Latest / The Peptide Research Podcast / Episode 90: Retatrutide "The Triple Agonist"

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Episode 90: Retatrutide "The Triple Agonist" · The Peptide Research Podcast

• 0:45
  SPEAKER_01: Todd, here's the part of the story nobody tells.
• 0:48
  SPEAKER_01: For about 20 years, the way you made one of these compounds better was to make it stronger.
• 0:53
  SPEAKER_01: And then that stopped working.
• 0:55
  SPEAKER_00: It stopped working in a really specific way.
• 0:57
  SPEAKER_01: Right.
• 0:58
  SPEAKER_01: And what researchers did next is the whole episode.
• 1:01
  SPEAKER_01: They quit turning it up.
• 1:02
  SPEAKER_01: They started adding.
• 1:04
  SPEAKER_00: We publish new peptide breakdowns several times a week.
• 1:06
  SPEAKER_00: Tap follow so you catch them all.
• 1:08
  SPEAKER_01: I'm Amy Andrews, and this is the peptideresearch.us podcast.
• 1:12
  SPEAKER_01: Todd Collins is with me.
• 1:14
  SPEAKER_01: Today isn't a compound, it's the idea underneath one.
• 1:17
  SPEAKER_01: Why three signals instead of one?
• 1:20
  SPEAKER_01: Todd, what does somebody walk away knowing?
• 1:23
  SPEAKER_00: Why adding was the move and not multiplying?
• 1:25
  SPEAKER_00: Get that, and the last 10 years of this field reads like one sentence.
• 1:29
  SPEAKER_00: One note before we start: all peptides discussed in this podcast relate to research use only.
• 1:35
  SPEAKER_00: Any references to data from animals, cells, or human studies relate exclusively to scientific literature and not to products from NRG biolabs.
• 1:43
  SPEAKER_00: These compounds are not approved drugs or dietary supplements and are not for human consumption.
• 1:49
  SPEAKER_00: Nothing in this podcast is medical advice.
• 1:51
  SPEAKER_01: Start me at zero.
• 1:53
  SPEAKER_00: What does a signal even land on?
• 1:55
  SPEAKER_00: Here's the simple version.
• 1:56
  SPEAKER_00: Every cell has little docking points on its outside.
• 1:59
  SPEAKER_00: Each one only takes a molecule shaped to fit it, like a lock that accepts one key.
• 2:05
  SPEAKER_00: Researchers call a docking point a receptor.
• 2:07
  SPEAKER_00: And the key is the signal.
• 2:09
  SPEAKER_00: Whatever fits and turns it.
• 2:10
  SPEAKER_00: A molecule that fits the lock and switches the cell on, researchers call that an agonist, a key that turns.
• 2:17
  SPEAKER_01: And the compound everybody's talking about turns three different locks.
• 2:21
  SPEAKER_00: Three locks, one molecule.
• 2:23
  SPEAKER_00: That's all anybody means by a triple agonist.
• 2:26
  SPEAKER_00: One key cut to open three doors.
• 2:28
  SPEAKER_01: Oh, so it's a chord.
• 2:30
  SPEAKER_01: You put one hand down and three notes sound at the same moment.
• 2:34
  SPEAKER_01: And what you hear isn't any one of them, it's the shape they make together.
• 2:38
  SPEAKER_00: That's better than how I usually say it.
• 2:40
  SPEAKER_01: Then here's my follow-up.
• 2:41
  SPEAKER_01: Do three notes just add up?
• 2:43
  SPEAKER_01: Is this one plus one plus one?
• 2:46
  SPEAKER_00: No, hold that question because it's where we end up.
• 2:48
  SPEAKER_01: Okay, so why add at all?
• 2:50
  SPEAKER_01: Why not take the one signal that worked and lean on it harder?
• 2:54
  SPEAKER_00: People did try.
• 2:55
  SPEAKER_00: The first compounds in this family carried a single signal, the note your gut sends out after a meal.
• 3:01
  SPEAKER_00: Researchers call that one GLP1.
• 3:04
  SPEAKER_01: Give me that one in a line.
• 3:06
  SPEAKER_00: It's all about the meal coming in.
• 3:07
  SPEAKER_00: It tells the pancreas to get ready for sugar, it slows how fast the stomach passes food along, and it reaches the parts of the brain that track having had enough.
• 3:16
  SPEAKER_01: Three jobs, but all of them on the same side of the ledger.
• 3:19
  SPEAKER_00: That's the wall exactly.
• 3:21
  SPEAKER_00: Every one of those jobs is about what comes in, not one of them touches what the body spends.
• 3:26
  SPEAKER_00: So pushing that signal harder buys you a louder version of the same half.
• 3:31
  SPEAKER_01: Oh, that's a pit crew where all four people are changing the same tire.
• 3:35
  SPEAKER_01: They're fast, they're good, car still hasn't been fueled, and nobody standing there is the fuel guy.
• 3:41
  SPEAKER_00: I'm stealing that one.
• 3:42
  SPEAKER_01: So my level two question, how did anybody work out which job was missing?
• 3:47
  SPEAKER_00: By taking pizzas away and watching what changed shape.
• 3:50
  SPEAKER_00: Here's what a researcher sees on the bench.
