Whole-body Insulin Sensitivity Index Research Articles

Validation of a screening panel for pediatric metabolic dysfunction-associated steatotic liver disease using metabolomics.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as NAFLD, is the most common liver disease in children. Liver biopsy remains the gold standard for diagnosis, although more efficient screening methods are needed. We previously developed a novel NAFLD screening panel in youth using machine learning applied to high-resolution metabolomics and clinical phenotype data. Our objective was to validate this panel in a separate cohort, which consisted of a combined cross-sectional sample of 161 children with stored frozen samples (75% male, 12.8±2.6 years of age, body mass index 31.0±7.0kg/m2, 81% with MASLD, 58% Hispanic race/ethnicity). Clinical data were collected from all children, and high-resolution metabolomics was performed using their fasting serum samples. MASLD was assessed by MRI-proton density fat fraction or liver biopsy and cardiometabolic factors. Our previously developed panel included waist circumference, triglycerides, whole-body insulin sensitivity index, 3 amino acids, 2 phospholipids, dihydrothymine, and 2 unknowns. To improve feasibility, a simplified version without the unknowns was utilized in the present study. Since the panel was modified, the data were split into training (67%) and test (33%) sets to assess the validity of the panel. Our present highest-performing modified model, with 4 clinical variables and 8 metabolomics features, achieved an AUROC of 0.92, 95% sensitivity, and 80% specificity for detecting MASLD in the test set. Therefore, this panel has promising potential for use as a screening tool for MASLD in youth.

The lncOb rs10487505 polymorphism impairs insulin sensitivity and glucose tolerance in children and adolescents with obesity.

Leptin plays a key role in the regulation of body weight and other endocrine systems. Recently, impairment of leptin gene transcription due to genetic variations in a long noncoding RNA (lncOb) has been described. This retrospective study aims to characterize the clinical and metabolic phenotype of children and adolescents with obesity who were homozygous for the lncOb rs10487505 leptin lowering allele. Enrolled children underwent an anthropometrical evaluation, biochemical assessment, and genotyping for lncOb rs10487505. Plasma leptin levels were assessed in 150 participants. A total of 434 patients were included and divided into two groups according to rs10487505 recessive inheritance (CC vs. GG/GC). Children who were homozygous for the C allele showed higher fasting insulin (p = 0.01), homeostasis model assessment of insulin resistance (p = 0.01), lower whole-body insulin sensitivity index (p = 0.02), and lower disposition index (p = 0.03). Moreover, CC patients presented with a higher prevalence of prediabetes (9.3% vs. 3.4%, p = 0.04) and a 2.9-fold (95% CI: 1.1-7.9, p = 0.04) higher risk of prediabetes compared with G-carriers independently from confounders. Leptin plasma levels were significantly lower in the CC group (p = 0.002). Hormone levels correlated with BMI z score (r = 0.19, p = 0.04), fasting insulin (r = -0.34, p < 0.0001), homeostasis model assessment of insulin resistance (r = -0.33, p < 0.0001), and disposition index (r = 0.20, p = 0.04). The lncOb rs10487505 polymorphism affects leptin circulating levels, worsens insulin resistance, and heightens the risk of prediabetes in children and adolescents with obesity.

1093-P: Incretins and Cardiac Autonomic Function in Youth with Obesity across the Glycemia Spectrum

Incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) have been related to vascular function with variable effects depending on obesity status in adults. The relationship of incretins to vascular function in youth is unclear. We hypothesized that endothelial and cardiac autonomic dysfunction (CAD) are related to lower GLP-1 and GIP in response to glucose ingestion in youth with dysglycemia compared with those with overweight (OW) or normal weight (NW) and normal glucose tolerance (NGT). Adolescents [50 male/52 female; 15.6±1.8 yrs; 24 NW-NGT, 22 OW-NGT, 27 prediabetes and 29 with type 2 diabetes (T2D)] underwent assessment of body composition (DXA scan), 2-hour oral glucose tolerance test (OGTT) with calculation of whole body insulin sensitivity index (WBISI), area under the curve (AUC) of glucose (BG), GLP-1 and GIP. Reactive hyperemia index (RHI), and heart rate variability (HRV), were measured by peripheral arterial tonometry. For HRV, a higher LF/HF (low frequency to high frequency ratio) is indicative of CAD with loss of parasympathetic tone and decreased HRV. The ratios of AUC-GLP-1 and AUC-GIP to AUC-BG were lower in the groups with dysglycemia compared NGT groups (p=0.016 and 0.001, respectively). GLP-1 and GIP were not related to RHI. Fasting and AUC-GLP-1, but not GIP, negatively related to LF/HF (r=-0.37, p=0.002 and r=-0.43, p&amp;lt;0.001 respectively). In a linear regression model with LnLF/HF as the dependent variable, AUC-BG (β=0.31, p=0.04) and AUC-GLP-1 (β=-0.44, p=0.002) contributed to the variance in LnLF/HF independent of %body fat, hs-CRP, WBISI, age, sex, race-ethnicity and Tanner stage (R2= 0.27, p=0.04). Youth with obesity and dysglycemia have impaired incretin response. Glycemia is negatively, whereas GLP-1 is positively associated with HRV after accounting for adiposity, WBIS and inflammation. GLP-1 may be an important determinant of CA function in youth with obesity across the glycemia spectrum. Disclosure H.El ayash: None. F.Bacha: Other Relationship; Takeda Pharmaceutical Co., Ltd., AstraZeneca. Funding U.S. Department of Agriculture-Agricultural Research Service

