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author:("schenke, Dawn")
1.  Baseline Adiponectin Levels Do Not Influence the Response to Pioglitazone in ACT NOW 
Diabetes Care  2014;37(6):1706-1711.
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.
A 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.
Pioglitazone 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.
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.
PMCID: PMC4179517  PMID: 24705615
2.  Prediction of Diabetes Based on Baseline Metabolic Characteristics in Individuals at High Risk 
Diabetes Care  2013;36(11):3607-3612.
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.
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.
In 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.
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).
PMCID: PMC3816921  PMID: 24062330
3.  Prevention of Diabetes With Pioglitazone in ACT NOW 
Diabetes  2013;62(11):3920-3926.
We examined the metabolic characteristics that attend the development of type 2 diabetes (T2DM) in 441 impaired glucose tolerance (IGT) subjects who participated in the ACT NOW Study and had complete end-of-study metabolic measurements. Subjects were randomized to receive pioglitazone (PGZ; 45 mg/day) or placebo and were observed for a median of 2.4 years. Indices of insulin sensitivity (Matsuda index [MI]), insulin secretion (IS)/insulin resistance (IR; ΔI0–120/ΔG0–120, ΔIS rate [ISR]0–120/ΔG0–120), and β-cell function (ΔI/ΔG × MI and ΔISR/ΔG × MI) were calculated from plasma glucose, insulin, and C-peptide concentrations during oral glucose tolerance tests at baseline and study end. Diabetes developed in 45 placebo-treated vs. 15 PGZ-treated subjects (odds ratio [OR] 0.28 [95% CI 0.15–0.49]; P < 0.0001); 48% of PGZ-treated subjects reverted to normal glucose tolerance (NGT) versus 28% of placebo-treated subjects (P < 0.005). Higher final glucose tolerance status (NGT > IGT > T2DM) was associated with improvements in insulin sensitivity (OR 0.61 [95% CI 0.54–0.80]), IS (OR 0.61 [95% CI 0.50–0.75]), and β-cell function (ln IS/IR index and ln ISR/IR index) (OR 0.26 [95% CI 0.19–0.37]; all P < 0.0001). Of the factors measured, improved β-cell function was most closely associated with final glucose tolerance status.
PMCID: PMC3806596  PMID: 23863810
4.  Parallel Workflow for High-Throughput (>1,000 Samples/Day) Quantitative Analysis of Human Insulin-Like Growth Factor 1 Using Mass Spectrometric Immunoassay 
PLoS ONE  2014;9(3):e92801.
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.
PMCID: PMC3963945  PMID: 24664114
5.  Pioglitazone slows progression of atherosclerosis in prediabetes independent of changes in cardiovascular risk factors 
To determine whether changes in standard and novel risk factors during the ACT NOW trial explained the slower rate of CIMT progression with pioglitazone treatment in persons with prediabetes.
Methods and Results
CIMT was measured in 382 participants at the beginning and up to three additional times during follow-up of the ACT NOW trial. During an average follow-up of 2.3 years, the mean unadjusted annual rate of CIMT progression was significantly (P=0.01) lower with pioglitazone treatment (4.76 × 10−3 mm/year, 95% CI, 2.39 × 10−3 – 7.14 × 10−3 mm/year) compared with placebo (9.69 × 10−3 mm/year, 95% CI, 7.24 × 10−3 – 12.15 × 10−3 mm/year). High-density lipoprotein cholesterol, fasting and 2-hour glucose, HbA1c, fasting insulin, Matsuda insulin sensitivity index, adiponectin and plasminogen activator inhibitor-1 levels improved significantly with pioglitazone treatment compared with placebo (P < 0.001). However, the effect of pioglitazone on CIMT progression was not attenuated by multiple methods of adjustment for traditional, metabolic and inflammatory risk factors and concomitant medications, and was independent of changes in risk factors during pioglitazone treatment.
Pioglitazone slowed progression of CIMT, independent of improvement in hyperglycemia, insulin resistance, dyslipidemia and systemic inflammation in prediabetes. These results suggest a possible direct vascular benefit of pioglitazone.
