Lipoprotein Insulin Resistance Score Research Articles

The Nutri-Score nutrition label: Associations between the underlying nutritional profile of foods and lipoprotein particle subclass profiles in adults

Background and aimsLipoprotein particle concentrations and size are associated with increased risk for atherosclerosis and premature cardiovascular disease. Certain dietary behaviours may be cardioprotective and public health strategies are needed to guide consumers’ dietary choices and help prevent diet-related disease. The Food Standards Agency nutrient profiling system (FSAm-NPS) constitutes the basis of the five-colour front-of-pack Nutri-Score labelling system. No study has examined FSAm-NPS index associations with a wide range of lipoprotein particle subclasses. MethodsThis was a cross-sectional study of 2006 middle-to older-aged men and women randomly selected from a large primary care centre. Individual participant FSAm-NPS dietary scores were derived from validated food frequency questionnaires. Lipoprotein particle subclass concentrations and size were determined using nuclear magnetic resonance spectroscopy. Multivariate-adjusted linear regression analyses were performed to examine FSAm-NPS relationships with lipoprotein particle subclasses. ResultsIn fully adjusted models which accounted for multiple testing, higher FSAm-NPS scores, indicating poorer dietary quality, were positively associated with intermediate-density lipoprotein (β = 0.096, p = 0.005) and small high-density lipoprotein (HDL) (β = 0.492, p = 0.006) concentrations, a lipoprotein insulin resistance score (β = 0.063, p = 0.02), reflecting greater lipoprotein-related insulin resistance, and inversely associated with HDL size (β = −0.030, p = 0.045). ConclusionsA higher FSAm-NPS score is associated with a less favourable lipoprotein particle subclass profile in middle-to older-aged adults which may be a potential mechanism underlying reported health benefits of a healthy diet according to Nutri-Score rating.

Lipoprotein Insulin Resistance Score and Mortality Risk Stratification in Heart Failure

BackgroundHigher total serum cholesterol is associated with lower mortality in heart failure. Evaluating associations between lipoprotein subfractions and mortality among people with heart failure may provide insights into this observation. MethodsWe prospectively enrolled a community cohort of people with heart failure from 2003 to 2012 and assessed vital status through 2021. Plasma collected at enrollment was used to measure lipoprotein subfractions via nuclear magnetic resonance spectroscopy. A composite score of 6 lipoprotein subfractions was generated using the lipoprotein insulin resistance index (LP-IR) algorithm. Using covariate-adjusted proportional hazards regression models, we evaluated associations between LP-IR score and all-cause mortality. ResultsAmong 1382 patients with heart failure (median follow-up 13.9 years), a one-standard-deviation (SD) increment in LP-IR score was associated with lower mortality (hazard ratio [HR] 0.93; 95% confidence interval [CI], 0.97-0.99). Among LP-IR parameters, mean high-density lipoprotein (HDL) particle size was significantly associated with lower mortality (HR per 1-SD decrement in mean HDL particle size = 0.83; 95% CI, 0.78-0.89), suggesting that the inverse association between LP-IR score and mortality may be driven by smaller mean HDL particle size. ConclusionsLP-IR score was inversely associated with mortality among patients with heart failure and may be driven by smaller HDL particle size.

Triglyceride/HDL cholesterol ratio and lipoprotein insulin resistance Score: Associations with subclinical atherosclerosis and incident cardiovascular disease

BackgroundThe triglyceride/HDL cholesterol (TG/HDL-C) ratio and the Lipoprotein Insulin Resistance (LP-IR) score are lipid markers of insulin resistance. Their associations with carotid intima media thickness (cIMT; subclinical atherosclerosis) and incident cardiovascular disease (CVD) have not been thoroughly investigated. MethodsIn a cross-sectional cohort (89 subjects without type 2 diabetes (T2D) and 81 subjects with T2D we determined cIMT (ultrasound), homeostasis model assessment of insulin resistance (HOMA-IR) and the TG/HDL-C ratio. The LP-IR score, based on 6 lipoprotein characteristics determined by nuclear magnetic resonance spectroscopy, was measured in 123 participants. A prospective study was carried out among 6232 participants (Prevention of REnal and Vascular ENd-stage Disease study). ResultsCross-sectionally, the adjusted associations of HOMA-IR, the TG/HDL-C ratio and the LP-IR score with cIMT were approximately similar (standardized β = 0.34 (95 % CI 0.19–0.48), 0.24 (95 % CI 0.09–039) and 0.41 (95 % CI 0.23––0.59), respectively). Prospectively, 507 new cases of CVD were observed after a median follow-up of 8.2 (interquartile range 7.5–8.8) years. HOMA-IR, the TG/HDL-C ratio and LP-IR were each associated with incident CVD independent of potential confounders (HR 1.12, 95 % CI 1.02–1.24;1.22, 95 % CI 1.11–1.35 and 1.15. 95 % CI 1.01–1.31, respectively). The association of the TG/HDL-C ratio with incident CVD was somewhat stronger than that of HOMA-IR. ConclusionLipoprotein-based markers of insulin resistance are at least as strongly associated with subclinical atherosclerosis and clinical atherosclerosis development as HOMA-IR, obviating the need to measure insulin to determine the impact of insulin resistance. For practical purposes, the easily obtainable TG/HDL-C ratio may suffice.

