Peter D Reaven

Phoenix VA Health Care System, Phoenix, Arizona, United States

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Publications (106)635.24 Total impact

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    ABSTRACT: GLP-1 receptor (GLP-1R) agonists may improve endothelial function (EF) via metabolic improvement and direct vascular action. The present study determined the effect of GLP-1R agonist exenatide on postprandial EF in type 2 diabetes and the mechanisms underlying GLP-1R agonists-mediated vasodilation.Two crossover studies were conducted: 36 participants with type 2 diabetes received subcutaneous exenatide or placebo for 11 days and EF, glucose and lipid responses to breakfast and lunch were determined; 32 participants with impaired glucose tolerance (IGT) or diet-controlled type 2 diabetes had EF measured before and after intravenous exenatide, with or without the GLP-1R antagonist exendin-9. Mechanisms of GLP-1R agonist action were studied ex vivo on human subcutaneous adipose tissue arterioles and endothelial cells.Subcutaneous exenatide increased postprandial EF independent of reductions in plasma glucose and triglycerides. Intravenous exenatide increased fasting EF and exendin-9 abolished this effect. Ex vivo, exenatide elicited a dose-dependent vasorelaxation and reduced high-glucose or lipid-induced endothelial dysfunction in arterioles, and eNOS activation and NO production in endothelial cells. These effects were reduced with AMP-kinase inhibition.Exenatide augmented postprandial EF in subjects with diabetes and prevented high-glucose and lipid-induced endothelial dysfunction in human arterioles. These effects were largely direct, via GLP-1R and AMP-kinase activation. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
    Diabetes 02/2015; DOI:10.2337/db14-0976 · 7.90 Impact Factor
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    ABSTRACT: Objective: To test the clinical utility of Quantose M(Q) to monitor changes in insulin sensitivity following pioglitazone therapy in prediabetic subjects. M(Q) is derived from fasting measurements of insulin, α-hydroxybutyrate, linoleoyl-glycerophosphocholine, and oleate, three non-glucose metabolites shown to correlate with insulin-stimulated glucose disposal., Research design and methods: Participants were 428 of the total of 602 ACT NOW IGT subjects randomized to pioglitazone (45 mg/day) or placebo and followed for, 2.4 years. At baseline and study end fasting plasma metabolites required for determination of Quantose, HbA1c, and OGTT with frequent plasma insulin and glucose measurements to calculate, Matsuda Index of insulin sensitivity were obtained. Results: Pioglitazone treatment lowered IGT conversion to diabetes (HR=0.25, 95%CI = 0.13-0.50, p<0.0001). While HbA1c did not track with insulin sensitivity, M(Q) increased in pioglitazone-treated subjects (by 1.45[3.45] mg(.)min(-1.)kgwbm(-1) (median[interquartile range]), (p<0.001 vs placebo) as did, Matsuda Index (by 3.05[4.77] units, p<0.0001). M(Q) correlated with Matsuda Index at baseline and change in Matsuda Index from baseline (rho's of 0.85 and 0.79, respectively, p<0.0001) and was progressively higher across close-out glucose tolerance status (diabetes, IGT, NGT). In logistic models including only anthropometric and fasting measurements, M(Q) outperformed both Matsuda and fasting insulin in predicting incident diabetes. Conclusions: In IGT subjects, Quantose M(Q) parallels changes in insulin sensitivity and glucose tolerance with pioglitazone therapy. Due to its strong correlation with improved insulin sensitivity and its ease of use, Quantose M(Q) may serve as a useful clinical test to identify and monitor therapy in insulin resistant patients.
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    ABSTRACT: Using mass spectrometric immunoassay, the abundance of SAA truncations relative to the native variants was examined in plasma of 91 participants with type 2 diabetes and chronic kidney disease and 69 participants without diabetes. The ratio of SAA 1.1 (missing N-terminal arginine) to native SAA 1.1 was lower in diabetics compared to non-diabetics (p = 0.004), and in males compared to females (p<0.001). This ratio was negatively correlated with glycated hemoglobin (r = -0.32, p<0.001) and triglyceride concentrations (r = -0.37, p<0.001), and positively correlated with HDL cholesterol concentrations (r = 0.32, p<0.001). The relative abundance of the N-terminal arginine truncation of SAA1.1 is significantly decreased in diabetes and negatively correlates with measures of glycemic and lipid control.
