[13C]glucose breath testing provides a noninvasive measure of insulin resistance: calibration analyses against clamp studies

Abstract

Background: Exhaled (13)CO2 following ingestion of [(13)C]glucose with a standard oral glucose tolerance load correlates with blood glucose values but is determined by tissue glucose uptake. Therefore exhaled (13)CO2 may also be a surrogate measure of the whole-body glucose disposal rate (GDR) measured by the gold standard hyperinsulinemic euglycemic clamp.

Subjects and methods: Subjects from across the glycemia range were studied on 2 consecutive days under fasting conditions. On Day 1, a 75-g oral glucose load spiked with [(13)C]glucose was administered. On Day 2, a hyperinsulinemic euglycemic clamp was performed. Correlations between breath parameters and clamp-derived GDR were evaluated, and calibration analyses were performed to evaluate the precision of breath parameter predictions of clamp measures.

Results: Correlations of breath parameters with GDR and GDR per kilogram of fat-free mass (GDRffm) ranged from 0.54 to 0.61 and 0.54 to 0.66, respectively (all P<0.001). In calibration analyses the root mean square error for breath parameters predicting GDR and GDRffm ranged from 2.32 to 2.46 and from 3.23 to 3.51, respectively. Cross-validation prediction error (CVPE) estimates were 2.35-2.51 (GDR) and 3.29-3.57 (GDRffm). Prediction precision of breath enrichment at 180 min predicting GDR (CVPE=2.35) was superior to that for inverse insulin (2.68) and the Matsuda Index (2.51) but inferior to that for the log of homeostasis model assessment (2.21) and Quantitative Insulin Sensitivity Check Index (2.29) (all P<10(-5)). Similar patterns were seen for predictions of GDRffm.

Conclusions: (13)CO2 appearance in exhaled breath following a standard oral glucose load with added [(13)C]glucose provides a valid surrogate index of clamp-derived measures of whole-body insulin resistance, with good accuracy and precision. This noninvasive breath test-based approach can provide a useful measure of whole-body insulin resistance in physiologic and epidemiologic studies.

Figures

FIG. 1.

Calibration analyses for selected breath enrichment and traditional surrogate measures against clamp-derived insulin resistance (glucose disposal rate [GDR]). AUC, area under the curve; HOMA, homeostasis model assessment; QUICKI, Quantitative Insulin Sensitivity Check Index.

FIG. 2.

Residual plots for calibrations against glucose disposal rate (GDR). AUC, area under the curve; HOMA, homeostasis model assessment; QUICKI, Quantitative Insulin Sensitivity Check Index.

FIG. 3.

Calibration analyses for selected breath enrichment and traditional surrogate measures against clamp-derived insulin resistance (glucose disposal rate) per kilogram of fat-free mass (GDRffm). AUC, area under the curve; HOMA, homeostasis model assessment; QUICKI, Quantitative Insulin Sensitivity Check Index.

FIG. 4.

Residual plots for calibrations against glucose disposal rate per kilogram of fat-free mass (GDRffm). AUC, area under the curve; HOMA, homeostasis model assessment; QUICKI, Quantitative Insulin Sensitivity Check Index.