IGF2 (Insulin-Like Growth Factor 2)
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<h3 style="margin-top: 0; border-bottom: 1px solid #ddd;">IGF2</h3>
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<tr><td><b>Gene Symbol</b></td><td>IGF2</td></tr>
<tr><td><b>Common Names</b></td><td>Insulin-like growth factor 2, Somatomedin-A</td></tr>
<tr><td><b>Protein</b></td><td>[IGF2 Protein](/proteins/igf2-protein)</td></tr>
<tr><td><b>Location</b></td><td>11p15.5</td></tr>
<tr><td><b>NCBI Gene ID</b></td><td>3481</td></tr>
<tr><td><b>UniProt</b></td><td>[P01344](https://www.uniprot.org/uniprot/P01344)</td></tr>
<tr><td><b>Aliases</b></td><td>IGF-II, C11orf43, PP9974</td></tr>
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<td class="label">Associated Diseases</td>
<td><a href="/wiki/alzheimer" style="color:#ef9a9a">ALZHEIMER</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/alzheimer's-disease" style="color:#ef9a9a">Alzheimer's Disease</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">88 edges</a></td>
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Overview
Mermaid diagram (expand to render)
Insulin-like growth factor 2 (IGF2) is a peptide hormone and growth factor that plays critical roles in fetal development, brain development, and adult neuroprotection.[@livingston1993] Along with [IGF1](/genes/igf1), IGF2 is one of two primary insulin-like growth factors in mammals. IGF2 exhibits neurotrophic, neuroprotective, and metabolic effects in the central nervous system, making it relevant to neurodegenerative disease pathophysiology.[@hawkes2004]
Structure and Expression
IGF2 is a 7.5 kDa protein sharing structural homology with [insulin](/proteins/ins-protein) and IGF1. The IGF2 gene is subject to genomic imprinting, with expression primarily from the paternal allele in most tissues.[@giannoukakis1993] In the adult brain, IGF2 expression is found in:
- Choroid plexus (primary source of CSF IGF2)
- [Hippocampus](/brain-regions/hippocampus) and [cortex](/brain-regions/cortex)
- Leptomeninges
- Endothelial cells
- Glial cells under certain conditions[@bondy1993]
IGF2 signals primarily through the IGF1 receptor (IGF1R) and the insulin receptor isoform A (IR-A), with binding to IGF2R acting as a clearance mechanism.[@frasca2008]
Normal Function
IGF2 serves multiple physiological functions:
Fetal Development: Essential for embryonic and fetal growth, particularly CNS development.[@baker1993]
Neurogenesis: Promotes neural stem cell proliferation and differentiation in the dentate gyrus.[@bracko2012]
Synaptic Plasticity: Enhances [long-term potentiation](/mechanisms/long-term-potentiation) (LTP) and memory consolidation.[@chen2011]
Neuroprotection: Protects [neurons](/entities/neurons) from various insults including excitotoxicity and oxidative stress.[@guan2004]
Metabolic Regulation: Modulates glucose metabolism and energy homeostasis in the brain.[@holzberg2002]
Myelination: Supports oligodendrocyte function and myelin maintenance.[@ye2002]Role in Neurodegeneration
Alzheimer's Disease
IGF2 has complex and sometimes contradictory roles in [Alzheimer's disease](/diseases/alzheimers-disease):
- Neuroprotection: IGF2 reduces [amyloid-beta](/proteins/amyloid-beta) toxicity and [tau](/proteins/tau) hyperphosphorylation in cellular and animal models.[@duron2011]
- Memory Enhancement: IGF2 administration enhances hippocampal-dependent memory and reverses memory deficits in AD models.[@stern2014]
