsTriglyceride-glucose (TyG) index, a surrogate measure of insulin resistance, is associated with hypertension mediated organ damage (HMOD) and cardiovascular disease. This study investigated the association between TyG index and major adverse cardiovascular events (MACE) and its interaction with traditional risk factors and HMOD. Methods and resultsHealthy subjects recruited from the general population were thoroughly examined and followed for MACE using nation-wide registries. Cox proportional hazard models were used to calculate the association between TyG index and MACE occurrence. Models were adjusted for Systematic Coronary Risk Evaluation (SCORE) risk factors, pulse wave velocity, left ventricular mass index, carotid atherosclerotic plaque status, and microalbuminuria. Continuous net reclassification and Harrell's Concordance index (C-index) were used to assess the added prognostic value of TyG index.During a follow-up period of mean 15.4 ± 4.7 years, MACE were observed in 332 (17%) of 1970 included participants. TyG index was associated with MACE; HR = 1.44 [95%CI:1.30–1.59] per standard deviation. After adjustment for traditional cardiovascular (CV) risk factors, HR was 1.16 [95%CI:1.03–1.31]. The association between TyG index and MACE remained significant after further adjustment for each HMOD component. However, this finding was evident only in subjects aged 41 or 51 years (HR = 1.39; 95%CI:1.15–1.69). Including TyG index in a risk model based on traditional CV risk factors improved C-index with 0.005 (P = 0.042). ConclusionIn this population-based study of healthy middle-aged subjects, TyG index was associated with MACE independently of traditional CV risk factors and HMOD. TyG index may have a potential role in future risk prediction systems.

Factors associated with body weight gain and insulin-resistance: a longitudinal study

BackgroundObesity is the result of energy intake (EI) chronically exceeding energy expenditure. However, the potential metabolic factors, including insulin resistance, remain unclear. This study longitudinally investigated factors associated with changes in body weight.SubjectsA cohort of 707 adults without diabetes were investigated at the 4-year follow-up visit. The habitual intake of energy and macronutrients during the past 12 months was assessed using a validated Food Frequency Questionnaire for the local population. Homeostatic model assessment of β-cell function and insulin resistance (HOMA-IR) was used as a surrogate measure of insulin resistance. Additionally, PNPLA3 was genotyped.ResultsEighty-seven participants were weight gainers (G; cutoff value = 5 kg), and 620 were non-gainers (NG). Initial anthropometric (G vs. NG: age, 44 ± 13 vs 51 ± 13 years, P < 0.001; body mass index, 27.8 ± 6.5 vs 28.1 ± 5.1 kg/m2, P = ns; body weight, 76.7 ± 22.1 vs 74.2 ± 14.7 kg, P = ns; final body weight, 86.3 ± 23.7 vs 72.9 ± 14.2 kg, P < 0.001) and diet characteristics, as well as insulin concentrations and HOMA-IR values, were similar in both groups. Four years later, G showed significantly increased EI, insulin concentrations, and HOMA-IR values. G had a higher prevalence of the PNPLA3 CG and GG alleles than NG (P < 0.05). The presence of G was independently associated with age (OR = 1.031), EI change (OR = 2.257), and unfavorable alleles of PNPLA3 gene (OR = 1.700). Final body mass index, waist circumference, and EI were independently associated with final HOMA-IR (P < 0.001).ConclusionsEI is associated with body weight gain, and genetic factors may influence the energy balance. Insulin resistance is a consequence of weight gain, suggesting a possible intracellular protective mechanism against substrate overflow.Clinical trial registrationISRCTN15840340.

Association between triglyceride glycemic index and ejection fraction preserved heart failure in hypertensive patients.

The triglyceride-glucose (TyG) index is regarded as an independent predictor of cardiovascular disease consequences and a reliable surrogate measure of insulin resistance (IR). However, the correlation analysis between triglyceride glucose index and heart failure with preserved ejection fraction in patients with essential hypertension remains unknown. A single-center, retrospective study was conducted with patients diagnosed with essential hypertension at the First Affiliated Hospital of Xinjiang Medical University, from December 2018 to September 2020. Participants were selected based on specific inclusion and exclusion criteria, with their clinical data and laboratory tests collected. The study employed Spearman's correlation analysis, logistic regression models, restricted cubic spline plots, and receiver operating characteristic (ROC) curves to investigate the relationships between the TyG index and HFpEF. Out of 1,602 enrolled hypertensive patients, 992 were included in the analysis after applying exclusion criteria. Patients were categorized into tertiles based on the TyG index, which showed that patients in the highest tertile had characteristics associated with a higher risk of HFpEF, including age, body mass index (BMI), systolic blood pressure (SBP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and left ventricular mass index (LVMI). A significant, independent association between the TyG index and HFpEF was confirmed, with an odds ratio (OR) of 5.127 (95% CI [3.894-6.856]). Furthermore, an S-shaped nonlinear relationship was observed between the TyG index and the incidence of HFpEF (nonlinear p < 0.001). TyG index (AUC: 0.824, 95% CI [0.795-0.854]), NT-proBNP (AUC: 0.840, 95% CI [0.816-0.864]), and LVMI (AUC: 0.847, 95% CI [0.820-0.875]) showed good predictive ability for HFpEF. In addition, the TyG+LVMI combination demonstrated the strongest predictive ability (AUC: 0.907, 95% CI [0.887-0.927]). The study underscores a significant association between IR, as indicated by the TyG index, and the development of HFpEF in hypertensive patients. It highlights the critical role of metabolic dysfunction in the pathophysiology of HFpEF, advocating for a broader perspective on cardiovascular risk management.

