The insulin-like growth factors (IGFs) are

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

s with high sequence similarity to

insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism ...

. IGFs are part of a

complex system A complex system is a system composed of many components which may interact with each other. Examples of complex systems are Earth's global climate, organisms, the human brain, infrastructure such as power grid, transportation or communication sy ...

that cells use to communicate with their

physiologic Physiology (; ) is the scientific study of functions and mechanisms in a living system. As a sub-discipline of biology, physiology focuses on how organisms, organ systems, individual organs, cells, and biomolecules carry out the chemical a ...

environment. This complex system (often referred to as the IGF "axis") consists of two

cell-surface receptor Cell surface receptors (membrane receptors, transmembrane receptors) are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving (binding to) extracellular molecules. They are specialized integral me ...

s (

IGF1R The insulin-like growth factor 1 (IGF-1) receptor is a protein found on the surface of human cells. It is a transmembrane receptor that is activated by a hormone called insulin-like growth factor 1 (IGF-1) and by a related hormone called IGF-2. ...

and IGF2R), two

ligand In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's elect ...

s (

IGF-1 Insulin-like growth factor 1 (IGF-1), also called somatomedin C, is a hormone similar in molecular structure to insulin which plays an important role in childhood growth, and has anabolic effects in adults. IGF-1 is a protein that in humans is ...

and IGF-2), a family of seven high-affinity IGF-binding proteins ( IGFBP1 to IGFBP7), as well as associated IGFBP degrading

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...

s, referred to collectively as

protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...

IGF1/GH axis

The IGF "axis" is also commonly referred to as the Growth Hormone/IGF-1 Axis.

Insulin-like growth factor 1 Insulin-like growth factor 1 (IGF-1), also called somatomedin C, is a hormone similar in molecular structure to insulin which plays an important role in childhood growth, and has anabolic effects in adults. IGF-1 is a protein that in humans ...

(commonly referred to as IGF-1 or at times using

Roman numerals Roman numerals are a numeral system that originated in ancient Rome and remained the usual way of writing numbers throughout Europe well into the Late Middle Ages. Numbers are written with combinations of letters from the Latin alphabet, ...

as IGF-I) is mainly secreted by the liver as a result of stimulation by

growth hormone Growth hormone (GH) or somatotropin, also known as human growth hormone (hGH or HGH) in its human form, is a peptide hormone that stimulates growth, cell reproduction, and cell regeneration in humans and other animals. It is thus important in ...

(GH). IGF-1 is important for both the regulation of normal physiology, as well as a number of pathological states, including

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

. The IGF axis has been shown to play roles in the promotion of

cell proliferation Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth. Cell proliferation r ...

and the inhibition of cell death (

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes in ...

). Insulin-like growth factor 2 (IGF-2, at times IGF-II) is thought to be a primary growth factor required for early development while

expression is required for achieving maximal growth.

Gene knockout A gene knockout (abbreviation: KO) is a genetic technique in which one of an organism's genes is made inoperative ("knocked out" of the organism). However, KO can also refer to the gene that is knocked out or the organism that carries the gene kno ...

studies in mice have confirmed this, though other animals are likely to regulate the expression of these genes in distinct ways. While IGF-2 may be primarily fetal in action it is also essential for development and function of organs such as the

brain A brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as Visual perception, vision. I ...

liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it i ...

, and

kidney The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blo ...

. Factors that are thought to cause variation in the levels of GH and IGF-1 in the circulation include an individual's genetic make-up, the time of day, age, sex, exercise status, stress levels, nutrition level,

body mass index Body mass index (BMI) is a value derived from the mass ( weight) and height of a person. The BMI is defined as the body mass divided by the square of the body height, and is expressed in units of kg/m2, resulting from mass in kilograms and ...