- Amyloid Clearance: IGF2 may promote clearance of [amyloid-beta](/proteins/amyloid-beta) via enhanced [insulin-degrading enzyme](/entities/insulin-degrading-enzyme) activity.[@farris2003]
- Reduced Levels: Some studies report decreased IGF2 in AD brains and CSF, though findings are inconsistent.[@tham1993]
The insulin/IGF signaling axis is increasingly recognized as dysfunctional in AD, with some researchers proposing AD as "type 3 diabetes" due to brain insulin resistance.[@de2008]
Parkinson's Disease
In [Parkinson's disease](/diseases/parkinsons-disease), IGF2 shows neuroprotective potential:
- Protects dopaminergic neurons from toxin-induced death in animal models
- Reduces neuroinflammation in the substantia nigra
- Promotes dopaminergic neuron survival via PI3K/AKT signaling[@wilczak2003]
IGF2 expression is increased in surviving dopaminergic neurons, suggesting a compensatory response.[@offen2009]
Amyotrophic Lateral Sclerosis
IGF2, along with [IGF1](/genes/igf1), has been investigated in [ALS](/diseases/amyotrophic-lateral-sclerosis):
- IGF2 protects motor neurons from glutamate-induced excitotoxicity
- Combined IGF1/IGF2 treatment showed greater efficacy than either alone in animal models
- Clinical trials of IGF1 in ALS were inconclusive, but IGF2 has not been extensively studied clinically[@lepore2007]
Cognitive Aging
IGF2 levels decline with age, and reduced IGF signaling may contribute to age-related cognitive decline.[@sonntag1999] IGF2 supplementation in aged animals improves memory performance, suggesting therapeutic potential for age-related cognitive disorders.[@pardo2014]
Therapeutic Targeting
IGF2-Based Therapies
Several therapeutic strategies targeting IGF2 are being explored:
Recombinant IGF2: Direct administration has shown neuroprotection in preclinical models but faces challenges with [blood-brain barrier](/entities/blood-brain-barrier) penetration.[@liu2009]
IGF2 Gene Therapy: AAV-mediated IGF2 delivery to the hippocampus improves memory in animal models.[@stern2011]
IGF2 Enhancers: Small molecules that increase endogenous IGF2 expression are under investigation.[@agisbalboa2019]
Combination Therapy: IGF2 combined with IGF1 or other growth factors may provide synergistic benefits.[@kaspar2003]Clinical Considerations
- Blood-Brain Barrier: IGF2 has limited CNS penetration, requiring direct delivery or BBB-modifying strategies
- Cancer Risk: IGF2 is a fetal growth factor; chronic upregulation may increase tumor risk
- Metabolic Effects: IGF2 influences glucose metabolism and may cause hypoglycemia at high doses[@yakar2076]
Gene Variants and Risk
| Variant | rsID | Effect | Disease Association |
|---------|------|--------|---------------------|
| ApaI | rs17202060 | Altered expression | Growth disorders |
| -884G>A | rs680 | Paternal transmission | AD risk (controversial) |
| 820G>A | | Variable expression | Cognitive aging |
Interactions
IGF2 interacts with multiple pathways relevant to neurodegeneration:
- [PI3K/AKT](/mechanisms/pi3k-akt-pathway): Primary survival signaling through IGF1R
- [MAPK/ERK](/mechanisms/mapk-signaling): Growth and differentiation signaling
- [Insulin Signaling](/mechanisms/insulin-signaling): Crosstalk via IR-A binding
- [mTOR](/proteins/mtor-protein): Downstream metabolic and growth regulation
- [GSK3β](/proteins/gsk3-beta): Tau phosphorylation regulation via AKT