Triglyceride-glucose index in patients of coronary artery disease presenting with or without cardiovascular event.

INTRODUCTION: Insulin resistance is a significant risk factor for coronary artery disease. A helpful surrogate test for insulin resistance is the triglyceride-glucose index, which measures how well glucose and triglycerides are metabolized. The triglyceride-glucose index, which is the combination of both indicators, has been observed to be highly connected with insulin resistance. Furthermore, it has been recommended as a viable surrogate measure of insulin resistance as a result of this significant correlation. The purpose of this research is to determine the frequency of cardiovascular event after coronary artery diseases and compare the triglyceride-glucose index in patients presenting with or without cardiovascular event after coronary artery disease.&#x0D; MEYHODOLOGY: The study was conducted at the Department of Cardiology, Punjab Institute of Cardiology in Lahore from June 5, 2020 to December 5, 2020. Total 150 patients were enrolled in the study. A sterile syringe containing 5 millilitres of blood was used to withdraw the sample, and it was followed by an 8-hour period of abstinence before the sample was transported to the laboratory of the hospital for analysis of the lipid and glucose levels. Patients who had and did not have a cardiovascular incident had their reports evaluated, and the triglyceride-glucose index was determined for both groups. Statistical analysis using SPSS version 25.0 was performed on the data that was gathered. Triglyceride-glucose index was compared in patients with or without cardiovascular event by using independent samples t-test.&#x0D; RESULTS: In patients having coronary artery disease, the frequency of cardiovascular events was 32, which represents 21.3%. The individuals who had a cardiovascular incident had a mean value of the triglyceride-glucose index of 9.48±0.52 and in patients of without cardiovascular event was 8.75±0.56. The level of triglyceride-glucose index was high in patients of cardiovascular event than the patients of without cardiovascular event when compared by using independent sample t-test the difference is significant (p=0.000001).&#x0D; CONCLUSION: There is significant difference in triglyceride-glucose index in patients with or without cardiovascular event and the index is high in patients of cardiovascular event (p&lt;0.05). On the basis of these results we recommend the regular screening of patients for triglyceride-glucose index in order to predict the adverse consequences after coronary artery disease.

Predictive Effect of Triglyceride-Glucose Index on Adverse Prognostic Events in Patients with Type 2 Diabetes Mellitus and Ischemic Cardiomyopathy.

The triglyceride-glucose (TyG) index is regarded as an independent predictor of cardiovascular (CV) consequences and a reliable surrogate measure of insulin resistance (IR). However, the predictive significance of the TyG index in patients with type 2 diabetes mellitus (T2DM) and ischemic cardiomyopathy (ICM) remains unknown. This study included 1514 consecutive subjects with ICM and T2DM. The tertile of the TyG index values was used to categorize these patients into three groups. Major adverse cardiac and cerebral events (MACCEs) were also noted. The TyG index was calculated using the [fasting triglycerides (mg/dL) × fasting plasma glucose (mg/dL)/2] equation. After adjusting for age, BMI, and other potential confounders, the scores of multivariate Cox proportional hazards regression models for chest pain [9.056 (4.370 to 18.767), p<0.001], acute myocardial infarction [4.437 (1.420 to 13.869), p=0.010], heart failure [7.334 (3.424 to 15.708), p<0.001], cardiogenic shock [3.707 (1.207 to 11.384), p=0.022], malignant arrhythmia [5.309 (2.367 to 11.908), p<0.001], cerebral infarction [3.127 (1.596 to 6.128), p<0.001], gastrointestinal bleeding [4.326 (1.612 to 11.613), p=0.004], all-cause death [4.502 (3.478 to 5.827), p<0.001] and cumulative incidence of MACCEs [4.856 (3.842 to 6.136), p<0.001] increased significantly with an increase in TyG index levels (all p<0.05). Time-dependent ROC analysis revealed that the area under the TyG index curve (AUC) reached 0.653 in the 3rd year, 0.688 in the 5th year, and 0.764 in the 10th year. The predictive efficiency of this model on MACCEs improved [net reclassification improvement (NRI): 0.361 (0.253 to 0.454); C-index: 0.678 (0.658 to 0.698); integrated discrimination improvement (IDI): 0.138 (0.098 to 0.175), all p<0.05] following the incorporation of the TyG index into the base risk model. TyG index could be useful in predicting MACCEs and initiating preventive measures in subjects with ICM and T2DM.

