Abstract
BackgroundWomen 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.MethodsIn 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.ResultsWe 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).ConclusionsIn 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 registrationClinicalTrials.gov NCT01967030.
Highlights
Women with a history of gestational diabetes mellitus (GDM) have a 7-fold higher risk of developing type 2 diabetes (T2D)
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
Overview of cohort and study design In the Study of Women (SWIFT) cohort (1035 women in total), women diagnosed with diabetes at baseline (n = 21), 2 dropouts, and 2 ineligible women were excluded from the followup
Summary
Women with a history of gestational diabetes mellitus (GDM) have a 7-fold higher risk of developing type 2 diabetes (T2D). This may result from inability to breastfeed, lack of an extended period for paid maternity leave, inadequate information and social support, in women with high pre-pregnancy obesity, professional career demands, and older or younger maternal age [1, 3] This is concerning as lactation is a postpartum behavior associated with several beneficial effects including reduced infant morbidity and mortality, preventing breast and ovarian cancer in mothers, as well as having a negative association with their risk of developing future diabetes and other cardiovascular diseases in mid to later life [2, 4,5,6,7,8,9]. Other large epidemiologic studies followed women starting at older ages and reported much weaker protective effects of lactation on future T2D (3-15% lower relative risk for each year of lactation) [11,12,13]; these studies were limited by self-report of diabetes and inability to account for GDM history, potentially biasing estimates towards the null
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