PMCID: PMC3908828  PMID: 23175674
Carotid atherosclerosis progression; Impaired glucose tolerance; Insulin resistance; Inflammation; Pioglitazone
6.  Metabolic factors, adipose tissue and plasminogen activator inhibitor-1 levels in type 2 diabetes: Findings from the Look AHEAD Study 
Plasminogen activator inhibitor-1 (PAI-1) production by adipose tissue is increased in obesity and its circulating levels are high in type 2 diabetes. PAI-1 increases cardiovascular risk by favoring clot stability and/or interfering with vascular remodeling. We investigated in obese diabetic persons whether an intensive lifestyle intervention for weight loss (ILI) would decrease PAI-1 levels independently of weight loss and whether PAI-1 reduction would be associated with changes in fibrinogen, an acute phase reactant, and/or fibrin fragment D-dimer (D-dimer), a marker of ambient coagulation balance.
Methods and Results
We examined 1-year changes in PAI-1, D-dimer and fibrinogen levels, adiposity, fitness, glucose and lipid control with ILI in 1,817 participants from Look AHEAD, a randomized trial investigating the effects of ILI, compared to usual care, on cardiovascular events in overweight/obese diabetic persons. Median PAI-1 levels decreased 29% with ILI, 2.5% with usual care (p<0.0001). Improvements in fitness, glucose control and HDL-cholesterol were associated with decreased PAI-1, independently of weight loss (p=0.03 for fitness, p<0.0001 for others). Fibrinogen and D-dimer remained unchanged.
Reductions in PAI-1 levels with ILI in obese diabetic individuals may reflect an improvement in adipose tissue health that could impact cardiovascular risk without changing fibrinogen or D-dimer levels.
PMCID: PMC3130500  PMID: 21512162
7.  A 1-Year Lifestyle Intervention for Weight Loss in Individuals With Type 2 Diabetes Reduces High C-Reactive Protein Levels and Identifies Metabolic Predictors of Change 
Diabetes Care  2010;33(11):2297-2303.
We examined whether a 1-year intensive lifestyle intervention (ILI) for weight loss reduced elevated high-sensitivity C-reactive protein (hs-CRP) levels in obese individuals with diabetes and identified metabolic and fitness predictors of hs-CRP change.
Look AHEAD (Action for Health in Diabetes) is an ongoing multicenter clinical trial examining the effects of weight loss achieved through ILI on cardiovascular events and overall mortality in obese/overweight adults with type 2 diabetes. We report on 1,759 Look AHEAD participants who had hs-CRP and fitness data at baseline and 1 year. Subjects were randomly assigned to ILI or to usual care (diabetes support and education [DSE]). ILI involved frequent counseling to increase moderate-intensity exercise to 175 min/week, reduce caloric and saturated fat intake, and change macronutrient composition to improve glycemic control.
ILI reduced median hs-CRP by 43.6% from baseline to 1 year, compared with a 16.7% reduction with DSE (P < 0.001). ILI decreased weight (8.8%), A1C (0.7%), and triglycerides (17%) and increased fitness (19%) and HDL cholesterol (7.5%) (P < 0.0001 vs. changes with DSE). Changes in adiposity and glucose control with ILI remained independent predictors of hs-CRP change at 1 year (P < 0.0001 for each) after adjustment for demographics, smoking, cardiovascular history, statin and thiazolidinedione use, and changes in fitness and lipid control. Neither statin nor insulin therapy modified the association between ILI and hs-CRP.
A 1-year lifestyle intervention for weight loss in obese individuals with diabetes was associated with substantial reductions in hs-CRP. Improved glycemic control and reduced adiposity had comparable effects on hs-CRP change.
PMCID: PMC2963483  PMID: 20682679
8.  Improvement of Postprandial Endothelial Function After a Single Dose of Exenatide in Individuals With Impaired Glucose Tolerance and Recent-Onset Type 2 Diabetes 
Diabetes Care  2010;33(5):1028-1030.