Association between triglyceride glucose-body mass index and cardiovascular outcomes in patients undergoing percutaneous coronary intervention: a retrospective study

BackgroundThe triglyceride glucose-body mass index (TyG-BMI index) has been considered a reliable surrogate measure of insulin resistance; however, its ability to predict the incidence of cardiovascular disease in individuals with coronary artery disease (CAD) remains uncertain. The aim of this study was to demonstrate the correlation between the TyG-BMI index and cardiovascular incidence.MethodsA total of 2533 consecutive participants who underwent percutaneous coronary intervention (PCI) and drug-eluting stent (DES) implantation were included. Data from 1438 patients was analyzed in the study. The endpoint was defined as a composite of acute myocardial infarction, repeat revascularization, stroke, and all-cause mortality (major adverse cardiac and cerebrovascular events, MACCEs) at 34-month follow-up. The formula for calculating the TyG-BMI index is ln [fasting triglyceride (mg/dL) × fasting blood glucose (mg/dL)/2] × BMI.ResultsAmong the 1438 participants, 195 incident patient cases of MACCEs were ascertained. The incidence of MACCEs showed no statistically significant differences in the TyG-BMI index tertiles in the overall population. Further exploratory subgroup analysis and multivariable logistic regression analysis revealed a linear relationship between the TyG-BMI index (per 1 SD increased) and MACCEs in the elderly patients (OR = 1.22, 95% CI 1.011–1.467, p = 0.038) and in the female patients (OR = 1.33, 95% CI 1.004–1.764, p = 0.047). The addition of the TyG-BMI index to traditional risk factor models in elderly and female patients did not improve risk prediction for MACCEs.ConclusionA higher TyG-BMI index was proportionally related to an increased incidence of MACCEs in the elderly or female patients. However, the inclusion of the TyG-BMI index did not provide better predictive performance for MACCEs in the elderly, specifically in female patients.

Diagnostic markers of insulin resistance to discriminate between prediabetes and diabetes in menopausal women.

Menopause is an important transition period in a woman's reproductive life during which hormonal changes occur, resulting in an increased risk of cardiovascular disease and type 2 diabetes. In this study, we assessed the possibility of using surrogate measures of insulin resistance (IR) to predict the risk of insulin resistance in perimenopausal women. The study involved 252 perimenopausal women living in the West Pomeranian Voivodeship. The methods employed in this study were diagnostic survey based on the original questionnaire, anthropometric measurement, and laboratory tests performed to determine the levels of selected biochemical parameters. In the entire study population, the highest area under the curve was found for the homeostasis model assessment-insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI). Triglyceride-glucose index (TyG index) showed a higher diagnostic value as a distinction tool between prediabetes and diabetes in perimenopausal women than the other markers. HOMA-IR significantly positively correlated with fasting blood glucose (r = 0.72; p = 0.001), glycated hemoglobin (HbA1C, r = 0.74; p = 0.001), triglycerides (TG, r = 0.18; p < 0.005), and systolic blood pressure (SBP, r = 0.15; p= 0.021), and negatively with high-density lipoprotein (HDL, r = -0.28; p = 0.001). QUICKI negatively correlated with fasting blood (r = -0.051; p = 0.001), HbA1C (r = -0.51; p = 0.001), TG (r = -0.25; p = 0.001), low-density lipoprotein (LDL, r = -0.13; p= 0.045), and SBP (r = -0.16; p = 0.011), and positively with HDL (r = 0.39; p = 0.001). Anthropometric and cardiometabolic parameters were found to significantly correlate with IR markers. HOMA-beta, the McAuley index (McA), visceral adiposity index (VAI), and lipid accumulation product (LAP) may be useful as predictors of pre-diabetes and diabetes in postmenopausal women.

METS-IR vs. HOMA-AD and Metabolic Syndrome in Obese Adolescents.