FRI099 Advanced Lipoprotein Analysis In Patients With Cushing’s Syndrome

Abstract Disclosure: R.T. Varghese: None. R. McGlotten: None. M. Sampson: None. A. Prakash: None. R. Shamburek: None. A.T. Remaley: None. R. Muniyappa: None. L.K. Nieman: None. Introduction: Cushing syndrome (CS) patients have a higher mortality rate due to increased cardiovascular disease (CVD). Analysis of lipoprotein particles with nuclear magnetic resonance (NMR) spectroscopy provides additional insights into CVD risk beyond the standard lipid panel. The goal of the study was to better characterize the lipid abnormalities in patients with CS by using high-resolution separation of lipoprotein particles. Methods: We measured plasma lipids (Cholesterol, TC; calculated low density lipoprotein, LDL; triglycerides, TG; high density lipoprotein, HDL) by the traditional enzymatic assay and lipoprotein particles by NMR spectroscopy. Measures of inflammation and insulin resistance were also derived from NMR spectra. Values are shown as mean ± SEM or median [IQR]. Results: After initial evaluation, 42 subjects (mean age 47.4 ± 2.5 years; 28 females; weight 85.0 ± 3.1 kg) had Cushing's disease (n=23), ectopic ACTH secretion (n=17), or adrenal adenoma (n=2). Ten patients were on chronic statin therapy, and 14 subjects had type 2 diabetes mellitus (T2DM). The control group comprised 45 subjects without T2DM [mean age 45.4 ± 2.1 years and weight (83.5 ± 2.7) kg]. None in the control group were on statin therapy. Compared to controls, CS patients had significantly higher systolic (135 ±2 vs. 119 ±2 mm Hg, p<0.001) and diastolic blood pressure (79 ±2 vs. 71 ±1 mm Hg, p<0.001), HbA1c (6.1 [5.4-7.5] vs. 5.4 [5.0-5.7], p<0.001), plasma glucose (103 [90-137] vs 94 [89-100] mg/dL, p=0.003), and insulin (17[12-26] vs 11[7-15] uU/mL, p=0.01) levels. Compared to controls, patients with CS had significantly higher triglyceride concentration (116 [84 -146] vs 87 [62-120] mg/dL, p=0.02) and lower LDL concentration (90 [69 -113] vs 108 [90 -125] mg/dL, p=0.04). However, total cholesterol and HDL cholesterol concentrations were not different. LDL particle size in CS was smaller (20.5[20.0-21.0] vs 21.0 [20.7-21.2] nm, p=0.01) and VLDL particle size was larger (49.8 ± 0.9 vs 45.7 ± 1.0 nm, p=0.002) than in controls. No difference was noted between groups in HDL particle number or size or in LDL and VLDL particle number. In the group with CS, a marker of inflammation, GlycA (Glycan N-acetylglucosamine) (494.5 ± 18.2 vs. 382.5 ± 9.0 µmol/L, p<0.001) and Lipoprotein Insulin Resistance score (LPIR) (46.4 ± 3.1 vs. 36.2 ± 3.1, p=0.02) were significantly higher. There were no group differences in branch-chained amino acids (BCCA) levels. These differences remained even when patients with type 2 diabetes and those on statin therapy were excluded. Conclusions: These data suggest that the higher inflammatory and insulin resistance state, dysglycemia, hypertension, and altered lipoprotein profiles may contribute to the increased CV risk in patients with Cushing’s syndrome. Early detection and treatment for these abnormalities may attenuate CV risk. Presentation: Friday, June 16, 2023

Elevated de novo lipogenesis, slow liver triglyceride turnover, and clinical correlations in nonalcoholic steatohepatitis patients

AbstractDe novo lipogenesis (DNL) converts carbon substrates to lipids. Increased hepatic DNL could contribute to pathogenic liver triglyceride accumulation in nonalcoholic steatohepatitis (NASH) and therefore may be a potential target for pharmacological intervention. Here, we measured hepatic DNL using heavy water in 123 patients with NASH with fibrosis or cirrhosis, calculated the turnover of hepatic triglycerides to allow repeat labeling studies, and determined the associations of hepatic DNL with metabolic, fibrotic, and imaging markers. We found that hepatic DNL was higher in patients with fibrotic NASH [median (IQR), 40.7% contribution to palmitate (32.1, 47.5), n=103] than has been previously reported in healthy volunteers and remained elevated [median (IQR), 36.8% (31.0, 44.5), n=20] in patients with cirrhosis, despite lower liver fat content. We also showed that turnover of intrahepatic triglyceride pools was slow (t½ >10 days). Furthermore, DNL contribution was determined to be independent of liver stiffness by magnetic resonance imaging but was positively associated with the number of large very low density lipoprotein (VLDL) particles, the size of VLDL, the lipoprotein insulin resistance score, and levels of ApoB100, and trended toward negative associations with the fibrosis markers FIB-4, FibroSure, and APRI. Finally, we found treatment with the acetyl-CoA carboxylase inhibitor firsocostat reduced hepatic DNL at 4 and 12 weeks, using a correction model for residual label that accounts for hepatic triglyceride turnover. Taken together, these data support an important pathophysiological role for elevated hepatic DNL in NASH and demonstrate that response to pharmacological agents targeting DNL can be correlated with pretreatment DNL.

