Today we’re diving into how medications like semaglutide, tirzepatide, and retatrutide work in the body—and how they compare to the hormones your body naturally produces. Once you understand the biology behind them, their effects start to make a lot more sense.
What is a peptide?
Let’s start with the basics. A peptide is a molecule made of short chains of amino acids linked together by peptide bonds. Amino acids are the building blocks of proteins, so peptides are closely related, just smaller. In general, chains of about 2 to 50 amino acids are called peptides, while longer chains are typically considered proteins. We will talk a bit more about this later.
Peptides act as signaling molecules in the body and show up everywhere—as hormones like insulin and GLP-1, neurotransmitters in the brain, growth factors, and immune signals. Because they’re so specific and biologically active, peptides are widely used in medicine.
Now, your gut naturally produces several peptide hormones after you eat. One of the most important is GLP-1, or glucagon-like peptide-1. GLP-1 plays a central role in regulating blood sugar, appetite, digestion, and fullness. It signals your brain that you’ve eaten, slows how fast food leaves your stomach, increases insulin release when glucose is present, and suppresses glucagon—the hormone that raises blood sugar.
GLP-1 is incredibly powerful, but it has one major limitation: it’s extremely short-lived. Natural GLP-1 lasts only one to two minutes in the bloodstream before it’s broken down by an enzyme called DPP-4. That’s why your body releases GLP-1 in short bursts after meals rather than using it as a long-acting signal.
This is where medications come in.
Semaglutide was designed to mimic GLP-1 but last long enough to be clinically useful. Structurally, it’s not identical to natural GLP-1. Scientists made small but important changes to its amino-acid sequence and added a fatty-acid side chain. Those modifications do two critical things: they make semaglutide resistant to DPP-4, so it isn’t destroyed in minutes, and they allow it to bind to albumin, a protein in your blood that acts like a slow-release carrier. Because of this, semaglutide has a half-life of about seven days, which is why it can be given as a once-weekly injection.
Functionally, semaglutide activates the same GLP-1 receptor as your natural hormone, but in a steady, sustained way. That leads to reduced appetite and food noise, slower gastric emptying so you feel full longer, improved insulin release when glucose is present, and lower glucagon levels. This prolonged signaling is why people often find themselves eating less without consciously trying—the brain is consistently receiving a “you’re satisfied” message.
Tirzepatide takes this concept a step further. In addition to activating the GLP-1 receptor, it also activates the GIP receptor. GIP, or glucose-dependent insulinotropic polypeptide, is another gut peptide hormone released after eating. It plays a complementary role by enhancing insulin sensitivity and supporting overall metabolic health.
What’s interesting is that in people with obesity or insulin resistance, the GIP pathway often doesn’t function well. Tirzepatide doesn’t overwhelm that system—it appears to restore and optimize it. Structurally, tirzepatide is a hybrid peptide, engineered to interact with both GLP-1 and GIP receptors. Like semaglutide, it’s modified to resist enzymatic breakdown and bind to albumin, giving it a half-life of about five days and allowing for once-weekly dosing.
By activating both pathways together, tirzepatide provides strong appetite suppression, better insulin sensitivity, and sometimes a greater total weight loss than GLP-1–only medications.
Then we have retatrutide, which represents the next evolution in this class of peptides. Although it’s not available on the market currently, it’s expected to be available later this year.
Retatrutide is a triple agonist, meaning it activates three receptors: GLP-1, GIP, and the glucagon receptor. GLP-1 controls appetite and glucose, GIP improves insulin sensitivity and metabolic efficiency, and glucagon—despite its bad reputation—plays a key role in fat breakdown, energy use, and thermogenesis, or how many calories you burn at rest.
When glucagon is carefully balanced with GLP-1 and GIP, the result isn’t high blood sugar. Instead, you see increased calorie burn, enhanced fat oxidation, and preserved glucose control through GLP-1–mediated insulin effects.
Retatrutide doesn’t exist naturally in the body—it’s a highly engineered peptide—but like the others we just discussed, it’s modified to resist DPP-4 and bind to albumin, allowing for once-weekly dosing.
One last point that often causes confusion: you’ll sometimes hear different definitions of what counts as a peptide. Scientifically, peptides and proteins exist on a continuum, which is why many textbooks say peptides go up to about 50 amino acids. But from a regulatory standpoint, the FDA uses a strict cutoff of 40 amino acids to classify peptides versus proteins for drug approval. That’s a legal distinction, not a biological one.
We don’t really need to worry about the exact number of amino acids. What matters is that, functionally and structurally, semaglutide, tirzepatide, and retatrutide are all clearly peptides—they’re made from amino acids and designed to mimic and enhance the body’s natural peptide hormones.
Thanks again for listening to The Peptide Podcast.
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Until next time, be well, and have a happy, healthy week.
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