Intensive lactation among women with recent gestational diabetes significantly alters the early postpartum circulating lipid profile: the SWIFT study

Abstract

Background Women with a history of gestational diabetes mellitus (GDM) have a 7-fold higher risk of developing type 2 diabetes (T2D). It is estimated that 20-50% of women with GDM history will progress to T2D within 10 years after delivery. Intensive lactation could be negatively associated with this risk, but the mechanisms behind a protective effect remain unknown. Methods In this study, we utilized a prospective GDM cohort of 1010 women without T2D at 6-9 weeks postpartum (study baseline) and tested for T2D onset up to 8 years post-baseline (n=980). Targeted metabolic profiling was performed on fasting plasma samples collected at both baseline and follow-up (1-2 years post-baseline) during research exams in a subset of 350 women (216 intensive breastfeeding, IBF vs. 134 intensive formula feeding or mixed feeding, IFF/Mixed). The relationship between lactation intensity and circulating metabolites at both baseline and follow-up were evaluated to discover underlying metabolic responses of lactation and to explore the link between these metabolites and T2D risk. Results We observed that lactation intensity was strongly associated with decreased glycerolipids (TAGs/DAGs) and increased phospholipids/sphingolipids at baseline. This lipid profile suggested decreased lipogenesis caused by a shift away from the glycerolipid metabolism pathway towards the phospholipid/sphingolipid metabolism pathway as a component of the mechanism underlying the benefits of lactation. Longitudinal analysis demonstrated that this favorable lipid profile was transient and diminished at 1-2 years postpartum, coinciding with the cessation of lactation. Importantly, when stratifying these 350 women by future T2D status during the follow-up (171 future T2D vs. 179 no T2D), we discovered that lactation induced robust lipid changes only in women who did not develop incident T2D. Subsequently, we identified a cluster of metabolites that strongly associated with future T2D risk from which we developed a predictive metabolic signature with a discriminating power (AUC) of 0.78, superior to common clinical variables (i.e., fasting glucose, AUC 0.56 or 2-h glucose, AUC 0.62). Conclusions In this study, we show that intensive lactation significantly alters the circulating lipid profile at early postpartum and that women who do not respond metabolically to lactation are more likely to develop T2D. We also discovered a 10-analyte metabolic signature capable of predicting future onset of T2D in IBF women. Our findings provide novel insight into how lactation affects maternal metabolism and its link to future diabetes onset. Trial registration ClinicalTrials.gov NCT01967030.

Azelaic Acid Esters as Pluripotent Immunomodulatory Molecules: Nutritional Supplements or Drugs

“…This value is comparable with the daily oral dose of DEA in adult humans (1 mg/kg or 0.1 g dose of DEA for an individual weighing 100 kg) in a three-week clinical study whereby significant health benefits of lowering insulin resistance have been achieved without adverse side effects [17]. Incidentally, the lactation has been reported to correlate with a decrease in the incidence of Type 2 diabetes and circulating lipids in women [56,57].…”

Adaptive Changes in Glucose Homeostasis and Islet Function During Pregnancy: A Targeted Metabolomics Study in Mice

“…The metabolomics analyses were carried out as described previously ( 12 , 13 ). A total of 500 islets were isolated and collected from the pregnant or non-pregnant group in each trimester.…”

“…Targeted metabolomics is a quantitative assay platformed to assess specific metabolites associated with known biochemical pathways or disease processes. Metabolomic profiling has been instrumental in developing metabolic databases and identifying potential disease biomarkers or metabolic pathways associated with diseases like GDM and T2D associated with a GDM history ( 10 – 13 ). Our previous studies have demonstrated the onset of future T2D after GDM pregnancy was associated with upregulation of glycolipid metabolism involving triacylglycerol and diacylglycerol biosynthesis; but decreased sphingolipid/phospholipid metabolism ( 11 , 12 , 14 ).…”

Gestational Diabetes Mellitus: Diagnostic Approaches and Maternal-Offspring Complications

“…Therefore, lactation has persistent favorable effects on the cardiometabolic health of women. Recent metabolomic analysis has discovered that lactation decreases circulating glycerolipids (triglycerides and diacylglycerol species) and increases phospholipids and sphingolipids, possibly as a result of suppressing endogenous lipogenesis and upregulating catabolism of lipids to produce breastmilk [ 78 ].…”