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e-Letters: Observations

Exhaled Breath Isoprene Rises During Hypoglycemia in Type 1 Diabetes

  1. Sankalpa Neupane1,
  2. Robert Peverall2,3,
  3. Graham Richmond2,
  4. Tom P.J. Blaikie2,
  5. David Taylor2,
  6. Gus Hancock2,3 and
  7. Mark L. Evans1⇑
  1. 1Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Institute of Metabolic Science–Metabolic Research Laboratories, Addenbrookes Hospital, Cambridge, U.K.
  2. 2Oxford Medical Diagnostics, Centre for Innovation & Enterprise, Begbroke Science Park, Begbroke, U.K.
  3. 3Physical & Theoretical Chemistry Laboratory, Department of Chemistry, University of Oxford, Oxford, U.K.
  1. Corresponding author: Mark L. Evans, mle24{at}cam.ac.uk.
Diabetes Care 2016 Jul; 39(7): e97-e98. https://doi.org/10.2337/dc16-0461
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Hypoglycemia and/or fear of hypoglycemia are major challenges for many with type 1 diabetes (T1D), limiting ability to lower glycemia. Given anecdotal reports of domestic pets alerting owners to blood glucose changes, especially hypoglycemia (1), we hypothesized that volatile organic compounds (VOCs) in exhaled breath might change at low glucose.

We studied eight female nonsmoking participants with T1D (aged 46 ± 5 years, diabetes duration 23 ± 7 years, none treated with statins) twice using a single-blinded, computer code–randomized crossover design. An independent research ethics committee approved studies in advance, and subjects provided written consent. Using a stepped insulin clamp (Actrapid; Novo Nordisk, Crawley, U.K.; 0.3 mU/kg/min increasing to 1.5 mU/kg/min), on one occasion (STEP), arterialized plasma glucose (Yellow Springs Instrument 2300 STAT Plus Analyzer) was raised sequentially (7.1 ± 0.8, 8.7 ± 0.4, and 10.7 ± 0.1 mmol/L) then lowered with higher insulin infusion to 4.3 ± 0.3 and 2.8 ± 0.1 mmol/L. On control days (CON), procedures were identical except that plasma glucose was maintained at 6.2 ± 0.1 mmol/L (Fig. 1).

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Figure 1

Exhaled breath isoprene during studies. *P < 0.01 compared with nonhypoglycemia.

For breath collection, subjects held their breath for 3 s, partially exhaled, and then breathed into a 1.1-L breath bag (Fischer Analysen Instrumente GmbH). VOCs were measured by soft-ionization mass spectrometry (V&F AIRSENSE Compact Ion Molecule Reaction Mass Spectrometer) by a researcher blinded to clamp glucose values (2). VOC values were adjusted to 5% exhaled CO2. To look specifically for a biomarker of low blood glucose, we compared VOC values (two-sample Student t test; SPSS Statistics 21) during hypoglycemia (2.8 mmol/L STEP) with values from nonhypoglycemia. We also examined the correlation between plasma glucose and VOCs (STEP–CON values) across the range of experimental glucose values (Spearman correlation). Data are presented as mean ± SEM.

Plasma insulin (DiaSorin LIAISON XL chemiluminescence immunoassay) was similar on study days (275 ± 109 vs. 268 ± 95 pmol/L at 120 min and 1,001 ± 194 vs. 978 ± 171 pmol/L at 220 min; STEP vs. CON). Strikingly, exhaled breath isoprene rose significantly at hypoglycemia (220-min values) compared with nonhypoglycemia (Fig. 1). Outside hypoglycemia, there was no correlation between exhaled isoprene and plasma glucose across the broader range of experimental plasma glucose values and no significant associations with other measured VOCs (acetone, methyl nitrate, ethanol, ethyl benzene, and propane).

It is unclear how hypoglycemia could increase isoprene. Despite being one of the most common VOCs in human breath, the source of endogenous isoprene remains undetermined. At least in part, isoprene may be a by-product of cholesterol biosynthesis (3). Although glucose can alter fatty acid formation via carbohydrate response element–binding protein (CHrEBP), this has not been described for cholesterol biosynthesis (4). Alternatively, during hypoglycemia, tachycardia and increased blood flow could increase pulmonary delivery of isoprene. Against this, we saw no changes in other VOCs. Of note, a previous study using insulin clamps in T1D reported that clusters of VOCs rather than an individual VOC correlated with plasma glucose, although hypoglycemia was not examined (5).

