Underlying dyslipidemia postpartum in women with a recent GDM pregnancy who develop Type 2 diabetes
- University of Toronto, Canada
- Kaiser Permanente Northern California, United States
Abstract
Approximately 35% of women with Gestational Diabetes (GDM) progress to Type2 Diabetes (T2D) within 10 years. However, links between GDM and T2D are not well understood. We used a well-characterised GDM prospective cohort of 1,035 women following up to 8 years postpartum. Lipidomics profiling covering >1000 lipids, was performed on fasting plasma samples from participants 6-9week postpartum (171 incident T2D vs. 179 controls). We discovered 311 lipids positively and 70 lipids negatively associated with T2D risk. The upregulation of glycerolipid metabolism involving triacylglycerol and diacylglycerol biosynthesis suggested activated lipid storage before diabetes onset. In contrast, decreased sphingomyelines, hexosylceramide and lactosylceramide indicated impaired sphingolipid metabolism. Additionally, a lipid signature was identified to effectively predict future diabetes risk. These findings demonstrate an underlying dyslipidemia during the early postpartum in those GDM women who progress to T2D and suggest endogenous lipogenesis may be a driving force for future diabetes onset.
Data availability
Lipidomic data have been deposited in Harvard Dataverse: https://doi.org/10.7910/DVN/KUDDSF.Source data files have been provided for Figures 2, 3 , 4 and 6 as supporting files.
Article and author information
Author details
Funding
Canadian Institutes of Health Research (FRN 143219)
- Michael B Wheeler
Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01 HD050625)
- Erica P Gunderson
The National Institute of Digestive, Diabetes and Kidney Disease (R01 DK118409)
- Erica P Gunderson
Janssen Pharmaceuticals (430086739)
- Erica P Gunderson
- Michael B Wheeler
Banting and Best Diabetes Centre, University of Toronto (postdoctoral fellowships)
- Mi Lai
Ontario Graduate Scholarship (Graduate Student Fellowship)
- Dana Al Rijjal
Banting and Best Diabetes Centre, University of Toronto (Graduate Student Fellowship)
- Dana Al Rijjal
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: The study design and all procedures were approved by the Kaiser Permanente Northern California Institutional Review Board (protocol numbers #CN-04EGund-03-H and #1279812-10) and Office of Research Ethics at University of Toronto (protocol number #38188). All participants gave written informed consent before taking part in the research exams.
Copyright
© 2020, Lai et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Underlying dyslipidemia postpartum in women with a recent GDM pregnancy who develop Type 2 diabetes
eLife 9:e59153.
https://doi.org/10.7554/eLife.59153
Further reading
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Background:
Individuals with Down syndrome (DS), the genetic condition caused by trisomy 21 (T21), display clear signs of immune dysregulation, including high rates of autoimmunity and severe complications from infections. Although it is well established that T21 causes increased interferon responses and JAK/STAT signaling, elevated autoantibodies, global immune remodeling, and hypercytokinemia, the interplay between these processes, the clinical manifestations of DS, and potential therapeutic interventions remain ill defined.
Methods:
We report a comprehensive analysis of immune dysregulation at the clinical, cellular, and molecular level in hundreds of individuals with DS, including autoantibody profiling, cytokine analysis, and deep immune mapping. We also report the interim analysis of a Phase II clinical trial investigating the safety and efficacy of the JAK inhibitor tofacitinib through multiple clinical and molecular endpoints.
Results:
We demonstrate multi-organ autoimmunity of pediatric onset concurrent with unexpected autoantibody-phenotype associations in DS. Importantly, constitutive immune remodeling and hypercytokinemia occur from an early age prior to autoimmune diagnoses or autoantibody production. Analysis of the first 10 participants to complete 16 weeks of tofacitinib treatment shows a good safety profile and no serious adverse events. Treatment reduced skin pathology in alopecia areata, psoriasis, and atopic dermatitis, while decreasing interferon scores, cytokine scores, and levels of pathogenic autoantibodies without overt immune suppression.
Conclusions:
JAK inhibition is a valid strategy to treat autoimmune conditions in DS. Additional research is needed to define the effects of JAK inhibition on the broader developmental and clinical hallmarks of DS.
Funding:
NIAMS, Global Down Syndrome Foundation.
Clinical trial number:
