IGF-1/IGFBP3 complex

[JohnnieFreeze]

P.A. posted this article in response to me on another forum..



ORIGINAL RESEARCH ARTICLE
Effects of Insulin-Like Growth Factor-1/Binding Protein-3 Complex on Muscle Atrophy in Rats

Martin M. Zdanowicz*,1 and Saul Teichberg

* Department of Pharmaceutical Sciences, Massachusetts College of Pharmacy and Health Sciences, Boston, Massachusetts 02115 and
Departments of Pediatrics and Laboratories, North Shore University Hospital, Manhasset, New York 11030
Abstract Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References

Muscle atrophy and wasting is a serious problem that occurs in patients with prolonged debilitating illness, burn injury, spinal injury, as well as with space flight. Current treatment for such atrophy, which often relies on nutritional supplementation and physical therapy, is of limited value in preventing the muscle wasting that occurs. Considerable recent attention has focused on the use of anabolic growth factors such as insulin-like growth factor (IGF-1) in preventing muscle atrophy during limb disuse or with various catabolic conditions. However, potential side effects such as hypoglycemia appear to be limiting factors in the usefulness of IGF-1 for clinical treatment of muscle wasting conditions. The formulation of IGF-1 used in this study (IGF-1/BP3) is already bound to its endogenous-binding protein (BP3) and, as a result, has a greater specificity of action and significantly less hypoglycemic effect. Using a rat model of hind limb suspension (HLS) for 10 days, we induced marked muscle atrophy that was accompanied by enhanced muscle proteolysis and reduced muscle protein content. When HLS rats were treated with IGF-1/BP3 (50 mg/kg, b.i.d.), they retained greater body and muscle mass. Muscle protein degradation was significantly reduced and muscle protein content was preserved. The rate of protein synthesis, although somewhat reduced in HLS muscle, was not significantly elevated by IGF-1/BP3 treatment. Volume density of HLS-treated muscles were increased compared to untreated HLS rats and the actual number of fibers per area of muscle was likewise increased. The results of the current study suggest that IGF-1/BP3 might be useful for inhibiting muscle proteolysis in catabolic conditions and thus preserving muscle protein content and mass

A limiting factor in the use of IGF-1 as a therapeutic agent is its significant glucose-lowering effect, which restricts the dose that can be used and thus the anabolic potential of this agent. In this study, we used a novel IGF-1/BP3 complex (kindly provided by Celtrix Pharmaceuticals, Santa Clara, CA) in which recombinant human IGF-1 is administered already bound to its endogenous-binding protein, IGF-1-binding protein-3 (IGF-1/BP3). Administration of IGF-1 in this form may not only enhance the bioavailability of IGF-1 (17), but because the IGF-1/BP3 complex does not readily interact with insulin receptors and may be given at significantly higher doses without marked hypoglycemia

 

[datBtrue]

Decreased protein degradation is a good thing.

As for failure to see an increase in protein synthesis...from the DISCUSSION:

In our previous studies with subcutaneously administered rhIGF-1 in dystrophic mice and hamsters, we did not see significant increases in muscle protein synthesis with rhIGF-1 (0.50 mg/kg) (21, 29). However, we did see an increase in muscle protein synthesis rates in dystrophic mice when rhIGF-1 was given in conjunction with a high-protein diet, something we may try in the future with IGF-1/BP3.​

A readily available pool of amino acids is ALWAYS needed!

Why look for increased protein synthesis w/o a surplus of protein?

This from the DISCUSSION this is interesting:

The major beneficial effect of IGF-1/BP3 in this study appeared to be reduced muscle proteolysis. IGF-1/BP3 significantly reduced net protein degradation rates in muscles from HLS rats. Preservation of muscle weight and protein content paralleled this reduced muscle proteolysis. In a previous study with highly catabolic muscle from dystrophic hamsters, we reported a 27% decrease in muscle protein degradation rates with rhIGF-1 (29); here with IGF-1/BP3, we report a near 40% decrease.​

Also in the DISCUSSION running through the results of recent studies is very interesting:

1. In severely burned adults, IGF-1/BP3 (1-4 mg/kg/day) increased net protein synthesis in leg muscles (36).
   
2. Children with severe burns showed reduced levels of proinflammatory mediators such as IL-1 and TNF-alpha after IGF-1/BP3 administration and decreased muscle protein catabolism (37, 38).
   
3. In another recent study in semistarved rats, IGF-1/BP3 complex but not IGF-1 alone was able to stimulate muscle protein synthesis under these catabolic conditions (17).
   
4. A second study by Wang et al. (39) in rats with cancer cachexia showed that IGF-1/BP3 was able to increase food intake, attenuate weight loss, and improve glucose metabolism without effecting tumor size.

REFERENCES

36. Debroy MA, Wolf SE, Zhang XJ, Chinkes DL, Ferrando AA, Wolfe RR, Herndon DN. Anabolic effects of insulin-like growth factor in combination with insulin-like growth factor binding protein-3 in severely burned adults. J Trauma Inj Crit Care 47:904–910, 1999.

37. Herndon DN, Ramzy PI, DebRoy MA, Zheng M, Ferrando AA,
Chinkes DL, Barret JP, Wolfe RR, Wolfe SE. Muscle protein catabolism after severe burn: effects of IGF-1/IGFBP-3 treatment. Ann Surg 229:713–720, 1999.

38. Jeschke MG, Barrow RE, Herndon DN. Insulin like growth factor I plus insulin like growth factor binding protein 3 attenuates the proinflammatory acute phase response in severely burned children. Ann Surg 231:246–252, 2000.

17. Svanberg E, Ohlsson C, Kimball SR, Lundholm K. rhIGF-I/IGFBP3 complex, but not free rhIGF-I, supports muscle protein biosynthesis in rats during semi-starvation. Eur J Clin Invest 30:438–446, 2000.

39. Wang W, Iresjo BM, Karlsson L, Svanberg E. Provision of rhIGF-1/BP-3 complex attenuated development of cancer cachexia in an experimental tumor model. Clin Nutr 19:127–132, 2000.
​

Thanks JohnnieFreeze for posting this up.

 

[JohnnieFreeze]

Thanks JohnnieFreeze for posting this up.

..and thank you for adding this very interesting info...
IGF-1/BP3 complex sounds very promising.

 

[Bobaslaw]

..and thank you for adding this very interesting info...
IGF-1/BP3 complex sounds very promising.

Insmed seemed to think so as well when they brought out IPLEX (mecasermin rinfabate) to compete with Tercica's Increlex (mecasermin).

IPLEX is an rhIGF-1/rhIGFBP-3 complex vs. Increlex, which is just rh1GF-1.

 

[JohnnieFreeze]

Insmed seemed to think so as well when they brought out IPLEX (mecasermin rinfabate) to compete with Tercica's Increlex (mecasermin).

IPLEX is an rhIGF-1/rhIGFBP-3 complex vs. Increlex, which is just rh1GF-1.

Interesting.
I checked some sites and IGFBP 3 Human alone can go for as much as $2,800 per mg.

 

[IJL]

i can't remember where i read it but i know there's some kind of relationship between exogenous insulin and IGFBP 3. maybe look into stacking insulin with IGF-1. makes the IGF-1 stay active in your system longer if i remember correctly.

i had pretty good results using ID's IGF-1 LR3 and insulin