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This report is written by MaltSci based on the latest literature and research findings

What is the role of insulin-like growth factors? ​

Abstract ​

Insulin-like growth factors (IGFs), primarily IGF-1 and IGF-2, are critical polypeptides that play pivotal roles in growth, development, and metabolic regulation. These factors, predominantly produced in the liver, exert their effects through a complex network of signaling pathways, influencing cellular proliferation, differentiation, and survival. The understanding of IGFs has evolved significantly over the past few decades, particularly in light of their involvement in various physiological and pathological conditions. Their significance extends beyond mere growth regulation, implicating them in metabolic disorders, cancer, and even neurodegenerative diseases. This review aims to elucidate the multifaceted roles of IGFs, emphasizing their production, regulation, biological functions, and therapeutic implications. Research has demonstrated that IGF-1 and IGF-2 are involved in numerous biological processes, including the regulation of body composition, bone density, and muscle growth. Furthermore, alterations in IGF signaling pathways have been linked to a range of disorders, such as obesity, diabetes, and various cancers. Understanding the mechanisms through which IGFs operate is essential for developing targeted therapies, particularly in oncology and endocrinology. Current research highlights the complexity of IGF signaling, which is modulated by a family of IGF-binding proteins (IGFBPs). These proteins regulate the availability and biological activity of IGFs, adding another layer of complexity to their function. The interactions between IGFs and their binding proteins not only influence growth and metabolism but also have implications in reproductive health and the aging process. This review synthesizes current knowledge on IGFs, providing a comprehensive resource for researchers and clinicians alike, fostering a deeper understanding of the intricate roles these factors play in health and disease.

Outline ​

This report will discuss the following questions.

  • 1 Introduction
  • 2 Overview of Insulin-like Growth Factors
    • 2.1 Structure and Types of IGFs
    • 2.2 Production and Regulation of IGFs
  • 3 Biological Functions of IGFs
    • 3.1 Role in Growth and Development
    • 3.2 IGFs in Metabolism
  • 4 IGFs in Disease Contexts
    • 4.1 IGFs and Cancer
    • 4.2 IGFs in Metabolic Disorders
  • 5 Therapeutic Implications
    • 5.1 Targeting IGF Signaling in Cancer Therapy
    • 5.2 Potential Interventions in Metabolic Syndromes
  • 6 Future Directions in IGF Research
    • 6.1 Emerging Technologies and Approaches
    • 6.2 Unexplored Roles of IGFs
  • 7 Conclusion

1 Introduction ​

Insulin-like growth factors (IGFs), primarily IGF-1 and IGF-2, are critical polypeptides that play pivotal roles in growth, development, and metabolic regulation. These factors, predominantly produced in the liver, exert their effects through a complex network of signaling pathways, influencing cellular proliferation, differentiation, and survival. The understanding of IGFs has evolved significantly over the past few decades, particularly in light of their involvement in various physiological and pathological conditions. Their significance extends beyond mere growth regulation, implicating them in metabolic disorders, cancer, and even neurodegenerative diseases. This review aims to elucidate the multifaceted roles of IGFs, emphasizing their production, regulation, biological functions, and therapeutic implications.

The importance of IGFs in health and disease cannot be overstated. Research has demonstrated that IGF-1 and IGF-2 are involved in numerous biological processes, including the regulation of body composition, bone density, and muscle growth [1]. Furthermore, alterations in IGF signaling pathways have been linked to a range of disorders, such as obesity, diabetes, and various cancers [2][3]. Understanding the mechanisms through which IGFs operate is essential for developing targeted therapies, particularly in oncology and endocrinology, where manipulating IGF signaling could provide new avenues for treatment [2].

Current research highlights the complexity of IGF signaling, which is modulated by a family of IGF-binding proteins (IGFBPs). These proteins regulate the availability and biological activity of IGFs, adding another layer of complexity to their function [4]. The interactions between IGFs and their binding proteins not only influence growth and metabolism but also have implications in reproductive health and the aging process [4][5]. The role of IGFs in sexual development and reproduction has garnered attention, revealing their significance in gonadogenesis and reproductive performance [6].

