Physiological parameters regulating circulating levels of the IGFBP-4/Stanniocalcin-2/PAPP-A axis

Metabolism. 2017 Oct:75:16-24. doi: 10.1016/j.metabol.2017.07.003. Epub 2017 Jul 19.


Background: Insulin Growth Factor Binding Protein 4 (IGFBP-4), Stanniocalcin-2 (STC-2) and Pregnancy-Associated Plasma Protein-A (PAPP-A) have a well-documented involvement in several physiological functions in humans but predictors of their circulating levels remain largely unknown. We aimed to identify anthropometric and biochemical parameters associated with circulating levels of IGFBP-4/STC-2/PAPP-A axis (ISPa) cross-sectionally and to study their day-night variation and their regulation in response to mixed meal and exercise.

Methods: One hundred twenty two healthy individuals were evaluated cross-sectionally. Subgroups were subjected to standardized mixed meal ingestion in increasing quantities of 125mL or 250mL, or aerobic exercise for 30min, or day-night rhythm study. Main outcome measurements were circulating IGFBP-4 (total and intact), STC-2 and PAPP-A levels.

Results: In multivariate models, the main predictors of serum total IGFBP-4 were PAPP-A and female gender. Intact IGFBP-4 was positively associated with serum creatinine. Height was inversely and female gender and % of total body fat were positively correlated with STC-2. PAPP-A decreased after ingesting both the 125mL (p=0.03) and 250mL quantities (p=0.001), while total IGFBP-4 was reduced after the 250mL quantity (p=0.001). Exercise increased STC-2 and PAPP-A levels (p<0.001 for both). Intact, and to a lesser extent total, IGFBP-4 displayed a cortisol-like day/night variation.

Conclusions: We report for the first time anthropometric and physiological modulators of ISPa serum levels in healthy humans.

Keywords: Day-night rhythm; Exercise; Healthy humans; Metabolism; Physiology.

MeSH terms

  • Adult
  • Circadian Rhythm
  • Creatine / blood
  • Cross-Sectional Studies
  • Exercise
  • Female
  • Glycoproteins / blood*
  • Humans
  • Insulin-Like Growth Factor Binding Protein 4 / blood*
  • Intercellular Signaling Peptides and Proteins / blood*
  • Male
  • Pregnancy-Associated Plasma Protein-A / analysis*
  • Sex Factors
  • Young Adult


  • Glycoproteins
  • Insulin-Like Growth Factor Binding Protein 4
  • Intercellular Signaling Peptides and Proteins
  • STC2 protein, human
  • Pregnancy-Associated Plasma Protein-A
  • Creatine