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

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.

Impaired cardiometabolic responses to glucagon-like peptide 1 in obesity and type 2 diabetes mellitus.

Glucagon-like peptide 1 (GLP-1) has insulin-like effects on myocardial glucose uptake which may contribute to its beneficial effects in the setting of myocardial ischemia. Whether these effects are different in the setting of obesity or type 2 diabetes (T2DM) requires investigation. We examined the cardiometabolic actions of GLP-1 (7-36) in lean and obese/T2DM humans, and in lean and obese Ossabaw swine. GLP-1 significantly augmented myocardial glucose uptake under resting conditions in lean humans, but this effect was impaired in T2DM. This observation was confirmed and extended in swine, where GLP-1 effects to augment myocardial glucose uptake during exercise were seen in lean but not in obese swine. GLP-1 did not increase myocardial oxygen consumption or blood flow in humans or in swine. Impaired myocardial responsiveness to GLP-1 in obesity was not associated with any apparent alterations in myocardial or coronary GLP1-R expression. No evidence for GLP-1-mediated activation of cAMP/PKA or AMPK signaling in lean or obese hearts was observed. GLP-1 treatment augmented p38-MAPK activity in lean, but not obese cardiac tissue. Taken together, these data provide novel evidence indicating that the cardiometabolic effects of GLP-1 are attenuated in obesity and T2DM, via mechanisms that may involve impaired p38-MAPK signaling.