Obesity is associated with chronic low-grade inflammation in which is the key in the pathogenesis Insulin Resistance (IR) and Metabolic Syndrome (MetS). Homeostasis model assessment of insulin resistance (HOMA-IR) has been validated as a surrogate measure of IR. The combination of HOMA and adiponectin, known as HOMA-AD was proposed to measure IR in adults. However, study on these indicators in obese adolescents is still limited. This study aims to analyse METS-IR and HOMA-AD to determine MetS and IR in obese adolescents. A cross-sectional study was conducted on obese adolescents who looked healthy from secondary schools in Surabaya and Sidoarjo, East Java, aged 12-18 years. Subjects were selected randomly and grouped into 2, namely MetS and non-MetS based on IDF 2000. Anthropometric examination and blood measurements, such as fasting blood glucose levels, lipid profiles, insulin, and adiponectin level were carried out according to standards. HOMA-IR, HOMA-AD, AND METS-IR were calculated using formula. Spearman's Rho correlation were conducted between assessment tools (METS-IR and HOMA-AD) to identify the correlation with MetS component (lipid profile, FBG, and blood pressures). A receiving operation curve (ROC) performed to find area under curve (AUC) and cut-off points based on the biggest Youden index. A total of 250 subjects were enrolled the study, and found 103 subjects had MetS. METS-IR correlates with all lipid profile and blood pressures (p?<?0.05). While HOMA-AD correlated with TG (r?=?0.356, p?=?0.000), systolic-BP (r?=?0.188, p?=?0.003), and HDL-c levels (r=-0.249, p?=?0.000). Cut-off point for METS-IR to determines MetS in obese adolescents was???46.53 (sensitivity of 64.24% and specificity of 75.76%), while HOMA-AD was???0.43 (sensitivity of 71.52% and specificity of 59.60%). Cut-off point for METS-IR index to determines IR was???52.01 (sensitivity of 83.44% and specificity of 44.44%). Cut-off point for HOMA-AD to determine IR was???0.37 (sensitivity of 74.17% and specificity of 84.85%). METS-IR is better surrogate to determine MetS with cut-off point of???46.53, while HOMA-AD is better to determine IR with cut-off point???0.37 in obese adolescents. J. Med. Invest. 70 : 7-16, February, 2023.

Establishing a Reference Interval for an Estimate of Peripheral Insulin Resistance in a Group of Iraqi People

Background and aims: Insulin resistance (IR) is the cornerstone in pathophysiology of T2DM. Identifying people with IR can slow the progress to diabetes. Triglyceride and glucose index (TyG index) is a simple tool to assess IR without insulin measurement. This study aims at establishing the reference interval for TyG index in apparently healthy Iraqis. Material and method: This study involved (77) apparently healthy adults (41 men and 36 women) in Mosul, Iraq. Fasting Serum lipids, glucose and insulin were measured and BMI was calculated. The modified TyG index was calculated and compared to other surrogate measures of IR and its reference interval was calculated. Results: TyG index values were normally distributed and significantly correlated with HOMA-IR, Mc-Auley index, QUICKI, and triglycerides/ HDL-c index (r= 0.322, p= 0.004; r=-0.68, p&lt;0001; r= -0.29, p=0.01; r=0.84, p&lt;0.0001respectively). ANOVA and PostHoc Duncan’s analyses revealed significant differences in mean TyG between (lean people) and (overweight and obese subjects), (p=0.02). BMI- based TyG reference intervals were calculated as (4.11- 4.91) and (4.25- 5.05) respectively. This is the first study in Iraq to set a reference interval for TyG index. Values should be interpreted according to BMI.&#x0D;

The Triglycerides and Glucose Index is Negatively Associated with Insulin Secretion in Young Adults with Normal Weight.

Several studies have supported the usefulness of the triglycerides and glucose (TyG) index as a surrogate measure of insulin resistance; however, it has not been evaluated in insulin secretion. The aim of this study was to assess the association between the TyG index and insulin secretion in young adults with normal weight. Apparently healthy non-pregnant women and men, aged 18 to 23 years, were enrolled in a cross-sectional study. Overweight, obesity, pregnancy, smoking, alcohol consumption, diabetes, liver disease, renal disease, cardiovascular disease, and neoplasia were the exclusion criteria. Normal weight was defined by a body mass index (BMI)≥18.5<25.0 kg/m2 and the TyG index was calculated as the Ln [fasting triglycerides (mg/dl) x fasting glucose (mg/dl)]/2. A total of 1676 young adults with normal-weight, 1141 (68%) women, and 535 (32%) men were enrolled. Of them, 269 (16%) individuals exhibited insulin resistance; 213 (12.7%) women and 56 (3.3%) men. The linear regression analysis adjusted by gender, BMI, and waist circumference showed a significant association between the TyG index and HOMA-B (B=-35.90; 95% CI:-68.25 to-3.54, p=0.03) in the overall population. An additional analysis adjusted by BMI and waist circumference revealed that the TyG index is significantly associated with HOMA-B in subjects with and without insulin resistance (B=-104.73; 95% CI:-204.28 to-5.18, p=0.03 and B=-74.72; 95% CI:-108.04 to-41.40, p<0.001). The results of this study showed that the TyG index is negatively associated with insulin secretion in young adults with normal weight.