This review will be organized into several sections, beginning with an overview of IGFs, including their structure, types, and the mechanisms governing their production and regulation. Following this, we will delve into the biological functions of IGFs, focusing on their roles in growth, development, and metabolism. The discussion will then shift to the involvement of IGFs in various disease contexts, particularly cancer and metabolic disorders. Therapeutic implications will be explored, highlighting potential strategies for targeting IGF signaling pathways in clinical settings. Finally, we will outline future directions in IGF research, considering emerging technologies and unexplored roles of these critical growth factors.

By synthesizing current knowledge on IGFs, this review aims to provide a comprehensive resource for researchers and clinicians alike, fostering a deeper understanding of the intricate roles these factors play in health and disease. As the field continues to evolve, it is imperative to stay abreast of the latest findings and their implications for therapeutic strategies aimed at modulating IGF signaling.

2 Overview of Insulin-like Growth Factors ​

2.1 Structure and Types of IGFs ​

Insulin-like growth factors (IGFs), specifically IGF-I and IGF-II, are a pair of highly conserved secreted proteins that play crucial roles in a wide array of physiological processes, including growth, differentiation, and metabolism. They are structurally similar to insulin and are encoded by single, large genes that facilitate the transcription of multiple mRNAs. The actions of IGFs are initiated upon binding to specific cell-surface receptors, namely the insulin-like growth factor 1 receptor (IGF-IR) and, to a lesser extent, the insulin receptor (IR), particularly at higher concentrations of IGFs [7][8].

The physiological roles of IGFs are diverse and have been elucidated through biochemical, cellular, and molecular genetic studies. These factors are central regulators of cell proliferation, survival, and organismal growth, with IGF-I predominantly mediating many of the effects of growth hormone (GH) and linking anabolic processes to nutrient availability [9][10]. The expression of IGFs is regulated by various developmental factors, nutritional status, and hormonal signals. For instance, in the fetal stage, IGF-II is primarily expressed, while IGF-I expression is significant postnatally, regulated mainly by growth hormone and nutritional status [11].

Moreover, the biological effects of IGFs are modulated by insulin-like growth factor binding proteins (IGFBPs), which can either augment or inhibit IGF actions depending on their nature and the context of other regulatory factors. This complex interplay suggests that IGFs have critical roles in the growth and development of multiple organs, including skeletal muscle, bone, and the lung [10][12].

In addition to their growth-promoting properties, IGFs are implicated in the pathogenesis of various conditions, including insulin resistance, diabetes mellitus, and neoplasia. Recent studies have highlighted the involvement of non-coding RNAs in IGF signaling, further indicating the complexity of their regulatory mechanisms and potential therapeutic targets for conditions like cancer [13][14].

The structural features of IGFs include their peptide nature, with both IGF-I and IGF-II consisting of approximately 7,500 Da and exhibiting a high degree of structural homology with proinsulin. This similarity facilitates their binding to IGF receptors and underscores their evolutionary conservation across vertebrates [12]. The presence of IGF family genes, such as IGF1, IGF2, and IGF3, has been identified in various species, including fish, where they are shown to play significant roles in physiological processes related to growth and reproduction [15].

In summary, insulin-like growth factors are vital for normal physiological functions, influencing cellular growth, differentiation, and metabolism while also playing significant roles in various pathologies. Their complex regulatory mechanisms, involving binding proteins and various signaling pathways, underscore their importance in health and disease.

2.2 Production and Regulation of IGFs ​

Insulin-like growth factors (IGFs), specifically IGF-I and IGF-II, are pivotal hormones that significantly influence various physiological processes, including growth, development, and metabolism. They are part of a complex signaling system that encompasses ligands, receptors, and binding proteins, which collectively modulate their effects on target tissues.

IGFs are produced primarily in the liver, but their expression is also found in various tissues throughout the body. Their synthesis is regulated by several factors, including growth hormone (GH), nutritional status, and developmental cues. For instance, IGF-II levels are highest during prenatal development, where it plays a crucial role in fetal growth. Postnatally, IGF-I becomes more prominent and is involved in the regulation of cellular growth, differentiation, and survival across various tissues[10].

