Mette Søeby

Metabolic improvement after gastric bypass correlates with changes in IGF-regulatory proteins stanniocalcin-2 and IGFBP-4

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  • Rikke Hjortebjerg, University of Southern Denmark, Steno Diabetes Centre
  • ,
  • Kirstine N. Bojsen-Møller, University of Copenhagen
  • ,
  • Mette Søeby
  • Claus Oxvig
  • Sten Madsbad, University of Copenhagen
  • ,
  • Jan Frystyk

Background: Pregnancy-associated plasma protein-A (PAPP-A) is an enzyme that increases IGF-activity through cleavage of IGF-binding proteins (IGFBPs), primarily IGFBP-4, whereby bound IGF-I becomes released as a free molecule. The enzymatic activity of PAPP-A is irreversibly suppressed by the glycoprotein stanniocalcin-2 (STC2). Pre-clinical and clinical studies suggest that the STC2 – PAPP-A – IGFBP-4 axis is important in controlling local IGF-action. STC2, PAPP-A and IGFBP-4 are expressed in adipose tissue, and as bariatric surgery markedly reduces the amount of fat, we found it relevant to study the impact of Roux-en-Y gastric bypass (RYGB) on circulating concentrations of this IGF-regulatory network. Methods: Analysis of fasting blood samples from 20 obese subjects, hereof 10 with preoperative type 2 diabetes, investigated before RYGB, and 1 week, 3 months and 12 months post-surgery. Members of the IGF-system were analyzed by immunoassays, bioactive IGF by cell-based IGF-I receptor activation assay. We compared changes in IGF-system components with changes in fasting plasma insulin and glucose, and HbA1c. Results: PAPP-A remained unchanged, but STC2 decreased following RYGB (p < 0.05). The PAPP-A substrate IGFBP-4 declined (p < 0.01), whereas levels of PAPP-A specific IGFBP-4 fragments increased (p < 0.05), indicating an increased PAPP-A enzymatic activity post-RYGB. Further, the reduction in intact IGFBP-4 correlated with increased levels of bioactive IGF (p < 0.05). In multivariable regression analyses, an improved glucose metabolism correlated with reductions in STC2 and IGFBP-4, and with increases in bioactive IGF and IGF-I (p < 0.05). Conclusion: After 12 months, RYGB caused reduced serum concentrations of intact IGFBP-4 and STC2, whereas serum PAPP-A remained at pre-operative levels. However, concentrations of PAPP-A generated IGFBP-4 fragments increased, pointing to an overall increased PAPP-A enzymatic activity following RYGB. Notably, reductions in intact IGFBP-4 and STC2 associated with improvements in glucose metabolism. Therefore, we propose that STC2 and IGFBP-4 are involved in the metabolic improvement that follows RYGB.

Original languageEnglish
Article number154886
JournalMetabolism: Clinical and Experimental
Number of pages8
Publication statusPublished - Nov 2021

    Research areas

  • Insulin like growth factor binding protein 4 (IGFBP-4), Insulin like growth factor I (IGF-I), Pregnancy associated plasma protein (PAPP-A), Roux-en-Y-gastric bypass (RYGB), Stanniocalcin-2 (STC2), Intercellular Signaling Peptides and Proteins/blood, Gastric Bypass, Humans, Middle Aged, Pregnancy-Associated Plasma Protein-A/analysis, Male, Obesity, Morbid/blood, Glycoproteins/blood, Insulin-Like Growth Factor Binding Protein 4/blood, Adult, Female, Insulin-Like Growth Factor I/analysis

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