Incident Major Depressive Disorder Predicted by Three Measures of Insulin Resistance: A Dutch Cohort Study.

Major depressive disorder is the leading cause of disability worldwide. Yet, there remain significant challenges in predicting new cases of major depression and devising strategies to prevent the disorder. An important first step in this process is identifying risk factors for the incidence of major depression. There is accumulating biological evidence linking insulin resistance, another highly prevalent condition, and depressive disorders. The objectives of this study were to examine whether three surrogate measures of insulin resistance (high triglyceride-HDL [high-density lipoprotein] ratio; prediabetes, as indicated by fasting plasma glucose level; and high central adiposity, as measured by waist circumference) at the time of study enrollment were associated with an increased rate of incident major depressive disorder over a 9-year follow-up period and to assess whether the new onset of these surrogate measures during the first 2 years after study enrollment was predictive of incident major depressive disorder during the subsequent follow-up period. The Netherlands Study of Depression and Anxiety (NESDA) is a multisite longitudinal study of the course and consequences of depressive and anxiety disorders in adults. The study population comprised 601 NESDA participants (18-65 years old) without a lifetime history of depression or anxiety disorders. The study's outcome was incident major depressive disorder, defined using DSM-IV criteria. Exposure measures included triglyceride-HDL ratio, fasting plasma glucose level, and waist circumference. Fourteen percent of the sample developed major depressive disorder during follow-up. Cox proportional hazards models indicated that higher triglyceride-HDL ratio was positively associated with an increased risk for incident major depression (hazard ratio=1.89, 95% CI=1.15, 3.11), as were higher fasting plasma glucose levels (hazard ratio=1.37, 95% CI=1.05, 1.77) and higher waist circumference (hazard ratio=1.11 95% CI=1.01, 1.21). The development of prediabetes in the 2-year period after study enrollment was positively associated with incident major depressive disorder (hazard ratio=2.66, 95% CI=1.13, 6.27). The development of high triglyceride-HDL ratio and high central adiposity (cut-point ≥100 cm) in the same period was not associated with incident major depression. Three surrogate measures of insulin resistance positively predicted incident major depressive disorder in a 9-year follow-up period among adults with no history of depression or anxiety disorder. In addition, the development of prediabetes between enrollment and the 2-year study visit was positively associated with incident major depressive disorder. These findings may have utility for evaluating the risk for the development of major depression among patients with insulin resistance or metabolic pathology.

Effects of Micronutrient Supplementation on Glucose and Hepatic Lipid Metabolism in a Rat Model of Diet Induced Obesity.

Obesity increases the risk of metabolic disorders, partly through increased oxidative stress. Here, we examined the effects of a dietary micronutrient supplement (consisting of folate, vitamin B6, choline, betaine, and zinc) with antioxidant and methyl donor activities. Male Sprague Dawley rats (3 weeks old, 17/group) were weaned onto control (C) or high-fat diet (HFD) or same diets with added micronutrient supplement (CS; HS). At 14.5 weeks of age, body composition was measured by magnetic resonance imaging. At 21 weeks of age, respiratory quotient and energy expenditure was measured using Comprehensive Lab Animal Monitoring System. At 22 weeks of age, an oral glucose tolerance test (OGTT) was performed, and using fasting glucose and insulin values, Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) was calculated as a surrogate measure of insulin resistance. At 30.5 weeks of age, blood and liver tissues were harvested. Liver antioxidant capacity, lipids and expression of genes involved in lipid metabolism (Cd36, Fabp1, Acaca, Fasn, Cpt1a, Srebf1) were measured. HFD increased adiposity (p < 0.001) and body weight (p < 0.001), both of which did not occur in the HS group. The animals fed HFD developed impaired fasting glucose, impaired glucose tolerance, and fasting hyperinsulinemia compared to control fed animals. Interestingly, HS animals demonstrated an improvement in fasting glucose and fasting insulin. Based on insulin release during OGTT and HOMA-IR, the supplement appeared to reduce the insulin resistance developed by HFD feeding. Supplementation increased hepatic glutathione content (p < 0.05) and reduced hepatic triglyceride accumulation (p < 0.001) regardless of diet; this was accompanied by altered gene expression (particularly of CPT-1). Our findings show that dietary micronutrient supplementation can reduce weight gain and adiposity, improve glucose metabolism, and improve hepatic antioxidant capacity and lipid metabolism in response to HFD intake.

Role of ERβ in adipocyte metabolic response to wheel running following ovariectomy.

