Sex differences in exogenous glucose oxidation are attenuated by obesity: insights from a [U-¹³C₆]glucose home breath...

Biological sex influences whole body glucose metabolism, with females generally displaying greater insulin sensitivity than males, yet paradoxically similar or poorer glucose tolerance when assessed with oral glucose tolerance tests (OGTTs). This discrepancy suggests that plasma glucose concentrations alone may not capture sex-specific differences in postprandial glucose metabolism. Measuring exogenous glucose oxidation during a [U-¹³C₆]glucose-enriched OGTT may offer a noninvasive approach to detect such differences, but this method has not yet been applied to examine sex differences. Forty adults (18-65 yr; n = 20/sex) classified as normal-weight (NW; n = 10/sex) or obese (OB; n = 10/sex) based on body mass index completed a virtually monitored metabolic trial. After a 10-h overnight fast, participants ingested a 75-g glucose beverage enriched with 75-mg (0.1%) [U-¹³C₆]d-glucose. Capillary glucose concentration, salivary insulin, and exogenous glucose oxidation were measured fasted and across the 3-h postprandial period. Compared with NW, participants with OB had higher 3-h mean blood glucose (P < 0.001) and salivary insulin (P < 0.001) concentrations, with no differences between sexes (all P > 0.05). A sex × obesity interaction was observed for exogenous glucose oxidation, such that it was higher in females than males in NW (69.1 ± 5.4 vs. 48.2 ± 7.5; P < 0.0001) but not in OB (40.9 ± 8.4 vs. 36.0 ± 9.3 mg/kg/h; P = 0.53). OB participants also exhibited lower overall exogenous glucose oxidation compared with NW (38.4 ± 8.8 vs. 58.7 ± 6.4 mg/kg/h; P < 0.001). These findings suggest that despite no sex differences in glucose or insulin responses during the OGTT, females exhibit higher exogenous glucose oxidation than males, but this elevated metabolic response is attenuated in obesity.NEW & NOTEWORTHY Using a [U-¹³C₆]glucose breath test during a 3-h OGTT, we show that normal-weight females oxidize a greater proportion of ingested glucose than males despite similar blood glucose and insulin responses. This sex difference is attenuated in obesity, which reduces overall glucose oxidation. These findings reveal sex-specific regulation of postprandial glucose metabolism not captured by conventional OGTT metrics and highlight breath testing as a sensitive, noninvasive approach for assessing glucose metabolism outside the laboratory.