    PLoS ONE 01/2015; 10(1):e0115320. DOI:10.1371/journal.pone.0115320 · 3.53 Impact Factor
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    ABSTRACT: The chemokine RANTES plays a key role in inflammation, cell recruitment and T cell activation. RANTES is heterogenic and exists as multiple variants in vivo. Herein we describe the development and characterization of a fully quantitative mass spectrometric immunoassay (MSIA) for analysis of intact RANTES and its proteoforms in human serum and plasma samples. The assay exhibits linearity over a wide concentration range (1.56 - 200ng/mL), intra- and inter-assay precision with CVs <10%, and good linearity and recovery correlations. The assay was tested in different biological matrices, and it was benchmarked against an existing RANTES ELISA. The new RANTES MSIA was used to analyze RANTES and its proteoforms in a small clinical cohort, revealing the quantitative distribution and frequency of the native and truncated RANTES proteoforms. In the last two decades, RANTES has been studied extensively due to its association with numerous clinical conditions, including kidney-related, autoimmune, cardiovascular, viral and metabolic pathologies. Although a single gene product, RANTES is expressed in a range of cells and tissues presenting with different endogenously produced variants and PTMs. The structural variety and population diversity that has been identified for RANTES necessitate developing advanced methodologies that can provide insight into the protein heterogeneity and its function and regulation in disease. In this work we present a simple, efficient and high-throughput mass spectrometric immunoassay (MSIA) method for analysis of RANTES proteoforms. RANTES MSIA can detect and analyze RANTES proteoforms and provide an insight into the endogenous protein modifications. Copyright © 2014. Published by Elsevier B.V.
    Journal of Proteomics 12/2014; 116. DOI:10.1016/j.jprot.2014.12.011 · 3.93 Impact Factor
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    ABSTRACT: The oxidative modification of apolipoprotein A-I’s methionine148 (M148) is associated with defective HDL function in vitro. Multiple reaction monitoring (MRM) is a mass spectrometric technique that can be used to quantitate post-translational modifications. In this study, we developed an MRM assay to monitor the abundance ratio of the peptide containing oxidized M148 to the native peptide in ApoA-I. Measurement of the oxidized-to-unoxidized-M148 ratio was reproducible (CV < 5%). The extent of methionine M148 oxidation in the HDL of healthy controls, and type 2 diabetic participants with and without prior cardiovascular events (CVD) were then examined. The results suggest a significant increase in the relative ratio of the peptide containing oxidized M148 to the unmodified peptide in the HDL of participants with diabetes and CVD (p < 0.001), compared to participants without CVD. Monitoring the abundance ratio of the peptides containing oxidized and unoxidized M148 by MRM provides a means of examining the relationship between M148 oxidation and vascular complications in CVD.
    12/2014; 4-5. DOI:10.1016/j.trprot.2014.10.001
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    ABSTRACT: Objective To examine the effect of intensive glycemic control on cardiovascular disease events (CVD) among the major race/ethnic groups in a post-hoc analysis of the VADT. Materials and Methods Participants included 1111 non-Hispanic Whites, 307 Hispanics and 306 non-Hispanic Blacks randomized to intensive or standard glucose treatment in VADT. Multivariable Cox proportional hazards models were constructed to assess the effect of intensive glucose treatment on CVD events among race/ethnic groups. Results Mean age was 60.4 years and median follow-up was 5.6 years. By design, modifiable risk factors were managed equally well in both treatment arms and only differed modestly between race/ethnic groups. HbA1c decreased significantly from baseline with intensive glucose treatment in each race/ethnic group, with a trend for a greater response in Hispanics (P = 0.01 for overall comparison between groups). Intensive glucose treatment was associated with reduced risk of CVD events for Hispanics but not for others (hazard ratios ranged from 0.54 to 0.75 for Hispanics whereas they were consistently close to 1 for others). Sensitivity analyses with different definitions of race/ethnicity or limited to individuals free of previous known CVD yielded similar results. Conclusions The results of these analyses support the hypothesis that race/ethnicity is worthy of consideration when tailoring intensive treatment for individuals with long-standing type 2 diabetes. However, additional studies are needed to confirm the findings of this post-hoc analysis.
