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

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@article{8975a5b169094a2e8108b4225412806e,
title = "Metabolic improvement after gastric bypass correlates with changes in IGF-regulatory proteins stanniocalcin-2 and IGFBP-4",
abstract = "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.",
keywords = "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)",
author = "Rikke Hjortebjerg and Bojsen-M{\o}ller, {Kirstine N} and Mette S{\o}eby and Claus Oxvig and Sten Madsbad and Jan Frystyk",
note = "Copyright {\textcopyright} 2021. Published by Elsevier Inc.",
year = "2021",
month = sep,
day = "7",
doi = "10.1016/j.metabol.2021.154886",
language = "English",
volume = "124",
journal = "Metabolism",
issn = "0026-0495",
publisher = "W.B./Saunders Co",

}

RIS

TY - JOUR

T1 - Metabolic improvement after gastric bypass correlates with changes in IGF-regulatory proteins stanniocalcin-2 and IGFBP-4

AU - Hjortebjerg, Rikke

AU - Bojsen-Møller, Kirstine N

AU - Søeby, Mette

AU - Oxvig, Claus

AU - Madsbad, Sten

AU - Frystyk, Jan

N1 - Copyright © 2021. Published by Elsevier Inc.

PY - 2021/9/7

Y1 - 2021/9/7

N2 - 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.

AB - 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.

KW - Insulin like growth factor binding protein 4 (IGFBP-4)

KW - Insulin like growth factor I (IGF-I)

KW - Pregnancy associated plasma protein (PAPP-A)

KW - Roux-en-Y-gastric bypass (RYGB)

KW - Stanniocalcin-2 (STC2)

UR - http://www.scopus.com/inward/record.url?scp=85114909977&partnerID=8YFLogxK

U2 - 10.1016/j.metabol.2021.154886

DO - 10.1016/j.metabol.2021.154886

M3 - Journal article

C2 - 34506805

VL - 124

JO - Metabolism

JF - Metabolism

SN - 0026-0495

M1 - 154886

ER -

ID: 67611330