The Insulin/IGF-1 Signaling Pathway: Mechanisms, Function, and Therapeutic Potential

The insulin/insulin-like growth factor-1 (IGF-1) signaling pathway represents one of the most evolutionarily conserved and biologically significant cellular communication systems in the body. This pathway plays a crucial role in regulating growth, development, metabolism, cell survival, and longevity across species ranging from nematodes to humans. Before delving into the intricate mechanisms of this pathway, it is worth noting that research has identified several genetic variations in this pathway associated with human longevity, underscoring its fundamental importance to our understanding of both normal physiology and disease states1.

Historical Context and Molecular Components

The discovery of insulin-like growth factor-1 dates back to the late 1950s when researchers investigating growth hormone mechanisms identified a serum-borne mediator termed 'sulfation factor,' which was directly responsible for the anabolic activities of growth hormone. This factor was subsequently renamed 'somatomedin' and eventually became known as insulin-like growth factor-1 (IGF1)3. IGF1 is a peptide growth factor (~7.65-kDa) consisting of 70 amino acids that shares structural similarity with insulin but maintains distinct physiological functions3.

The IGF1 system comprises several key components. At the center is IGF1 itself, a peptide hormone primarily produced by the liver in response to growth hormone stimulation, though many tissues can produce IGF1 locally. The biological actions of IGF1 are mediated by the IGF1 receptor (IGF1R), a cell-surface tyrosine kinase receptor evolutionarily related to the insulin receptor3. Additionally, the effects of IGF1 are modulated by a family of at least six IGF-binding proteins (IGFBPs) that bind and transport IGF1 in the circulation and extracellular fluids, thereby regulating its bioavailability3.

The IGF1 receptor is a heterotetrameric structure that includes two extracellular α-subunits involved in ligand binding and two transmembrane β-subunits containing a tyrosine kinase domain in their cytoplasmic portion. This structure is crucial for transducing the signal from the extracellular environment to intracellular signaling cascades3.

Signal Transduction Mechanisms

The signaling cascade initiated by IGF1 binding to its receptor represents a complex and finely regulated process that ultimately influences multiple cellular functions. When IGF1 binds to the IGF1R, it induces conformational changes that lead to autophosphorylation of the receptor's β-subunit tyrosine kinase domain and subsequent ubiquitination3. The phosphorylated tyrosine residues serve as docking elements for other signaling molecules such as insulin receptor substrate (IRS) proteins and Shc adaptor proteins3.

This molecular interaction triggers two major downstream signaling pathways: the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and the Ras/mitogen-activated protein kinase (MAPK) pathway3. The PI3K pathway predominantly mediates the metabolic and anti-apoptotic effects of IGF1, while the MAPK pathway primarily regulates cell growth and proliferation.

In the PI3K pathway, phosphorylated IRS proteins activate the 85-kDa regulatory subunit of PI3K, leading to the activation of various downstream substrates, including Akt/PKB. Akt phosphorylation stimulates protein synthesis via mammalian target of rapamycin (mTOR) activation and elicits anti-apoptotic effects via inactivation of BAD3. Meanwhile, in the MAPK pathway, recruitment of Grb2/SOS by phosphorylated IRS or Shc leads to Ras activation and subsequent activation of the Raf/MEK/ERK signaling cascade3.

Additionally, the IGF1R can signal through the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Particularly, activation of STAT3 is critical for the potentially transforming activity of IGF1R3. Recent research has also revealed that IGF1R can migrate to the cell nucleus after modification by small ubiquitin-like modifier protein (SUMO)-1, where it functions as a transcriptional activator, adding another layer of complexity to its signaling mechanisms3.

Biological Functions and Physiological Roles

The insulin/IGF1 signaling pathway influences numerous physiological processes throughout the lifespan. During development, IGF1 signaling is essential for normal growth and development. Studies have shown that mice with targeted disruption of the IGF1R gene exhibit severe growth retardation and die shortly after birth, highlighting the pathway's critical role in developmental processes3.

In the postnatal period, IGF1 signaling continues to regulate bone growth through both endocrine and paracrine mechanisms. The longitudinal bone growth resulting from the ossification of the growth plate is under IGF1 influence, and recent studies have begun to explore the connection between IGF1, the intestinal microbiome, and bone growth, suggesting a complex interplay between nutritional status, gut microbiota, and bone development8.

Beyond its role in growth and development, the insulin/IGF1 pathway plays a central role in metabolism. It regulates glucose homeostasis, protein synthesis, and lipid metabolism. For instance, in the liver, dysregulation of the IGF1/PI3K/AKT pathway can lead to alterations in gluconeogenic and lipogenic enzymes, contributing to conditions such as non-alcoholic fatty liver disease (NAFLD)13.

