Novel measures of inflammation and insulin resistance are related to obesity and fitness in a diverse sample of 11-14 year-olds:The HEALTHY Study

BACKGROUND: GlycA is a novel serum marker of systemic inflammation. There is no information on GlycA in pediatric populations, how it differs by gender or its association with body mass index (BMI) or fitness. LP-IR is a serum measure of insulin resistance which is related to changes in BMI group in adolescents, but its relationship with fitness is unknown. The current study examined the independent associations between fitness and BMI with GlycA and LP-IR among US adolescents. METHODS: Participants were 1664 US adolescents from the HEALTHY study with complete 6th and 8th grade BMI, fitness and blood data. GlycA and LP-IR were measured by NMR spectroscopy. Three BMI groups and three fitness groups were created. Linear mixed models examined associations between GlycA, LP-IR, fitness and BMI. RESULTS: LP-IR decreased between 6th and 8th grade. GlycA increased among girls but decreased among boys. At 8th grade, median GlycA values were 27 (7.6%) μmol/l higher (381 versus 354) for girls than boys. Median GlycA 6th grade values were 9% higher in obese girls than healthy weight girls. Overall there was strong evidence (P CONCLUSIONS: GlycA was associated with BMI and fitness among in US adolescents. These findings suggest that there are independent effects for BMI and fitness group with both GlycA and LP-IR. Future studies should validate the role of GlycA and LP-IR to evaluate the effects of interventions to modify obesity and fitness in order to improve systemic inflammation and insulin resistance.International Journal of Obesity accepted article preview online, 04 May 2016. doi:10.1038/ijo.2016.84

A Newly Developed Diabetes Risk Index, Based on Lipoprotein Subfractions and Branched Chain Amino Acids, is Associated with Incident Type 2 Diabetes Mellitus in the PREVEND Cohort

Objective: Evaluate the ability of a newly developed diabetes risk score, the Diabetes Risk Index (DRI), to predict incident type 2 diabetes mellitus (T2D) in a large adult population. Methods: The DRI was developed by combining the Lipoprotein Insulin Resistance Index (LP-IR), calculated from 6 lipoprotein subspecies and size parameters, and the branched chain amino acids, valine and leucine, all of which have been shown previously to be associated with future T2D. DRI scores were calculated in a total of 6134 nondiabetic men and women in the Prevention of Renal and Vascular End-Stage Disease (PREVEND) Study. Cox proportional hazards regression was used to evaluate the association of DRI scores with incident T2D. Results: During a median follow-up of 8.5 years, 306 new T2D cases were ascertained. In analyses adjusted for age and sex, there was a significant association between DRI scores and incident T2D with the hazard ratio (HR) for the highest versus lowest quartile being 12.07 (95% confidence interval: 6.97-20.89, p &lt;0.001). After additional adjustment for body mass index (BMI), family history of T2D, alcohol consumption, diastolic blood pressure, total cholesterol, triglycerides, HDL cholesterol and HOMA-IR, the HR was attenuated but remained significant (HR 3.20 (1.73-5.95), p = 0.001). Similar results were obtained when DRI was analyzed as HR per 1 SD increase (HR 1.37 (1.14-1.65), p &lt;0.001). The Kaplan-Meier plot demonstrated that patients in the highest quartile of DRI scores presented at higher risk (p-value for log-rank test</p

A Newly Developed Diabetes Risk Index, Based on Lipoprotein Subfractions and Branched Chain Amino Acids, is Associated with Incident Type 2 Diabetes Mellitus in the PREVEND Cohort

Objective: Evaluate the ability of a newly developed diabetes risk score, the Diabetes Risk Index (DRI), to predict incident type 2 diabetes mellitus (T2D) in a large adult population. Methods: The DRI was developed by combining the Lipoprotein Insulin Resistance Index (LP-IR), calculated from 6 lipoprotein subspecies and size parameters, and the branched chain amino acids, valine and leucine, all of which have been shown previously to be associated with future T2D. DRI scores were calculated in a total of 6134 nondiabetic men and women in the Prevention of Renal and Vascular End-Stage Disease (PREVEND) Study. Cox proportional hazards regression was used to evaluate the association of DRI scores with incident T2D. Results: During a median follow-up of 8.5 years, 306 new T2D cases were ascertained. In analyses adjusted for age and sex, there was a significant association between DRI scores and incident T2D with the hazard ratio (HR) for the highest versus lowest quartile being 12.07 (95% confidence interval: 6.97-20.89, p <0.001). After additional adjustment for body mass index (BMI), family history of T2D, alcohol consumption, diastolic blood pressure, total cholesterol, triglycerides, HDL cholesterol and HOMA-IR, the HR was attenuated but remained significant (HR 3.20 (1.73-5.95), p = 0.001). Similar results were obtained when DRI was analyzed as HR per 1 SD increase (HR 1.37 (1.14-1.65), p <0.001). The Kaplan-Meier plot demonstrated that patients in the highest quartile of DRI scores presented at higher risk (p-value for log-rank tes