Association between serum S100A11 levels and glucose metabolism in diabetic process

BackgroundDiabetes mellitus (DM) is a prevalent non-communicable metabolic disease, and S100A11 is a newly identified gene closely related to metabolism. The association of S100A11 with diabetes is unclear. This study aimed to assess the relationship between S100A11 and markers of glucose metabolism in patients with different glucose tolerance and gender.MethodsThis study included 97 participants. Baseline data were obtained, and the serum levels of S100A11 and metabolic markers (glycated hemoglobin [HbA1c], insulin release test, and oral glucose tolerance test) were measured. Linear and nonlinear correlations between serum S100A11 levels and HOMA-IR, HOMA of β, HbA1c, insulin sensitivity index (ISI), corrected insulin response (CIR), and oral disposition index (DIo) were analyzed. The expression of S100A11 was also detected in mice.ResultsSerum S100A11 levels increased in patients with impaired glucose tolerance (IGT) of both genders. S100A11 mRNA and protein expression increased in obese mice. There were nonlinear correlations between S10011 levels and CIR, FPI, HOMA-IR, whole-body ISI in the IGT group. S100A11 was nonlinearly correlated with HOMA-IR, hepatic ISI, FPG, FPI, and HbA1c in the DM group. In the male group, S100A11 was linearly correlated with HOMA-IR and nonlinearly correlated with DIo (derived from hepatic ISI) and HbA1c. In the female population, S100A11 was nonlinearly correlated with CIR.ConclusionsSerum S100A11 levels were highly expressed in patients with IGT and in the liver of obese mice. In addition, there were linear and nonlinear correlations between S100A11 and markers of glucose metabolism, demonstrating that S100A11 has a role in diabetes.Trial registration ChiCTR1900026990

Glucose metabolism in systemic juvenile idiopathic arthritis

BackgroundSystemic juvenile idiopathic arthritis (SJIA) is a chronic systemic inflammatory disease in children. Overproduction of inflammatory cytokines in SJIA resembles that in adult onset Still disease. Chronic inflammation causes insulin resistance and consequently leading to abnormal glucose metabolism. Adults with rheumatoid arthritis (RA) have increased risks of abnormal glucose metabolism and diabetes. To date, glucose metabolism in patients with SJIA has not been elucidated.MethodsPatients with SJIA aged 4–25 years were recruited. All patients underwent an oral glucose tolerance test (OGTT). Indices of insulin sensitivity [homeostasis model assessment for insulin resistance (HOMA-IR) and whole-body insulin sensitivity index (WBISI)] and β-cell function [insulinogenic index (IGI) and disposition index (DI)] were calculated. Obese children with normoglycemia who underwent the OGTT were served as a control group.ResultsA total of 39 patients with SJIA, aged 4–25 years, median (IQR) BMI SDS was 0.1 (-0.5 to 1.7). Patients were divided into 2 groups, overweight/obese (OW/OB) (n = 11) and lean (n = 28). Only one obese patient had prediabetes and none had diabetes. In comparison with sex- and age-matched OW/OB controls (n = 33), OW/OB patients with SJIA had higher insulin resistance [median (IQR) HOMA-IR: 2.6 (2.1–3.3) vs 1.5 (0.8–2.0), p = 0.001], lower insulin sensitivity [median (IQR) WBISI: 3.7 (2.7–5.9) vs 5.4 (4.5–8.7), p = 0.024], and higher insulin secretion [median (IQR) IGI: 2.5 (2.0–3.5) vs 1.0 (0.8–1.9), p = 0.001]. In lean patients with SJIA, insulin sensitivity indices seemed to be comparable with those of lean controls.ConclusionsOverweight/obese children with SJIA seemed to have increased insulin resistance and thus may have an increased risk for developing diabetes.