    Metabolism 10/2014; 64(2). DOI:10.1016/j.metabol.2014.10.010 · 3.61 Impact Factor
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    ABSTRACT: Insulin resistance is a significant factor in the development of type 2 diabetes mellitus, however the connection between the Western diet and the development of insulin resistance has not been fully explained. Dietary macronutrient composition has been examined in a number of articles, and diets enriched in saturated fatty acids, and possibly in fructose, appear to be most consistently associated with the development of insulin resistance. However, mechanistic insights into the metabolic effects of such diets are lacking, and merit further study.
    Metabolism 09/2014; 64(2). DOI:10.1016/j.metabol.2014.08.013 · 3.61 Impact Factor
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    ABSTRACT: Evidence point to vascular dysfunction and hypoperfusion as early abnormalities in Alzheimer's disease (AD); probing their mechanistic bases can lead to new therapeutic approaches. We tested the hypotheses that β-amyloid peptide induces endothelial dysfunction and oxidative stress in human microvasculature and that response will be similar between peripheral adipose and brain leptomeningeal arterioles.
    Journal of Neuroscience Methods 07/2014; 235. DOI:10.1016/j.jneumeth.2014.06.014 · 1.96 Impact Factor
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    ABSTRACT: Rationale: The mechanisms underlying lipotoxic/diabetic cardiomyopathy remain poorly understood. Saturated fatty acid (SFA) levels, elevated in obesity and type 2 diabetes, induce apoptosis in many cell types including cardiomyocytes. Signaling pathways, including the p38 alpha mitogen-activated kinase (MAPK)-dependent pathway, have been implicated in apoptosis due to a diverse range of insults. Objective: We tested the hypothesis that SFA-induced cardiomyocyte apoptosis is dependent on p38 alpha, activation. Methods and results: Human adult ventricular cardiomyocytes (AC16 cells) were exposed to high physiological levels of palmitate (PA), a SFA. The apoptotic response was measured using annexin-V by flow cytometry, and the p38 alpha-dependent pathway was evaluated using a p38 inhibitor PD169316, and by p38 alpha, small interfering RNA (siRNA) knockdown. PA exposure for 16 h dose-dependently increased apoptosis in AC16 cardiomyocytes (control: 2.6 +/- 0.6%, 150 mu M PA: 3.5 +/- 0.9%, 300 mu M PA: 11.5 +/- 1.6%, n = 4, p < 0.01). PA did not change total p38 alpha, protein levels, but increased p38 alpha, phosphorylation dose-dependently (n = 5, p <0.01). PD169316 tended to reduce PA-induced apoptosis (n = 4, p = 0.05). Specific p38 alpha siRNA markedly reduced the expression of p38 alpha but not p38 beta (n = 3, p < 0.0001), and dose-dependently attenuated PA-induced apoptosis (control siRNA: 7.7 +/- 1.0%, 300 mu M PA: 34.4 +/- 5.0%, 300 mu M PA + 30 pmol siRNA: 23.7 +/- 4.4%, 300 mu M PA + 60 pmol siRNA: 19.7 +/- 2.6%, 300 mu M PA + 120 pmol siRNA: 17.3 +/- 2.8%, n = 4, p < 0.0001). Conclusions: These results demonstrate that PA induces p38 alpha activation, and reducing p38 alpha expression attenuates PA-induced cardiomyocyte apoptosis. Our results support a potential mechanism by which high plasma SFA levels through p38 alpha activation may lead to the development of lipotoxic/diabetic cardiomyopathy. Published by Elsevier Inc.
    Biochemical and Biophysical Research Communications 06/2014; 450(1). DOI:10.1016/j.bbrc.2014.06.023 · 2.28 Impact Factor
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    ABSTRACT: Objective Our objective was to examine the role of hypertriglyceridemia on the capacity of HDL to facilitate ABCA-1 mediated cholesterol efflux in type 2 diabetes (T2DM). Methods HDL mediated cholesterol efflux through the ABCA-1 transporter was measured using BHK cell lines in samples of 71 participants with T2DM in presence or absence of high triglyceride levels (TG). Additionally, HDL mediated efflux was measured in 13 diabetic and non-diabetic participants fasting and four hours after a high-fat test challenge. Results HDL mediated cholesterol efflux function was increased in participants with T2DM with hypertriglyceridemia when compared to participants with T2DM without hypertriglyceridemia (efflux ratio mean ± standard deviation (SD), T2DM + TG: 1.17 ± 0.25 vs. T2DM – TG: 1.03 ± 0.19, p = 0.0098). In the fat challenge study, we observed a significant increase in ABCA-1 mediated cholesterol efflux capacity following an ingestion of high-fat test meal by participants in both groups of T2DM (n = 6, efflux ratio, mean ± SD, pre: 0.86 ± 0.4 vs. post: 1.34 ± 0.6, p = 0.01) and non-diabetic participants (n = 7, efflux ratio mean ± SD pre : 1.24 ± 0.31 vs. post: 1.39 ± 0.42, p = 0.04) that was partly explained by the difference in CETP activity (r = 0.6, p = 0.03). Conclusion Our study suggests that high triglyceride levels facilitate ABCA-1 mediated efflux function of HDL in part by activating CETP.