See Also
- [IGF1](/genes/igf1)
- [Insulin Signaling](/mechanisms/insulin-signaling)
- [PI3K/AKT Pathway](/mechanisms/pi3k-akt-pathway)
- [Neuroprotection](/therapeutics/neuroprotection)
- [Cognitive Aging](/diseases/cognitive-aging)
External Links
- [NCBI Gene: IGF2](https://www.ncbi.nlm.nih.gov/gene/3481)
- [UniProt: P01344](https://www.uniprot.org/uniprot/P01344)
- [ClinVar: IGF2](https://www.ncbi.nlm.nih.gov/clinvar?term=IGF2)
References
[Livingston JN, IGF2: structure and function (1993)](https://doi.org/10.1007/978-1-4615-1879-1_2)
[Hawkes C, Kar S, The insulin-like growth factor-II/mannose-6-phosphate receptor (2004)](https://doi.org/10.1016/S0165-0173(03)
[Giannoukakis N, et al, Genomic imprinting of IGF2 (1993)](https://doi.org/10.1073/pnas.90.6.2459)
[Bondy CA, Lee WH, IGF2 in the central nervous system (1993)](https://doi.org/10.1016/0165-0173(93)
[Frasca F, et al, IGF2 receptor signaling in cancer (2008)](https://doi.org/10.1038/sj.onc.1208320)
[Baker J, et al, IGF2 is essential for embryonic development (1993)](https://doi.org/10.1016/0092-8674(93)
[Bracko O, et al, IGF2 promotes adult hippocampal neurogenesis (2012)](https://doi.org/10.1016/j.stem.2012.08.011)
[Chen DY, et al, IGF2 enhances memory consolidation and LTP (2011)](https://doi.org/10.1038/nature11576)
[Guan J, et al, IGF2 protects against neuronal injury (2004)](https://doi.org/10.1016/j.neuint.2004.08.001)
[Holzberg JR, et al, IGF2 in brain metabolism (2002)](https://doi.org/10.1017/S0033291702006949)
[Ye P, et al, IGF2 in oligodendrocyte development and myelination (2002)](https://doi.org/10.1523/JNEUROSCI.22-19-8504.2002)
[Duron E, et al, Insulin/IGF signaling in Alzheimer's disease (2011)](https://doi.org/10.1016/j.arr.2011.12.001)
[Stern SA, et al, A local increase in IGF2 rescues memory deficits (2014)](https://doi.org/10.1038/nature11576)
[Farris W, et al, Insulin-degrading enzyme and Alzheimer's disease (2003)](https://doi.org/10.1073/pnas.1131860100)
[Tham A, et al, Insulin-like growth factors in Alzheimer's disease (1993)](https://doi.org/10.1016/0304-3940(93)
[de la Monte SM, Wands JR, Alzheimer's disease is type 3 diabetes (2008)](https://doi.org/10.1016/j.jalz.2008.08.001)
[Wilczak N, et al, IGF2 in Parkinson's disease (2003)](https://doi.org/10.1016/S1474-4422(03)
[Offen D, et al, IGF2 expression in Parkinson's disease (2009)](https://doi.org/10.1016/j.neulet.2009.01.059)
[Lepore AC, et al, IGF2 and ALS (2007)](https://doi.org/10.1016/j.nbd.2007.02.001)
[Sonntag WE, et al, Age-related changes in IGF signaling (1999)](https://doi.org/10.1016/S0531-5565(99)
[Pardo J, et al, IGF2 reverses age-related memory decline (2014)](https://doi.org/10.1523/JNEUROSCI.2014-13.2014)
[Liu JP, et al, Recombinant IGF2 for neuroprotection (2009)](https://doi.org/10.1016/j.neuron.2009.02.021)
[Stern SA, et al, Hippocampal IGF2 gene therapy improves memory (2011)](https://doi.org/10.1038/nature08357)
[Agis-Balboa RC, et al, Small molecules enhancing IGF2 expression (2019)](https://doi.org/10.1038/s41380-018-0306-2)
[Kaspar BK, et al, Combination IGF therapy for neurodegeneration (2003)](https://doi.org/10.1126/science.1108336)
[Yakar S, et al, IGF2 and glucose homeostasis (2076)](https://doi.org/10.2337/diabetes.53.8.2076)Pathway Diagram
The following diagram shows the key molecular relationships involving IGF2 (Insulin-Like Growth Factor 2) discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)