Liver Enzymes in Early to Mid-pregnancy, Insulin Resistance, and Gestational Diabetes Risk: A Longitudinal Analysis

Background: Liver enzymes may be implicated in glucose homeostasis; liver enzymes progressively change during pregnancy but longitudinal data during pregnancy in relation to insulin resistance and gestational diabetes (GDM) risk are lacking. We investigated longitudinal associations of γ-glutamyl transferase (GGT) and alanine aminotransferase (ALT) with insulin secretion and resistance markers across early to mid-pregnancy and subsequent GDM risk. Methods: Within the prospective Pregnancy Environment and Lifestyle Study cohort, 117 GDM cases were ascertained and matched to 232 non-GDM controls in a nested case-control study. Fasting blood samples were collected at two clinic visits (CV1, gestational weeks 10–13; CV2, gestational weeks 16–19). Linear mixed model and conditional logistic regression were used, adjusting for major risk factors for GDM. Results: In repeated measure analysis, after adjusting for confounders including body mass index and waist-to-hip ratio, GGT per standard deviation increment was associated with elevated fasting glucose and HOMA-IR (% change = 1.51%, 95% CI 0.56–2.46% and 7.43%, 95% CI 1.76–13.11%, respectively) and decreased adiponectin (% change = −2.86%, 95% CI−5.53 to −0.20%) from CV1 to CV2. At CV1 and CV2, GGT levels comparing the highest versus lowest quartile were associated with 3.01-fold (95% CI 1.32–6.85) and 3.51-fold (95% CI 1.37–8.97) increased risk of GDM, respectively. Progressively increased (<median at CV1, ≥median at CV2) and stably high (≥median at both CV1 and CV2) GGT levels were associated with 3.89- and 2.39-fold increased risk of GDM, compared to stably low levels (<median at both CV1 and CV2), respectively (both P < 0.05). Similar but non-significant trends were observed for ALT. Conclusion: Elevated levels of GGT in early and mid-pregnancy, even within the conventional normal range, and its progressive increase from early to mid-pregnancy may be implicated in the pathogenesis of GDM, highlighting its potential to inform early screening or preventive strategies to mitigate subsequent risk of GDM.