Endothelial dysfunction is frequently present in individuals with insulin resistance or type 2 diabetes and can be induced by high-fat or high-carbohydrate meals. Because exenatide reduces postprandial glucose and lipid excursions, we hypothesized that it may also improve postprandial endothelial function.
In a double-blinded randomized crossover design, postprandial endothelial function was examined in 28 individuals with impaired glucose tolerance or recent-onset type 2 diabetes after a single injection of exenatide or placebo given just before a high-fat meal. Endothelial function was determined with peripheral arterial tonometry pre- and postprandially.
Postprandial endothelial function was higher after exenatide compared with placebo (P = 0.0002). In the placebo phase, postprandial change in endothelial function was inversely associated with mean postprandial concentrations of triglycerides (r = −0.62, P = 0.0004). Changes in postprandial triglyceride concentrations explained 64% of exenatide's effect on postprandial endothelial function.
Exenatide ameliorates postprandial endothelial dysfunction after a high-fat meal.
PMCID: PMC2858168  PMID: 20200309
9.  Marine ω-3 Fatty Acid Intake 
Diabetes Care  2009;33(1):197-199.
To examine usual marine ω-3 fatty acid (mO-3FA) intake in individuals with diabetes; its association with adiposity, lipid, and glucose control; and its changes with behavioral lifestyle intervention for weight loss.
Cross-sectional and 1-year longitudinal analyses were performed on 2,397 Look AHEAD (Action for Health in Diabetes) participants. Look AHEAD is a cardiovascular outcome trial evaluating the effects of intensive lifestyle intervention for weight loss in overweight/obese subjects with type 2 diabetes.
Baseline mO-3FA intake was 162 ± 138 mg/day. It was inversely associated with triglycerides (β = −0.41, P < 0.001) and weakly with HDL (β = 4.14, P = 0.050), after multiple covariate adjustment. One-year mO-3FA and fried/sandwich fish intake decreased with intensive lifestyle intervention (P < 0.001).
mO-3FA intake in Look AHEAD participants was low but associated favorably with lipids. These results encourage investigation on the potential benefits of increasing mO-3FA intake in lifestyle interventions for weight loss in individuals with diabetes.
PMCID: PMC2797972  PMID: 19841042
10.  Intensive Glucose-Lowering Therapy Reduces Cardiovascular Disease Events in Veterans Affairs Diabetes Trial Participants With Lower Calcified Coronary Atherosclerosis 
Diabetes  2009;58(11):2642-2648.
This study investigated the hypothesis that baseline calcified coronary atherosclerosis may determine cardiovascular disease events in response to intensive glycemic control within the Veterans Affairs Diabetes Trial (VADT).
At baseline, 301 type 2 diabetic participants in the VADT, a randomized trial comparing the effects of intensive versus standard glucose lowering on cardiovascular events, had baseline coronary atherosclerosis assessed by coronary artery calcium (CAC) measured by computed tomography. Participants were followed over the 7.5-year study for development of cardiovascular end points.
During a median follow-up duration of 5.2 years, 89 cardiovascular events occurred. Although intensive glucose-lowering therapy did not significantly reduce cardiovascular events in the substudy cohort as a whole, there was evidence that the response was modified by baseline CAC, as indicated by significant P values for treatment by log(CAC + 1) interaction terms in unadjusted and multivariable-adjusted models (0.01 and 0.03, respectively). Multivariable-adjusted hazard ratios (HRs) for the effect of treatment indicated a progressive diminution of benefit with increasing CAC. Subgroup analyses were also conducted for clinically relevant CAC categories: those above and below an Agatston score of 100. Among those randomized to intensive treatment, for the subgroup with CAC >100, 11 of 62 individuals had events, while only 1 of 52 individuals with CAC ≤100 had an event. The multivariable HR for intensive treatment for those with CAC >100 was 0.74 (95% CI 0.46–1.20; P = 0.21), while for the subgroup with CAC ≤100, the corresponding HR was 0.08 (0.008–0.77; P = 0.03), with event rates of 39 and 4 per 1,000 person-years, respectively.