High Plasma Branched-Chain Amino Acids Are Associated with Higher Risk of Post-Transplant Diabetes Mellitus in Renal Transplant Recipients

Post-transplant diabetes mellitus (PTDM) is a serious complication in renal transplant recipients. Branched-chain amino acids (BCAAs) are involved in the pathogenesis of insulin resistance. We determined the association of plasma BCAAs with PTDM and included adult renal transplant recipients (>= 18 y) with a functioning graft for >= 1 year in this cross-sectional cohort study with prospective follow-up. Plasma BCAAs were measured in 518 subjects using nuclear magnetic resonance spectroscopy. We excluded subjects with a history of diabetes, leaving 368 non-diabetic renal transplant recipients eligible for analyses. Cox proportional hazards analyses were used to assess the association of BCAAs with the development of PTDM. Mean age was 51.1 +/- 13.6 y (53.6% men) and plasma BCAA was 377.6 +/- 82.5 mu M. During median follow-up of 5.3 (IQR, 4.2-6.0) y, 38 (9.8%) patients developed PTDM. BCAAs were associated with a higher risk of developing PTDM (HR: 1.43, 95% CI 1.08-1.89) per SD change (p = 0.01), independent of age and sex. Adjustment for other potential confounders did not significantly change this association, although adjustment for HbA1c eliminated it. The association was mediated to a considerable extent (53%) by HbA1c. The association was also modified by HbA1c; BCAAs were only associated with renal transplant recipients without prediabetes (HbA1c <5.7%). In conclusion, high concentrations of plasma BCAAs are associated with developing PTDM in renal transplant recipients. Alterations in BCAAs may represent an early predictive biomarker for PTDM

Towards Independent Particle Reconstruction from Cryogenic Transmission Electron Microscopy

Coronary heart disease is the single largest killer of Americans so improved means of detecting risk factors before arterial obstructions appear are expected to lead to a improvement in quality of life with a reduced cost. This paper introduces a new approach to 3-D reconstruction of individual particles based on statistical modeling from a sparse set of 2-D projection images. This paper introduces a new approach to 3-D reconstruction of individual particles based on statistical modeling from a sparse set of 2-D projection images. The method is in contrast to the current state of practice where reconstruction is performed via signal processing or Bayesian methods that use averaged images acquired from an ensemble of particles. As such, this new approach has its impetus in use for novel diagnostic tests such as LDL and HDL particle shape characterization. The approach is also expected to have uses in areas such as quality assurance for drug delivery nano-technologies and for general proteomic studies. The individual particle reconstruction algorithm is based on a hidden Markov model. Higher order Markov chain statistics, which are generated from the a priori model of the target of interest, can be derived from traditional methods such as single particle reconstruction and/or the underlying physical properties of the particle. By placing the reconstruction voxel space at a 45° angle to the projection image, 4-passes of the HMM processing can be performed from a single image. Reconstruction results from a simple model and a single projection image resulted in better than 98% reconstruction accuracy as compared to the original target

High Betaine, a Trimethylamine N-Oxide Related Metabolite, Is Prospectively Associated with Low Future Risk of Type 2 Diabetes Mellitus in the PREVEND Study