The production of IGFs is intricately linked to the growth hormone axis. GH stimulates the liver to produce IGF-I, which then circulates and exerts systemic effects. Additionally, local tissues can produce IGFs in response to local stimuli, acting in a paracrine or autocrine manner. This dual regulation highlights the complexity of IGF signaling, as both systemic and local IGF actions are critical for proper physiological functioning[16].

The role of IGFs extends beyond mere growth stimulation. They are involved in metabolic regulation, influencing processes such as glucose homeostasis and energy metabolism. IGF-I, for instance, has been shown to enhance insulin sensitivity, thus playing a crucial role in metabolic health[17]. Moreover, IGFs interact with a family of binding proteins (IGFBPs), which modulate their bioavailability and activity. IGFBPs can prolong the half-life of IGFs in circulation and regulate their access to target tissues, effectively controlling IGF function[18].

In terms of developmental regulation, IGFs are essential during embryogenesis, where they facilitate growth and differentiation. They are also critical for maintaining stem cell populations in adults, thereby contributing to tissue homeostasis and regeneration[10].

In summary, insulin-like growth factors are integral to a myriad of biological processes, including growth, differentiation, and metabolic regulation. Their production is finely tuned by hormonal and nutritional signals, while their actions are modulated by binding proteins, reflecting their complex roles in both normal physiology and disease states[7][9][19].

3 Biological Functions of IGFs ​

3.1 Role in Growth and Development ​

Insulin-like growth factors (IGFs), primarily IGF-I and IGF-II, are pivotal polypeptides that play essential roles in growth and development across various biological systems. They are involved in numerous physiological processes, including cellular growth, differentiation, metabolism, and survival. The mechanisms through which IGFs exert their effects are mediated primarily by their interaction with specific receptors, notably the insulin-like growth factor 1 receptor (IGF-1R), and through the modulation of IGF-binding proteins (IGFBPs).

In the context of growth and development, IGFs are crucial during both prenatal and postnatal stages. For instance, the IGF system has been identified as a key regulator of embryonic and fetal development. Disruption of IGF signaling, as observed in IGF-I, IGF-II, or IGF-1 receptor knockout models, leads to significant growth retardation and developmental abnormalities, indicating their vital role in normal organismal growth [12].

The physiological effects of IGFs are multifaceted. They promote cellular proliferation and differentiation in various tissues, which is critical during developmental stages. For example, IGF-I is known to stimulate the growth of various organs, including the liver and muscles, by enhancing protein synthesis and inhibiting apoptosis [7]. Additionally, IGFs are implicated in the regulation of metabolic processes, influencing glucose metabolism and the balance of energy homeostasis [20].

In the cornea, IGFs are involved in maintaining tissue homeostasis through their actions on proliferation, differentiation, and migration of corneal epithelial cells. The presence of IGF receptors, such as IGF-1R and insulin receptors, in the cornea indicates that IGFs play a significant role in ocular health and function [20]. Moreover, IGF-I has been shown to facilitate wound healing processes, underscoring its importance in tissue repair and regeneration [20].

The IGF system also plays a role in regulating metabolic functions and responses to nutritional status. In conditions such as chronic liver disease, IGF levels are often reduced, correlating with metabolic disturbances and dysfunction [16]. The complex interactions between IGFs, their receptors, and binding proteins underscore their critical involvement in both growth and metabolic regulation.

Furthermore, IGFs are not only important for growth but also in the context of aging and longevity. They have been associated with the maintenance of muscle mass and function in aging populations, suggesting a protective role against age-related decline [21].

In summary, insulin-like growth factors are fundamental to the processes of growth and development. Their roles extend from promoting cellular proliferation and differentiation to regulating metabolic pathways and facilitating tissue repair. The diverse physiological functions of IGFs highlight their significance in both health and disease, marking them as crucial factors in developmental biology and potential therapeutic targets in various conditions.

3.2 IGFs in Metabolism ​

Insulin-like growth factors (IGFs), primarily IGF-I and IGF-II, play crucial roles in various biological processes, particularly in growth, development, and metabolism. These polypeptides are significant regulators of cellular growth, differentiation, and survival, acting through their specific receptors, IGF-1R and IGF-2R, which initiate signaling cascades that influence metabolic pathways.