The pathway also demonstrates important functions in tissue regeneration and repair. In the liver, Notch-IGF1 signaling during liver regeneration drives biliary epithelial cell expansion, though it inhibits hepatocyte differentiation, suggesting a complex role in tissue repair processes2.

Perhaps one of the most intriguing aspects of the insulin/IGF1 pathway is its role in aging and longevity. Studies across multiple species have shown that reduced signaling through this pathway is associated with extended lifespan1. In humans, a study examining genetic variation in the insulin/IGF1 signaling pathway found that certain variants are associated with longevity, suggesting evolutionary conservation of this relationship1.

Insulin/IGF1 Signaling in Disease States

Dysregulation of the insulin/IGF1 signaling pathway is implicated in various pathological conditions, ranging from metabolic disorders to cancer and neurological diseases.

Cancer

The insulin/IGF1 pathway has been extensively studied in the context of cancer due to its potent anti-apoptotic and pro-survival functions. The IGF1R is expressed in most types of cancer and plays a crucial role in malignant transformation and tumor progression3. Constitutive phosphorylation of IGF1R is considered a universal feature of malignantly transformed cells3.

The relationship between IGF1R and tumor suppressor genes further underscores its importance in cancer biology. Tumor suppressor p53, the most frequently mutated molecule in human cancer, suppresses IGF1R promoter activity by approximately 90%3. In contrast, tumor-derived mutant forms of p53 enhance promoter activity, leading to increased IGF1R expression and reduced apoptosis, thereby conferring an augmented survival capacity to cancer cells3.

Recent research has also identified metformin, a widely used antidiabetic drug, as a potential anticancer agent through its effects on the insulin/IGF1 pathway. Metformin has been shown to increase the sensitivity of crizotinib-resistant non-small cell lung cancer cells to crizotinib by inhibiting the IGF1R signaling pathway4. Similarly, in breast cancer, metformin reduces circulating insulin levels and increases insulin sensitivity, potentially attenuating the tumor-promoting effects of hyperinsulinemia9.

Metabolic Disorders

The insulin/IGF1 pathway is intrinsically linked to metabolic health, and its dysregulation contributes to various metabolic disorders. In non-alcoholic fatty liver disease (NAFLD), for instance, the AKT pathway is over-activated through PI3K-active mTOR and FOXO recruitment, leading to alterations in gluconeogenic and lipogenic enzymes, insulin resistance, reduced autophagy, and liver cell apoptosis13. Caloric restriction has been shown to potentially reverse these changes by downregulating the insulin-signaling pathway IGF1/PI3K/AKT13.

Interestingly, dietary interventions such as caloric restriction and fasting have been shown to modulate the insulin/IGF1 pathway in ways that may be beneficial for metabolic health. These interventions typically lead to decreased circulating IGF1 levels and increased insulin sensitivity, which may help explain their beneficial effects on various health parameters135.

Neurological Conditions

Emerging evidence suggests that the insulin/IGF1 pathway plays a role in various neurological conditions. For instance, abnormal IGF1/IGF1R signaling has been shown to contribute to neuropathic pain by exacerbating autophagy dysfunction and neuroinflammation in the spinal cord11. In a mouse model of chronic constriction injury of the sciatic nerve, intrathecal injection of an IGF1R inhibitor or anti-IGF1 neutralizing antibodies attenuated pain behaviors, relieved mTOR-related suppression of autophagy, and mitigated neuroinflammation in the spinal cord11.

Therapeutic Interventions Targeting the Insulin/IGF1 Pathway

Given the involvement of the insulin/IGF1 pathway in various diseases, it has emerged as an attractive therapeutic target, particularly in oncology. Several approaches have been developed to modulate this pathway for therapeutic benefit.

Targeting IGF1R in Cancer

Three major classes of compounds have been studied for targeting IGF1R in cancer: antibodies directed against IGF1R, small-molecular-weight tyrosine kinase inhibitors, and antibodies directed against IGF ligands3. Additional therapeutic modalities include antisense oligonucleotides and small interfering RNA3.

IGF1R antibodies work by blocking signaling through two mechanisms: preventing ligand binding and inducing receptor internalization and degradation3. In vitro and preclinical models have demonstrated that monoclonal antibodies targeting IGF1R inhibit IGF1/2-stimulated proliferation of different solid tumors and certain hematologic cancers3.

Several specific IGF1R antibodies have been evaluated in Phase I and II clinical trials, both as monotherapy and in combination with chemotherapy, radiotherapy, or other antibodies3. However, the objective response to IGF1R-directed targeting as monotherapy has generally been low, suggesting that these therapies may be more effective when combined with other treatments3. Unfortunately, few of these IGF1R antibody trials have progressed to or completed Phase III studies, indicating challenges in translating preclinical success to clinical benefit3.