In summary, our data suggest that breath VOCs such as isoprene offer a noninvasive alternative for monitoring changes in blood glucose in diabetes, including detection of hypoglycemia.

Article Information

Acknowledgments. Hormonal assays were performed by Keith Burling and colleagues in the National Institute of Health Research Cambridge Biomedical Research Centre Core Biochemical Assay Laboratory. Clamp studies were performed in the Cambridge National Institute of Health Research Wellcome Trust Clinical Research Facility.

Funding. This work was supported by the National Institute of Health Research Cambridge Biomedical Research Centre, including salary support for S.N.

Duality of Interest. R.P., G.R., T.P.J.B., and D.T. are employees and G.H. is a director of Oxford Medical Diagnostics, a developer and supplier of breath analysis technology. Studies were funded in part by Oxford Medical Diagnostics. In addition, M.L.E. has received speaker/writer fees and/or served on advisory boards for Abbott Diabetes Care, Medtronic, and Roche (manufacturers of glucose-sensing technology). No other potential conflicts of interest relevant to this article were reported.

Author Contributions. S.N. and M.L.E. designed the studies and performed insulin clamps. R.P., G.R., T.P.J.B., D.T., and G.H. analyzed breath samples. All authors interpreted data and contributed to, reviewed, and approved the manuscript. M.L.E. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Prior Presentation. An abstract containing the data was presented at the Diabetes UK Professional Conference 2015, London, U.K., 11–13 March 2015.

  • Received March 2, 2016.
  • Accepted April 16, 2016.
  • © 2016 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.

References

  1. ↵
    1. Wells DL,
    2. Lawson SW,
    3. Siriwardena AN
    . Canine responses to hypoglycemia in patients with type 1 diabetes. J Altern Complement Med 2008;14:1235–1241
    OpenUrlCrossRefPubMed
  2. ↵
    1. Blaikie TPJ,
    2. Edge JA,
    3. Hancock G, et al
    . Comparison of breath gases, including acetone, with blood glucose and blood ketones in children and adolescents with type 1 diabetes. J Breath Res 2014;8:046010
    OpenUrlCrossRefPubMed
  3. ↵
    1. Stone BG,
    2. Besse TJ,
    3. Duane WC,
    4. Evans CD,
    5. DeMaster EG
    . Effect of regulating cholesterol biosynthesis on breath isoprene excretion in men. Lipids 1993;28:705–708
    OpenUrlCrossRefPubMedWeb of Science
  4. ↵
    1. Iizuka K,
    2. Bruick RK,
    3. Liang G,
    4. Horton JD,
    5. Uyeda K
    . Deficiency of carbohydrate response element-binding protein (ChREBP) reduces lipogenesis as well as glycolysis. Proc Natl Acad Sci U S A 2004;101:7281–7286
    OpenUrlAbstract/FREE Full Text
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    1. Minh TD,
    2. Oliver SR,
    3. Ngo J, et al
    . Noninvasive measurement of plasma glucose from exhaled breath in healthy and type 1 diabetic subjects. Am J Physiol Endocrinol Metab 2011;300:E1166–E1175
    OpenUrlAbstract/FREE Full Text
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Exhaled Breath Isoprene Rises During Hypoglycemia in Type 1 Diabetes
Sankalpa Neupane, Robert Peverall, Graham Richmond, Tom P.J. Blaikie, David Taylor, Gus Hancock, Mark L. Evans
Diabetes Care Jul 2016, 39 (7) e97-e98; DOI: 10.2337/dc16-0461

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Exhaled Breath Isoprene Rises During Hypoglycemia in Type 1 Diabetes
Sankalpa Neupane, Robert Peverall, Graham Richmond, Tom P.J. Blaikie, David Taylor, Gus Hancock, Mark L. Evans
Diabetes Care Jul 2016, 39 (7) e97-e98; DOI: 10.2337/dc16-0461
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