    Metabolism: clinical and experimental 05/2014; DOI:10.1016/j.metabol.2014.03.001 · 3.61 Impact Factor
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    ABSTRACT: OBJECTIVE Plasma adiponectin levels are reduced in type 2 diabetes mellitus (T2DM) and other insulin-resistant states. We examined whether plasma adiponectin levels at baseline and after pioglitazone treatment in impaired glucose tolerance (IGT) subjects were associated with improved insulin sensitivity (SI) and glucose tolerance status.RESEARCH DESIGN AND METHODSA total of 602 high-risk IGT subjects in ACT NOW were randomized to receive pioglitazone or placebo with a median follow-up of 2.4 years.RESULTSPioglitazone reduced IGT conversion to diabetes by 72% in association with improved β-cell function by 64% (insulin secretion/insulin resistance index) and increased tissue sensitivity by 88% (Matsuda index). In pioglitazone-treated subjects, plasma adiponectin concentration increased threefold from 13 ± 0.5 to 38 ± 2.5 μg/mL (P < 0.001) and was strongly correlated with the improvement in SI (r = 0.436, P < 0.001) and modestly correlated with glucose area under the curve during oral glucose tolerance test (r = 0.238, P < 0.005) and insulin secretion/insulin resistance index (r = 0.306, P < 0.005). The increase in adiponectin was a strong predictor of reversion to normal glucose tolerance and prevention of T2DM. In the placebo group, plasma adiponectin did not change and was not correlated with changes in glucose levels. There was an inverse association between baseline plasma adiponectin concentration and progression to diabetes in the placebo group but not in the pioglitazone group.CONCLUSIONS Baseline adiponectin does not predict the response to pioglitazone. The increase in plasma adiponectin concentration after pioglitazone therapy in IGT subjects is strongly related to improved glucose tolerance status and enhanced tissue sensitivity to insulin.
    Diabetes care 04/2014; 37(6). DOI:10.2337/dc13-1745 · 7.74 Impact Factor
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    ABSTRACT: Insulin-like growth factor 1 (IGF1) is an important biomarker for the management of growth hormone disorders. Recently there has been rising interest in deploying mass spectrometric (MS) methods of detection for measuring IGF1. However, widespread clinical adoption of any MS-based IGF1 assay will require increased throughput and speed to justify the costs of analyses, and robust industrial platforms that are reproducible across laboratories. Presented here is an MS-based quantitative IGF1 assay with performance rating of >1,000 samples/day, and a capability of quantifying IGF1 point mutations and posttranslational modifications. The throughput of the IGF1 mass spectrometric immunoassay (MSIA) benefited from a simplified sample preparation step, IGF1 immunocapture in a tip format, and high-throughput MALDI-TOF MS analysis. The Limit of Detection and Limit of Quantification of the resulting assay were 1.5 μg/L and 5 μg/L, respectively, with intra- and inter-assay precision CVs of less than 10%, and good linearity and recovery characteristics. The IGF1 MSIA was benchmarked against commercially available IGF1 ELISA via Bland-Altman method comparison test, resulting in a slight positive bias of 16%. The IGF1 MSIA was employed in an optimized parallel workflow utilizing two pipetting robots and MALDI-TOF-MS instruments synced into one-hour phases of sample preparation, extraction and MSIA pipette tip elution, MS data collection, and data processing. Using this workflow, high-throughput IGF1 quantification of 1,054 human samples was achieved in approximately 9 hours. This rate of assaying is a significant improvement over existing MS-based IGF1 assays, and is on par with that of the enzyme-based immunoassays. Furthermore, a mutation was detected in ∼1% of the samples (SNP: rs17884626, creating an A→T substitution at position 67 of the IGF1), demonstrating the capability of IGF1 MSIA to detect point mutations and posttranslational modifications.
