AOD-9604 and Carbohydrate Metabolism

Growth hormone is known not only for its fat-burning action but also for its ability to reduce insulin sensitivity. The developers of AOD-9604 claimed that their fragment was free of this drawback. The editorial team examines how growth hormone affects carbohydrate metabolism, what is known specifically about AOD-9604, and which questions remain open.

Growth hormone and glucose: basic physiology

Growth hormone belongs to the so-called counter-insulin hormones — together with cortisol, glucagon, and adrenaline. Its physiological role during periods of hunger is to preserve glucose for the brain and proteins for the muscles, switching other tissues to the use of fats as fuel.

The review by Møller and Jørgensen (2009) in Endocrine Reviews describes these effects in detail: growth hormone stimulates lipolysis, raises the concentration of free fatty acids in the blood, and reduces glucose uptake by the muscles. As a result, tissue sensitivity to insulin decreases, and the pancreas is forced to produce more insulin.

Clinically this is clearly seen in the example of acromegaly: a significant proportion of patients with a chronic excess of growth hormone develop impaired glucose tolerance or diabetes mellitus. In growth hormone replacement therapy in adults, glucose indicators are also monitored, because a slight worsening of insulin resistance is an expected effect.

That is exactly why, for the developers of an anti-obesity drug, the complete growth hormone molecule was unacceptable. People with obesity often already have insulin resistance, and to worsen it for the sake of fat loss is a bad bargain.

What was claimed about AOD-9604

In preclinical work by the Ng group, the authors reported that the synthetic lipolytic domain of growth hormone affected fat metabolism in rodents without signs of hyperglycemia or reduced insulin sensitivity (Ng et al., 2000). This was considered the main advantage of the fragment over the complete molecule.

A study on obese mice (Heffernan et al., 2001) compared the effects of growth hormone and AOD9604 with long-term administration. Both substances affected fat metabolism, but for the fragment the diabetogenic changes characteristic of growth hormone were not described.

In humans, a synthesis of randomized studies (Stier et al., 2013) states that AOD9604 did not worsen glucose tolerance indicators and did not change IGF-1 levels compared with placebo. For the database of a candidate anti-obesity drug this was an important safety result.

However, it is worth remembering the context: in those same studies the peptide did not demonstrate a significant advantage over placebo in reducing body weight. If a substance at clinical doses has minimal effect on adipose tissue, then the absence of metabolic changes is less surprising — it may reflect generally weak pharmacological activity.

Fatty acids as a hidden link

There is a direct connection between lipolysis and carbohydrate metabolism. When adipose tissue releases more fatty acids, the muscles and liver receive a “competing” fuel. Classic studies, in particular the work of Roden and colleagues (1996), showed that raising the level of free fatty acids in human blood causes insulin resistance in the muscles.

From this follows a theoretical question: if AOD-9604 really substantially enhances lipolysis, as the marketing claims, then why should it not affect insulin sensitivity at least indirectly? The correct answer is that the effect depends on the scale of lipolysis and on whether the fatty acids are oxidized rather than accumulated in the tissues.

Physical exercise, for example, also increases lipolysis, but at the same time increases the use of fatty acids by the muscles, so insulin sensitivity as a result improves. Therefore the mere fact of stimulating lipolysis is not unambiguously negative — the balance between release and oxidation is important.

For AOD-9604 there are no detailed studies with the “gold standard” of assessment — the hyperinsulinemic euglycemic clamp. Therefore one can speak of the peptide's neutrality regarding carbohydrate metabolism only within the limits of the methods used in the published works.

Who should be attentive

The most questions arise regarding people with already existing disorders: prediabetes, type 2 diabetes mellitus, polycystic ovary syndrome with insulin resistance. It is precisely they who often seek a “fat burner”, and it is precisely in them that any changes in insulin sensitivity have the greatest clinical significance.

Patients receiving glucose-lowering therapy — metformin, GLP-1 receptor agonists, sulfonylurea drugs, or insulin — risk getting unpredictable glucose fluctuations if they add unregistered substances to their regimen on their own. Even a neutral molecule can have an indirect effect — through a change in appetite or eating behavior.

A separate risk group is people who combine peptides with other hormonally active agents. Combinations with growth hormone, its secretagogues, or, all the more, with insulin fundamentally change the picture, and then the “neutrality” of AOD-9604 has no practical significance.

• Prediabetes or type 2 diabetes, especially on drug treatment.
• Polycystic ovary syndrome with insulin resistance.
• Simultaneous use of growth hormone, its secretagogues, or insulin.
• Sharp calorie restriction against the background of intense training.

Which tests are informative

Basic indicators of carbohydrate metabolism are available in any laboratory. Fasting glucose reflects the current state, and glycated hemoglobin (HbA1c) the average glucose level over about three months. The criteria for diagnosing prediabetes and diabetes are given in the annual Standards of Care of the American Diabetes Association.

To assess insulin resistance, fasting insulin and the calculated HOMA-IR index are often used. It is not ideal, but it allows a trend to be seen, especially with repeated measurements at the same laboratory and under the same conditions.

If a person has risk factors, an oral glucose tolerance test provides much more information than a single fasting test: it detects disorders that are not yet visible from basal glucose. Prescribing it and interpreting the results should be done by a doctor.

It is important to understand: no test makes the use of an unregistered peptide safe. Tests are a way to see a problem, not a safeguard against it. The decision about any intervention in metabolism should be made together with an endocrinologist.

Editorial conclusions

Growth hormone naturally reduces insulin sensitivity, and it was precisely this drawback that they tried to avoid when creating AOD-9604.

Published studies did not describe a worsening of carbohydrate metabolism with the peptide, but there are few of them, they are short, and the “neutrality” may be partly explained by a weak clinical effect overall.

For people with prediabetes, diabetes, or on glucose-lowering therapy, the risk of unpredictable interactions is higher, and the real benefit is not proven.

Our articles “Myths About AOD-9604”, “AOD-9604 and Cancer Risks: What Studies Say” and “Epitalon and Carbohydrate Metabolism” will help continue the topic.

References

1. Møller N, Jørgensen JOL. Effects of growth hormone on glucose, lipid, and protein metabolism in human subjects. Endocr Rev. 2009;30(2):152–177.
2. Roden M, Price TB, Perseghin G, et al. Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest. 1996;97(12):2859–2865.
3. Ng FM, Sun J, Sharma L, et al. Metabolic studies of a synthetic lipolytic domain (AOD9604) of human growth hormone. Horm Res. 2000;53(6):274–278.
4. Heffernan M, Summers RJ, Thorburn A, et al. The effects of human GH and its lipolytic fragment (AOD9604) on lipid metabolism following chronic treatment in obese mice and β3-AR knock-out mice. Endocrinology. 2001;142(12):5182–5189.
5. Stier H, Vos E, Kenley D. Safety and tolerability of the hexadecapeptide AOD9604 in humans. J Endocrinol Metab. 2013;3(1-2):7–15.
6. American Diabetes Association Professional Practice Committee. Standards of Care in Diabetes—2024. Diabetes Care. 2024;47(Suppl 1).