Background and Rationale:
The world-wide diabetes pandemic has heightened the need for early screening and prevention. Type 2 diabetes develops slowly and insidiously, with the earliest stages going undetected. Our laboratory is utilizing compact magnetic resonance technology to develop unique screening and monitoring tools for metabolic health and diabetes risk. The ultimate goal is to pair these new tools with effective therapies in order to improve outcomes for diabetes prevention.
In prior work, we discovered that plasma water T2 is a practical tool for assessing cardiometabolic health and identifying hidden diabetes risk in apparently healthy subjects. The initial study had an observational, cross-sectional design and did not examine how T2 responds to treatment. In the current study, we tested the hypothesis that plasma water T2 measures the impact of lifestyle modification on cardiometabolic health status. This is a NIH-funded ancillary study of PREMIER, a multi-site randomized controlled trial. The PREMIER interventions incorporated physical activity, weight loss, decreased sodium and alcohol intake, and the DASH diet into three treatment arms: “Established”, “Established+DASH” and “Advice Only”. The subjects were monitored at baseline (before treatment) and at 6- and 18-months after treatment.
Methods:
The target population for the parent PREMIER trial was generally healthy adults with mild-to-moderately elevated blood pressure, not taking anti-hypertensive medications. The exclusion criteria were diabetes, prior cardiovascular event, congestive heart failure, angina, cancer diagnosis or treatment within the past 2 years, high alcohol consumption (>21 drinks per week), lactation, or current/planned pregnancy. After the initial screening, a total of 810 subjects were enrolled and randomized into three treatment arms. The study population was 62% female and 34% black, with an age range of 25 to 75 and a baseline median body-mass index (BMI) of 32.3. At baseline, 62.7% of subjects met the criteria for prediabetes and/or metabolic syndrome.
Water T2 values were recorded in triplicate for 2,282 bio-banked plasma samples collected at baseline and at 6- and 18-month post-treatment. The total acquisition time for each data set (16 signal-averaged transients) was 3 minutes. Each sample consisted of 40 microliters of unmodified plasma in a 3 mm co-axial insert (Model NE-10-CIC-SB, New Era, Inc.) held within an otherwise empty 10 mm outer tube (NE-L10-7). The 3 mm insert has a fill mark at 1 cm to achieve a consistent sample height and volume. The use of a small sample volume is critical for two reasons: (i) it makes optimal use of precious and limited bio-banked human blood samples, and (ii) it eliminates radiation damping, which can introduce non-exponential artifacts into the decay curve.
Multi-exponential transverse relaxation decay curves were recorded at 37°C using a modified Carr-Purcell-Meiboom-Gill pulse sequence and a 0.47T Bruker mq20 benchtop magnetic resonance device equipped with a 10 mm probe (model H20-10-25AVGX4). Water T2 was de-convoluted from the fast-relaxing non-water lipid/protein T2 components using a discrete inverse Laplace transformation as implemented in XpFIT (SoftScientific.com, Alango, Ltd.). The number of exponential terms was fixed to 3 across all plasma samples to enable meaningful subject-to-subject comparisons of water T2 values.
To quantify the response of plasma water T2 to 6- and 18-months of lifestyle modification, T2 served as the dependent variable in linear mixed effects regression models developed using the statistical modeling package JMP Pro v14.2 (SAS, Inc.). The mixed effects models adjusted for baseline T2 and other variables as fixed effects; unmeasured subject-to-subject variability over time was included as a random effect. In addition, the mixed effects models were stratified by baseline factors to assess heterogeneity in the treatment effect on plasma water T2 values.
Results:
For the primary regression model, all three treatment arms showed progressive increases in plasma water T2 at 6- and 18-months post-intervention. Mean T2 values at 18 months were 789.5 msec (14.8 increase from baseline, p=0.0123) for the Established treatment arm; 793.6 msec (21.0 increase from baseline, p=0.0004) for Established+DASH; and 792.4 msec (23.1 increase from baseline, p<.0001) for the Advice-Only arm. Subsequent models were stratified by gender, race, baseline age, baseline BMI or baseline fitness. A heterogeneous T2 response to treatment was observed for different groups. For example, men responded best to Established+DASH, whereas women responded best to Advice Only. Subjects with high BMI at baseline responded well to the Established intervention. By contrast, those with low BMI at baseline showed no response to Established, but responded well to Established+DASH. Conclusions: Plasma water T2 values showed substantial increases in response to the PREMIER lifestyle interventions. These findings validate plasma water T2 as a global, practical and effective tool for monitoring improvement in cardiometabolic health in response to lifestyle modification. The heterogeneous response to different treatments based on gender, race, age, baseline BMI and baseline fitness highlights the need for tailored treatment strategies.