    PLoS ONE 03/2014; 9(3):e92801. DOI:10.1371/journal.pone.0092801 · 3.53 Impact Factor
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    ABSTRACT: The aim of this study was to test the hypothesis that intensive glycaemic control (INT) and higher plasma C-peptide levels in patients with poorly controlled diabetes would be associated with better eye outcomes. The incidence and progression of diabetic retinopathy (DR) was assessed by grading seven-field stereoscopic fundus photographs at baseline and 5 years later in 858 of 1,791 participants in the Veterans Affairs Diabetes Trial (VADT). After adjustment for all covariates, risk of progression (but not incidence) of DR increased by 30% for each 1% increase in baseline HbA1c (OR 1.3; 95% CI 1.123, 1.503; p = 0.0004). Neither assignment to INT nor age was independently associated with DR in the entire cohort. However, INT showed a biphasic interaction with age. The incidence of DR was decreased in INT participants ≤55 years of age (OR 0.49; 95% CI 0.24, 1.0) but increased in those ≥70 years old (OR 2.88; 95% CI 1.0, 8.24) (p = 0.0043). The incidence of DR was reduced by 67.2% with each 1 pmol/ml increment in baseline C-peptide (OR 0.328; 95% CI 0.155, 0.7; p = 0.0037). Baseline C-peptide was also an independent inverse risk factor for the progression of DR, with a reduction of 47% with each 1 pmol/ml increase in C-peptide (OR 0.53; 95% CI 0.305, 0.921; p = 0.0244). Poor glucose control at baseline was associated with an increased risk of progression of DR. INT was associated with a decreased incidence of DR in younger patients but with an increased risk of DR in older patients. Higher C-peptide at baseline was associated with reduced incidence and progression of DR.
    Diabetologia 03/2014; 57(6). DOI:10.1007/s00125-014-3199-7 · 6.88 Impact Factor
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    ABSTRACT: HDL carries a rich protein cargo and examining HDL protein composition promises to improve our understanding of its functions. Conventional mass spectrometry methods can be lengthy and difficult to extend to large populations. In addition, without prior enrichment of the sample, the ability of these methods to detect low abundance proteins is limited. Our objective was to develop a high-throughput approach to examine HDL protein composition applicable to diabetes and cardiovascular disease (CVD). We optimized two multiplexed assays to examine HDL proteins using a quantitative immunoassay (Multi-Analyte Profiling- MAP) and mass spectrometric-based quantitative proteomics (Multiple Reaction Monitoring-MRM). We screened HDL proteins using human xMAP (90 protein panel) and MRM (56 protein panel). We extended the application of these two methods to HDL isolated from a group of participants with diabetes and prior cardiovascular events and a group of non-diabetic controls. We were able to quantitate 69 HDL proteins using MAP and 32 proteins using MRM. For several common proteins, the use of MRM and MAP was highly correlated (p < 0.01). Using MAP, several low abundance proteins implicated in atherosclerosis and inflammation were found on HDL. On the hand, MRM allowed the examination of several HDL proteins not available by MAP. MAP and MRM offer a sensitive and high-throughput approach to examine changes in HDL proteins in diabetes and CVD. This approach can be used to measure the presented HDL proteins in large clinical studies.
    Lipids in Health and Disease 01/2014; 13(1):8. DOI:10.1186/1476-511X-13-8 · 2.31 Impact Factor
  • Diabetes 10/2013; 62(11):3920-3926. DOI:10.2337/db13-0265 · 8.47 Impact Factor
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    ABSTRACT: Objective To test the hypothesis that high levels of plasminogen activating inhibitor -1(PAI-1) and fibrinogen at baseline were associated with the onset and/or progression of diabetic retinopathy (DR) during the VADT.Research Design and Methods The VADT was an open-label, prospective, randomized controlled trial to test standard glycemic control (STD) compared to intensive control (INT) on cardiovascular events in patients with advanced type 2 diabetes mellitus (T2DM). Retinopathy (DR) outcomes were also collected. Incidence and progression of DR was assessed by grading 7-field stereoscopic fundus photographs at baseline and 5 years later taken in 858 of a total of 1791 participants who completed both eye examinations.ResultsOnset of DR during the study: Assignment to INT was not independently associated with decreased risk of onset of DR. However, after adjusting for multiple covariates (CVs), baseline level of PAI-1 was an independent risk factor for the onset of DR. The risk for incidence of DR increased by 12% for each 10 ng/dl increase in baseline PAI-1 concentration (OR 1.012 CI 1.00-1.024, p = 0.042).Progression of DR during the Study: Assignment to INT was not independently associated with decreased risk of progression of DR. However, there was an interaction between glycemic treatment assignment and fibrinogen level at baseline. INT was associated with decreased progression of retinopathy in those with fibrinogen less than 296 mg/dl (OR=0.55 CI 0.31- 1, p=0.03.Conclusion The results require confirmation but are consistent with greater hypercoagulabilty and inflammation, as measured by higher levels of PAI-1 and fibrinogen, being related to DR and responsiveness to INT.