Estrogen receptor β (ERb), one of the two major estrogen receptors, acts via genomic and non-genomic signaling pathways to affect many metabolic functions, including mitochondrial biogenesis and respiration. This study assessed the effect of ERb classical genomic activity on adipocyte-specific and -systemic metabolic responses to wheel running exercise in a rodent model of menopause. Female mice lacking the ERb DNA-binding domain (ERbDBDKO, n = 20) and WT (n = 21) littermate controls were fed a high-fat diet (HFD), ovariectomized (OVX), and randomized to control (no running wheel) and exercise (running wheel access) groups and were followed for 8 weeks. Wheel running did not confer protection against metabolic dysfunction associated with HFD+OVX in either ERbDBDKO or WT mice, despite increased energy expenditure. Unexpectedly, in the ERbDBDKO group, wheel running increased fasting insulin and surrogate measures of insulin resistance, and modestly increased adipose tissue inflammatory gene expression (P ≤ 0.05). These changes were not accompanied by significant changes in adipocyte mitochondrial respiration. It was demonstrated for the first time that female WT OVX mice do experience exercise-induced browning of white adipose tissue, indicated by a robust increase in uncoupling protein 1 (UCP1) (P ≤ 0.05). However, KO mice were completely resistant to this effect, indicating that full ERb genomic activity is required for exercise-induced browning. The inability to upregulate UCP1 with exercise following OVX may have resulted in the increased insulin resistance observed in KO mice, a hypothesis requiring further investigation.

Associations of Metabolic/Obesity Phenotypes with Insulin Resistance and C-Reactive Protein: Results from the CNTR Study.

BackgroundObesity is a heterogeneous condition in terms of metabolic status. Different obesity phenotypes have various health risks. The aim of this work was to define different subtypes of obesity and investigate their relationship with inflammatory-cardiometabolic abnormalities among Chinese adult twins.MethodsThe analyses used data from 1113 adult twins in 4 provinces (Shandong, Zhejiang, Jiangsu and Sichuan) from Chinese National Twin Registry (CNTR) which collected detailed information. We defined those with 0 or 1 metabolic syndrome (MetS) components excluding waist circumference as metabolically healthy, and those with waist circumference ≥90 cm (for men) and ≥85 cm (for women) as obese. The two-category obesity status and metabolic states are combined to generate four metabolic/obesity phenotypes. High sensitivity C reactive protein (hsCRP) was measured to assess underlying inflammation and homeostasis model assessment of insulin resistance (HOMA-IR) was calculated as surrogate measure of insulin resistance. Mixed-effect linear regression models and fixed-effect linear regression models were used to analyse the correlation between HOMA-IR, hsCRP and different metabolic/obesity phenotypes.ResultsIn cross-sectional analyses of 1113 individuals (mean [SD] age, 46.6 [12.9] years; 463 obese [41.6%]), 20.3% obese twins were metabolic healthy and 64.2% non-obese twins were metabolic unhealthy. Serum HOMA-IR level was higher in metabolically unhealthy non-obesity (MUNO) (β=0.42, 95% CI: 0.21–0.64), metabolically healthy obesity (MHO) (β=0.68, 95% CI: 0.36–1.00) and metabolically unhealthy obesity (MUO) (β=0.69, 95% CI: 0.46–0.91) twins, compared with their metabolically healthy non-obesity (MHNO) counterparts. HsCRP was similar between MHO and MUO, which differed significantly to metabolic healthy non-obesity (MHNO).ConclusionMHO and MUNO phenotypes were common in Chinese twin population. Both phenotypes were associated with elevated IR and hsCRP which may not be benign and need to be concerned.

Insulin resistance and the adiponectin/leptin ratio as a surrogate measure of insulin resistance in Japanese collegiate baseball players.

No study has previously investigated insulin resistance in collegiate baseball players. The purposes of this study were to examine: 1) the insulin resistance; and 2) the usefulness of the adiponectin/leptin (A/L) ratio compared with the homeostasis model assessment of insulin resistance (HOMA-IR) for assessing insulin resistance in collegiate baseball players. Twenty collegiate baseball players with abdominal obesity (AO group) defined by a waist circumference (WC) ≥85 cm, 65 lean baseball players with a WC<85 cm (L group), and 20 controls who were sedentary for at least 1 year (C group) were compared. The Body Mass Index, WC, systolic and diastolic blood pressures, fasting plasma glucose, total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, apolipoprotein B, insulin, leptin, adiponectin, and high-sensitivity C-reactive protein (hs-CRP) were measured. The AO group had a significantly higher insulin level, HOMA-IR, and leptin level, and lower A/L ratio than the L and C groups. The AO group had a significantly higher prevalence of insulin resistance (50%) than the L (14%) group. The A/L ratio was significantly negatively correlated with body weight, Body Mass Index, WC, triglycerides, triglycerides/HDL-C ratio, apolipoprotein B, hs-CRP, insulin, HOMA-IR, and leptin, and positively correlated with HDL-C, whereas HOMA-IR was significantly positively correlated with body weight, Body Mass Index, WC, systolic and diastolic blood pressures, fasting plasma glucose, and insulin, and negatively correlated with adiponectin and the A/L ratio. In the forward stepwise multiple regression analysis, WC, triglycerides, and hs-CRP were the significant determinants for the A/L ratio, whereas diastolic blood pressure and WC were the significant determinants for HOMA-IR. This model explained 53.7% of the variance in the A/L ratio and 13.6% of the variance in HOMA-IR. The present study suggested that the baseball players with abdominal obesity had a significantly higher prevalence of insulin resistance than the lean baseball group. The A/L ratio may be more useful than HOMA-IR to accurately assess insulin resistance in male collegiate baseball players.