In the context of metabolism, IGFs exhibit a complex interplay with insulin, contributing to the regulation of glucose and lipid metabolism. Insulin-like growth factors primarily mediate long-term actions on cell fates, while insulin predominantly influences metabolic activity. Insulin is known for its anabolic effects, including promoting glucose and amino acid transport, lipid and protein synthesis, and inhibiting gluconeogenesis, lipolysis, and protein degradation. However, the overlapping actions of IGF signaling with insulin complicate the understanding of their distinct metabolic roles[22].

IGFs are involved in the regulation of energy metabolism by promoting cell proliferation and survival, thus contributing to tissue growth and repair. For instance, IGF-I has been shown to enhance glucose uptake and utilization in various tissues, and its signaling is essential for maintaining metabolic homeostasis. In muscle and adipose tissues, IGFs facilitate nutrient uptake and storage, thus playing a critical role in energy balance and metabolic health[7].

Moreover, IGFs are implicated in the modulation of mitochondrial function, which is crucial for cellular energy metabolism. Recent studies have highlighted the distinct roles of IGF-1 in CD4+ T cells, where it influences mitochondrial dynamics and metabolism, showcasing its importance in immune cell function and metabolic regulation[23]. Additionally, IGFs have been linked to the adaptation of muscle and bone to mechanical stimuli, further underscoring their significance in metabolic regulation during growth and in response to physical activity[24].

The interaction between IGFs and insulin signaling pathways also has implications for various metabolic disorders, including obesity and type 2 diabetes. Dysregulation of IGF signaling has been associated with insulin resistance, suggesting that therapeutic strategies targeting IGF pathways could provide new avenues for managing metabolic diseases[25].

In summary, insulin-like growth factors are integral to metabolic processes, influencing energy homeostasis, cellular growth, and differentiation. Their overlapping yet distinct roles in metabolism, particularly in conjunction with insulin, highlight their importance in both normal physiological functions and in the context of metabolic diseases. Further research is necessary to elucidate the precise mechanisms through which IGFs regulate metabolic pathways and their potential therapeutic implications.

4 IGFs in Disease Contexts ​

4.1 IGFs and Cancer ​

Insulin-like growth factors (IGFs) play a crucial role in various biological processes, particularly in the context of cancer. These factors are mitogens that significantly influence cell proliferation, differentiation, and apoptosis. The effects of IGFs are primarily mediated through the insulin-like growth factor I receptor (IGF-IR), which is involved in cell transformation induced by oncogenic factors. Elevated levels of circulating IGF-I and low levels of IGF-binding protein-3 (IGFBP-3) have been associated with an increased risk of several common cancers, including prostate, breast, colorectal, and lung cancers [26].

IGFs exert strong mitogenic and anti-apoptotic actions on various cancer cells, acting synergistically with other growth factors and antagonizing the effects of antiproliferative molecules [26]. This indicates that IGFs not only promote cancer cell growth but also help cancer cells evade programmed cell death, thereby contributing to tumor progression. Furthermore, the complex interactions between IGFs and their binding proteins, particularly IGFBPs, can either inhibit or enhance the actions of IGFs, depending on the specific structural characteristics of the binding proteins [27].

The role of IGFs extends beyond mere cell proliferation; they also influence the tumor microenvironment by affecting immune cell interactions, which can lead to immune escape mechanisms in tumors [28]. Moreover, the dysregulation of IGF signaling pathways has been implicated in resistance to chemotherapeutic agents, thereby complicating treatment strategies for cancer [28].

Clinical studies have focused on targeting the IGF system as a potential therapeutic approach in cancer treatment. Various strategies have been employed, including the use of neutralizing antibodies against IGF ligands and receptor signaling inhibitors [29]. However, despite the promising preclinical data, many clinical trials targeting the IGF system have reported limited efficacy, highlighting the need for further research to understand the complexities of IGF signaling in cancer [29].

In summary, IGFs are integral to the regulation of cancer biology through their roles in promoting cell growth, survival, and resistance to therapy. Their interactions with various cellular pathways and components of the tumor microenvironment underscore their significance in cancer development and progression, making them a critical focus for ongoing cancer research and therapeutic development.

4.2 IGFs in Metabolic Disorders ​

Insulin-like growth factors (IGFs) play a critical role in various metabolic disorders, influencing both cellular growth and metabolism. The complexities of IGF signaling, particularly in relation to insulin, are pivotal in understanding their roles in health and disease.