    Diabetes care 10/2013; 37(2). DOI:10.2337/dc13-1193 · 7.74 Impact Factor
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    ABSTRACT: OBJECTIVE Individuals with impaired glucose tolerance (IGT) are at high risk for developing type 2 diabetes mellitus (T2DM). We examined which characteristics at baseline predicted the development of T2DM versus maintenance of IGT or conversion to normal glucose tolerance.RESEARCH DESIGN AND METHODS We studied 228 subjects at high risk with IGT who received treatment with placebo in ACT NOW and who underwent baseline anthropometric measures and oral glucose tolerance test (OGTT) at baseline and after a mean follow-up of 2.4 years.RESULTSIn a univariate analysis, 45 of 228 (19.7%) IGT individuals developed diabetes. After adjusting for age, sex, and center, increased fasting plasma glucose, 2-h plasma glucose, G0-120 during OGTT, HbA1c, adipocyte insulin resistance index, ln fasting plasma insulin, and ln I0-120, as well as family history of diabetes and presence of metabolic syndrome, were associated with increased risk of diabetes. At baseline, higher insulin secretion (ln [I0-120/G0-120]) during the OGTT was associated with decreased risk of diabetes. Higher β-cell function (insulin secretion/insulin resistance or disposition index; ln [I0-120/G0-120 × Matsuda index of insulin sensitivity]; odds ratio 0.11; P < 0.0001) was the variable most closely associated with reduced risk of diabetes.CONCLUSIONS In a stepwise multiple-variable analysis, only HbA1c and β-cell function (ln insulin secretion/insulin resistance index) predicted the development of diabetes (r = 0.49; P < 0.0001).
    Diabetes care 09/2013; 36(11). DOI:10.2337/dc13-0520 · 7.74 Impact Factor
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    ABSTRACT: Type 2 diabetes (T2DM) is an important risk factor for cardiovascular disease (CVD)-the leading cause of death in the US. Yet not all subjects with T2DM are at equal risk for CVD complications; the challenge lies in identifying those at greatest risk. Therapies directed towards treating conventional risk factors have failed to significantly reduce this residual risk in T2DM patients. Thus newer targets and markers are needed for the development and testing of novel therapies. Herein we review two complementary mass spectrometry-based approaches-Mass Spectrometric Immunoassay (MSIA) and tandem mass spectrometry as multiple reaction monitoring (MRM)-for the analysis of plasma proteins and post translational modifications (PTMs) of relevance to T2DM and CVD. Together, these complementary approaches allow for high-throughput monitoring of many PTMs and the absolute quantification of proteins near the low picomolar range. In this review article, we discuss the clinical relevance of the HDL proteome and Apolipoprotein A-I PTMs to T2DM and CVD as well as provide illustrative MSIA and MRM data on high density lipoprotein (HDL) proteins from T2DM patients to provide examples of how these mass spectrometry approaches can be applied to gain new insight regarding cardiovascular risk factors. Also discussed are the reproducibility, interpretation and limitations of each technique with an emphasis on their capacities to facilitate the translation of new biomarkers into clinical practice. This article is protected by copyright. All rights reserved.
