IGF1 SAfETY Assessment

The major role of somatotropin in young animals is to promote postnatal growth. This is accomplished in part through stimulation of hepatic synthesis of a secondary endocrine mediator of skeletal growth known as insulin-like growth factor (IGF-1) (Figure 7.4).86 IGF-1 is a 70-amino-acid protein that is structurally related to proinsulin and, like insulin, the amino acid sequence has been highly conserved across species.94 For example, the amino acid sequence of bovine and human IGF-1 are identical.95 Although the liver is the major site for production of IGF-1, other tissues have also been found to produce this endocrine mediator, including lung, heart, testes, etc.95 IGF-1 acts both locally on tissues in an autocrine or paracrine manner and

TABLE 7.3

Concentration of bST and IGF (pg/kg) in Biopsied Tissues of Dairy Cattle Injected with Posilaca

Days Tissues Biopsied after

Injection Muscle (Control) Muscle (Treated) Liver (Control) Liver (Treated)

bST

0

2.6 ± 2.1b

2.8 ± 1.3

13 ± 2.5

16 ± 3.8

7

2.1 ± 1.9

3.1 ± 1.7

11 ± 2.1

24 ± 9.5

14

2.9 ± 1.8

4.0 ± 2.2

12 ± 2.6

18 ± 7.4

21

3.7 ± 2.7

4.2 ± 2.2

11 ± 3.6

25 ± 5.6

28

2.1 ± 1.7

3.7 ± 0.7

9 ± 3.0

16 ± 6.8

IGF-1

0

80 ± 16

91 ± 26

77 ± 6.2

72 ± 9.0

7

272 ± 160c

312 ± 130c

72 ± 9.1

162 ± 36

14

252±141c

152 ± 62c

72 ± 15

112 ± 11

21

68 ± 20

126 ± 58

70 ± 8.3

142 ± 52

28

215 ± 173c

135 ± 19c

70 ± 14

92 ± 15

a Five lactating cows were administered 500 mg sometribove every 14 days. While on treatment, the muscle and liver were biopsied at each of the listed times. Days 7 and 21 were in the middle of each injection cycle, which correlated with the times of maximum circulating bST and IGF-1. Blood levels returned to baseline 14 days after each injection. b Values are means ± S.D.

c Elevated IGF-1 levels are associated with wound healing, as biopsies at these intervals were collected from the same anatomical locations.76

Insulin-like Growth Factor-I Insulin

FIGURE 7.4 Insulin-like growth factor (IGF-1). (Structure courtesy of GroPep Limited.)

distantly on other tissues in an endocrine manner.96 Very little free IGF-1 circulates in blood, as it is largely bound in a noncovalent manner to carrier or binding proteins whose production in liver is also regulated by somatotropin.96

IGFs possess insulin-like biologic activity, including acute effects on glucose homeostasis and metabolism in insulin target tissues such as adipose tissue, striated and heart muscle.95 On a molar basis, IGF-1 is only 6% as potent as insulin in its ability to induce hypoglycemia when administered as an intravenous bolus dose to humans.97 In contrast, administration of equivalent doses of IGF-1 by slow intravenous infusion does not produce hypoglycemia as there is less free IGF-1 (unlike bolus dosing) due to the binding of IGF-1 by carrier proteins as it slowly enters the circulation during infusion. IGF-1 bound to carrier proteins does not exert acute insulin effects.98 IGFs also affect differentiated cell function and promote cellular growth, which will be discussed in more depth later. In humans, blood levels of IGF-1 increase two to three times adult levels (~200 ng/ml) during adolescence.95,99,100

Administration of primate somatotropin to humans and bovine somatotropin to dairy cows produce increased blood levels of IGF-1*.99,101 In the bovine, IGF-1 may play a role in somatotropin-induced galactopoiesis based on the temporal relationship between increased blood levels of IGF-1 within hours of bST injection followed by an increase in milk production the next day.14 Attempts to inject IGF-1 into goats to increase milk production have led to mixed results, which may be influenced by the presence of IGF-1 carrier proteins in the blood that would remove free IGF-1 from circulation. IGF-1 has been shown to have a stimulatory effect on protein production by mammary cells.14 Since IGF-1 receptors are present in the bovine mammary gland,102 increases in blood levels of IGF-1 could lead to increased concentrations of IGF-1 in milk. This was reported in a preliminary study in which administration of 30 mg/day bovine somatotropin (bST) to a small number of dairy cows for seven consecutive days increased concentrations of IGF-1 in blood from a baseline of 109 ng/ml to 400 ng/ml and milk concentrations from a baseline of 3 ng/ml up to 11 ng/ml.103

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