Mechanisms of Fetal Overgrowth in Gestational Diabetes: The Potential Role of SOCS2
Abstract
1. Introduction
2. Endocrine–Metabolic Sketch of Pregnancy
3. Embryonic and Fetal Growth
4. Gestational Diabetes
5. Macrosomia
6. Biomarkers of Gestational Diabetes and Macrosomia
6.1. Gestational Diabetes Mellitus Biomarkers
- a.
- Maternal serum biomarkers
- b.
- Placental and cord blood biomarkers
6.2. Macrosomia Biomarkers
- a.
- Maternal serum biomarkers
- b.
- Placental and cord blood biomarkers
Biomarker | Origin | Up (↑)/Down (↓) Regulation | Role/Function | Type of Study | Evidence |
---|---|---|---|---|---|
2-Hydroxybutyric ## 3-Hydroxybutyric ## | Maternal | ↑ | Ketone body derived from fatty acid oxidation | Metabolic plasma analysis (maternal blood samples) | [57,104] |
Adiponectin #& | Maternal | ↓ | Stimulation of FAO, enhancement glucose metabolism and reduction in insulin resistance throughout | Primary cell culture of human placentas/Human placenta and maternal blood samples | [22,82] |
AMPK && | Placental | ↓ | Activation of cellular metabolism | Human placenta and maternal blood samples | [44] |
ANGPL-3-4-8 #& | Placental | ↑ | Increased transplacental nutrition and lipid and glucose metabolism | Maternal and cord blood and human placenta samples | [122] |
ARHGEF11 ## | Placental | ↑ | Activation of G protein signaling and cellular processes such as insulin secretion, insulin signaling, and lipid metabolism | Human placenta samples | [38] |
BCAA ## Valine, Isoleucine, Leucine | Maternal | ↑ | Essential amino acids that cannot be produced by the body and must be primarily obtained from the diet. Related with GDM. | Metabolic plasma analysis (maternal blood samples) | [57] |
C-peptide #& | Maternal | ↑ | Marker of endogenous insulin secretion. Derived from the cleavage of proinsulin in insulin. | Maternal and cord blood samples | [86] |
E2 ## | Maternal/Cord blood | ↓ | Sex female steroid that maintains β-cell survival and glucose homeostasis | Clinical, anthropometrical data and maternal blood samples/Cord blood samples | [71,108] |
EL | Placental | ↑ | Mediation of the uptake of fatty acids from high-density lipoproteins | Human placenta samples | [68] |
ER-α $$ | Placental | ↑ | Enhancement glucose uptake capacity | Human placenta samples | [75] |
FAO #& | Placental | ↓ | Breakdown of fatty acids into CoA for use as an energy resource | Human placenta and maternal blood samples | [85,95] |
FFA #& | Cord Blood/Maternal | ↑/= | Source of energy for the body | Maternal blood samples/Maternal and cord blood samples | [97,98] |
FGF21 #& | Maternal | ↑ | Enhancement carbohydrate and lipid metabolism | Blood samples/Meta-analysis | [101,102] |
GHR $$ | Placental | ↑ | Regulation of GH function in growth, metabolism, and other physiological functions | In vitro analysis with Sprague Dawley rats embryo samples | [47] |
Gluconeogenic AA ## (Glutamine and Glutamate) | Maternal | ↑ | Aminoacids related to glucose metabolism | Metabolomics (maternal blood and urine samples) | [57,103] |
GLUT4 ## | Placental | ↓ | Insulin-regulated glucose uptake transporter | Human placenta samples | [38] |
I-CAM-1 && | Maternal | ↑ | Cell adhesion molecule related with a proinflammatory state | Prospective case–control study | [58] |
IGF-1 #$ | Placental/ Maternal | ↑/↓ | Increased fetal growth | Human placenta samples/Human placenta and maternal blood samples | [38,44,46] |
