@tomvet93
Retatrutide depends on a precisely tuned receptor ratio, roughly GLP-1 : GIP : glucagon = 1 : 1 : 0.3 that keeps glucagon driven fuel burning balanced by incretin driven fuel storage.
This balance lets the liver make and use glucose in harmony, providing energy without needing to break down protein for fuel.
Adding tirzepatide breaks that balance.
Its GLP-1 and GIP receptor activity is several times stronger than Retatutride’s (about 2× at GLP-1 and 5× at GIP).
When both drugs are present, Tirzepatide dominates the shared receptors, so Retatrutide’s incretin (GLP/GIP) side gets drowned out.
That leaves Retatrutide’s glucagon receptor as the only part still working at full strength. Now the perfectly calibrated push/pull of these hormones is lost.
Glucagon, fully active, tells the liver to make and release glucose (and oxidize it for energy).
Tirzepatide makes the body extremely sensitive to increases in blood glucose, and sends the opposite signal via a rapid, amplified insulin release, ie, “stop producing glucose and store energy”. This makes Tirz excellent for glucose control, but when glucagon is continuously stimulating glucose production in the liver, you don’t want insulin response to be quite this strong.
Normally those two signals are never sent to the liver at the same time.
It’s like pressing the accelerator and brake pedal. The engine (your liver) strains, burning fuel inefficiently.
Glucose release is now impaired by insulin, and when the liver can’t produce glucose properly, it switches fuels from carbs. First to fatty acids, and then to amino acids taken from muscle.
This “substrate shift” creates a catabolic state. The body starts breaking down muscle protein to feed the liver’s glucose production and energy needs.
The liver continues oxidizing fat and amino acids but still can’t efficiently release glucose.
Plasma amino acids fall, nitrogen waste rises, and ALT/AST increase.
Muscle tissue becomes a primary substrate source for liver glucose production. (aka hepatic gluconeogenesis) accelerating lean mass loss.
This mechanistic instability, glucagon drive with simultaneous amplified insulin release is what led to earlier GLP-1/glucagon dual-agonists (e.g., MEDI0382, PF-06291874) to be abandoned for safety and effectiveness failures, causing liver stress, enzyme elevation, and catabolism. .
Retatrutide broke the “glucagon curse” through 20 years of experimentation to find the perfect balance of GLP/ GIP/ Glucagon receptor binding proportionality that works and is safe.
Until Dr. Reddit decided the most effective weight loss compounds ever known to man don’t work well enough, so they throw them together in random combinations, yet few, if any, ever seem to achieve the success rate that patients in the trials using one do.
