How does the new obesity treatment drug 'Retatrutide' avoid the pitfalls of GLP-1 receptor agonists?
In recent years,
The Biochemical Beauty of Retatrutide: How GLP-1s Actually Work – Aceso Under Glass
https://acesounderglass.com/2025/10/13/the-biochemical-beauty-of-retatrutide-how-glp-1s-actually-work/
Before explaining GLP-1 receptor agonists and lettultide, Dr. Nostrand states that it is necessary to first understand energy metabolism and hormonal action in the body. Essentially, within the body, mitochondria, organelles in cells, take in sugars ( glucose ) and fats and produce adenosine triphosphate (ATP), which is used in chemical reactions within cells.
Glucose is a desirable energy source because it can produce ATP very quickly, and in emergencies, it can even produce ATP without using oxygen. The body works to maintain a constant blood sugar level so that cells can take in glucose from the blood when needed. However, it also has disadvantages, such as occupying a lot of storage space and being prone to undesirable reactions with surrounding proteins.
On the other hand, excess glucose and fat that is not burned immediately after ingestion are stored in fat cells in the body. Fat is an excellent way to store energy in the long term because it is highly space-efficient for energy, but it has disadvantages such as the time it takes to break down into fatty acids that can be used for ATP production, and the fact that a lot of energy is lost in the process of converting sugar into fat.
Glycogen , composed of numerous glucose molecules, can be considered an intermediate between glucose and fat in ATP production. Although glycogen is broken down into glucose faster than fat produces fatty acids, it is more stable than glucose in its pure form.
Muscles have glycogen stores that can be used during strenuous exercise, and the liver also stores glycogen to regulate blood sugar levels throughout the body. When blood sugar levels are low, the liver breaks down glycogen and releases glucose into the bloodstream. The process of using fat again as energy is less efficient and faster than the storage and breakdown of glycogen, so the body generally preferentially consumes glycogen over fat.
The body's complex hormonal network manages energy sources such as glucose, fat, and glycogen. When blood sugar levels are high, the hormone
In contrast, when blood sugar levels are low, glucagon acts on the liver to break down glycogen, releasing glucose into the bloodstream and raising blood sugar levels. Glucagon also promotes the breakdown of fat and stimulates the secretion of cortisol , known as a stress hormone. While cortisol increases blood sugar and energy levels, it is also said to promote fat accumulation, muscle breakdown, and insulin resistance.
Glucagon-like peptide-1 (GLP-1) is a hormone that signals to the brain that 'you are eating.' It is secreted when calories are present in the intestines or when the body recognizes that it is about to eat. GLP-1 suppresses appetite and glucagon, while increasing insulin and slowing down the movement of food in the intestines. Additionally, glucose-dependent insulinotropic polypeptide (GIP) is also secreted in response to calories in the intestines. GIP increases insulin sensitivity and promotes fat accumulation.
These hormones don't cause various effects themselves, but rather act by activating specific 'hormone receptors.' The relationship between hormones and receptors is like a 'key and lock'; the hormone, acting as the key, unlocks the receptor, which then triggers a reaction in the receptor.
One point to note here, as Nostrand points out, is that hormones and receptors don't need to fit together perfectly like a lock and key; if there is sufficient affinity, the hormone can still bind to the receptor. For example, the GLP-1 receptor has a strong affinity for GLP-1, but also a weak affinity for glucagon, which has a similar shape to GLP-1. Some 'GLP-1 receptor agonists' on the market utilize this mechanism to bind not only to the GLP-1 receptor but also to other receptors.
When GLP-1 binds to the GLP-1 receptor, a signal is sent to the brain saying, 'I've already eaten, so I don't need to eat any more.' Semaglutide, a GLP-1 receptor agonist also known as Ozempic, activates only the GLP-1 receptor. In contrast, tilzepatide, also known as Manjaro, acts on both the GLP-1 receptor and the GIP receptor.
Eli Lilly's new obesity treatment drug, letatrutide, activates not only GLP-1 receptors and GIP receptors, but also glucagon receptors. Glucagon receptors promote the breakdown of glycogen and fat, which the body uses as energy. If this continues, blood sugar levels in the body will rise to dangerous levels, but the activation of GLP-1 receptors increases insulin secretion, which helps to control blood sugar levels.
GLP-1 receptor agonists are generally known to cause fatigue as a side effect. Although there is not yet enough data, it is possible that letatrutide's glucagon-mimicking action may counteract fatigue or increase energy levels. Nostrand argued that the mechanism by which letatrutide counteracts the side effects of GLP-1 receptor agonists is very sophisticated and beautiful.
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