IGFs, particularly IGF-I, are polypeptides that regulate cell growth, development, and maturation. They are integral to the regulation of metabolism, impacting glucose and lipid homeostasis. The interaction between IGF signaling and metabolic pathways is significant; for instance, in chronic liver disease, IGF levels are typically decreased, correlating with hepatocellular dysfunction and metabolic disturbances such as insulin resistance and malnutrition. Patients with cirrhosis often exhibit complications linked to IGF-I deficiency, suggesting that restoration of IGF-I levels could ameliorate these issues, as evidenced by studies showing that recombinant human IGF-I can halt or reverse fibrotic degeneration in the liver (Bonefeld & Møller, 2011) [16].

In the context of gestational diabetes mellitus (GDM), IGFs are crucial for fetal growth and development. The pathogenesis of GDM involves β-cell dysfunction and impaired insulin secretion, with IGF signaling playing a vital role in glucose transport to the fetus. Research indicates that during GDM, serum levels of IGF-1 and IGF-2 increase, while levels of IGF-binding proteins (IGFBPs) decrease, further implicating the insulin/IGF system in metabolic disorders associated with pregnancy (Martín-Estal & Castorena-Torres, 2022) [30].

Moreover, IGFs have been associated with insulin resistance and diabetes mellitus. Studies have shown that IGF-I can improve metabolic control in patients with severe insulin resistance and enhance the effects of insulin therapy in both type 1 and type 2 diabetes. The anabolic effects of IGF-I, such as promoting protein synthesis and reducing glucose and triglyceride levels, are under investigation for their therapeutic potential in managing diabetes-related complications (Ranke, 2005) [31].

Additionally, the interplay between IGFs and non-coding RNAs has been highlighted in the context of neoplasia and metabolic disorders, suggesting that this interaction could be a target for novel therapeutic strategies aimed at modifying IGF signaling pathways (Ghafouri-Fard et al., 2021) [13].

Overall, IGFs serve multifaceted roles in metabolic disorders, influencing growth, development, and cellular regulation, while their dysregulation can lead to significant health issues, including insulin resistance and diabetes. Understanding the mechanisms of IGF action is essential for developing effective interventions in metabolic diseases.

5 Therapeutic Implications ​

5.1 Targeting IGF Signaling in Cancer Therapy ​

Insulin-like growth factors (IGFs), primarily IGF-1 and IGF-2, play pivotal roles in regulating cell growth, differentiation, and metabolism. Their signaling pathways are crucial in various biological processes, including normal mammary gland biology, as well as tumorigenesis in breast cancer and other malignancies. Dysregulation of IGF signaling is often associated with increased cancer risk and progression, largely due to the activation of downstream signaling effectors that promote cell proliferation and survival, particularly through the type I IGF receptor (IGF-1R) [32].

In cancer therapy, the targeting of IGF signaling has garnered significant interest due to its potential to inhibit tumor growth and overcome resistance to existing treatments. The IGF signaling pathway has been implicated in resistance to various therapeutic strategies, including those targeting estrogen receptors (ER) and HER2 in breast cancer [32]. However, despite the theoretical promise of targeting the IGF axis, clinical studies have often yielded disappointing results. For instance, phase III trials of IGF-1R-targeted therapies have not demonstrated a significant benefit compared to standard care [33].

Several approaches have been employed to disrupt IGF signaling in cancer, including the development of monoclonal antibodies and small molecule inhibitors targeting IGF-1R. These strategies aim to block the proliferative and anti-apoptotic signals mediated by IGFs. However, challenges remain due to the complexity of IGF signaling, which can also involve the insulin receptor (IR) and hybrid receptors formed between IGF-1R and IR. This cross-talk can potentially undermine the effectiveness of therapies aimed solely at IGF-1R [34].

Furthermore, the IGF signaling pathway has been associated with resistance mechanisms to chemotherapy and other targeted therapies. Studies have indicated that aberrant IGF signaling can lead to the promotion of tumorigenesis and contribute to the development of drug resistance [35]. Consequently, understanding the multifaceted roles of IGFs in cancer biology is critical for the development of effective therapeutic strategies.

