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

Hjortebjerg, Rikke; Bojsen‐Møller, Kirstine N.; Søeby, Mette; Oxvig, Claus; Madsbad, Sten; Frystyk, Jan

doi:10.1016/j.metabol.2021.154886

Cited by 11 publications

(13 citation statements)

References 47 publications

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“…We also show here a significant association between the change in HOMA IR and STC2 during metformin treatment, which indicates that the greater the improvement in insulin sensitivity, the greater the reduction in STC2. This is supported by a recent study showing that following gastric bypass surgery, STC2 decreased and the reduction in STC2 correlated with improvements in fasting glucose, insulin, and HbA1C (53). Because STC2 can directly modify cancer growth and metastasis, the reduction in STC2 associated with metformin treatment may be another plausible mechanism for the antineoplastic effect of metformin.…”

Section: Discussionmentioning

confidence: 52%

“…Previous studies have found that circulating IGF-2 is higher by about 15% in people with obesity compared to lean individuals and IGF-2 decreases following weight loss due to caloric restriction or gastric bypass surgery (49,50,51,52,53). Adipose tissue produces more IGF-2 than IGF-1, with IGF-2 being the highest in the visceral adipose tissue compared to the s.c. adipose tissue (54).…”

Section: Discussionmentioning

confidence: 99%

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Insulin-like growth factor role in determining the anti-cancer effect of metformin: RCT in prostate cancer patients

Birzniece

Lam

McLean

et al. 2022

Endocrine Connections

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Objective: Androgen deprivation therapy (ADT), a principal therapy in patients with prostate cancer, is associated with the development of obesity, insulin resistance and hyperinsulinemia. Recent evidence indicates that metformin may slow cancer progression and improves survival in prostate cancer patients, but the mechanism is not well understood. Circulating insulin-like growth factors (IGFs) are bound to high affinity binding proteins, which not only modulate the bioavailability and signalling of IGFs, but also have independent actions on cell growth and survival. The aim of this study was to investigate whether metformin modulates IGFs, IGF-binding proteins (IGFBPs), and the pregnancy-associated plasma protein-A (PAPP-A) – stanniocalcin-2 (STC2) axis. Design and methods: In a blinded randomized cross-over design, fifteen patients with prostate cancer on stable ADT received metformin and placebo treatment for 6 weeks each. Glucose metabolism along with circulating IGFs and IGFBPs were assessed. Results: Metformin significantly reduced the homeostasis model assessment as an index of insulin resistance (HOMA IR) and hepatic insulin resistance. Metformin also reduced circulating IGF-2 (p<0.05) and IGFBP-3 (p<0.01), but increased IGF bioactivity (p<0.05). At baseline, IGF-2 correlated significantly with the hepatic insulin resistance (r2=0.28, p<0.05). PAPP-A remained unchanged but STC2 declined significantly (p<0.05) following metformin administration. During metformin treatment, change in HOMA IR correlated with the change in STC2 (r2=0.35, p<0.05). Conclusion: Metformin administration alters many components of the circulating IGF-system, either directly or indirectly via an improved insulin sensitivity. Reduction in IGF-2 and STC2 may provide a novel mechanism for a potential metformin-induced antineoplastic effect.

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Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Insulin-like growth factor role in determining the anti-cancer effect of metformin: RCT in prostate cancer patients

Birzniece

Lam

McLean

et al. 2022

Endocrine Connections

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“…Ortega et al demonstrated increased PAPP-A and decreased STC-2 gene expression in patients with chronic venous disease [ 36 ]. Hjortebjerg et al revealed unchanged PAPP-A and but decreased STC-2 expression after Roux-en-Y gastric bypass operation in obese subjects [ 37 ]. In pulmonary disease patients, plasma and tissue fluid were compared and results showed a negative correlation between PAPP-A and STC-2 in tissue fluid but did not show in serum [ 38 ].…”