(BMI), disease state, race, estrogen status, and

xenobiotic A xenobiotic is a chemical substance found within an organism that is not naturally produced or expected to be present within the organism. It can also cover substances that are present in much higher concentrations than are usual. Natural compo ...

intake. IGF-1 has an involvement in regulating

neural development The development of the nervous system, or neural development (neurodevelopment), refers to the processes that generate, shape, and reshape the nervous system of animals, from the earliest stages of embryonic development to adulthood. The fiel ...

including

neurogenesis Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). It occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells (NEC ...

myelination Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be ...

, synaptogenesis, and

dendritic Dendrite derives from the Greek word "dendron" meaning ( "tree-like"), and may refer to: Biology *Dendrite, a branched projection of a neuron * Dendrite (non-neuronal), branching projections of certain skin cells and immune cells Physical *Dendr ...

branching and neuroprotection after neuronal damage. Increased serum levels of IGF-I in children have been associated with higher IQ. IGF-1 shapes the development of the

cochlea The cochlea is the part of the inner ear involved in hearing. It is a spiral-shaped cavity in the bony labyrinth, in humans making 2.75 turns around its axis, the modiolus. A core component of the cochlea is the Organ of Corti, the sensory o ...

through controlling

. Its deficit can cause

hearing Hearing, or auditory perception, is the ability to perceive sounds through an organ, such as an ear, by detecting vibrations as periodic changes in the pressure of a surrounding medium. The academic field concerned with hearing is audit ...

loss. Serum level of it also underlies a correlation between short

height Height is measure of vertical distance, either vertical extent (how "tall" something or someone is) or vertical position (how "high" a point is). For example, "The height of that building is 50 m" or "The height of an airplane in-flight is ab ...

and reduced hearing abilities particularly around 3–5 years of age, and at age 18 (late

puberty Puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction. It is initiated by hormonal signals from the brain to the gonads: the ovaries in a girl, the testes in a ...

IGF receptors

The IGFs are known to bind the IGF-1 receptor, the

insulin receptor The insulin receptor (IR) is a transmembrane receptor that is activated by insulin, IGF-I, IGF-II and belongs to the large class of receptor tyrosine kinase. Metabolically, the insulin receptor plays a key role in the regulation of glucose ho ...

, the IGF-2 receptor, the insulin-related receptor and possibly other receptors. The IGF-1 receptor is the "physiological" receptor,

binds to it at significantly higher affinity than it binds the insulin receptor. Like the insulin receptor, the IGF-1 receptor is a

receptor tyrosine kinase Receptor tyrosine kinases (RTKs) are the high- affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kin ...

—meaning the receptor signals by causing the addition of a phosphate molecule on particular tyrosines. The IGF-2 receptor only binds IGF-2 and acts as a "clearance receptor"—it activates no intracellular signaling pathways, functioning only as an IGF-2 sequestering agent and preventing IGF-2 signaling.

Organs and tissues affected by IGF-1

Since many distinct tissue types express the IGF-1 receptor, IGF-1's effects are diverse. It acts as a

neurotrophic Neurotrophic factors (NTFs) are a family of biomolecules – nearly all of which are peptides or small proteins – that support the growth, survival, and differentiation of both developing and mature neurons. Most NTFs exert their tro ...

factor, inducing the survival of neurons. It may catalyse

skeletal muscle Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of m ...

hypertrophy Hypertrophy is the increase in the volume of an organ or tissue due to the enlargement of its component cells. It is distinguished from hyperplasia, in which the cells remain approximately the same size but increase in number.Updated by Linda J. ...

, by inducing

protein synthesis Protein biosynthesis (or protein synthesis) is a core biological process, occurring inside cells, balancing the loss of cellular proteins (via degradation or export) through the production of new proteins. Proteins perform a number of critical ...

, and by blocking

muscle atrophy Muscle atrophy is the loss of skeletal muscle mass. It can be caused by immobility, aging, malnutrition, medications, or a wide range of injuries or diseases that impact the musculoskeletal or nervous system. Muscle atrophy leads to muscle weakness ...