Distribution of seven ApoC-III glycoforms in plasma, VLDL, IDL, LDL and HDL of healthy subjects

Glycosylation of ApoC-III modulates its function in TG metabolism, with some variants being associated with a more atherogenic lipid profile. These associations have been studied in whole plasma but rarely in individual lipoprotein fractions. In this study, we aimed to measure the relative content of ApoC-III glycoforms in each lipoprotein fraction as a potential biomarker for TG metabolism and cardiovascular risk. Lipoprotein fractions were separated by differential ultracentrifugation of plasma samples from healthy subjects. Relative concentrations of seven ApoC-III variants were measured by MSIA. ApoC-III1, ApoC-III0b and ApoC-III2 were the most abundant glycoforms. There was high interindividual variability in the distribution of glycoforms across the study population but a uniform proportion in all lipoprotein fractions of each given subject. Two ApoC-III variants, ApoC-III0b and ApoC-III1d, negatively correlated with plasma and VLDL triglycerides irrespectively of VLDL size and were associated with increased LDL size when transported in LDL particles. ApoC-III0b also showed a negative correlation with lipoprotein-insulin resistance score. We have been able to measure seven ApoC-III glycoforms in each lipoprotein fraction, setting the basis for future studies exploring their role on cardiovascular risk. Some glycoforms suggest a less proatherogenic role on TG and lipoprotein metabolism. SignificanceApo CIII has an important role on plasma TG metabolism through different mechanisms and it is also involved in type 1 and type 2 Diabetes Mellitus. Different glycosylated forms of Apo CIII exist and they show different roles. For this reason, this protein has gained interest in the las years and the relationship between ApoC-III glycoforms and lipids, lipoproteins and metabolic disorders has been increasingly studied in the last years.Apo CIII glycoforms have been previously analysed in plasma, and the function of the main four glycoforms has been assessed in a variety of cohorts; but in the present study, ApoC-III glycoforms are measured in each lipoprotein fraction, which may be of clinical interest.

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.

Protective lifestyle behaviours and lipoprotein particle subclass profiles in a middle-to older-aged population

Background and aimsLipoprotein particle size is associated with increased atherosclerosis and cardiovascular disease risk. Certain lifestyle behaviours may be cardioprotective. We examined lipoprotein particle size and concentration relationships with a protective lifestyle behaviour (PLB) score. MethodsThis was a cross-sectional analysis of 2045 middle-to older-aged adults. Lipoprotein particle subclass size and concentrations were determined using nuclear magnetic resonance spectroscopy. Five protective behaviours included never smoking, moderate alcohol intake, moderate to vigorous physical activity, a high-quality diet (upper 40% Dietary Approaches to Stop Hypertension score) and a normal body mass index (BMI) (18.5–24.9 kg/m2). Linear and logistic regression analyses tested individual protective behaviour and PLB score associations with lipoprotein subclasses. ResultsIndividual behaviour associations varied according to lipoprotein subclass, with normal BMI showing the greatest number of significant relationships. Logistic regression analyses revealed that subjects with the fewest number of protective behaviours had 1.4–2.8 increased odds of having less favourable lipoprotein profiles defined as above or below median level lipoprotein particle subclass size or concentration. Following additional adjustment for BMI, significant trend relationships were observed between the PLB score and large and medium very low-density lipoprotein (p = 0.001 and p < 0.001), total and smaller low-density lipoprotein (LDL) concentrations (p = 0.008 and p < 0.001), LDL size (p = 0.003) and a lipoprotein insulin resistance score (p = 0.003). ConclusionsResults show a cumulative protective effect of healthy lifestyle behaviours against an unfavourable potentially pro-atherogenic lipoprotein profile in middle-to older-aged adults, highlighting the importance of lifestyle promotion in healthy ageing.

The dual glucose-dependent insulinotropic peptide and glucagon-like peptide-1 receptor agonist, tirzepatide, improves lipoprotein biomarkers associated with insulin resistance and cardiovascular risk in patients with type 2 diabetes.