Dysglycemia screening with oral glucose tolerance test in adolescents with polycystic ovary syndrome and relationship with obesity

BackgroundAdolescents with polycystic ovary syndrome (PCOS) are at increased risk of impaired glucose tolerance (IGT) and type 2 diabetes mellitus. The aim of this study is to evaluate dysglycemia and biochemical differences based on BMI status and assess the prognostic ability of elevated hemoglobin A1c (HbA1c) in predicting an abnormal 2 hour oral glucose tolerance test (OGTT).MethodsRetrospective cohort of female patients aged 11-18 years who underwent 75-g OGTT and were evaluated for PCOS at an urban tertiary care hospital between January 2002 to December 2017.ResultsIn 106 adolescents with PCOS who had OGTT results available, IGT was markedly pronounced in the ≥95th percentile BMI group (17 out of 72; 23.6%) compared with <95th percentile BMI group (4 out of 34; 11.7%). One patient with obesity met the criteria for type 2 diabetes. Patients with obesity had significantly higher homeostasis model assessment (HOMA-IR) and lower whole body insulin sensitivity index (WBISI) (p < 0.001) compared to patients without obesity. Free testosterone levels were also higher in patients with obesity (p< 0.03) and were significantly associated with HOMA-IR when controlling for body mass index (BMI). HbA1c did not demonstrate a strong ability to predict abnormal OGTT on receiver operating characteristic (ROC) curve analysis [Area under the curve (AUC) = 0.572, 95% CI: 0.428, 0.939]).ConclusionsIn a study to assess glucose abnormalities in adolescents with PCOS, IGT was found to be markedly increased in patients with obesity, with abnormal glucose metabolism identified in over one-fifth of the patients. HbA1c alone may be a poor test to assess IGT and we recommend that adolescents diagnosed with PCOS and obesity undergo formal oral glucose tolerance testing.

Abstract P100: Changes In Adiponectin But Not Tnfα Predict Changes In Insulin Sensitivity Following Health Behavior Intervention Among Latino Youth

Background: Pediatric obesity is characterized by an imbalance in pro- and anti-inflammatory markers that are associated with cardiometabolic diseases. Adiponectin (Adpn), an anti-inflammatory marker, is associated with insulin sensitivity, while tumor necrosis factor-alpha (TNFα) has been associated with insulin resistance among youth with obesity. However, it is unknown whether longitudinal changes in Adpn or TNFα predict changes in insulin sensitivity among high-risk youth. Methods: A total of 73 Latino youth with obesity (age 13.3±1.4 y, Female 40.3%, BMIz 2.2±0.3) were enrolled in either a lifestyle intervention or usual care. Given that there were no between-group differences in changes in insulin sensitivity at 6-months, groups were combined for the present analysis. Fasting serum samples were used to measure high-molecular weight Adpn and TNFα before and after intervention. Insulin sensitivity was estimated by the whole-body insulin sensitivity index (WBISI) using insulin and glucose concentrations from a 75-g, 2-h oral glucose tolerance test. Baseline associations were analyzed using Pearson correlations. Linear regression was used to analyze whether changes in Adpn or TNFα predict changes in WBISI, adjusting for age, sex, and intervention assignment. Data from linear regressions are presented as betas (β) and standard errors (SE). Results: At baseline, WBISI was positively and significantly associated with Adpn (r=0.296, p=0.015) but not with TNFα (r=-0.171, p=0.168), adjusting for age and sex. Increases in Adpn were associated with increases in WBISI, whereby for every 1 μg/dL increase in Adpn, there was a 0.7 unit increase in WBISI (SE=0.3, p=0.027). Changes in TNFα did not significantly predict changes in WBISI (β=0.1, SE=0.5, p=0.915). Conclusion: Changes in Adpn but not TNFα were associated with changes in insulin sensitivity following intervention among Latino youth with obesity. Whether Adpn is the mechanism by which health behavior changes increase insulin sensitivity warrants further investigation among high-risk youth populations.

Autonomic Nervous System Function in Newly Diagnosed Multiple Sclerosis: Association With Lipid Levels and Insulin Resistance.

Autonomic nervous system (ANS) disorders are common in multiple sclerosis (MS). Previous studies showed differences in insulin resistance (IR) and lipoprotein levels in MS subjects compared to controls. Lipolysis caused by increased sympathetic activity could be one of the possible linking mechanisms leading to dyslipidemia in MS. Our study aimed to evaluate ANS activity in the context of glucose and lipid metabolism in people with MS. We prospectively measured short-term heart rate variability (HRV), fasting lipoprotein concentrations, and calculated IR indices based on plasma glucose and insulin levels during oral glucose tolerance test (oGTT) in 32 patients with MS and 29 healthy controls matched for age, sex and body mass index in our study. There was no significant difference in HRV parameters and lipoprotein levels between MS and controls. A significant positive correlation was found between low/high-frequency power ratio (LF/HF) and triglycerides (r=0.413, p=0.021) in MS subjects but not in controls. A significantly lower whole-body insulin sensitivity index (ISIMat) was found in patients with MS compared to the control group (7.3±3.7 vs. 9.8±5.6, p=0.041). No significant correlations were found between LF/HF and IR parameters. In MS subjects, the positive correlation of LF/HF with triglycerides could reflect the effects of sympathetic activity on lipolysis. Positive correlations of sympathetic activity with increased lipoprotein levels could rather reflect processes associated with immune system activation/inflammation, than processes involved in glucose homeostasis maintenance.

