Placental Insulin/IGF-1 Signaling, PGC-1α, and Inflammatory Pathways Are Associated With Metabolic Outcomes at 4-6 Years of Age: The ECHO Healthy Start Cohort

Diabetes. 2021 Mar;70(3):745-751. doi: 10.2337/db20-0902. Epub 2021 Jan 7.


An adverse intrauterine environment is associated with the future risk of obesity and type 2 diabetes. Changes in placental function may underpin the intrauterine origins of adult disease, but longitudinal studies linking placental function with childhood outcomes are rare. Here, we determined the abundance and phosphorylation of protein intermediates involved in insulin signaling, inflammation, cortisol metabolism, protein glycosylation, and mitochondrial biogenesis in placental villus samples from healthy mothers from the Healthy Start cohort. Using MANOVA, we tested the association between placental proteins and offspring adiposity (fat mass percentage) at birth (n = 109) and infancy (4-6 months, n = 104), and adiposity, skinfold thickness, triglycerides, and insulin in children (4-6 years, n = 66). Placental IGF-1 receptor protein was positively associated with serum triglycerides in children. GSK3β phosphorylation at serine 9, a readout of insulin and growth factor signaling, and the ratio of phosphorylated to total JNK2 were both positively associated with midthigh skinfold thickness in children. Moreover, peroxisome proliferator-activated receptor γ coactivator (PGC)-1α abundance was positively associated with insulin in children. In conclusion, placental insulin/IGF-1 signaling, PGC-1α, and inflammation pathways were positively associated with metabolic outcomes in 4- to 6-year-old children, identifying a novel link between placental function and long-term metabolic outcomes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 2 / genetics
  • 11-beta-Hydroxysteroid Dehydrogenase Type 2 / metabolism*
  • Body Mass Index
  • Child
  • Child, Preschool
  • Female
  • Humans
  • In Vitro Techniques
  • Infant
  • Insulin / metabolism*
  • Insulin-Like Growth Factor I / metabolism*
  • Mitogen-Activated Protein Kinase 9 / genetics
  • Mitogen-Activated Protein Kinase 9 / metabolism*
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / genetics
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism*
  • Phosphorylation
  • Placenta / metabolism*
  • Pregnancy
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Insulin
  • PPARGC1A protein, human
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Insulin-Like Growth Factor I
  • 11-beta-Hydroxysteroid Dehydrogenase Type 2
  • Mitogen-Activated Protein Kinase 9
  • p38 Mitogen-Activated Protein Kinases

Associated data

  • figshare/10.2337/figshare.13491417