MGF (mechano-growth factor) and carbohydrate metabolism

When it comes to peptides of the IGF-1 family, the question of carbohydrate metabolism is one of the first to arise: mature IGF-1 is structurally similar to insulin and is able to lower glucose levels. Does this apply to mechano-growth factor (MGF)? The editorial team looked into how the E-peptide of MGF differs from IGF-1 from a metabolic point of view, what studies say and where the confusion comes from.

IGF-1 and insulin: common roots

Insulin and insulin-like growth factor 1 are evolutionary "relatives." Their molecules have a similar spatial structure, and their receptors — the insulin (IR) and IGF-1R — belong to the same family of tyrosine kinase receptors and can even form hybrid complexes. That is why IGF-1 in high concentrations is able to act like insulin: to enhance the uptake of glucose by tissues and lower its level in the blood.

The metabolic role of IGF-1 was described in detail by Clemmons in a 2012 review. Under physiological conditions, most IGF-1 in the blood is bound to carrier proteins (IGFBP), so its insulin-like action is restrained. But free IGF-1 or an externally administered recombinant drug can noticeably affect glycemia.

The best clinical illustration is mecasermin, recombinant IGF-1, approved for treating severe primary IGF-1 deficiency in children. In the drug's instructions, hypoglycemia is listed as one of the most frequent adverse reactions, and patients are advised to administer it together with food. This is proof that mature IGF-1 is a real hypoglycemic agent.

At the same time, growth hormone, which stimulates the production of IGF-1, acts on carbohydrate metabolism in the opposite way: it increases insulin resistance and glucose levels. LeRoith and Yakar wrote about this complex mutual balancing in 2007. Therefore, the metabolic effect of any substance from the "growth family" depends on which link it acts upon.

How MGF differs from mature IGF-1

The key to understanding the metabolism of MGF is in its structure. The IGF-1 gene encodes a precursor protein consisting of a signal peptide, mature IGF-1 (domains B, C, A, D) and a terminal E-peptide. It is the domains of mature IGF-1 that are responsible for binding to IGF-1R and, partly, to the insulin receptor.

MGF, in the laboratory and commercial sense, is a synthetic fragment of the E-peptide of the IGF-1Ec isoform, containing about two and a half dozen amino acids. It does not include the sequence of mature IGF-1. So it does not have the classic mechanism of insulin-like action — binding to IR or IGF-1R through the "insulin" domain.

This does not mean that the E-peptide is metabolically "neutral." Scientists have still not identified its receptor, and if it acts through its own signaling pathways, then theoretically it can affect cellular metabolism indirectly. But a direct insulin-like action, like that of IGF-1, is not expected of it.

What is known about the metabolic effects of MGF

The honest answer is very little. Most works on MGF studied the proliferation and differentiation of myoblasts (Yang and Goldspink, 2002), the survival of heart cells and neurons in ischemia models, and tissue healing. There are no systematic studies of the effect of MGF on glucose levels, insulin secretion or sensitivity to it in humans.

The review by Matheny and colleagues in 2010, which gathered data on MGF, focuses on tissue repair rather than metabolism. In the work of Fornaro and colleagues in 2014, the synthetic peptide showed no noticeable effect on primary myoblasts at all, whereas mature IGF-1 acted as usual — this is another argument in favor of the fact that the biological activity of the E-peptide differs fundamentally from IGF-1.

So any claims on forums that MGF "improves insulin sensitivity" or "burns carbohydrates" have no scientific basis. Likewise, there is no basis for asserting the opposite — that it causes diabetes. The correct position is: there are no data.

Where the risk of hypoglycemia comes from in practice

Despite the fact that the E-peptide itself has no insulin-like domain, real risks for carbohydrate metabolism in people who administer "MGF" do exist. They are associated not with the pharmacology of the pure peptide, but with the circumstances of its use.