IGFBP-1 #$ | Placental | ↓ | Modulation of biological functions of IGFs | Human placenta | [116] |
Insulin ## | Maternal | ↑ | Reduction in blood glucose levels and induction of glucose storage in the liver | In vivo study with rat pancreas | [61] |
IR ## | Placental | ↑ | Promotion of cellular metabolism | Human placenta and maternal blood samples | [44] |
Irisin ## | Maternal | ↑ | Transformation of white adipose tissue to brown adipose tissue, inducing energy expenditure | Maternal blood, umbilical cord and placenta samples | [127] |
IRS-1 (ph) ## | Placental | ↑ | Docking protein for insulin signal transmission | Human placenta samples | [75] |
Kisspeptin $$ | Maternal | ↓ | Neuroactive hormone that adapts maternal physiology to pregnancy | Maternal and cord blood and human placenta samples/Review | [107,110] |
Leptin #& | Maternal | ↑ | Suppression of appetite and control of the energy expenditure in white adipose tissue. In pregnancy, maintains increased energy intake for the fetal growth | Maternal blood samples/Human placenta and maternal blood samples | [22,121] |
miR-21 $$ | ↑ | micro-RNA in JAK/STAT pathway linked to macrosomic babies. | Human placenta samples/Maternal blood samples/Review | [53,124,125] | |
miR-675 $$ | Maternal | micro-RNA increases placental growth | In vitro analysis (cell line culture) and in vivo analysis (C57/BL6 and H19Δ3 transgenic line)/Review | [53,126] | |
NEFA #& | Maternal | ↑ | Source of energy for skeletal muscle | Primary cell culture of human placentas | [95] |
p-S307 ## | Placental | ↓ | Phosphorylated Ser307 of IRS-1, blocks insulin action | Human placenta samples | [38] |
p-Y612 ## | Placental | ↓ | Phosphorylated site of IRS-1 intermediates with PI3K activity | Human placenta samples | [38] |
p58a $$ | Placental | ↑ | An ER molecular chaperone | Human placenta samples | [75] |
pAKT ## | Placental | ↓/↑ | Phosphorylation and regulation of multiple intracellular signaling pathways (metabolism, apoptosis, and proliferation) | Human placenta samples | [38] |
pGH $$ | Maternal | ↑ | Activation of maternal and fetal metabolism and growth | Maternal blood samples/Review | [54,115] |
PI3K ## | Placental | ↓ | Activation of multiple intracellular signaling pathways (growth, proliferation, migration, secretion, differentiation, transcription, and translation) | Human placenta samples | [38] |
Proinflamatory Cytokines && (TNF-a, IL-6, IL-1, MCP-1) | Maternal | ↑ | Activation of multiple cellular-mediated responses | A prospective case–control study | [58] |
Resistin ## | Placental | ↑ | Inflammation and impaired glucose tolerance | Human placenta and maternal blood samples | [22] |
SNAT1 #$ | Placental | ↑ | Amino acid transporter in the placenta | Human placenta and maternal blood samples | [44] |
SOCS2 #$& | Maternal | ↓ | Inhibition of GH and IGF-1 signaling, thus regulates body growth and development, immune response, lipid and glucose metabolism, and β-cell physiology | Human placenta samples/In vivo evaluation of Socs2−/− mice | [35,128,129] |
Succinic acid ## | Maternal | ↑ | Intermediate product of the Krebs cycle. To produce energy in Krebs cycle | Metabolic plasma analysis (maternal blood samples) | [57,104] |
TG #& | Placental/Cord Blood/Maternal | ↑/= | Source of energy for the body | Human placenta and maternal blood samples/Maternal and cord blood samples | [85,86,97] |
V-CAM-1 && | Maternal | ↑ | Cell adhesion molecule related to a proinflammatory state | A prospective case–control study | [58] |
