Diminished Sphingolipid Metabolism, a Hallmark of Future Type 2 Diabetes Pathogenesis, Is Linked to Pancreatic β Cell Dysfunction

Gestational diabetes mellitus (GDM) is the top risk factor for future type 2 diabetes (T2D) development. Ethnicity profoundly influences who will transition from GDM to T2D, with high risk observed in Hispanic women. To better understand this risk, a nested 1:1 pair-matched, Hispanic-specific, case-...

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Published in:iScience 2020-10, Vol.23 (10), p.101566-101566, Article 101566
Main Authors: Khan, Saifur R., Manialawy, Yousef, Obersterescu, Andreea, Cox, Brian J., Gunderson, Erica P., Wheeler, Michael B.
Format: Article
Language:English
Subjects:
Bioinformatics
Genomics
Human Physiology
Pathophysiology
Systems Biology
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Summary:Gestational diabetes mellitus (GDM) is the top risk factor for future type 2 diabetes (T2D) development. Ethnicity profoundly influences who will transition from GDM to T2D, with high risk observed in Hispanic women. To better understand this risk, a nested 1:1 pair-matched, Hispanic-specific, case-control design was applied to a prospective cohort with GDM history. Women who were non-diabetic 6–9 weeks postpartum (baseline) were monitored for the development of T2D. Metabolomics were performed on baseline plasma to identify metabolic pathways associated with T2D risk. Notably, diminished sphingolipid metabolism was highly associated with future T2D. Defects in sphingolipid metabolism were further implicated by integrating metabolomics and genome-wide association data, which identified two significantly enriched T2D-linked genes, CERS2 and CERS4. Follow-up experiments in mice and cells demonstrated that inhibiting sphingolipid metabolism impaired pancreatic β cell function. These data suggest early postpartum alterations in sphingolipid biosynthesis contribute to β cell dysfunction and T2D risk. [Display omitted] •Diminished sphingolipid metabolism is associated with a transition from GDM to T2D•Merging metabolomics and GWAS data identifies sphingolipid metabolism genes associated with T2D•Inhibiting sphingolipid metabolism impairs pancreatic β cell function•Incorporating sphingolipid SM C16:10 measurements with an OGTT improves T2D prediction Pathophysiology; Human Physiology; Genomics; Bioinformatics; Systems Biology
ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2020.101566