Correlation between total testosterone levels and insulin resistance in patients with acanthosis nigricans and non-acanthosis nigrican

To investigate the correlation of the total testosterone (TT) level with insulin secretion and resistance in patients with acanthosis nigricans (AN) and non-acanthosis nigricans (NAN). This study was conducted in a total of 639 overweight patients (body mass index ≥24 kg/m2), including 137 female AN patients, 277 female NAN patients, 129 male AN patients, and 146 male NAN patients. Each group was further divided into 4 subgroups according to the quartile of TT level for comparison of insulin secretion and insulin resistance parameters. Both female and male patients with AN showed obvious hyperinsulinemia with increased area under the curve for insulin (AUC-INS) (P < 0.05), increased homeostatic model assessment of insulin resistance (HOMA-IR) index (P < 0.05) and decreased whole-body insulin sensitivity index (WBISI) (P < 0.01) as compared with those in NAN groups, but these parameters did not show significant variations with the change of TT levels. In female patients with NAN, insulin secretion level increased progressively as the TT level increased; the AUC-INS increased (P < 0.01) and WBISI decreased significantly (P < 0.05) when the TT levels increased to Q4. In male patients with NAN, insulin secretion level increased progressively as the TT levels decreased, and the AUC-INS increased (P < 0.05) and the WBISI decreased significantly (P < 0.05) when the TT levels decreased to Q1. The TT level has a significant effect on insulin resistance and insulin secretion, but its effect varies between genders and is more significant in NAN patients than in AN patients.

Changes in OGTT-derived biomarkers in response to lifestyle intervention among Latino adolescents with obesity.

Glucose concentrations during an oral glucose tolerance test (OGTT) have been used as biomarkers to differentiate type 2 diabetes risk phenotypes. No studies have examined changes in OGTT-glucose phenotypes following lifestyle intervention among high-risk youth. To examine changes in OGTT-glucose phenotypes following lifestyle intervention and to explore differences in insulin sensitivity and β-cell function among post-intervention phenotypes. Latino adolescents with obesity (n=48, age 15.4 ± 1.0, BMI% 98.2 ± 1.4, female 56.3%) completed a 12-week lifestyle intervention that included weekly nutrition education and physical activity. At baseline and 12 weeks, youth completed a 2-h OGTT with glucose and insulin concentrations assessed at 0', 30', 60', 90' and 120'. Glucose concentrations during the OGTT were used to identify biomarkers, 1-h glucose, glucose response curve and time to glucose peak. Using these respective biomarkers, high-risk (1-h glucose ≥ 155 mg/dl, Monophasic, Late Peak) and lower-risk phenotypes (1-h glucose < 155 mg/dl, Biphasic, Early Peak) were categorized. Insulin sensitivity was estimated by whole-body insulin sensitivity index (WBISI) and β-cell function by oral disposition index (oDI). Following intervention, the prevalence of Monophasic phenotypes decreased from 81% to 67% (p=0.048) and 1-h glucose ≥ 155 mg/dl from 38% to 10% (p=0.054). Although Late Peak phenotypes did not significantly change (from 58% to 29%, p=0.200), Early Peak phenotypes at post-intervention demonstrated significantly higher WBISI compared to Late Peak (2.3 ± 0.1 vs 1.7 ± 0.2, p=0.023). OGTT-glucose phenotypes improve following lifestyle intervention among high-risk youth. These findings further support their potential utility as clinical biomarkers to identify diabetes risk and risk reduction in youth.

Reduced Insulin-Like Growth Factor 1 Is Associated with Insulin Resistance in Obese Prepubertal Boys.

As one of the most common features of obesity, insulin resistance is central to the pathogenesis of the metabolic syndrome. Low insulin-like growth factor 1 (IGF-1) levels have been proven to be associated with many traditional cardiovascular risk factors, but it still remains controversial with the relationship between IGF-1 and insulin resistance. Accordingly, the main purpose of this study is to investigate the relationship between IGF-1 and insulin resistance in obese prepubertal boys. We used the whole-body insulin sensitivity index (WBISI) to represent insulin resistance. 70 obese prepubertal boys were included in the study, and the obese subjects were divided into two groups by using 1.285 as a threshold value for WBISI. Clinical examination and laboratory examinations were assessed for all participants. Among obese boys, the group of children with WBISI ≤ 1.285 had lower IGF-1 standard deviation scores (SDS) (p = 0.021) than the WBISI > 1.285 group. The results of multiple linear analyses show that lg WBISI was positively correlated with IGF-1 SDS (p = 0.031) after adjusting for traditional cardiovascular risk factors. IGF-1 SDS was negatively associated with insulin resistance in obese prepubertal boys, independent of other traditional cardiovascular disease risk markers.

Changes in β-Cell Function in Offspring of Type-2 Diabetic Patients, as per Fasting and Two-Hour Plasma Glucose Levels.

