Altered relative GLP-1 response patterns in gestational diabetes mellitus: a matched nested case-control study

Circulating glucagon-like peptide−1 (GLP-1) findings in gestational diabetes mellitus (GDM) are inconsistent, and plasma GLP-1 concentrations do not directly measure incretin function. We characterized total GLP-1 profiles during the measured time points of an oral glucose tolerance test (OGTT) and explored their associations with metabolic parameters, OGTT-defined glycemic phenotypes, and pregnancy outcomes. This case–control study was nested within a cohort of pregnant women undergoing a 75-g OGTT. The analysis included 154 women with GDM and 154 women with normal glucose tolerance (NGT). Plasma glucose, insulin, and total GLP-1 concentrations were measured at fasting, 1 h, and 2 h. Temporal profiles were compared using linear mixed-effects models. Absolute GLP-1 measures and exploratory GLP-1/glucose and GLP-1/insulin ratios were evaluated in relation to metabolic parameters, glycemic phenotypes, and pregnancy outcomes, with correction for multiple testing as appropriate. Absolute GLP-1 concentrations did not differ significantly between the GDM and NGT groups at any measured time point, and GLP-1 area under the curve (AUC) was comparable. However, the time-by-GDM status interaction was significant ( P = 0.016), with an upward GLP-1 pattern in NGT and a relatively flat pattern in GDM. GLP-1 AUC/glucose AUC and GLP-1 AUC/insulin AUC were lower in GDM (both adjusted P < 0.001). Absolute GLP-1 measures showed negligible to weak correlations with metabolic indices. GLP-1 AUC did not differ among NGT, isolated fasting hyperglycemia (IFH), isolated post-load hyperglycemia (IPH), and combined hyperglycemia phenotypes (CH). Both AUC ratios were lower in the isolated post-load and combined hyperglycemia groups than in NGT, but did not differ significantly between isolated fasting hyperglycemia and NGT. No GLP-1-related measure was independently associated with the evaluated pregnancy outcomes after false discovery rate correction. Women with GDM and NGT had comparable absolute circulating GLP-1 concentrations and AUC but different temporal profiles across the measured OGTT time points. The exploratory GLP-1 AUC/glucose AUC and GLP-1 AUC/insulin AUC ratios were lower in GDM than in NGT. In phenotype-specific analyses, both ratios were lower in IPH and CH than in NGT, whereas the IFH–NGT comparisons and the direct pairwise comparisons among IFH, IPH, and CH were not statistically significant for either ratio.These denominator-dependent ratios should not be interpreted as validated measures of GLP-1 secretion, responsiveness, or incretin function. The limited number of obstetric events precluded excluding clinically relevant associations with pregnancy outcomes.