Triglyceride Glucose Index as a Surrogate Measure of Insulin Sensitivity in a Caucasian Pediatric Population

The triglyceride and glucose (TyG) index has been proposed as a simple surrogate of insulin resistance (IR) with high sensitivity as an IR index besides the well known homeostasis model assessment of IR (HOMA-IR). Limited data are reported in children. We investigated the sensitivity and specificity of TyG index in a pediatric Caucasian population, as a surrogate measure of IR and compared the results with HOMA-IR. We enrolled 541 children (11.7±2.71 yrs). According to body mass index (BMI) chart, the subjects were divided into three groups: normal weight BMI<75th percentile, overweight BMI 75th–95th percentile, and obese>95th percentile. TyG index was calculated as (ln[fasting triglycerides(mg/dl)×fasting plasma glucose(mg/dl)/2]) and considered pathological when exceeding 7.88. HOMA-IR was calculated as (insulin×glucose)/22.5 and defined pathological whenever exceeding 97.5th percentile for age and sex. In children with overweight/obesity TyG index was higher compared to normal weight subjects (p<0.001). TyG index was correlated with BMI (p<0.001); WHtR (p<0.001), total and HDL cholesterol (p<0.001); ALT (p<0.001), blood pressure (p<0.001). A correlation between TyG index and HOMAIR (p<0.001) as well as high TyG index and pathological HOMA-IR (p<0.001) were noted. The optimal cut-off for IR was considered 7.98 (sensitivity 60%; specificity 78%; AUC 0.69). TyG index is a useful and cost-effective index of IR among children and adolescents. The cutoff 7.98 may be used for IR risk screening in childhood obesity, but we recommend caution when used in other populations.

SUN-128 Impaired Fasting Glucose Is Associated with Insulin Resistance in Patients with Germline Mutations in the Multiple Endocrine Neoplasia Type 1 (MEN1) Gene

BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome characterized by hyperparathyroidism, pituitary adenomas, and gastro-entero-pancreatic neuroendocrine tumors. Patients with MEN1 mutations have impaired glucose homeostasis, but the role of insulin resistance and beta-cell function is unclear.METHODS: Using a case-control study design, a retrospective analysis of germline mutation-positive MEN 1 patients (n=289) seen at our institution between 1991-2019 was performed. Patients with diabetes and/or insulinoma were excluded. Subjects were age, BMI, sex and race matched 1:1 to unrelated, healthy controls. Fasting glucose, insulin, c-peptide, calcium, PTH, 25-OH vitamin D, cholesterol, LDL, HDL and triglycerides (TG) were compared between two groups. Homeostasis model assessment (HOMA-IR) and HOMA-beta cell function (HOMA-b) were used as surrogate measures of insulin resistance and beta-cell function, respectively. Data is presented as mean ± SD.RESULTS: MEN1 subjects (n=40; age 41±11 years; BMI 29.2±7.2 kg/m2) were matched to healthy controls (age 41±11 years; BMI 29.1±7.5 kg/m2). Only 3 MEN1 patients had no evidence of pancreatic neuroendocrine tumors. Impaired fasting glucose was more prevalent in MEN1 compared with controls (53% vs 10%, p<0.0001). HOMA-IR was positively associated with BMI, but not age, sex, calcium or vitamin D levels in either cohort. HOMA-IR adjusted for age, BMI, and sex was higher in patients with MEN1 compared with controls (4.01 vs. 2.44, adjusted ratio of means 1.54, 95% CI [1.14, 2.07], p=0.005). HOMA-b was not significantly different between the groups (177 vs. 129, adjusted ratio of means 1.17, 95% CI [0.86, 1.58], p=0.23). There were no significant differences in total cholesterol, LDL, HDL, and TG between the groups.CONCLUSION: Lower insulin sensitivity, but not impaired beta cell function may contribute to the higher prevalence of impaired fasting glucose in MEN1 patients compared with controls. Mechanistic studies into the role of menin loss in glucose homeostasis are warranted.