Background: Gut microbiota-related metabolites, trimethylamine-N-oxide (TMAO), choline, and betaine, have been shown to be associated with cardiovascular disease (CVD) risk. Moreover, lower plasma betaine concentrations have been reported in subjects with type 2 diabetes mellitus (T2DM). However, few studies have explored the association of betaine with incident T2DM, especially in the general population. The goals of this study were to evaluate the performance of a newly developed betaine assay and to prospectively explore the potential clinical associations of betaine and future risk of T2DM in a large population-based cohort. Methods: We developed a high-throughput, nuclear magnetic resonance (NMR) spectroscopy procedure for acquiring spectra that allow for the accurate quantification of plasma/serum betaine and TMAO. Assay performance for betaine quantification was assessed and Cox proportional hazards regression was employed to evaluate the association of betaine with incident T2DM in 4336 participants in the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study. Results: Betaine assay results were linear (y = 1.02X - 3.75) over a wide range of concentrations (26.0-1135 mu M). The limit of blank (LOB), limit of detection (LOD) and limit of quantitation (LOQ) were 6.4, 8.9, and 13.2 mu M, respectively. Coefficients of variation for intra- and inter-assay precision ranged from 1.5-4.3% and 2.5-5.5%, respectively. Deming regression analysis of results produced by NMR and liquid chromatography coupled to tandem mass spectrometry(LC-MS/MS) revealed an R-2 value of 0.94 (Y = 1.08x - 1.89) and a small bias for higher values by NMR. The reference interval, in a cohort of apparently healthy adult participants (n = 501), was determined to be 23.8 to 74.7 mu M (mean of 42.9 +/- 12.6 mu M). In the PREVEND study (n = 4336, excluding subjects with T2DM at baseline), higher betaine was associated with older age and lower body mass index, total cholesterol, triglycerides, and hsCRP. During a median follow-up of 7.3 (interquartile range (IQR), 5.9-7.7) years, 224 new T2DM cases were ascertained. Cox proportional hazards regression models revealed that the highest tertile of betaine was associated with a lower incidence of T2DM. Hazard ratio (HR) for the crude model was 0.61 (95% CI: 0.44-0.85, p = 0.004). The association remained significant even after adjusting for multiple clinical covariates and T2DM risk factors, including fasting glucose. HR for the fully-adjusted model was 0.50 (95% CI: 0.32-0.80, p = 0.003). Conclusions: The newly developed NMR-based betaine assay exhibits performance characteristics that are consistent with usage in the clinical laboratory. Betaine levels may be useful for assessing the risk of future T2DM

Achieving Secondary Prevention Low-Density Lipoprotein Particle Concentration Goals Using Lipoprotein Cholesterol-Based Data

BACKGROUND: Epidemiologic studies suggest that LDL particle concentration (LDL-P) may remain elevated at guideline recommended LDL cholesterol goals, representing a source of residual risk. We examined the following seven separate lipid parameters in achieving the LDL-P goal of <1000 nmol/L goal for very high risk secondary prevention: total cholesterol to HDL cholesterol ratio, TC/HDL, <3; a composite of ATP-III very high risk targets, LDL-C<70 mg/dL, non-HDL-C<100 mg/dL and TG<150 mg/dL; a composite of standard secondary risk targets, LDL-C<100, non-HDL-C<130, TG<150; LDL phenotype; HDL-C ≥ 40; TG<150; and TG/HDL-C<3. METHODS: We measured ApoB, ApoAI, ultracentrifugation lipoprotein cholesterol and NMR lipoprotein particle concentration in 148 unselected primary and secondary prevention patients. RESULTS: TC/HDL-C<3 effectively discriminated subjects by LDL-P goal (F = 84.1, p<10(-6)). The ATP-III very high risk composite target (LDL-C<70, nonHDL-C<100, TG<150) was also effective (F = 42.8, p<10(-5)). However, the standard secondary prevention composite (LDL-C<100, non-HDL-C<130, TG<150) was also effective but yielded higher LDL-P than the very high risk composite (F = 42.0, p<10(-5)) with upper 95% confidence interval of LDL-P less than 1000 nmol/L. TG<150 and TG/HDL-C<3 cutpoints both significantly discriminated subjects but the LDL-P upper 95% confidence intervals fell above goal of 1000 nmol/L (F = 15.8, p = 0.0001 and F = 9.7, p = 0.002 respectively). LDL density phenotype neared significance (F = 2.85, p = 0.094) and the HDL-C cutpoint of 40 mg/dL did not discriminate (F = 0.53, p = 0.47) alone or add discriminatory power to ATP-III targets. CONCLUSIONS: A simple composite of ATP-III very high risk lipoprotein cholesterol based treatment targets or TC/HDL-C ratio <3 most effectively identified subjects meeting the secondary prevention target level of LDL-P<1000 nmol/L, providing a potential alternative to advanced lipid testing in many clinical circumstances