AimTo better understand the marked decrease in serum triglycerides observed with tirzepatide in patients with type 2 diabetes, additional lipoprotein‐related biomarkers were measured post hoc in available samples from the same study.Materials and MethodsPatients were randomized to receive once‐weekly subcutaneous tirzepatide (1, 5, 10 or 15 mg), dulaglutide (1.5 mg) or placebo. Serum lipoprotein profile, apolipoprotein (apo) A‐I, B and C‐III and preheparin lipoprotein lipase (LPL) were measured at baseline and at 4, 12 and 26 weeks. Lipoprotein particle profile by nuclear magnetic resonance was assessed at baseline and 26 weeks. The lipoprotein insulin resistance (LPIR) score was calculated.ResultsAt 26 weeks, tirzepatide dose‐dependently decreased apoB and apoC‐III levels, and increased serum preheparin LPL compared with placebo. Tirzepatide 10 and 15 mg decreased large triglyceride‐rich lipoprotein particles (TRLP), small low‐density lipoprotein particles (LDLP) and LPIR score compared with both placebo and dulaglutide. Treatment with dulaglutide also reduced apoB and apoC‐III levels but had no effect on either serum LPL or large TRLP, small LDLP and LPIR score. The number of total LDLP was also decreased with tirzepatide 10 and 15 mg compared with placebo. A greater reduction in apoC‐III with tirzepatide was observed in patients with high compared with normal baseline triglycerides. At 26 weeks, change in apoC‐III, but not body weight, was the best predictor of changes in triglycerides with tirzepatide, explaining up to 22.9% of their variability.ConclusionsTirzepatide treatment dose‐dependently decreased levels of apoC‐III and apoB and the number of large TRLP and small LDLP, suggesting a net improvement in atherogenic lipoprotein profile.

A lipidome-wide association study of the lipoprotein insulin resistance index

BackgroundThe lipoprotein insulin resistance (LPIR) score was shown to predict insulin resistance (IR) and type 2 diabetes (T2D) in healthy adults. However, the molecular basis underlying the LPIR utility for classification remains unclear.ObjectiveTo identify small molecule lipids associated with variation in the LPIR score, a weighted index of lipoproteins measured by nuclear magnetic resonance, in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study (n = 980).MethodsLinear mixed effects models were used to test the association between the LPIR score and 413 lipid species and their principal component analysis-derived groups. Significant associations were tested for replication with homeostatic model assessment-IR (HOMA-IR), a phenotype correlated with the LPIR score (r = 0.48, p < 0.001), in the Heredity and Phenotype Intervention (HAPI) Heart Study (n = 590).ResultsIn GOLDN, 319 lipids were associated with the LPIR score (false discovery rate-adjusted p-values ranging from 4.59 × 10− 161 to 49.50 × 10− 3). Factors 1 (triglycerides and diglycerides/storage lipids) and 3 (mixed lipids) were positively (β = 0.025, p = 4.52 × 10− 71 and β = 0.021, p = 5.84 × 10− 41, respectively) and factor 2 (phospholipids/non-storage lipids) was inversely (β = − 0.013, p = 2.28 × 10− 18) associated with the LPIR score. These findings were replicated for HOMA-IR in the HAPI Heart Study (β = 0.10, p = 1.21 × 10− 02 for storage, β = − 0.13, p = 3.14 × 10− 04 for non-storage, and β = 0.19, p = 8.40 × 10− 07 for mixed lipids).ConclusionsNon-storage lipidomics species show a significant inverse association with the LPIR metabolic dysfunction score and present a promising focus for future therapeutic and prevention studies.

Lipoprotein insulin resistance score in nondiabetic patients with obesity after bariatric surgery.

Lipoprotein insulin resistance (LPIR) score is a composite biomarker representative of atherogenic dyslipidemia characteristic of early insulin resistance. It is elevated in obesity and may provide information not captured in glycosylated hemoglobin and homeostatic model assessment for insulin resistance. While bariatric surgery reduces diabetes incidence and resolves metabolic syndrome, the effect of bariatric surgery on LPIR is untested. We sought to assess the effects of Roux-en-Y gastric bypass and sleeve gastrectomy on LPIR in nondiabetic women with obesity. Nonsmoking, nondiabetic, premenopausal Hispanic women, age ≥18 years, undergoing Roux-en-Y gastric bypass or sleeve gastrectomy at Bellevue Hospital were recruited for a prospective observational study. Anthropometric measures and blood sampling were performed preoperatively and at 6 and 12 months postoperatively. LPIR was measured by nuclear magnetic resonance spectroscopy. Among 53 women (Roux-en-Y gastric bypass, n = 22; sleeve gastrectomy, n = 31), mean age was 32 ± 7 years and body mass index 44.1 ± 6.4 kg/m2. LPIR was reduced by 35 ± 4% and 46 ± 4% at 6 and 12 months after surgery, respectively, with no difference by procedure. Twenty-seven of 53 patients met International Diabetes Federation criteria for metabolic syndrome preoperatively and had concomitant higher homeostatic model assessment for insulin resistance, glycosylated hemoglobin, nonhigh-density lipoprotein-cholesterol and LPIR. Twenty-five of 27 patients experienced resolution of metabolic syndrome postoperatively. Concordantly, the preoperative differences in homeostatic model assessment for insulin resistance, glycosylated hemoglobin, and nonhigh-density lipoprotein-cholesterol between those with and without metabolic syndrome resolved at 6 and 12 months. In contrast, patients with metabolic syndrome preoperatively exhibited greater LPIR scores at 6 and 12 months postoperatively. This is the first study to demonstrate improvement in insulin resistance, as measured by LPIR, after bariatric surgery with no difference by procedure. This measure, but not traditional markers, was persistently higher in patients with a preoperative metabolic syndrome diagnosis, despite resolution of the condition.