BackgroundThe changes in β-cell function in high-risk populations who are apparently in the normal glucose tolerant stage are still under investigation for designing earlier prevention strategies. This study analyzes changes in β-cell function and insulin sensitivity across fasting and two-hour glucose categories spanning normal glucose tolerance (NGT) to impaired glucose tolerance (IGT), in offspring of subjects with type-2 diabetes mellitus (T2DM) compared to the controls without a known family history of T2DM.MethodsOffspring of T2DM patients (cases) and individuals without a family history of T2DM (controls) were the subjects for this cross-sectional study. All participants underwent a 75 g oral glucose tolerance test and blood samples were collected for plasma glucose, insulin, C-peptide and proinsulin, at zero, 30, 60, and 120 minutes. ResultsA total of 358 cases (age 23.0 ± 10.8 years, 54% males) and 287 controls (age 28.4 ± 8.10 years, 65% males) were the subjects of this study. Cases and controls were divided into subgroups based on fasting and two-hour glucose categories spanning NGT to IGT. Compared to the reference category of controls (< 80 mg/dL for fasting glucose and < 84 mg/dL for two-hour glucose), cases with IGT had ~60% decline in both β-cell compensation (as measured as disposition index {0-120}) and insulin sensitivity (as measured as whole-body insulin sensitivity index {0-120}); adjusted for age, gender, and body mass index. From lower to higher fasting and two-hour glucose categories, there was a continuous and significant decline in β-cell compensation in both cases and controls. Significant reduction in first-phase insulin secretion, as measured as insulinogenic (0-30) index, was only observed among two-hour glucose categories, not among the fasting glucose categories. In the transition from late NGT cases to IGT cases, there was a significant decline in β-cell compensation, first-phase insulin secretion (more prominent than a decline in overall β-cell secretion) and the changes in whole-body insulin sensitivity were not statistically significant.ConclusionsThe decline in β-cell compensation was continuous and significant in offspring of subjects with type-2 diabetes and controls without a known family history of diabetes from early normal glucose tolerant ranges to impaired glucose tolerant ranges. Compared to the strictest glucose controlled category of controls, approximately 60% decline was observed in β-cell compensation and insulin sensitivity, in impaired glucose tolerant offspring of subjects with type-2 diabetes mellitus.

Association of Omental Adipocyte Hypertrophy and Fibrosis with Human Obesity and Type 2 Diabetes.

Morphological alterations including adipocyte hypertrophy and fibrosis deposition are important surrogate markers of visceral adipose tissue function, but the relationships between these morphological changes and type 2 diabetes mellitus (T2DM) and impaired insulin sensitivity are poorly defined. Omental adipose tissue was obtained from 66 individuals with obesity but without T2DM (OB group), 93 individuals with both obesity and T2DM (T2DM group), and 15 individuals with normal BMI and normal glucose tolerance (NGT group). Adipocyte diameter and volume were measured through pathological section analysis. Pericellular and perilobular fibrosis was determined through picrosirius red staining and immunochemistry, while fibrosis-related genes were tested through gene expression and hydroxyproline content. Compared with the NGT and OB groups, individuals from the T2DM group displayed increased adipocyte diameter and volume levels. Increased adipocyte size (diameter and volume) was positively associated with hyperglycemia and insulin resistance and inversely correlated with insulin sensitivity (using the Matsuda whole-body insulin sensitivity index assessment of insulin sensitivity) and β-cell function (disposition index 30 and disposition index 120). The fibrosis levels of the OB group were the highest out of the three groups, whereas the fibrosis levels of T2DM individuals were lower than the OB group but higher than the NGT group. Although fibrosis was negatively correlated with T2DM, fibrosis deposition was not remarkably associated with impaired systemic insulin sensitivity and glucose metabolism. Compared with fibrosis deposition, adipocyte hypertrophy is more closely associated with T2DM and impaired systemic insulin sensitivity.

Lipoprotein Insulin Resistance Score: Validation and Utility in African Ancestry Populations