Influence of Genetic Ancestry on Human Serum Proteome

Disease risk varies significantly between ethnic groups, however, the clinical significance and implications of these observations are poorly understood. Investigating ethnic differences within the human proteome may shed light on the impact of ancestry on disease risk. We used admixture mapping to explore the impact of genetic ancestry on 237 cardiometabolic biomarkers in 2,216 Latin Americans within the Outcomes Reduction with an Initial Glargine Intervention (ORIGIN) study. We developed a variance component model in order to determine the proportion of variance explained by inter-ancestry differences, and we applied it to the biomarker panel. Multivariable linear regression was used to identify and localize genetic loci affecting biomarker variability between ethnicities. Variance component analysis revealed that 5% of biomarkers were significantly impacted by genetic admixture (p < 0.05/237), including C-peptide, apolipoprotein-E, and intercellular adhesion molecule 1. We also identified 46 regional associations across 40 different biomarkers (p < 1.13× 10-6). An independent analysis revealed that 34 of these 46 regions were associated at genome-wide significance (p < 5× 10-8) with their respective biomarker in either Europeans or Latin populations. Additional analyses revealed that an admixture mapping signal associated with increased C-peptide levels was also associated with an increase in diabetes risk (odds ratio [OR] = 6.07 per SD, 95% confidence interval [CI] 1.44 to 25.56, p = 0.01) and surrogate measures of insulin resistance. Our results demonstrate the impact of ancestry on biomarker levels, suggesting that some of the observed differences in disease prevalence have a biological basis, and that reference intervals for those biomarkers should be tailored to ancestry. Specifically, our results point to a strong role of ancestry in insulin resistance and diabetes risk.

Association of insulin resistance and β-cell dysfunction with incident diabetes among adults in China: a nationwide, population-based, prospective cohort study

National investigations on the interaction of insulin resistance, β-cell dysfunction, and obesity with the development of diabetes are scarce in China. We aimed to investigate the individual and joint associations of insulin resistance and β-cell dysfunction with incident diabetes, and to examine the modifying effect of BMI and waist circumference on these associations among adults with normal glucose tolerance and with prediabetes. In this nationwide, population-based, prospective cohort study, we analysed data from the China Cardiometabolic Disease and Cancer Cohort Study, which recruited adults aged 40 years or older during 2011-12 (baseline) and invited participants to attend follow-up visits in 2014-16. Patients with diabetes at baseline, missing data for baseline measures of glucose tolerance status, missing data for baseline homoeostasis model assessment (HOMA) indexes, missing data for baseline covariates, and missing data for measures of glucose tolerance status at follow-up visits were excluded. At baseline and follow-up visits, a comprehensive set of questionnaires, clinical measurements, oral glucose tolerance tests, and laboratory examinations were carried out following standardised protocols. Glucose tolerance status and prediabetes were defined according to the American Diabetes Association 2010 criteria. In the main analysis, we examined the contributions of insulin resistance (HOMA of insulin resistance [HOMA-IR]) and β-cell dysfunction (HOMA of β-cell function [HOMA-B]) to diabetes risk, and evaluated the impact of obesity on these associations. 94 952 participants (31 517 men and 63 435 women) were included in the analysis. High HOMA-IR was associated with a greater hazard of diabetes (quartile 4 vs 1: hazard ratio [HR] 6·70, 95% CI 6·08-7·39; per unit increase in Z score: HR 2·17, 95% CI 2·10-2·24) than low HOMA-B (quartile 1 vs 4: 4·08, 3·72-4·48; per unit decrease in Z score: 1·92, 1·85-2·00). Approximately 24·4% (95% CI 23·6-25·2) of the incident diabetes could be attributed to insulin resistance and 12·4% (11·2-13·7) could be attributed to β-cell dysfunction. The HRs for diabetes were 1·83 (95% CI 1·72-1·95) per unit increase in Z score of HOMA-IR and 2·03 (1·86-2·21) per unit decrease in Z score of HOMA-B among participants with normal weight; the corresponding HRs for diabetes were 2·02 (1·93-2·11) and 1·88 (1·79-1·98) among participants with obesity (pinteraction=0·0091). These associations and interactions were similar for participants with normal glucose tolerance or prediabetes. Insulin resistance shows a stronger association with incident diabetes than does β-cell dysfunction in Chinese adults, and this association pattern was more prominent among adults with obesity. Given the limitations of HOMA indexes as surrogate measures of insulin resistance and β-cell dysfunction, these findings should be interpreted with caution. National Natural Science Foundation of China.