What is IGF-1?

Kotaro Yoshimura

IGF-1: insulin-like growth factor-1; a growth factor with a configuration which closely resembles insulin, is produced in the liver and other tissues (skeletal muscles) by growth hormone. Many of the actions of the growth hormone (GH) are through IGF-1. While GH has a direct action in metabolizing fat, and glucose tolerance by anti-insulin action, IGF-1 does not have such actions. On the other hand, IGF-1 has a similar action to insulin. Insulin connects to insulin receptors on the cell membrane, and IGF-1 connects to IGF receptor type 1, and a signal is transmitted into a cell. These two kinds of receptors form a hybrid in diabetic patients, and this is one of the reasons for insulin resistance, but IGF- 1connects strongly with this hybrid receptor, and its main benefit is that it can show insulin-like action in diabetic patients, in which insulin cannot work well.

There have been many documents which compared insulin to IGF-1 and reviewed them as protein metabolism, glucose transport, glycogen or triglycerides compositions, but recently reports focusing on other aspects of IGF-1, are increasing, such as muscle differentiation, aging, injury treatment, and myopathy.

There are two signal-transduction pathways of IGF-1 in skeletal muscles.

1) PI3K (phosphatidylinositol 3-kinase) cascade ⇒ myoblast, satellite cell proliferation.

2) MAPK (mitogen-activated protein kinase) cascade ⇒ satellite cell fusion, protein synthesis, glucose uptake, hypertrophy, prevention of apoptosis. Among six kinds of binding proteins of IGF-1 found, 95% of IGFBP-3 connects with IGF-1in serum. Expression of IGFBP-3 is controlled by GH.
　

IGF-IR (type I IGF receptor) is known as a receptor of IGF-1, and binds to IGF-1 or IGF-2 (500 times higher affinity than that of insulin).
The receptor is composed of α2β2 subunits: α is the extracellular domain, β the transmembrane domain. IGF-2 connects to two kinds of other receptors, and plays other roles.

Administration of IGF-1 and Aging

Both GH and IGF-1 decrease with age from 30 years old. As for the expression of IGF-IR, there is an 80% decrease from infancy to young adulthood, and this trend continues with age. Furthermore, anabolic function (protein production) also falls with age, and it is thought to be due to increased turnover, because mRNA does not fall as well.

As for serum IGF-1in the aged, there are correlations between IGF-1 level and exercise: it is reported that exercise therapy brings about amelioration of IGF loss to some extent. IGF-1 clinical reports show the following results:
1) The GH deficient patients: increased lean body mass, muscle strength, muscle protein composition.
2) Young active patients: No increased effectiveness of GH. For decrease of IGF-IR?
3) Aged patients: �@With resistance training in 18 people: no effect.
�A GHRH 11 people exercised for six weeks; IGF-1 rise, muscle strength increase too.

IGF-1 Administration for Muscle Atrophy.

The following observations have been reported:

1) Fasting patients: Muscle catabolism is brought about. IGF-1 is reduced at protein and mRNA level. When under-nutrition continues for a long time, IGF-1 falls (in rats, humans).
2) The sepsis patient: TNFα rise brings about muscle catabolism, and IGF-1 is lowered (muscle assimilation by IGF-1 is disturbed in TNFα vitro administration). LPS (lipopolysaccharide) endotxin and IL-1 lower serum IGF-1 too (rats).
3) The muscle disuse atrophy patient: Muscle apoptosis is brought about. IGF-1 administration and exercise prevent this. In mice in a weightless environment, and with IGF-1 overexpression, atrophy was seen as well (influence on the downstream receptor?).

Clinical Results Examples Where IGF-1 Increased Muscle Mass
1) Burn patients (1998) GH.
2) Chronic obstructive pulmonary disease (1992)
3) Cancer (1992)
4) Severe osteoporosis (1999)
5) Renal disorder (1999)
There was no effect in weight loss due to HIV (1996).

DM Diabetes and IGF-1 Administration

In DM (diabetes mellitus), skeletal muscles develop resistance to insulin and IGF-1, and this tends to hasten aging in rats, and even a little in humans. There are two glucose transport materials: GLUT1 (a membrane) and GLUT4 (in cells). A decrease in GLUT1 expression is seen in most diabetics. Furthermore, there is influence by TNFα, and mRNA is 4 times higher in DM muscles. Receptor hybrid: insulinR and IGF-IR hybrid is related to increased insulin resistance, obesity and DM, but IGF-1 and the hybrid can be combined in almost the same manner and still function. In other words, regarding DM muscle wasting, IGF-1 acts to preserve muscle. IGF-1 works for insulin-resistant DM, and can be used to hold GH.
　

IGF-1 Administration for Myopathy

As glucocorticoids and HMGCoA (3-hydroxy-3-methylglutanyl coenzyme A) reductase inhibitor suppress IGF-1 signal (PI3K), though the mechanisms are different in each other. Glucocorticoid decreases IGF-1, IGF-2 upstream (in rats), increases IGFBP-1 expression in the liver, and therefore suppress effects of IGF-1 on muscle. Preventing effects of IGF-1 on muscle apoptosis is suppressed.
1) There is a clear effect on amyotrophic disorder in laboratory mice.
2) Steroids have a large effect on muscle atrophy in laboratory mice.
Local injection also produces a large effect.
3) There are no reports for humans.

Side Effects

Oedema, arthralgia, temporomandibular joint arthralgia, headaches (25-60%); Bell's palsy, and optic nerve myelin oedema (4%) are seen. There is a report of side effects being reduced by compound administration of IGF-1 and IGFBP-3 (DM patient; 2000). We have also seen a report that the effect of this combination treatment is massive in fasting laboratory mice.
　

Local Administration Method (Overexpression)
1) Adenovirus: An aged rat, 27% muscle strength increase, muscle mass constant. (1998)
2) Liposome: A burned rat, fast epithelialization, weight increase, muscle protein quantity increase. (1999)
3) Plasmid: There are reports of a muscle specific promoter being employed.