Lipoprotein insulin resistance (LPIR) is an emerging biomarker of insulin resistance (IR), and a score of >48 is a strong predictor of incident cardiometabolic disease disease in a predominantly European ancestry population. LPIR is derived from a composite score of nuclear magnetic resonance (NMR) lipoprotein (Lp) parameters: triglyceride-rich (TRLp), low density (LDLp), and high density (HDLp). Yet, there is a paucity of data in African ancestry population, in whom there is low-normal TRLp despite high rates of IR and diabetes. Therefore, we examined Lp profiles and LPIR in a large African ancestry cohort, stratified by sex to determine the relationship of LPIR with established markers of IR. This is a secondary analysis from 2 studies (The Africans in America and Federal Women’s Study) designed to evaluate the genetic, biological and socio-environmental factors of diabetes risk in those of African ancestry. All participants self-identified as healthy and lived in the DC metro area, n= 518: 87.7% African immigrant,12.3% African American; age 39±10 (20-65y); BMI 28.1±4.8 (18.2–45.2 kg/m2); 58% male; 31% with obesity, and 37% with abnormal glucose tolerance; mean±SD (range); median (25th-75th percentile). Fasting measures of IR (LPIR, triglyceride/HDL (TG/HDL) ratio and homeostasis model of insulin resistance (HOMA-IR)) were compared with the whole-body insulin sensitivity index (WBISI) obtained during a multi-sample 75g OGTT, using spearman correlations. Lp particle size and subclass concentrations were measured by the amplitudes of the lipid-methyl group signals (NMR LipoProfile®). Men had lower BMI (27.1±3.9 vs 29.3±5.6 kg/m2), fat mass (23.5±5.5 vs 37.9±6.8 %), insulin resistance (WBISI: 6.2 (3.7–10.1) vs 4.9 (3.2–8.6), HOMA-IR: 1.3 (0.7–2.0) vs 1.6 (0.9–2.4), TG/HDL: 1.4 (1.0–2.2) vs 1.1 (0.8–1.5)), all P<0.001. LDLp (1226 (959–1531) vs 1239 (981–1553) nmol/L) and HDLp (17.6 (16.2–19) vs 17.5 (15.9–19.7) µmol/L) were similar by sex, P>0.6, while small LDLp 734 (523–1039) vs 541 (370–805) nmol/L and TRLp 80.5 (52.2–116.4) vs 53.6 (28.7 -89.3) nmol/L were higher in men. The total mean LPIR score was 28.9±18.7 and was higher in men (34±19 vs. 23±17), P<0.001. LPIR and TG/HDL ratio correlated with WBISI (r≥-0.40) and HOMA-IR (r≥0.40), P<0.001 with no differences by sex. HOMA-IR correlated with WBISI (r=-0.95, P<0.001). Overall, African ancestry individuals had high rates of abnormal glucose tolerance, obesity and LDLp but LPIR was 20 points lower than the established score for predicting cardiometabolic disease. It’s utility for detecting IR was modest but it may be an important adjunct for early cardiometabolic risk stratification in African ancestry populations in whom traditional screening methods have lower sensitivity.

Prevalence and Features of Impaired Glucose Tolerance in Young Underweight Japanese Women.

In Japan, while it is known that underweight women over the age of 40 years have a high risk for type 2 diabetes, there is a lack of clarity on the association between glucose tolerance and underweight in younger women. Accordingly, we investigate the prevalence and features of impaired glucose tolerance (IGT) in young underweight Japanese women. In this cross-sectional study, we recruited 56 normal weight and 98 underweight young Japanese women and evaluated their glucose tolerance levels using an oral glucose tolerance test. Then, we compared the clinical characteristics associated with normal glucose tolerance (NGT) and IGT in the underweight women. Insulin secretion, whole-body insulin sensitivity, and adipose tissue insulin resistance values were measured using the insulinogenic index, whole-body insulin sensitivity index (Matsuda index), and adipose insulin resistance index (Adipo-IR), respectively. Fitness level (peak VO2) was measured using an ergometer. The prevalence of IGT was higher in the underweight women than the normal weight women (13.3% vs 1.8%). The underweight women with IGT showed a lower insulinogenic index, lower peak VO2, and Matsuda index and a higher fasting free fatty acid level and Adipo-IR than those with NGT. The whole-body composition was comparable between the NGT and IGT groups. The prevalence of IGT was higher in young Japanese women with underweight than those with a normal weight. The underweight women with IGT showed impaired early-phase insulin secretion, low fitness levels, and reduced whole-body and adipose tissue insulin sensitivity levels.

PSVIII-40 Late-Breaking Abstract: Variability in body composition is associated with insulin sensitivity in growing-finishing pigs

Abstract Growing pigs’ body composition variation can be associated with differences in insulin sensitivity given the insulin anabolic effect on protein and lipid synthesis. The objective of this study was to elucidate this association by relating the individual insulin response to the oral glucose tolerance test (OGTT) with the body composition of growing pigs. Thirty 95 kg jugular vein catheterized pigs received an oral dose of 1.75 g of glucose/kg of BW after 18 hours of fasting. Blood samples were collected at -20, -10, 5, 10, 15, 20, 25, 30, 45, 60, 90, 120, 150, 180, 210, 240, 300 and 360 min following glucose ingestion. Insulin sensitivity indexes were calculated and analyzed. Body lipids (LB, %) and protein (PB, %) composition were estimated by dual X-ray densitometry. Association between body composition and insulin sensitivity were studied by using partial least squares and correlations. Average LB and PB were 19.7% (CV = 7.6 %) and 16.2% (CV = 2.2%), respectively. Basal insulin blood concentration and area-under-the-curve (AUC) CV (51.9 % and 26.9 %, respectively) were larger than those for basal glucose and AUC (5.52 and 5.48 %, respectively). Additionally, insulin sensitivity (%S), steady-state beta cell function (%B), and insulin resistance (HOMA-IR) estimated with the Homeostasis Model Assessment (HOMA 2) and whole-body insulin sensitivity index (ISI) were highly variable between pigs which CV ranged from 30.1 % to 54.5 %. These results can indicate an early stage of insulin resistance in an important part of the studied pig population. LB and PB were affected by insulin sensitivity indexes (P &amp;lt; 0.05) which accounted, respectively, for 48% and 44% of the observed variation. In conclusion, lower insulin sensitivity was associated with higher body fat in growing pigs raised under similar conditions.

