Noninvasive measurement of plasma glucose from exhaled breath in healthy and type 1 diabetic subjects.

Effective management of diabetes mellitus, affecting tens of millions of patients, requires frequent assessment of plasma glucose. Patient compliance for sufficient testing is often reduced by the unpleasantness of current methodologies, which require blood samples and often cause pain and skin callusing. We propose that the analysis of volatile organic compounds (VOCs) in exhaled breath can be used as a novel, alternative, noninvasive means to monitor glycemia in these patients. Seventeen healthy (9 females and 8 males, 28.0 ± 1.0 yr) and eight type 1 diabetic (T1DM) volunteers (5 females and 3 males, 25.8 ± 1.7 yr) were enrolled in a 240-min triphasic intravenous dextrose infusion protocol (baseline, hyperglycemia, euglycemia-hyperinsulinemia). In T1DM patients, insulin was also administered (using differing protocols on 2 repeated visits to separate the effects of insulinemia on breath composition). Exhaled breath and room air samples were collected at 12 time points, and concentrations of ~100 VOCs were determined by gas chromatography and matched with direct plasma glucose measurements. Standard least squares regression was used on several subsets of exhaled gases to generate multilinear models to predict plasma glucose for each subject. Plasma glucose estimates based on two groups of four gases each (cluster A: acetone, methyl nitrate, ethanol, and ethyl benzene; cluster B: 2-pentyl nitrate, propane, methanol, and acetone) displayed very strong correlations with glucose concentrations (0.883 and 0.869 for clusters A and B, respectively) across nearly 300 measurements. Our study demonstrates the feasibility to accurately predict glycemia through exhaled breath analysis over a broad range of clinically relevant concentrations in both healthy and T1DM subjects.

Altered inflammatory, oxidative, and metabolic responses to exercise in pediatric obesity and type 1 diabetes.

Obesity (Ob) and type 1 diabetes (T1DM) are associated with increased inflammation and oxidative stress, which are major pathogenetic pathways toward higher cardiovascular risks. Although long-term exercise protects against systemic inflammation and oxidation, acute exercise actually exerts pro-inflammatory and oxidative effects, prompting the necessity for better defining these molecular processes in at-risk patients; in particular, very little is known regarding obese and T1DM children. We therefore examined key inflammatory and oxidative stress variables during exercise in 138 peripubertal children (47 Ob, 12.7 ± 0.4 yr, 22 F, BMI% 97.6 ± 0.2; 49 T1DM, 13.9 ± 0.2 yr, 20 F, body mass index% [BMI] 63.0 ± 3.6; 42 healthy, CL, 13.5 ± 0.5 yr, 24 F, BMI% 57.0 ± 3.6), who performed 10 bouts of 2-min cycling ~80% VO(2max) , separated by 1-min rest intervals. Blood samples were drawn at baseline and peak exercise. Ob displayed elevated baseline interleukin-6 (IL-6, 2.1 ± 0.2 pg/mL, p < 0.005) vs. CL (1.5 ± 0.3), whereas T1DM displayed the greatest maximum exercise-induced change in IL-6 (1.2 ± 0.3) than in both Ob (0.7 ± 0.1, p < 0.001) and CL (0.6 ± 0.1, p < 0.0167). Myeloperoxidase (MPO) was elevated in T1DM (143 ± 30 ng/mL, p < 0.0167) vs. CL (89 ± 10) and Ob (76 ± 6), whereas increases in exercise only occurred in Ob and CL. Disparate baseline and exercise responses were also observed for 8-hydroxy-2'-deoxyguanosine, glutathione, and F(2) -isoprostane. This data show distinct patterns of dysregulation in baseline and adaptive immunologic and oxidative responses to exercise in Ob and T1DM. A full understanding of these alterations is required so that developing exercise regimens aimed at maximizing health benefits for specific dysmetabolic states can be achieved based on complete scientific characterization rather than empirical implementation.

Improved predictive models for plasma glucose estimation from multi-linear regression analysis of exhaled volatile organic compounds.

Exhaled volatile organic compounds (VOCs) represent ideal biomarkers of endogenous metabolism and could be used to noninvasively measure circulating variables, including plasma glucose. We previously demonstrated that hyperglycemia in different metabolic settings (glucose ingestion in pediatric Type 1 diabetes) is paralleled by changes in exhaled ethanol, acetone, and methyl nitrate. In this study we integrated these gas changes along with three additional VOCs (2 forms of xylene and ethylbenzene) into multi-linear regression models to predict plasma glucose profiles in 10 healthy young adults, during the 2 h following an intravenous glucose bolus (matched samples of blood, exhaled and room air were collected at 12 separate time points). The four-gas model with highest predictive accuracy estimated plasma glucose in each subject with a mean R value of 0.91 (range 0.70-0.98); increasing the number of VOCs in the model only marginally improved predictions (average R with best 5-gas model = 0.93; with 6-gas model = 0.95). While practical development of this methodology into clinically usable devices will require optimization of predictive algorithms on large-scale populations, our data prove the feasibility and potential accuracy of breath-based glucose testing.

Noninvasive measurement of plasma triglycerides and free fatty acids from exhaled breath.

BACKGROUND: Although altered metabolism has long been known to affect human breath, generating clinically usable metabolic tests from exhaled compounds has proven challenging. If developed, a breath-based lipid test would greatly simplify management of diabetes and serious pathological conditions (e.g., obesity, familial hyperlipidemia, and coronary artery disease), in which systemic lipid levels are a critical risk factor for onset and development of future cardiovascular events. METHODS: We, therefore, induced controlled fluctuations of plasma lipids (insulin-induced lipid suppression or intravenous infusion of Intralipid) during 4-h in vivo experiments on 23 healthy volunteers (12 males/11 females, 28.0 ± 0.3 years) to find correlations between exhaled volatile organic compounds and plasma lipids. In each subject, plasma triglycerides (TG) and free fatty acids (FFA) concentrations were both directly measured and calculated via individualized prediction equations based on the multiple linear regression analysis of a cluster of 4 gases. In the lipid infusion protocol, we also generated common prediction equations using a maximum of 10 gases. RESULTS: This analysis yielded strong correlations between measured and predicted values during both lipid suppression (r = 0.97 for TG; r = 0.90 for FFA) and lipid infusion (r = 0.97 for TG; r = 0.94 for FFA) studies. In our most accurate common prediction model, measured and predicted TG and FFA values also displayed very strong statistical agreement (r = 0.86 and r = 0.81, respectively). CONCLUSIONS: Our results demonstrate the feasibility of measuring plasma lipids through breath analysis. Optimization of this technology may ultimately lead to the development of portable breath analyzers for plasma lipids, replacing blood-based bioassays.

Age-dependent sexual dimorphism in cognition and stress response in the 3xTg-AD mice.

We sought to determine if sex impacts the cognitive and neuropathological phenotype of the 3xTg-AD mice. We find that male and female 3xTg-AD mice show comparable impairments on Morris water maze (MWM) and inhibitory avoidance (IA) at 4 months. Shortly thereafter, however, the cognitive performance varies among the sexes, with females performing worse than males. These behavioral differences are not attributable to differences in Abeta or tau levels. The behavioral effect is transient as from 12 months onward, the disparity is no longer apparent. Because females perform worse than males on stressful tasks, we explored their corticosterone responses and find that young female 3xTg-AD mice show markedly heightened corticosterone response after 5 days of MWM training compared to age-matched male 3xTg-AD mice; this difference is no longer apparent in older mice. Thus, the enhanced corticosterone response of the young female mice likely underlies their poorer performance on stressful tasks.