Recent research highlights the need for a more nuanced approach to targeting the IGF system, including the consideration of combination therapies that might improve outcomes. There is also a growing emphasis on identifying predictive biomarkers to select patients who are most likely to benefit from IGF-targeted therapies [36]. Overall, while the therapeutic implications of targeting IGF signaling in cancer remain promising, substantial challenges must be addressed to translate this potential into clinical success.

5.2 Potential Interventions in Metabolic Syndromes ​

Insulin-like growth factors (IGFs), particularly IGF-I and IGF-II, play critical roles in various physiological processes, including growth, development, and metabolism. Their significance extends to therapeutic implications, especially in the context of metabolic syndromes.

IGFs are polypeptides that exhibit insulin-like properties and are integral in regulating cellular growth, differentiation, and metabolism. They interact with the insulin receptor signaling pathways and have been implicated in various conditions, including obesity, diabetes mellitus, and cardiovascular disorders. Specifically, IGF-I has been linked to the regulation of bone development and height during childhood, and it is also associated with the onset of puberty. Furthermore, IGF-I and IGF-II have been identified as potential biomarkers and therapeutic targets for metabolic dysfunction-associated liver disease and hepatocellular carcinoma, as they influence metabolic pathways and cellular responses to stress and injury [1].

The therapeutic potential of IGF-I has been explored in several clinical contexts. For instance, recombinant human IGF-I (rhIGF-I) has shown promise in improving metabolic control in patients with severe insulin resistance and in those with diabetes, by enhancing glucose metabolism and promoting growth in individuals with growth hormone insensitivity syndrome [31]. The anabolic effects of IGF-I may help in treating catabolic diseases and conditions characterized by relative insulin resistance, such as obesity and diabetes [37].

In terms of potential interventions for metabolic syndromes, research indicates that IGF signaling pathways may be leveraged to address complications arising from these conditions. For example, insulin resistance and its associated complications are linked to dysregulation of IGF levels, suggesting that therapies aimed at normalizing IGF signaling could be beneficial. The use of IGF-I in clinical settings has already demonstrated positive effects on glucose and lipid metabolism, which are crucial in managing diabetes and its complications [38]. Moreover, growth factors like IGF-I have been shown to have antifibrotic effects in liver diseases, indicating a potential avenue for treating metabolic syndrome-related liver dysfunction [16].

Additionally, the interplay between IGFs and other growth factors, such as fibroblast growth factor 21 (FGF21) and vascular endothelial growth factor (VEGF), highlights the complex regulatory networks involved in metabolism and tissue repair. These interactions suggest that targeted therapies that modulate IGF signaling, either through direct IGF administration or by influencing associated pathways, could provide innovative strategies for managing metabolic syndromes [38].

In conclusion, insulin-like growth factors are pivotal in metabolic regulation and hold substantial therapeutic potential for addressing metabolic syndromes. The development of interventions that harness IGF signaling could lead to improved outcomes in managing conditions like diabetes and associated complications, thus presenting both challenges and opportunities in healthcare [1][31][38].

6 Future Directions in IGF Research ​

6.1 Emerging Technologies and Approaches ​

Insulin-like growth factors (IGFs), specifically IGF-I and IGF-II, play crucial roles in various physiological processes, including growth, development, and metabolism. These polypeptides are secreted proteins that exert their effects primarily through binding to specific cell-surface receptors, with their actions being modulated by insulin-like growth factor binding proteins (IGFBPs) [7]. The IGF signaling pathway is intricately involved in cell proliferation, differentiation, survival, and the regulation of metabolic processes [25].

The importance of IGFs extends into pathological contexts, particularly in neoplasia, where they are implicated in cancer development and progression. The signaling networks regulated by IGFs and insulin have been identified as significant contributors to the pathogenesis of various cancers, including colorectal cancer [14]. Pharmacological strategies targeting the IGF signaling pathway, such as the use of receptor-specific antibodies and small molecular weight inhibitors, are under investigation for their potential in cancer therapy [36].

Emerging research has highlighted the interplay between non-coding RNAs and IGF signaling, suggesting that these interactions play fundamental roles in the development of various disorders, including cancer [13]. The identification of non-coding RNAs associated with IGF pathways could provide insights into novel therapeutic strategies aimed at modifying IGF signaling and predicting responses to treatments [13].