SAT-624 Predictive Ability of Lipoprotein Insulin Resistance (LPIR) Score in South Asians: A Comparison of Surrogate Indices of Insulin Sensitivity/Resistance

South Asians (SA) are at higher risk for developing insulin resistance (IR) and type 2 diabetes. Consequently, identifying IR in this population is important. Lack of standardization and harmonization of insulin assays limit the clinical use of insulin-based surrogate indexes of insulin resistance. The lipoprotein insulin resistance (LPIR) score, a metabolomic marker, reflects the lipoprotein abnormalities observed in insulin-resistant states. The reliability of the LPIR score to predict IR in South Asians is currently unknown. In this study, we aimed to evaluate the predictive accuracy of LPIR compared to other fasting-based surrogate indices in SA.In a cross-sectional study of 59 non-diabetic SA subjects (age 36 ± 8 years, BMI 26.5 ± 5.2 kg/m2), we used calibration model analysis to assess the ability of the LPIR score and other simple surrogate indices [homeostasis model assessment (HOMA-IR), quantitative insulin sensitivity check index (QUICKI) and Adipose tissue insulin sensitivity (Adipo-SI)] to predict insulin sensitivity derived from the reference frequently sampled intravenous glucose tolerance test (FSIVGTT) and Minimal Model analysis (SiMM). LPIR scores were calculated using six lipoprotein particle concentrations and sizes measured by nuclear magnetic resonance (NMR) spectroscopy. Further, quantitative predictive accuracy and index comparisons were determined by root mean squared error (RMSE) of prediction and leave-one-out cross-validation-type RMSE of prediction (CVPE). Receiver operating characteristic (ROC) curve analysis was performed to determine how well LPIR distinguished insulin resistant individuals, categorized as an SiMM < 3.As determined by calibration model analysis, Adipo-SI, HOMA-IR, and QUICKI showed moderate correlations with for SiMM (Adipo-SI: r = 0.66; HOMA-IR: r = 0.60; QUICKI: r = 0.57, p = <0.0001). No significant differences were noted among CVPE or RMSE from any of the routinely used surrogate indices when compared with LPIR. The ROC area under the curve was 0.76 (95% CI 0.64–0.87) suggesting that LPIR performed well in identifying insulin resistant subjects. The optimal cut-off in IR individuals was LPIR >46 (sensitivity: 75.9 %, specificity: 70.0%). We conclude that NMR-derived LPIR may be an appropriate index to assess insulin resistance in South Asians.

Lipoprotein insulin resistance score and branched-chain amino acids increase after adrenalectomy for unilateral aldosterone-producing adenoma: a preliminary study

Background and aimsPrimary aldosteronism (PA) due to unilateral aldosterone-producing adenoma (APA) is preferentially treated by unilateral adrenalectomy (ADX), but little is known about the changes in lipid and glucose metabolism that may occur after ADX.MethodsWe studied 19 non-diabetic patients who did not use lipid-lowering drugs with PA due to APA before and 6 months after unilateral ADX. Fasting plasma lipids, lipoprotein subfractions, branched-chain amino acids (BCAA), and GlycA, a pro-inflammatory glycoprotein biomarker, were measured by nuclear magnetic resonance (NMR) spectroscopy. The Lipoprotein Insulin Resistance (LP-IR) score, which is based on six lipoprotein variables, was calculated.ResultsIn all patients, hyperaldosteronism was resolved after ADX. Body mass index and fasting plasma glucose were unchanged, but HbA1c increased (p = 0.002). Plasma triglycerides, large triglyceride-rich lipoprotein (TRL) cholesterol, and large TRL particles were increased (p < 0.01), resulting in an increase in TRL size (p = 0.027). High-density lipoprotein size was decreased (p = 0.015). LP-IR scores (p = 0.001) and total BCAA (p = 0.017) were increased, but GlycA remained unaltered.ConclusionsBased on increases in LP-IR scores and BCAA, which each have been shown to predict new onset type 2 diabetes mellitus independent of conventional risk factors in the general population, this preliminary study suggests that diabetes risk is not improved but may even be increased after ADX for APA despite remission of PA.

Mechanisms underlying the cardiometabolic protective effect of walnut consumption in obese people: A cross-over, randomized, double-blind, controlled inpatient physiology study.