Ethinyl estradiol vs estradiol valerate in combined oral contraceptives – Effect on glucose tolerance: A randomized, controlled clinical trial

ObjectiveTo compare the effects of two formulations of combined oral contraceptives (COCs), estradiol valerate (EV) and ethinyl estradiol (EE) combined with dienogest (DNG), and DNG-only, on glucose tolerance. Study DesignWe performed a randomized, controlled 9-week clinical trial. Inclusion criteria were: age 18–35 years, regular menstrual cycle (28 ± 7 days), no polycystic ovaries, non-smoking, no contraindications for COC use and a 2-month wash-out from hormonal contraceptive use. The women were randomized to EV + DNG (n = 20), EE + DNG (n = 20), and DNG-only (n = 19), and evaluated at baseline, at 4–5 weeks and 8–9 weeks of treatment. Study medications were used continuously for 63 days. Primary outcome measure was change in the whole-body insulin sensitivity index (Matsuda index) derived from the oral glucose tolerance test (OGTT) over the treatment period. Secondary outcome measures were area under curves (AUC) of glucose and insulin, homeostatic model assessment – insulin resistance (HOMA-IR) and Insulin Sensitivity Index (ISI). ResultsFifty-nine women enrolled, and 56 women completed the study. The Matsuda index changed from baseline as follows (mean percentage change, mean change [95%CI]): DNG-only −12%, −1.45 [95%CI −3.22–0.325] P = 0.10; EV + DNG + 2.7%, −0.10 [−1.34 to 1.14] P = 0.86; EE + DNG −5.5%, −1.02 [−2.51 to 0.46] P = 0.16, comparing the groups P = 0.27. There were no clinically significant differences in glucose tolerance between the COC groups, but the DNG-only group showed an improvement in the 2-h glucose levels (5.5 [95%CI 5.0–6.0] to 4.7 mmol/l [4.2–5.2], P = 0.001). ConclusionWe found no clinically significant differences between EV and EE combined with DNG and DNG-only on glucose tolerance in healthy, young, normal-weight women, indicating that these preparations appear close to neutral regarding glucose metabolism when used continuously for nine weeks. ImplicationsCombinations of both ethinyl estradiol and natural estradiol (estradiol valerate) with dienogest (DNG), as well as DNG-only, seem metabolically safe in young and healthy women in short-term continuous use.

Uric acid, impaired fasting glucose and impaired glucose tolerance in youth with overweight and obesity

Background and aimThe relationships between uric acid (UA) and prediabetes is poorly explored in youth. We investigated the association between UA, impaired fasting glucose (IFG), impaired glucose tolerance (IGT), insulin resistance (IR) and low insulin sensitivity (IS) in youth with overweight/obesity (OW/OB). Methods and resultsA cross-sectional study was performed in 2248 youths with OW/OB (age 5–17 years). The sample was stratified in sex-specific quintiles (Q1 to Q5) of UA and the associations with fasting (FG), 2-h post-load glucose (2H-PG), IR and low IS were investigated. IR and low IS were estimated by assessment model of insulin resistance (HOMA-IR) and whole-body IS index (WBISI), respectively. IFG was defined as FG ≥ 100 < 126 mg/dL, IGT as 2H-PG ≥140 < 200 mg/dL, IR as HOMA-IR ≥75th percentile and low IS as WBISI ≤25th percentile by sex. Age, body mass index z-score, 2H-PG, HOMA-IR and WBISI, increased across sex-quintiles of UA while FG did not. The prevalence of IFG and IR were significantly increased in Q5 vs Q1 (reference quartile, P < 0.025). The prevalence of IGT increased from Q3 to Q5 vs Q1 (P < 0.025–0.0001) and that of low IS from Q2 to Q5 vs Q1 (P < 0.005–0.0001). ConclusionsIn youth with OW/OB, rates of IGT and low IS increased progressively across quintiles of UA. On the contrary, IFG and IR were associated only with the highest quintile of UA. Our data suggest that UA is a biomarker of impaired glucose metabolism prevalently in post–challenge condition rather than in fasting state.

1254-P: Trauma and Loss-of-Control (LOC) Eating Relate to Elevated Type 2 Diabetes (T2D) Risk in Adolescents