Future directions in IGF research will likely focus on understanding the molecular mechanisms underlying IGF action in greater detail, including the characterization of IGFBPs and their regulatory roles [7]. Additionally, advancements in technologies such as high-throughput sequencing and bioinformatics are expected to facilitate the exploration of IGF-related signaling pathways and their interactions with other cellular processes [39]. This integrative approach could yield new insights into the therapeutic potential of targeting IGF signaling in various diseases, including metabolic disorders and cancer, thereby enhancing patient outcomes through personalized medicine [36].

In summary, IGFs are pivotal in regulating numerous biological processes and hold significant promise as therapeutic targets in various diseases, particularly cancer. Ongoing research efforts are essential to elucidate the complexities of IGF signaling and to develop effective strategies for intervention.

6.2 Unexplored Roles of IGFs ​

Insulin-like growth factors (IGFs), specifically IGF-I and IGF-II, are crucial polypeptides that play diverse roles in various physiological processes, including growth, development, metabolism, and cell survival. These factors initiate their actions by binding to specific cell-surface receptors and are regulated through interactions with insulin-like growth factor binding proteins (IGFBPs) [7]. The recent surge in research has unveiled several unexplored roles of IGFs, particularly in the context of neoplasia, metabolic disorders, and aging.

One of the key roles of IGFs is their involvement in the pathogenesis of various cancers. The signaling pathways activated by IGFs are integral to cellular growth and proliferation, making them significant in cancer development. Studies have shown that insulin and IGF signaling pathways are essential in the development of colorectal carcinoma and other neoplasms [14]. Furthermore, pharmacological strategies targeting IGF signaling, such as receptor-specific antibodies and inhibitors, are being explored as potential cancer therapies [25].

Additionally, IGFs are implicated in metabolic regulation, influencing insulin sensitivity and energy homeostasis. Their interaction with signaling pathways, including MAPK, Akt, and PI3K, highlights their role in metabolic disorders such as insulin resistance and diabetes [13]. This connection between IGFs and metabolic regulation opens new avenues for therapeutic interventions aimed at managing metabolic diseases.

The evolving understanding of IGFs extends to their functions in aging and development. Recent studies suggest that IGF2, traditionally overlooked in postnatal life, is expressed across various life stages in amniotes, indicating its potential role in growth and development beyond infancy [40]. This challenges previous assumptions based on rodent models and suggests a need for further investigation into the IGF system's role in life-history traits.

Moreover, the interplay between non-coding RNAs and IGF signaling has emerged as a significant area of research, potentially influencing the response to therapeutic strategies targeting IGF pathways [13]. Identifying these interactions may provide insights into individual variability in treatment responses and the development of personalized medicine approaches.

In summary, the roles of insulin-like growth factors are multifaceted, encompassing essential functions in growth, metabolism, cancer development, and aging. Future research should focus on elucidating the mechanisms underlying these roles, exploring the therapeutic potential of targeting IGF signaling pathways, and understanding the implications of non-coding RNAs in this context. This comprehensive approach may lead to novel strategies for treating metabolic and neoplastic diseases, ultimately enhancing patient outcomes and advancing our understanding of IGF biology.

7 Conclusion ​

The multifaceted roles of insulin-like growth factors (IGFs), particularly IGF-I and IGF-II, underscore their significance in both normal physiological processes and various pathological conditions. Current research has established IGFs as critical regulators of growth, development, and metabolism, with their dysregulation implicated in diseases such as cancer, diabetes, and obesity. The intricate interplay between IGFs and their binding proteins adds complexity to their biological functions, influencing cellular proliferation, differentiation, and survival. Despite the promise of targeting IGF signaling pathways for therapeutic interventions, particularly in oncology and metabolic disorders, challenges remain in translating these findings into effective clinical applications. Future research should focus on elucidating the detailed mechanisms of IGF action, exploring their interactions with non-coding RNAs, and investigating their roles across different life stages and conditions. By advancing our understanding of IGF biology, we can develop targeted therapies that enhance patient outcomes and address the complexities of diseases associated with IGF dysregulation.

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