These data indicate that intensive glucose lowering reduces cardiovascular events in those with less extensive calcified coronary atherosclerosis.
PMCID: PMC2768182  PMID: 19651816
11.  Association Between IL-6 and the extent of Coronary Atherosclerosis in The Veterans Affairs Diabetes Trial (VADT) 
Atherosclerosis  2008;203(2):610-614.
The aim of the present study was to investigate the association of high sensitivity CRP, interleukin-6 (IL-6) and lipoprotein-associated phospholipase A2 (Lp-PLA2) with the extent of calcified coronary atherosclerosis in patients with type 2 diabetes mellitus (T2DM).
Materials and results
This is a cross-sectional study of 306 subjects aged 40 years or older who were enrolled into the Veterans Affair Diabetes Trial. Calcified coronary atherosclerosis was assessed using electron beam computed tomography scored by the Agatston method. Clinical parameters, traditional cardiovascular risk factors and plasma levels of CRP, IL-6 and Lp-PLA2 were measured at the time of the scan. Coronary artery calcium scores (CAC) increased stepwise across increasing categories of IL-6, but did not change across increasing categories of CRP and Lp-PLA2. After adjustment for traditional cardiovascular risk factors, IL-6 was significantly associated with CAC scores (p= 0.05). The association between IL-6 and CAC was largely in those with lower (below the median) abdominal artery calcium (AAC) levels (p= 0.03).
Despite a generally higher level of systemic inflammation in T2DM, the inflammatory marker IL-6 remained significantly associated with CAC score, particularly in those subjects with lower AAC scores.
PMCID: PMC2688903  PMID: 18804762
Inflammatory markers; Type 2 Diabetes; Atherosclerosis; Vascular calcification; CAC; AAC
12.  Actos Now for the prevention of diabetes (ACT NOW) study 
Impaired glucose tolerance (IGT) is a prediabetic state. If IGT can be prevented from progressing to overt diabetes, hyperglycemia-related complications can be avoided. The purpose of the present study was to examine whether pioglitazone (ACTOS®) can prevent progression of IGT to type 2 diabetes mellitus (T2DM) in a prospective randomized, double blind, placebo controlled trial.
602 IGT subjects were identified with OGTT (2-hour plasma glucose = 140–199 mg/dl). In addition, IGT subjects were required to have FPG = 95–125 mg/dl and at least one other high risk characteristic. Prior to randomization all subjects had measurement of ankle-arm blood pressure, systolic/diastolic blood pressure, HbA1C, lipid profile and a subset had frequently sampled intravenous glucose tolerance test (FSIVGTT), DEXA, and ultrasound determination of carotid intima-media thickness (IMT). Following this, subjects were randomized to receive pioglitazone (45 mg/day) or placebo, and returned every 2–3 months for FPG determination and annually for OGTT. Repeat carotid IMT measurement was performed at 18 months and study end. Recruitment took place over 24 months, and subjects were followed for an additional 24 months. At study end (48 months) or at time of diagnosis of diabetes the OGTT, FSIVGTT, DEXA, carotid IMT, and all other measurements were repeated.
Primary endpoint is conversion of IGT to T2DM based upon FPG ≥ 126 or 2-hour PG ≥ 200 mg/dl. Secondary endpoints include whether pioglitazone can: (i) improve glycemic control (ii) enhance insulin sensitivity, (iii) augment beta cell function, (iv) improve risk factors for cardiovascular disease, (v) cause regression/slow progression of carotid IMT, (vi) revert newly diagnosed diabetes to normal glucose tolerance.
ACT NOW is designed to determine if pioglitazone can prevent/delay progression to diabetes in high risk IGT subjects, and to define the mechanisms (improved insulin sensitivity and/or enhanced beta cell function) via which pioglitazone exerts its beneficial effect on glucose metabolism to prevent/delay onset of T2DM.
Trial Registration
clinical identifier: NCT00220961
PMCID: PMC2725044  PMID: 19640291

Results 1-12 (12)