Section: Resultsmentioning

confidence: 99%

Preliminary investigation of gene expression levels of PAPP-A, STC-2, and HIF-1α in SARS-Cov-2 infected patients

et al. 2022

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Background Coronavirus-19 is still considered a pandemic that influences the world. Other molecular alterations should be clearer besides the increasing cytokine storm and pro-inflammatory molecules. Hypoxic conditions that induce HIF-1α lead to stimulate gene expression of STC-2 that targets PAPP-A expression. This study aimed to determine gene expression levels of PAPP-A, STC-2, and HIF-1α in COVID-19 infection. We also aimed to reveal the relationship of these genes with laboratory and clinical data of COVID-19 patients. Materials and Results We extracted RNA from peripheral blood samples of COVID-19(+) and COVID-19(−) individuals. The real-time PCR method was used to measure mRNA expression of PAPP-A, STC-2, and HIF-1α. Gene expression analysis was evaluated by the 2 −ΔΔCt method. PAPP-A, STC-2, and HIF-1α mRNA expressions of severe patients were higher than healthy individuals ( p = 0.0451 , p = 0.4466 , p < 0.0001, respectively). Correlation analysis of gene expression patterns of severe patients demonstrated a positive correlation between PAPP-A and STC-2 ( p < 0.0001 , r = 0.8638). Conclusion This is the first study that investigates the relation of PAPP-A, STC-2, and HIF-1α gene expression in patients with COVID-19 infection. Besides the routine laboratory findings, PAPP-A, STC-2, and HIF-1α mRNA expressions may be considered to patients’ prognosis as a sign of increased cytokines and pro-inflammatory molecules.

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“…Indeed, preclinical studies suggest that STC2, but not PAPP-A, is related to glucose metabolism ( 36 , 37 ), and we have clinical studies supporting this. We recently examined the effect of gastric surgery on STC2 and PAPP-A ( 17 ). At 1 year follow-up after gastric surgery, STC2 had decreased and its reduction correlated with improvements in HbA1c, fasting insulin and fasting glucose, whereas PAPP-A levels remained unchanged.…”

Section: Discussionmentioning

confidence: 99%

“…As STC2 irreversibly binds and inactivates PAPP-A, it is likely that PAPP-A and STC2 act in concert to regulate IGF1 action ( 15 ). However, whereas PAPP-A is believed to serve solely as a regulator of IGF1 action, STC2 may have other physiological effects ( 16 , 17 ).…”

Section: Introductionmentioning

confidence: 99%

The STC2–PAPP-A–IGFBP4–IGF1 axis and its associations to mortality and CVD in T2D

Gude

Hjortebjerg

Bjerre

et al. 2023

Endocrine Connections

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Objective: Physiologically, pregnancy-associated plasma protein-A (PAPP-A) serves to liberate bound IGF1 by enzymatic cleavage of IGF-binding proteins (IGFBPs); IGFBP4 in particular. Clinically, PAPP-A has been linked to cardiovascular disease (CVD). Stanniocalcin-2 (STC2) is a natural inhibitor of PAPP-A enzymatic activity, but its association to CVD is unsettled. Therefore, we examined associations between the STC2 – PAPP-A – IGFBP4 – IGF1 axis and all-cause mortality and CVD in patients with type 2 diabetes (T2D). Design: We followed 1284 participants with T2D from the ADDITION trial for 5 years. Methods: Circulating concentrations of STC2, PAPP-A, total and intact IGFB-4, IGF1 and -2 were measured at inclusion. End-points were all-cause mortality and a composite CVD event: death from CVD, myocardial infarction, stroke, revascularisation or amputation. Survival analysis was performed by Cox Proportional Hazards model. Results: During follow-up, 179 subjects presented with an event. After multivariable adjustment, higher levels of STC2, PAPP-A as well as intact and total IGFBP4 associated with all-cause mortality; STC2: HR=1.84 [1.09-3.12] (95% confidence interval); p=0.023, PAPP-A: HR=2.81 [1.98-3.98]; p<0.001, intact IGFBP4: HR=1.43 [1.11-1.85]; p=0.006, and total IGFBP4: HR=3.06 [1.91-4.91]; p<0.001. Higher PAPP-A levels also associated with CVD events: HR=1.74 [1.16-2.62]; p=0.008, whereas lower IGF1 levels associated with all-cause mortality: HR=0.51 [0.34-0.76]; p=0.001. Conclusions: This study supports that PAPP-A promotes CVD and increases mortality. However, also STC2 associated with mortality. Given that STC2 inhibits the enzymatic effects of PAPP-A, we speculate that STC2 either serves to counteract harmful PAPP-A actions or possesses effects independently of the PAPP-A – IGF1 axis.

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

Cited by 11 publications

References 47 publications

Insulin-like growth factor role in determining the anti-cancer effect of metformin: RCT in prostate cancer patients

Insulin-like growth factor role in determining the anti-cancer effect of metformin: RCT in prostate cancer patients

Preliminary investigation of gene expression levels of PAPP-A, STC-2, and HIF-1α in SARS-Cov-2 infected patients

The STC2–PAPP-A–IGFBP4–IGF1 axis and its associations to mortality and CVD in T2D

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