• Substitution or impurities.Illegal vials may contain another peptide — for example, IGF-1 LR3 or another analog that has a pronounced hypoglycemic effect.
• Confusion of names.Users often do not distinguish between MGF, PEG-MGF, IGF-1 LR3 and IGF-1 DES and transfer ideas about some substances to others.
• Combination with insulin.In the bodybuilding milieu, peptides are not infrequently combined with exogenous insulin, which in itself can cause severe, potentially fatal hypoglycemia.
• Combination with growth hormone.Somatotropin acts in the opposite direction, raising glucose, and makes the overall picture unpredictable.

Symptoms of hypoglycemia — trembling, sweating, palpitations, sudden hunger, confusion — should not be ignored. Severe hypoglycemia can lead to seizures, loss of consciousness and death. For people with diabetes mellitus or impaired glucose tolerance, any experiments with peptides of the "growth family" are especially dangerous.

Another practical aspect is diagnosis. If a person uses unregistered peptides and has episodes of low sugar, it is important for the doctor to know about this, because a standard examination may not reveal the cause. Being open with the doctor here is a matter of safety.

Muscle, load and glucose without peptides

Interestingly, the very idea of MGF was born from the mechanosensitivity of muscle, and mechanical load is one of the most powerful natural regulators of carbohydrate metabolism. During contraction, muscle fibers move the glucose transporters GLUT4 to the surface of the cells independently of insulin. Richter and Hargreaves described this mechanism in detail in 2013.

Regular strength and aerobic training increases insulin sensitivity, increases glycogen stores and the mass of metabolically active muscle tissue. These effects are well proven, safe and available to everyone without any injections.

During training, the expression of IGF-1 splice variants in the muscles, including IGF-1Ec, naturally increases in the body. That is, what is advertised as "MGF in a vial" the body already produces locally — in the amount and in the place where it is needed.

For people who want to improve glucose control and body composition, the editorial team advises relying on proven tools: training, a sufficient amount of protein, calorie control, quality sleep and, if necessary, a consultation with an endocrinologist.

Editorial conclusions

MGF, as the E-peptide of the IGF-1Ec isoform, does not contain the domain that provides the insulin-like action of mature IGF-1, so a direct hypoglycemic effect from it is not theoretically expected.

However, there are no studies of the metabolic effects of MGF in humans, and the real risks are associated with substitution of the contents, confusion with IGF-1 analogs and combination with insulin or growth hormone.

The most effective and safest way to improve the carbohydrate metabolism of muscle is regular exercise, which itself triggers the natural local response of the IGF-1 system.

We also recommend reading our articles on PEG-MGF and carbohydrate metabolism, on the myths surrounding MGF and on the medical status of MGF.

References

1. Clemmons DR. Metabolic actions of insulin-like growth factor-I in normal physiology and diabetes. Endocrinol Metab Clin North Am. 2012;41(2):425–443.
2. LeRoith D, Yakar S. Mechanisms of disease: metabolic effects of growth hormone and insulin-like growth factor 1. Nat Clin Pract Endocrinol Metab. 2007;3(3):302–310.
3. Increlex (mecasermin) injection. Prescribing information. U.S. Food and Drug Administration.
4. Yang SY, Goldspink G. Different roles of the IGF-I Ec peptide (MGF) and mature IGF-I in myoblast proliferation and differentiation. FEBS Lett. 2002;522(1–3):156–160.
5. Matheny RW Jr, Nindl BC, Adamo ML. Minireview: Mechano-growth factor: a putative product of IGF-I gene expression involved in tissue repair and regeneration. Endocrinology. 2010;151(3):865–875.
6. Fornaro M, Hinken AC, Needle S, et al. Mechano-growth factor peptide, the COOH terminus of unprocessed insulin-like growth factor 1, has no apparent effect on myoblast primary cultures. Am J Physiol Endocrinol Metab. 2014;306(2):E150–E156.
7. Richter EA, Hargreaves M. Exercise, GLUT4, and skeletal muscle glucose uptake. Physiol Rev. 2013;93(3):993–1017.