Metabolic phenotyping by treatment modality in obese women with gestational diabetes suggests diverse pathophysiology: An exploratory study

Background and purpose Excess insulin resistance is considered the predominant pathophysiological mechanism in obese women who develop gestational diabetes (GDM). We hypothesised that obese women requiring differing treatment modalities for GDM may have diverse underlying metabolic pathways. Methods In this secondary analysis of the UK pregnancies Better Eating and Activity Trial (UPBEAT) we studied women from the control arm with complete biochemical data at three gestational time points; at 15-18+6 and 27-28+6 weeks (before treatment), and 34-36+0 weeks (after treatment). A total of 89 analytes were measured (plasma/serum) using a targeted nuclear magnetic resonance (NMR) platform and conventional assays. We used linear regression with appropriate adjustment to model metabolite concentration, stratified by treatment group. Main findings 300 women (median BMI 35kg/m(2); inter quartile range 32.8-38.2) were studied. 71 developed GDM; 28 received dietary treatment only, 20 metformin, and 23 received insulin. Prior to the initiation of treatment, multiple metabolites differed (p<0.05) between the diet and insulin-treated groups, especially very large density lipoprotein (VLDL) and high density lipoprotein (HDL) subclasses and constituents, with some differences maintained at 34-36 weeks' gestation despite treatment. Gestational lipid profiles of the diet treatment group were indicative of a lower insulin resistance profile, when compared to both insulin-treated women and those without GDM. At 28 weeks' the diet treatment group had lower plasma fasting glucose and insulin than women treated with insulin, yet similar to those without GDM, consistent with a glycaemic mechanism independent of insulin resistance. Conclusions/Interpretation This exploratory study suggests that GDM pathophysiological processes may differ amongst obese women who require different treatment modalities to achieve glucose control and can be revealed using metabolic profiling.