Metformin and IGF1 Signaling

Metformin, a widely prescribed antidiabetic drug, has shown promise in targeting the insulin/IGF1 pathway for cancer treatment. Metformin inhibits gluconeogenesis in the liver, increases glucose uptake in skeletal muscle, and decreases circulating insulin levels, thereby reducing insulin resistance-associated hyperinsulinemia9. At the molecular level, metformin activates adenosine mono-phosphate-activated protein kinase (AMPK), which can antagonize some effects of the insulin/IGF1 pathway9.

In preclinical studies, metformin has demonstrated anticancer effects across various cancer types, including breast cancer9. For instance, in crizotinib-resistant non-small cell lung cancer cells, metformin effectively increased sensitivity to crizotinib, decreased proliferation and invasion, and enhanced apoptosis through inhibition of the IGF1R signaling pathway4.

Dietary Interventions and Mimetics

Dietary interventions such as caloric restriction and fasting have been shown to modulate the insulin/IGF1 pathway in ways that may be beneficial for health and longevity. These interventions typically lead to decreased circulating IGF1 levels and increased insulin sensitivity135.

Research is also focused on developing caloric restriction mimetics (CRMs), small molecules that induce autophagy through the same pathways activated by fasting, including the reduction of cytoplasmic protein acetylation5. These compounds, along with ketone bodies like 3-hydroxybutyrate and pharmacological inhibitors of IGF1R, have shown promise in mimicking some of the beneficial effects of fasting on anticancer immunosurveillance5.

Pyrroloquinoline quinone (PQQ) is another compound that has been investigated for its effects on the insulin/IGF1 pathway and longevity. In the model organism Caenorhabditis elegans, PQQ has been shown to extend lifespan through the insulin/IGF1 signaling pathway-mediated activation of autophagy12. PQQ treatment increased locomotion and anti-stress ability while reducing fat accumulation and reactive oxygen species levels in these organisms12.

Proven vs. Unproven Therapeutic Approaches

While the basic structure and components of the insulin/IGF1 signaling pathway are well-established, the efficacy of various therapeutic interventions targeting this pathway varies in terms of supporting evidence.

Well-Established Approaches:

1. Metformin's effects on the insulin/IGF1 pathway: There is substantial evidence from both preclinical and clinical studies supporting metformin's ability to modulate the insulin/IGF1 pathway and its potential benefits in conditions such as diabetes and certain cancers49.

2. Caloric restriction for metabolic health: The benefits of caloric restriction for metabolic health, partly mediated through effects on the insulin/IGF1 pathway, are well-supported by research across multiple species13.

3. IGF1R signaling as a therapeutic target in specific cancers: While the overall efficacy of IGF1R-targeted therapies in cancer has been mixed, there is strong evidence supporting the role of IGF1R signaling in cancer development and the potential of targeting this pathway in specific cancer types or in combination with other therapies3.

Less Well-Established Approaches:

1. IGF1R-directed monotherapy in cancer: The objective response to IGF1R-directed targeting as monotherapy has generally been low, suggesting limitations to this approach in isolation3.

2. Caloric restriction mimetics: While promising, the development of compounds that effectively mimic the benefits of caloric restriction on the insulin/IGF1 pathway is still an evolving field5.

3. Manipulation of the gut microbiome to influence IGF1 signaling and bone growth: The role of the gut microbiota in modulating the somatotropic axis and bone growth is an emerging area of research, with potential therapeutic implications that require further investigation8.

4. PQQ and other compounds for extending longevity through IGF1 pathway modulation: Studies in model organisms like C. elegans show promising effects, but translation to humans remains uncertain12.

Conclusion and Future Directions

The insulin/IGF1 signaling pathway represents a complex and multifaceted system with profound implications for human health and disease. From its roles in normal growth and development to its involvement in conditions ranging from cancer to metabolic disorders and neurological diseases, this pathway offers numerous potential therapeutic targets.

While significant progress has been made in understanding the components and mechanisms of the insulin/IGF1 pathway, many challenges remain in translating this knowledge into effective therapies. The mixed results of IGF1R-targeted therapies in cancer highlight the need for better patient stratification and combination approaches. Similarly, the promising effects of dietary interventions and mimetics on the insulin/IGF1 pathway suggest potential for preventive strategies but require further refinement and validation.

Future research will likely focus on several key areas: identifying biomarkers that can predict responsiveness to IGF1R-directed therapies, developing more specific inhibitors of the pathway with fewer off-target effects, understanding the complex interactions between the insulin/IGF1 pathway and other signaling networks, and exploring the role of nuclear IGF1R in various physiological and pathological processes3.

As our understanding of this critical signaling pathway continues to evolve, so too will our ability to harness its therapeutic potential for a wide range of human diseases. The insulin/IGF1 signaling pathway, with its central role in regulating fundamental cellular processes and its conservation across species, remains a fascinating area of research with significant implications for human health and longevity.