To assess the effects of walnuts on cardiometabolic outcomes in obese people and to explore the underlying mechanisms using novel methods including metabolomic, lipidomic, glycomic and microbiome analysis, integrated with lipid particle fractionation, appetite-regulating hormones and haemodynamic measurements. A total of 10 obese individuals were enrolled in this cross-over, randomized, double-blind, placebo-controlled clinical trial. The participants had two 5-day inpatient stays, during which they consumed a smoothie containing 48 g walnuts or a macronutrient-matched placebo smoothie without nuts, with a 1-month washout period between the two visits. Walnut consumption improved aspects of the lipid profile; it reduced fasting small and dense LDL particles (P < 0.02) and increased postprandial large HDL particles (P < 0.01). Lipoprotein insulin resistance score, glucose and the insulin area under the curve (AUC) decreased significantly after walnut consumption (P < 0.01, P < 0.02 and P < 0.04, respectively). Consuming walnuts significantly increased 10 N-glycans, with eight of them carrying a fucose core. Lipidomic analysis showed a robust reduction in harmful ceramides, hexosylceramides and sphingomyelins, which have been shown to mediate effects on cardiometabolic risk. The peptide YY AUC significantly increased after walnut consumption (P < 0.03). No major significant changes in haemodynamic or metabolomic analysis or in microbiome host health-promoting bacteria such as Faecalibacterium were found. These data provide a more comprehensive mechanistic perspective of the effect of dietary walnut consumption on cardiometabolic variables. Lipidomic and lipid nuclear magnetic resonance spectroscopy analysis showed an early but significant reduction in ceramides and other atherogenic lipids with walnut consumption, which may explain the longer-term benefits of walnuts or other nuts on insulin resistance, cardiovascular risk and mortality.

1338-P: Lipoprotein Insulin Resistance Scores Decrease after a Lifestyle Intervention among Obese Adolescents with Prediabetes

Introduction: Insulin resistance (IR) is associated with impaired lipid metabolism. The Lipoprotein Insulin Resistance Index (LP-IR) is a novel composite biomarker that estimates IR from lipoprotein particle size and concentration, and prospectively predicts type 2 diabetes (T2D) in adults. Less is known about LP-IR and T2D risk in youth. This study evaluated the effect of a lifestyle intervention on LP-IR scores in obese Latino youths with prediabetes. Methods: Obese Latino adolescents (n=27, 15.5±1.1 years, 13 male/14 female) with prediabetes (defined as a 2-hour, post-challenge glucose ≥120 mg/dL) completed a 12-week intervention including nutrition education (one hour/week) and moderate-to-vigorous physical activity (three hours/week). Measurements at baseline and 12 weeks included anthropometrics, total, large, medium, and small lipoprotein particle concentrations (VLDL and chylomicron, LDL, and HDL), mean lipoprotein particle sizes (VLDL, LDL, HDL), lipid concentrations (total triglyceride, VLDL and chylomicron triglyceride, and HDL cholesterol), and LP-IR scores using nuclear magnetic resonance spectroscopy. Results: After adjusting for body fat and sex, significant reductions in LP-IR scores (63.2±14.4 vs. 59.0±15.5 units, p=0.013), large VLDL and chylomicron particle concentration (9.1±7.8 vs. 7.3±6.2 nmol/L, p=0.004), total HDL particle concentration (30.2±4.3 vs. 28.3±3.9 μmol/L, p=0.013), total triglyceride concentration (144.5±91.9 vs. 122.9±77.9 mg/dL, p=0.002), as well as VLDL and chylomicron triglyceride concentration (117.5±66.7 vs. 102.0±55.7 mg/dL, p=0.020) were observed following lifestyle intervention. Conclusion: Lifestyle intervention significantly reduces LP-IR scores and lipoprotein particle parameters in obese adolescents with prediabetes and may decrease future risk of cardiometabolic disorders through improvements in insulin resistance and lipoprotein metabolism. Disclosure A.M. Renteria-Mexia: None. M. Olson: None. M.A. Connelly: Employee; Self; LabCorp. S. Vega-López: None. A. Williams: None. G.Q. Shaibi: None. Funding National Institute on Minority Health and Health Disparities (P20MD002316, U54MD002316); Programa para el Desarrollo Profesional Docente, para el Tipo Superior, México (to A.M.R-M.)

Replacement of Sedentary Time with Physical Activity: Effect on Lipoproteins.

Limited data on the relationship between physical activity and lipoprotein particle profiles exist. Our objective was to investigate associations between objectively measured physical activity and lipoprotein particle size and number, and specifically whether substituting daily sedentary behavior with light activity or moderate-to-vigorous physical activity (MVPA) is associated with beneficial alterations to the lipoprotein profile among adults and those at increased cardiometabolic risk (obese and insulin-resistant subjects). Sedentary behavior and physical activity intensity and duration were measured for 7 consecutive days using the GENEActiv accelerometer in a cross-sectional adult cohort (n = 396; mean age, 59.6 ± 5.5 yr). Lipoprotein particle size and subclass concentrations were determined using nuclear magnetic resonance spectroscopy. Isotemporal substitution regression modeling quantified the associations between replacing 30 min·d of sedentary behavior with equal amounts of light activity and MVPA on lipoprotein profiles. Daily duration of MVPA was inversely associated with large VLDL particles and lipoprotein insulin resistance scores (P < 0.05, after adjustment for sedentary time and other confounding factors). Reallocating 30 min of sedentary time with MVPA, but not light activity, was associated with less large VLDL particles resulting in more favorable average VLDL particle size and improved lipoprotein insulin resistance score (P < 0.05). Analysis of high-cardiometabolic-risk groups revealed similar beneficial alterations to VLDL profiles (P < 0.05) with substitution of sedentary time for MVPA among the insulin-resistant (homeostasis model assessment for insulin resistance ≥75th percentile) but not the obese (body mass index ≥30 kg·m) individuals. Daily MVPA duration and theoretical replacement of sedentary time with MVPA, but not light activity, were associated with less atherogenic VLDL profiles, particularly among the insulin-resistant individuals. These findings, which require further investigation, highlight the need to develop physical activity interventions aimed at improving atherogenic dyslipidemia and lowering cardiometabolic risk.