. It is protective for

cartilage Cartilage is a resilient and smooth type of connective tissue. In tetrapods, it covers and protects the ends of long bones at the joints as articular cartilage, and is a structural component of many body parts including the rib cage, the neck ...

cells, and is associated with activation of

osteocytes An osteocyte, an oblate shaped type of bone cell with dendritic processes, is the most commonly found cell in mature bone. It can live as long as the organism itself. The adult human body has about 42 billion of them. Osteocytes do not divide and ...

, and thus may be an anabolic factor for

bone A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, ...

. Since at high concentrations it is capable of activating the

, it can also complement for the effects of

. Receptors for IGF-1 are found in vascular smooth muscle, while typical receptors for insulin are not found in vascular smooth muscle.

IGF-binding proteins

IGF-1 and IGF-2 are regulated by a family of proteins known as the IGF-binding proteins. These proteins help to modulate IGF action in complex ways that involve both inhibiting IGF action by preventing binding to the IGF-1 receptor as well as promoting IGF action possibly through aiding in delivery to the receptor and increasing IGF half-life. Currently, there are seven characterized IGF Binding Proteins (IGFBP1 to IGFBP7). There is currently significant data suggesting that IGFBPs play important roles in addition to their ability to regulate IGFs. IGF-1 and IGFBP-3 are GH dependent, whereas IGFBP-1 is insulin regulated. IGFBP-1 production from the liver is significantly elevated during insulinopenia while serum levels of bioactive IGF-1 is increased by insulin.

Diseases affected by IGF

Studies of recent interest show that the Insulin/IGF axis play an important role in

aging Ageing ( BE) or aging ( AE) is the process of becoming older. The term refers mainly to humans, many other animals, and fungi, whereas for example, bacteria, perennial plants and some simple animals are potentially biologically immortal. In ...

Nematode The nematodes ( or grc-gre, Νηματώδη; la, Nematoda) or roundworms constitute the phylum Nematoda (also called Nemathelminthes), with plant- parasitic nematodes also known as eelworms. They are a diverse animal phylum inhabiting a bro ...

s, fruit-flies, and other organisms have an increased life span when the gene equivalent to the mammalian insulin is

knocked out A knockout (abbreviated to KO or K.O.) is a fight-ending, winning criterion in several full-contact combat sports, such as boxing, kickboxing, muay thai, mixed martial arts, karate, some forms of taekwondo and other sports involving strikin ...

. It is somewhat difficult to relate this finding to the mammals, however, because in the smaller organism there are many genes (at least 37 in the nematode ''Caenorhabditis elegans'' ) that are "insulin-like" or "IGF-1-like", whereas in the mammals insulin-like proteins comprise only seven members (

, IGFs,

relaxin Relaxin is a protein hormone of about 6000 Da first described in 1926 by Frederick Hisaw. The relaxin family peptide hormones belong to the insulin superfamily and consists of seven peptides of high structural but low sequence similarity; re ...

s, EPIL, and relaxin-like factor). The human insulin-like genes have apparently distinct roles with some but less crosstalk presumably because there are multiple insulin-receptor-like proteins in humans. Simpler organisms typically have fewer receptors; for example, only one insulin-like receptor exists in the nematode ''C. elegans''. Additionally, ''C. elegans'' do not have specialized organs such as the ( Islets of Langerhans), which sense insulin in response to glucose homeostasis. Moreover, IGF1 affects lifespan in nematodes by causing dauer formation, a developmental stage of C. elegans larva. There is no mammalian correlate. Therefore, it is an open question as to whether either IGF-1 or insulin in the mammal may perturb aging, although there is the suggestion that dietary restriction phenomena may be related. Other studies are beginning to uncover the important role the IGFs play in diseases such as

and

diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...

, showing for instance that IGF-1 stimulates growth of both prostate and breast cancer cells. Researchers are not in complete agreement about the degree of cancer risk that IGF-1 poses.

References