Amino acid and lipid metabolism in post-gestational diabetes and progression to type 2 diabetes: A metabolic profiling study

Background Women with a history of gestational diabetes mellitus (GDM) have a 7-fold higher risk of developing type 2 diabetes (T2D) during midlife and an elevated risk of developing hypertension and cardiovascular disease. Glucose tolerance reclassification after delivery is recommended, but fewer than 40% of women with GDM are tested. Thus, improved risk stratification methods are needed, as is a deeper understanding of the pathology underlying the transition from GDM to T2D. We hypothesize that metabolites during the early postpartum period accurately distinguish risk of progression from GDM to T2D and that metabolite changes signify underlying pathophysiology for future disease development. Methods and findings The study utilized fasting plasma samples collected from a well-characterized prospective research study of 1,035 women diagnosed with GDM. The cohort included racially/ethnically diverse pregnant women (aged 20–45 years—33% primiparous, 37% biparous, 30% multiparous) who delivered at Kaiser Permanente Northern California hospitals from 2008 to 2011. Participants attended in-person research visits including 2-hour 75-g oral glucose tolerance tests (OGTTs) at study baseline (6–9 weeks postpartum) and annually thereafter for 2 years, and we retrieved diabetes diagnoses from electronic medical records for 8 years. In a nested case–control study design, we collected fasting plasma samples among women without diabetes at baseline (n = 1,010) to measure metabolites among those who later progressed to incident T2D or did not develop T2D (non-T2D). We studied 173 incident T2D cases and 485 controls (pair-matched on BMI, age, and race/ethnicity) to discover metabolites associated with new onset of T2D. Up to 2 years post-baseline, we analyzed samples from 98 T2D cases with 239 controls to reveal T2D-associated metabolic changes. The longitudinal analysis tracked metabolic changes within individuals from baseline to 2 years of follow-up as the trajectory of T2D progression. By building prediction models, we discovered a distinct metabolic signature in the early postpartum period that predicted future T2D with a median discriminating power area under the receiver operating characteristic curve of 0.883 (95% CI 0.820–0.945, p < 0.001). At baseline, the most striking finding was an overall increase in amino acids (AAs) as well as diacyl-glycerophospholipids and a decrease in sphingolipids and acyl-alkyl-glycerophospholipids among women with incident T2D. Pathway analysis revealed up-regulated AA metabolism, arginine/proline metabolism, and branched-chain AA (BCAA) metabolism at baseline. At follow-up after the onset of T2D, up-regulation of AAs and down-regulation of sphingolipids and acyl-alkyl-glycerophospholipids were sustained or strengthened. Notably, longitudinal analyses revealed only 10 metabolites associated with progression to T2D, implicating AA and phospholipid metabolism. A study limitation is that all of the analyses were performed with the same cohort. It would be ideal to validate our findings in an independent longitudinal cohort of women with GDM who had glucose tolerance tested during the early postpartum period. Conclusions In this study, we discovered a metabolic signature predicting the transition from GDM to T2D in the early postpartum period that was superior to clinical parameters (fasting plasma glucose, 2-hour plasma glucose). The findings suggest that metabolic dysregulation, particularly AA dysmetabolism, is present years prior to diabetes onset, and is revealed during the early postpartum period, preceding progression to T2D, among women with GDM. Trial registration ClinicalTrials.gov Identifier: NCT01967030.
Mi Lai and co-workers describe a metabolic signature associated with progression from gestational to type 2 diabetes.
Author summary Why was this study done? Women with a history of gestational diabetes mellitus (GDM) have a 7-fold higher risk of developing type 2 diabetes (T2D) later in life, and an estimated 35%–50% of GDM cases will progress to T2D within 10 years postpartum. Biological pathways and metabolites influencing progression from GDM to T2D have not been elucidated in humans. The main goal of the present work is to gain critical insight into the pathology of the transition from GDM to T2D, particularly metabolic changes involved in this process. A second goal is to devise more accurate means of identifying who will transition to T2D among women with GDM. What did the researchers do and find? We carried out a nested case–control study using a GDM prospective cohort of 1,010 women without T2D 6–9 weeks postpartum (study baseline). We performed metabolic profiling on fasting blood samples from women at 6–9 weeks postpartum (baseline) and up to 2 years post-baseline (follow-up). We found that significant dysmetabolism in lipids and amino acids in the early postpartum period was associated with future diabetes in women. Longitudinal analysis tracking changes in metabolic profiles over the course of diabetes progression revealed 10 specific metabolites that are associated with progression to T2D. We identified a small group of metabolites that could predict future T2D with great discriminative power, surpassing current clinical methods. What do these findings mean? A subclinical diabetes-like condition appears to already be present in the early postpartum period in women with previous GDM who later progress to T2D, and dysregulated amino acid metabolism is tightly associated with disease progression. Metabolites other than glucose may provide a simple and accurate alternative approach to assess risk of future T2D in women with a history of GDM.