    PROTEOMICS - CLINICAL APPLICATIONS 08/2013; 7(7-8). DOI:10.1002/prca.201200028 · 1.81 Impact Factor
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    ABSTRACT: AIMS: This study examined effects of pioglitazone on body weight and bone mineral density prospectively in patients with impaired glucose tolerance since pioglitazone (TZD) increases body weight and body fat in diabetic patients and increases the risk of bone fractures. MATERIALS AND METHODS: A total of 71 men and 163 women aged 49.3 (10.7) years [mean (SD)]; BMI, 34.5 (5.9) kg/m(2) were recruited at 5 sites for measurements of body composition by dual energy x-ray absorptiometry at baseline and at conversion to diabetes or study end, if they had not converted. RESULTS: Mean follow-up was 33.6 months in the pioglitazone group and 32.1 months in the placebo group. Body weight increased 4.63±0.60 (m±SE) kg in the pioglitazone group compared to 0.98±0.62 kg in the PIO group (p <0.0001). Body fat rose 4.89±0.42 kg in the pioglitazone group compared to 1.41±0.44 kg, p <0.0001) in placebo-treated subjects. The increase in fat was greater in legs and trunk than in the arms. Bone mineral density (BMD) was higher in all regions in men and significantly so in most. PIO decreased BMD significantly in the pelvis in men and women, decreased BMD in the thoracic spine and ribs of women and the lumbar spine and legs of men. Bone mineral content also decreased significantly in arms, legs, trunk, and in the total body. CONCLUSIONS: Pioglitazone increased peripheral fat more than truncal fat and decreased bone mineral density in several regions of the body.
    Diabetes Obesity and Metabolism 04/2013; DOI:10.1111/dom.12099 · 5.18 Impact Factor
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    ABSTRACT: OBJECTIVE Intensive glucose-lowering therapy (INT) did not reduce macrovascular events in the recent randomized trials, possibly because it did not improve or worsen other traditional or novel cardiovascular risk factors.RESEARCH DESIGN AND METHODS Standard plasma lipids, cholesterol content of lipoprotein subfractions, and plasma inflammatory and prothrombotic markers were determined in a subgroup of the Veterans Affairs Diabetes Trial (VADT) participants (n = 266) at baseline and after 9 months of INT or standard therapy.RESULTSINT lowered glycated hemoglobin (by a median of 2% vs. a median of 0.7% by standard treatment; P < 0.0001); increased BMI (4 vs. 1%; P < 0.001), total HDL (9 vs. 4%; P < 0.05), HDL2 (14 vs. 0%; P = 0.009), LDL2 (36 vs. 1%; P < 0.0001), and plasma adiponectin (130 vs. 80%; P < 0.01); and reduced triglycerides (-13 vs. -4%; P = 0.02) and small, dense LDL4 (-39 vs. -13%; P < 0.001), but had no effect on levels of plasma apolipoproteins B-100 and B-48, C-reactive protein, interleukin-6, lipoprotein-associated phospholipase A2, myeloperoxidase, fibrinogen, and plasminogen activator inhibitor 1. Incident macrovascular events were associated with baseline interleukin-6 (hazard ratio per each quartile increase 1.33 [95% CI 1.06-1.66]), total LDL (1.25 [1.01-1.55]), apolipoprotein B-100 (1.29 [1.01-1.65]), and fibrinogen (1.26 [1.01-1.57]) but not changes in any cardiovascular risk factors at 9 months.CONCLUSIONSINT was associated with improved adiponectin, lipid levels, and a favorable shift in LDL and HDL subfractions after 9 months. These data suggest that the failure of INT to lower cardiovascular outcomes occurred despite generally favorable changes in standard and novel risk factors early in the study.
    Diabetes care 03/2013; DOI:10.2337/dc12-2082 · 7.74 Impact Factor

Publication Stats

6k Citations
635.24 Total Impact Points

Institutions

  • 2008–2015
    • Phoenix VA Health Care System
      Phoenix, Arizona, United States
  • 2009
    • Arizona State University
      Phoenix, Arizona, United States
  • 2007
    • Stanford University
      • Department of Medicine
      Palo Alto, California, United States
  • 2006
    • United States Department of Veterans Affairs
      Bedford, Massachusetts, United States
  • 2003–2006
    • U.S. Department of Veterans Affairs
      Washington, Washington, D.C., United States
    • Stanford Medicine
      • Department of Medicine
      Stanford, California, United States
  • 1990–2005
    • University of California, San Diego
      • • Division of Endocrinology & Metabolism
      • • Department of Medicine
      San Diego, California, United States
  • 2002
    • University of Southern California
      • School of Pharmacy
      Los Angeles, California, United States
  • 1998
    • Indiana University-Purdue University Indianapolis
      Indianapolis, Indiana, United States