7. SOCS2 Mechanism in Gestational Diabetes and Macrosomia
8. Limitations, Directions for Future Research, and General Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
ACTH | Adrenocorticotropic hormone |
ADA | American Diabetes Association |
AKT | Protein kinase B |
AMPK | AMP-activated protein kinase |
ARHGEF11 | Rho guanine nucleotide exchange factor 11 |
ANGPTL | Angiopoietin-like protein |
BCAAs | Branched-chain amino acids |
BMI | Body mass index |
CBG | Corticosteroid-binding globulin |
CISH | Cytokine-inducible SH2 protein |
CRH | Corticotropin |
DOC | Deoxycorticosterone |
E2 | Estrogen Estradiol |
EL | Endothelial lipase |
ER | Estrogen receptor |
ER-stress | Endoplasmic reticulum stress |
FAO | Fatty acid oxidation |
FDA | United States Food and Drug Administration |
FFA | Free fatty acids |
G6PC | Glucose-6-phosphatase catalytic subunit |
GDM | Gestational diabetes mellitus |
GH | Growth hormone |
GHR | Growth hormone receptor |
GLUT | Glucose transporter |
HbAc1 | Glycated hemoglobin |
HFD | High fat diet |
HOMA-IR | Homeostasis model assessment-estimated insulin resistance |
HPA | Hypothalamus–pituitary–adrenal |
ICAM | Intracellular adhesion molecule |
IGF | Insulin growth factor |
IGFR | Insulin growth factor receptor |
IL | Interleukin |
IR | Insulin receptor |
IRS | Insulin receptor substrate |
IUGR | Intrauterine growth restriction |
JAK | Janus kinase |
LGA | Large for gestational age |
MCP | Monocyte chemoattractant protein |
mTOR | Mammalian target of rapamycin |
NEFA | Nonesterified fatty acids |
NF-kB | Nuclear factor kappa light chain enhancer of activated B cells |
PCK1 | Phosphoenolpyruvate carboxykinase 1 |
PI3K | Phosphatidyllinositol-3 kinase |
p58α | Phosphatidyllinositol-3 kinase subunit |
PL | Placental lactogen |
PRL | Prolactin |
PRLR | Prolactin receptor |
SNAT1 | Sodium-coupled neutral amino acid transporter |
SNPs | Single nucleotide polymorphisms SNPs |
SOCS | Suppressor of cytokine signaling |
STAT | Signal transducers and activator or transcription |
T2D | Type 2 diabetes |
T3 | Triiodothyronine |
T4 | Thyroxine |
TBG | Thyroxine-binding globulin |
TNF-α | Tumor necrosis factor α |
TSH | Thyroid-stimulating hormone |
VCAM | Vascular cell adhesion molecule |
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Hernández-Baraza, L.; Brito-Casillas, Y.; Valverde-Tercedor, C.; Recio, C.; Fernández-Pérez, L.; Guerra, B.; Wägner, A.M. Mechanisms of Fetal Overgrowth in Gestational Diabetes: The Potential Role of SOCS2. Nutrients 2025, 17, 1519. https://doi.org/10.3390/nu17091519
Hernández-Baraza L, Brito-Casillas Y, Valverde-Tercedor C, Recio C, Fernández-Pérez L, Guerra B, Wägner AM. Mechanisms of Fetal Overgrowth in Gestational Diabetes: The Potential Role of SOCS2. Nutrients. 2025; 17(9):1519. https://doi.org/10.3390/nu17091519
Chicago/Turabian StyleHernández-Baraza, Luisa, Yeray Brito-Casillas, Carmen Valverde-Tercedor, Carlota Recio, Leandro Fernández-Pérez, Borja Guerra, and Ana M. Wägner. 2025. "Mechanisms of Fetal Overgrowth in Gestational Diabetes: The Potential Role of SOCS2" Nutrients 17, no. 9: 1519. https://doi.org/10.3390/nu17091519
APA StyleHernández-Baraza, L., Brito-Casillas, Y., Valverde-Tercedor, C., Recio, C., Fernández-Pérez, L., Guerra, B., & Wägner, A. M. (2025). Mechanisms of Fetal Overgrowth in Gestational Diabetes: The Potential Role of SOCS2. Nutrients, 17(9), 1519. https://doi.org/10.3390/nu17091519