Abstract P036: Effects of Exercise Training and Increasing Non-Exercise Physical Activity on Lipoprotein Subclass and Size: Results From the I-CAN Study

Introduction: Previous studies have shown that lipoprotein particle size and lipoprotein subclasses are associated with cardiovascular and type 2 diabetes risk, and have independent prognostic value above traditional lipid concentrations. The impact of exercise training and increasing non-exercise physical activity on lipoprotein subclasses and size has not been previously investigated. Methods: In this pilot study, 35 obese adults were randomized to aerobic exercise training (50-75% of VO 2 max) (AERO, n=11), aerobic training and increasing non-exercise physical activity (AERO-PA, n=10, ~3,000 steps above baseline levels), or a non-exercise control group (n=14) for 6 months. Baseline and follow-up blood samples were analyzed for lipoprotein subclass, size, and lipoprotein insulin resistance score (LP-IR) using nuclear magnetic resonance spectroscopy (Liposcience, NC). Analysis of covariance was used to evaluate the change in outcome variables following the intervention across groups with adjustment for baseline value and age. Participants who changed lipid medications during the intervention (n=2) or who were non-adherent to exercise training (n=2) were excluded from the analysis. Results: Significant reductions were observed for mean VLDL size in the AERO-PA group (-4.7 nm, CI: -8.7 to -0.8) compared to control group (0.7 nm, CI: -2.7 to 4.4) and the AERO group (1.1 nm, CI: -2.9 to 5.0). Reductions in triglyceride concentrations were observed in the AERO-PA group (-28.3 mg/dL, CI: -50.3 to -6.4) compared to control (4.1 mg/dL, CI: -14.6 to 22.8). Additionally, we observed a trend for LP-IR index (p=0.055) and the concentration of small HDL particles (p=0.093) to decrease in the AERO-PA group compared to controls, with no differences compared to the AERO group (p&gt;0.10). No significant changes were observed for other notable lipoprotein measures, such as LDL size, HDL size, concentration of small LDL particles, or chylomicron measures (p&gt;0.05). In the AERO-PA group, the change in steps was associated with the change in LP-IR index (r= -0.71, p=0.013), but not with change in VLDL size (r= -0.24, p=0.463) or triglyceride concentrations (r=-0.28, p=0.388). Conclusions: Aerobic training combined with increasing non-exercise physical activity leads to favorable changes in the lipoprotein profile, specifically reductions in VLDL size and triglycerides, and may have promise for other lipoprotein traits (reductions in LP-IR and small HDL particles) that were not observed with aerobic training alone.

N-3 polyunsaturated fatty acids improve lipoprotein particle size and concentration in Japanese patients with type 2 diabetes and hypertriglyceridemia: a pilot study

BackgroundPatients with type 2 diabetes are at high risk for cardiovascular disease. Although hydroxymethylglutaryl-CoA reductase inhibitors (statins) can reduce cardiovascular events, residual risk remains even after target low-density lipoprotein cholesterol (LDL-C) levels have been achieved. Lipoprotein particle size and fraction changes are thought to contribute to such risks. The purpose of this study was to evaluate the effects of n-3 polyunsaturated fatty acids (n-3 PUFAs), predominantly eicosapentaenoic acid and docosahexaenoic acid, on lipoprotein particle size, concentration, and glycemic control in Japanese patients with type 2 diabetes and hypertriglyceridemia.MethodsThis was a multicenter, prospective, open-label, single arm study. We enrolled 14 patients with type 2 diabetes and hypertriglyceridemia treated with statins and dipeptidyl peptidase-4 inhibitors with glycated hemoglobin (HbA1c) < 8.0%, LDL-C < 120 mg/dL, and fasting triglyceride ≥150 mg/dL. After a 12-week observation period, they were treated with 4 g/day n-3 PUFAs for 12 weeks. Lipoprotein particle sizes, concentrations, lipoprotein insulin resistance (LPIR) scores, lipid profiles, HbA1c, and fasting plasma glucose (FPG) were measured before and after treatment. Lipoprotein profiles were measured by nuclear magnetic resonance spectroscopy. Data were analyzed using Wilcoxon signed-rank tests.ResultsConcentrations of total cholesterol (P < 0.001), LDL-C (P = 0.003), and triglyceride (P < 0.001) decreased following n-3 PUFA administration. N-3 PUFAs decreased the size of very low-density lipoprotein (VLDL; P < 0.001) particles, but did not affect LDL or high-density lipoprotein (HDL) particles. The concentration of large LDL increased, whereas small LDL decreased, causing the large to small LDL ratio to increase significantly (P = 0.042). Large VLDL and chylomicron concentrations significantly decreased, as did the large to small VLDL ratio (all P < 0.001). FPG levels unchanged, whereas HbA1c levels slightly increased. LPIR scores improved significantly (P = 0.001).ConclusionsN-3 PUFAs partly improved atherogenic lipoprotein particle size and concentration, and produced less atherogenic lipoprotein subclass ratios in patients that achieved target LDL-C levels and glycemic control. These results suggest that n-3 PUFAs may reduce residual cardiovascular risk factors in statin-treated patients with type 2 diabetes and hypertriglyceridemia.Trial registrationThe study was registered at UMIN-ID: UMIN000013776.