Objective: Traumatic events, including abuse, neglect, and other dangerous/shocking experiences, are commonly observed in adolescents with T2D. Research has shown there is a link between trauma and poorer health outcomes, yet, the extent to which trauma increases risk for developing T2D is not well understood. Trauma may heighten T2D risk through LOC eating, which can arise to cope with negative emotions. Our aim was to evaluate the links of trauma and LOC eating with T2D risk in adolescent girls with obesity. Methods: Participants (n=65, mean±SD 15.2±1.6y) were girls at-risk for T2D based on BMI ≥85%ile, ≥1 family member with T2D, and elevated depression (Center for Epidemiologic Studies Depression [CES-D] score ≥21). Trauma history (presence vs. absence) was assessed with the Schedule for Affective Disorders and Schizophrenia for School-Aged Children, and LOC eating (presence vs. absence) with the Eating Disorder Examination. T2D risk was assessed as HbA1c and Matsuda Whole Body Insulin Sensitivity Index (WBISI), derived from a 7-sample 2-hr OGTT. ANCOVA tested differences in HbA1c and WBISI by trauma and LOC, controlling for age, BMIz, race/ethnicity, and depression. Results: Trauma history was endorsed in 40.6% and LOC eating in 36.4% of girls. Girls with and without a trauma history reported similar rates of LOC (36.4% vs. 37.5%, p=.93). Girls with trauma had higher HbA1c (5.7±0.06%) vs. those with no trauma (5.5±0.05%, p=0.04), with no difference in WBISI (p=0.32). Girls with LOC had worse WBISI vs. those with no LOC (3.0±0.53 vs. 4.8±0.40, p&amp;lt;0.01), with no difference in HbA1c (p=0.21). Conclusions: Trauma history and LOC eating were unrelated to each other, but each related to different aspects of elevated T2D risk. Attention to both factors may warrant consideration in intervening to lessen T2D risk in teens with obesity and elevated depression. Disclosure V. Jimenez: None. A.M. Hilkin: None. M.M. Verros: None. E.L. Clark: None. M. Casamassima: None. R.L. Miller: None. L. Pyle: None. M.M. Kelsey: Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Janssen Pharmaceuticals, Inc., Merck Sharp &amp; Dohme Corp. L.B. Shomaker: None.

SAT-431 Insulin Resistance, Lipid Profile and High-Sensitivity C-Reactive Protein in Patients with Autoimmune Thyroiditis

Introduction: Thyroid function and autoimmunity has been associated with cardiovascular events in patients with autoimmune thyroiditis. Objectives: To evaluate the association between thyroid function, antithyroid antibodies levels, insulin resistance and markers of cardiovascular risk in patients with autoimmune thyroiditis. Methods: We evaluated 228 patients with autoimmune thyroiditis, 93.9 % female, with a mean age of 47.06 ± 15.35 years. We analyzed thyroid function, anti-thyroglobulin antibodies (anti-Tg), anti-thyroid peroxidase antibodies (anti-TPO), HOMA-IR, HOMA-B, QUICKI, HISI (Hepatic Insulin Sensitivity Index), WBISI (Whole-Body Insulin Sensitivity Index), the levels of lipid profile, high-sensitivity C-reactive protein (hs-CRP), homocysteine, folic acid, and vitamin B12. We defined 3 groups based on TSH levels: TSH between 0.35-2.49 µUI/ml, (n = 166), TSH between 2.50-4.94 µUI/ml, (n = 43) and TSH over 4.95 µUI/ml, (n = 19), and normal levels of free T4 and free T3. A 75-g OGTT was performed in the morning and blood samples were obtained every 30 min for 120 min for measurements of plasma glucose, insulin, and C-peptide. For the statistical analysis we used the Mann-Whitney test and Spearman correlations. Results are expressed as means ± SD or percentages. A two-tailed p<0.05 was considered statistically significant. Results: There were no significant differences regarding median age or median BMI between groups. We did not find any significant differences comparing group with TSH 0.35-2.49 and group with TSH 2.50-4.94, in all parameters evaluated. Group with TSH 2.50-4.94 had higher indexes of QUICKI (0.69 ± 0.39 vs 0.48 ± 0.13; p = 0.02) and HISI (79.83 ± 63.72 vs 41.73 ± 29.02; p = 0.01) than group with TSH over 4.95. The group with TSH over 4.95 demonstrated a higher index of HOMA-IR than group with TSH 2.50-4.94 (3.77 ± 2.93 vs 1.95 ± 1.24; p = 0.01). In the TSH 0.35-2.49 group we found significant correlations between TSH and HOMA-IR (r= 0.18; p = 0.01), total cholesterol and anti-TPO (r =0.23; p = 0.002), anti-Tg and HDL-cholesterol (r= -0.17; p=0.002), anti-Tg and triglycerides (r=0.34; p < 0.001), and anti-Tg and LDL-cholesterol (r=0.16; p=0.03). In the TSH 2.50-4.94 group we observed positive correlation between Apo A1 and HOMA-B (r=0.58; p<0.001), HOMA-IR and LDL-cholesterol (r=0.34; p=0.02) and WBISI and HDL-cholesterol (r=0.34; p=0.02). In the TSH over 4.95 group we observed a correlation between TSH and triglycerides (r=0.70; p<0.001) and between anti-Tg and hs-CRP (r=0.64; p=0.004). Conclusions: The association among TSH, lipid profile, insulin resistance, hs-CRP and antithyroid antibodies in patients with autoimmune thyroiditis may contribute to an increased cardiovascular risk, not only in patients with subclinical hypothyroidism but also in those classified as euthyroid.