CHICAGO, IL, United States
CHICAGO, IL, United States

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Singal P.,Indiana University | Janghorbani M.,Biochemanalysis Corporation | Janghorbani M.,Center for Stable Isotope Research Inc. | Schuette S.A.,Biochemanalysis Corporation | And 2 more authors.
Diabetes Technology and Therapeutics | Year: 2010

Background: Glucose tolerance can be assessed noninvasively using 13C-labeled glucose added to a standard oral glucose load, by measuring isotope-enriched CO2 in exhaled air. In addition to the clear advantage of the noninvasive measurements, this approach may be of value in overcoming the high variability in blood glucose determination. Methods: We compared within-individual variability of breath CO2 isotope enrichment with that for blood glucose in a 75-g oral glucose tolerance test (OGTT) by adding 150 mg of D-[13C]glucose (13C 99%) to a standard 75-g glucose load. Measurements of whole blood glucose (by glucose oxidase) and breath isotope enrichment (by isotope ratio mass spectrometry) were made every 30 min for 3 h. Subjects underwent three repeat tests over a 3-week period. Values for variability of breath isotope enrichment at 3 h (∂‰180) and of area under the curve for enrichment to 180 min (AUC180) were compared with variability of the 2-h OGTT blood glucose. Results: Breath test-derived measures exhibited lower within-subject variability than the 2-h OGTT glucose. The coefficient of variation for ∂‰180 was 7.4 ± 3.9% (mean ± SD), for AUC180 was 9.4 ± 6.3%, and for 2-h OGTT blood glucose was 13 ± 7.1% (P = 0.005 comparing ∂‰180 versus 2-h blood glucose; P = 0.061 comparing AUC180 versus 2-h blood glucose; P = 0.03 comparing ∂‰180 versus AUC180). Conclusions: Breath test-derived measurements of glucose handling had lower within-subject variability versus the standard 2-h blood glucose reading used in clinical practice. These findings support further development of this noninvasive method for evaluating glucose tolerance. Copyright 2010, Mary Ann Liebert, Inc.

Sheffield-Moore M.,University of Texas Medical Branch | Dillon E.L.,University of Texas Medical Branch | Randolph K.M.,University of Texas Medical Branch | Casperson S.L.,University of Texas Medical Branch | And 9 more authors.
Journal of Cachexia, Sarcopenia and Muscle | Year: 2014

Background: Skeletal muscle loss accompanying aging or cancer is associated with reduced physical function and predicts morbidity and mortality. 3-Methylhistidine (3MH) has been proposed as a biomarker of myofibrillar proteolysis, which may contribute to skeletal muscle loss. Methods: We hypothesized that the terminal portion of the isotope decay curve following an oral dose of isotopically labeled 3MH can be measured non-invasively from timed spot urine samples. We investigated the feasibility of this approach by determining isotope enrichment in spot urine samples and corresponding plasma samples and whether meat intake up to the time of dosing influences the isotope decay. Results: Isotope decay constants (k) were similar in plasma and urine, regardless of diet. Post hoc comparison of hourly sampling over 10 h with three samples distributed over 10 or fewer hours suggests that three distributed samples over 5-6 h of plasma or urine sampling yield decay constants similar to those obtained over 10 h of hourly sampling. Conclusion: The findings from this study suggest that an index of 3MH production can be obtained from an easily administered test involving oral administration of a stable isotope tracer of 3MH followed by three plasma or urine samples collected over 5-6 h the next day. © 2013 Springer-Verlag Berlin Heidelberg.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 906.08K | Year: 2012

DESCRIPTION (provided by applicant): Abstract The long-term objective of this research is to develop a non-invasive approach for assessment of de novo 3MH production in cancer patients early in the course of the disease as a way of assessing which patients are at high risk for future development of skeletal muscle atrophy. The approach is based on: 1) the known increase in de novo production of 3-methylhistidine (3MH) from muscle protein breakdown in said patients as a consequence of their unique disease-host interactions, and 2) earlier demonstration that de novo 3MH production can be measured in vivo using isotope dilution. We envision a relatively simple method that is totally non-invasive yet able to assess the course of skeletal muscle loss in cancer patients. The approach depends on the hypothesis that after an oral dose of deuterated 3-methylhistidine (D-3MH), the slope of the terminal portion of the decay curve (gt 12 hours post-dosing) for the tracer/tracee (D-3MH/3MH) in the free 3MH pool is directly proportional to the rate constant for myofibrillar protein degradation and can be determined from spot urine samples. During our Phase I research we established the feasibility of our overall approach by testing the following hypotheses in nine healthy adult males (four young, five older) by showing: (i) isotope enrichment in spot urine samples is identical with the corresponding plasma samples, (ii) meat intake up to and including the time of dosing does not influence the slope of the terminal portion of the isotope decay curve, and (iii) that the method is sufficiently sensitive to measure differences in the rate of 3MH production between young and older individuals. Testing the validity of these hypotheses was the central focus of the Phase-I research and crucial to the development of an approach that is both scientifically sound as well as non-invasive and clinically relevant. During Phase-II, we propose to conduct a statistically powerful prospective investigation to demonstrate that measurementof slope of the terminal decay curve (rate constant) with our approach in newly diagnosed cancer patients predicts future development of muscle wasting. We expect the outcome of the combined Phase-I and Phase-II research to lead to the manufacture and marketing of a suitable Test Kit for early identification of elevated muscle catabolism in at-risk patients so that medical intervention can take place and prevent future muscle atrophy. PUBLIC HEALTH RELEVANCE: Project Narrative Skeletal muscle loss is an important, but unpredictable, occurrence in many patients with different types of cancer and other chronic diseases. Early assessment is important because it would permit selection of high risk patients for preventive strategies. Once a clinically significant amount of skeletal muscle is lost in these patients it cannot be reversed and has poor prognostic implications. The purpose of this project is to develop a non-invasive method for early assessment of increased skeletal muscle degradationin non-small cell lung cancer patients. As a group, these patients have a high likelihood of weight- and skeletal muscle loss, but the results are expected to be applicable to other cancer types in which weight-loss is an important component. Our approachis based on development of a (non-radioactive) stable isotope tracer approach to permit accurate quantitative measurement of skeletal muscle degradation early in the course of the disease by monitoring spot urine samples for the ratio of labeled/unlabeled3-methylhistidine the morning after consuming a small amount of labeled 3-methylhistidine along with a meat-free dinner.

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