Lipoprotein insulin resistance score and risk of incident diabetes during extended follow-up of 20 years: The Women's Health Study

Type II diabetes (T2D) is preceded by prolonged insulin resistance and relative insulin deficiency incompletely captured by glucose metabolism parameters, high-density lipoprotein (HDL) cholesterol and triglycerides. Whether lipoprotein insulin resistance (LPIR) score, a metabolomic marker, is associated with incident diabetes and improves risk reclassification over traditional markers on extended follow-up. Among 25,925 nondiabetic women aged 45years or older, LPIR was measured by nuclear magnetic resonance spectroscopy as a weighted score of very low density lipoprotein, low-density lipoprotein, and HDL particle sizes, and their subsets concentrations. We run adjusted cox regression models for LPIR with incident T2D (20.4years median follow-up). Adjusting for demographics, body mass index, life style factors, blood pressure, and T2D family history, the LPIR hazard ratio for T2D (hazard ratio [HR] per standard deviation, 95% confidence interval) was 1.95 (1.85, 2.06). Further adjusting for HbA1c, C-reactive protein, triglycerides, HDL and low-density lipoprotein cholesterol, LPIR HR was attenuated to 1.41 (1.31, 1.53) and had the strongest association with T2D after HbA1C in mutually adjusted models. The association persisted even in those with optimal clinical profiles, adjusted HR per standard deviation 1.91 (1.17, 3.13). In participants deemed at intermediate T2D risk by the Framingham Offspring T2D score, LPIR led to a net reclassification of 0.145 (0.117, 0.175). In middle-aged or older healthy women followed prospectively for over 20years, LPIR was robustly associated with incident T2D, including among those with an optimal clinical metabolic profile. LPIR improved T2D risk classification and may guide early and targeted prevention strategies.

Impact of Subclinical Hypothyroidism on Cardiometabolic Biomarkers in Women.

Context:Whether subclinical hypothyroidism (SCH) is associated with cardiometabolic abnormalities is uncertain.Objective:To examine diverse cardiometabolic biomarkers across euthyroid, SCH, and overt hypothyroidism (HT) in women free of cardiovascular disease.Design:Cross-sectional adjusted associations for lipids, lipoprotein subclasses, lipoprotein insulin resistance score, inflammatory, coagulation, and glycemic biomarkers by analysis of covariance for thyroid categories or thyroid stimulating hormone (TSH) quintiles on a Women’s Health Study subcohort.Setting:Outpatient.Patients or Other Participants:Randomly sampled 3914 middle-aged and older women for thyroid function analysis (TSH, free T4), of whom 3321 were not on lipid-lowering therapy.Intervention:None.Main Outcome Measure:Associations of SCH and HT with cardiometabolic markers.Results:Going from euthyroid to HT, the lipoprotein subclass profiles were indicative of insulin resistance (respective values and P for trend): larger very-low-density lipoprotein size (nm) (51.5 [95% confidence interval (CI), 51.2, 51.8] to 52.9 [51.8, 54.1], P = 0.001); higher low-density lipoprotein (LDL) particle concentration (nmol/L) [1283 (95% CI, 1267, 1299) to 1358 (1298, 1418), P = 0.004], and smaller LDL size. There was worsening lipoprotein insulin resistance score from euthyroid (49.2; 95% CI, 48.3, 50.2) to SCH (52.1; 95% CI, 50.1, 54.0) and HT (52.1; 95% CI, 48.6, 55.6); P for trend of 0.008. Of the other biomarkers, SCH and HT were associated with higher high-sensitivity C-reactive protein and hemoglobin A1c. For increasing TSH quintiles, results were overall similar.Conclusions:In apparently healthy women, SCH cardiometabolic profiles indicated worsening insulin resistance and higher cardiovascular disease risk markers compared with euthyroid individuals, despite similar LDL and total cholesterol. These findings suggest that cardiometabolic risk may increase early in the progression toward SCH and overt HT.