Insulin sensitivity index (ISI_{0, 120}) potentially linked to carbon isotopes of breath CO₂ for pre-diabetes and type 2 diabetes

New strategies for an accurate and early detection of insulin resistance are important to delay or prevent the acute onset of type 2 diabetes (T2D). Currently, insulin sensitivity index (ISI_0,120) is considered to be a viable invasive method of whole-body insulin resistance for use in clinical settings in comparison with other invasive sensitivity indexes like homeostasis model assessment (HOMA), and quantitative insulin sensitivity check index (QUICKI). To investigate how these sensitivity indexes link the ¹³C/¹² C-carbon isotopes of exhaled breath CO₂ to pre-diabetes (PD) and type 2 diabetes in response to glucose ingestion, we studied excretion dynamics of ¹³C/¹²C-isotopic fractionations of breath CO₂. Here, we show that ¹³C/¹²C-isotope ratios of breath CO₂ were well correlated with blood glucose, insulin, glycosylated-hemoglobin as well as with HOMA-IR and 1/QUICKI. Conversely, the strongest correlation was observed between 1/ISI_0,120 and breath CO₂ isotopes. Consequently, we determined several optimal diagnostic cut-off points of 1/ISI_0,120 and ¹³CO₂/¹²CO₂-isotope ratios to distinctively track the evolution of PD prior to the onset of T2D. Our findings suggest that isotopic breath CO₂ is a novel method for accurate estimation of ISI_0,120 and thus may open new perspectives into the isotope-specific non-invasive evaluation of insulin resistance for large-scale real-time diabetes screening purposes.