• 3:52
  SPEAKER_00: In animal studies, you can switch off one arm and run the very same experiment.
• 3:57
  SPEAKER_00: The response doesn't just get smaller, it goes missing in one direction while everything else stays put.
• 4:03
  SPEAKER_01: So the map got drawn by subtraction.
• 4:06
  SPEAKER_00: Most of this map did.
• 4:07
  SPEAKER_01: Okay.
• 4:08
  SPEAKER_01: Step two, what got added first?
• 4:10
  SPEAKER_00: A second gut signal.
• 4:12
  SPEAKER_00: Because your gut doesn't send one note after a meal, it sends two.
• 4:16
  SPEAKER_00: The second messenger is the other meal messenger.
• 4:19
  SPEAKER_00: Researchers label it GIP.
• 4:21
  SPEAKER_00: And what does the second messenger bring that the first one didn't?
• 4:24
  SPEAKER_00: A different point of contact with the same organ, a second seat at the same table, rather than a second conversation.
• 4:31
  SPEAKER_00: Tears epitide is the compound built around those two.
• 4:34
  SPEAKER_00: And on the bench?
• 4:35
  SPEAKER_00: Same trick.
• 4:36
  SPEAKER_00: In animal work, the version carrying both messengers reaches the pancreas in a way neither one manages alone.
• 4:42
  SPEAKER_01: Right.
• 4:43
  SPEAKER_01: Okay.
• 4:43
  SPEAKER_01: And step three is the one that raised eyebrows.
• 4:46
  SPEAKER_00: Step three crossed the ledger.
• 4:49
  SPEAKER_00: Everything so far was the in column.
• 4:51
  SPEAKER_00: The third signal is the one that tells the body to open its reserves and spend.
• 4:55
  SPEAKER_00: Researchers call it glucagon.
• 4:57
  SPEAKER_00: Retitrutide is the compound described as reaching all three.
• 5:01
  SPEAKER_01: Two messengers about what's coming in and one about what's going out.
• 5:05
  SPEAKER_00: That's the whole departure in one line.
• 5:07
  SPEAKER_01: Okay, Todd.
• 5:08
  SPEAKER_01: The thing I got wrong for years.
• 5:10
  SPEAKER_01: My apartment had one lamp.
• 5:13
  SPEAKER_01: One.
• 5:13
  SPEAKER_01: Every winter I'd decide the room was too dark, so I'd buy a brighter bulb, then a brighter one.
• 5:18
  SPEAKER_01: Room stayed gloomy.
• 5:20
  SPEAKER_00: What fixed it?
• 5:21
  SPEAKER_01: A friend put a second lamp in the opposite corner, half the wattage of the one I'd been fighting with.
• 5:27
  SPEAKER_01: Room transformed.
• 5:28
  SPEAKER_01: The problem was never how bright the bulb was, it was that everything was coming from one place.
• 5:34
  SPEAKER_00: That's the field's last decade in a living room.
• 5:37
  SPEAKER_01: So then three is better than two, and two is better than one.
• 5:41
  SPEAKER_01: Why isn't everybody just stacking to ten?
• 5:44
  SPEAKER_00: Because every signal you add is another thing that can argue with the others.
• 5:49
  SPEAKER_01: Oh, it's a group text.
• 5:51
  SPEAKER_01: Two people is a conversation.
• 5:52
  SPEAKER_01: At a third, and you've got three conversations happening at once.
• 5:56
  SPEAKER_01: Add a fourth, and it's a mess nobody can follow.
• 5:59
  SPEAKER_01: You didn't add one voice, you multiplied the crosstalk.
• 6:03
  SPEAKER_00: And that's measurable.
• 6:04
  SPEAKER_00: Two arms in one molecule can push against each other.
• 6:07
  SPEAKER_00: One can quietly cancel part of what another is doing.
• 6:10
  SPEAKER_00: So the work isn't collecting receptors, it's tuning how hard each arm pulls.
• 6:15
  SPEAKER_00: And you learned that the hard way.
• 6:17
  SPEAKER_00: In the most humbling way there is.
• 6:19
  SPEAKER_00: Early on, I ran a combination expecting arithmetic, two things that each did something, put them together, and surely you get both.
• 6:26
  SPEAKER_00: What I got was less than either alone.
• 6:29
  SPEAKER_00: I spent a week convinced I'd ruined the samples.
• 6:32
  SPEAKER_00: I hadn't.
• 6:33
  SPEAKER_00: The two arms were interfering.
• 6:35
  SPEAKER_00: That week taught me more than any result I've ever had confirmed.
• 6:39
  SPEAKER_01: Which is exactly why the material in the vial has to be what the label says.
• 6:43
  SPEAKER_00: That's the floor under all of it.
• 6:45
  SPEAKER_00: If what you're studying is the balance between three arms, then the last thing you can afford is doubt about what's in there.
• 6:51
  SPEAKER_00: That's why NRG Biolabs is the foundational partner behind this show.
• 6:55
  SPEAKER_00: Third-party testing, batch-by-batch documentation, certificates of analysis that state what's actually in the vial.
• 7:02
  SPEAKER_00: You can see the COAs and view the lab standards at peptidesearch.us.
• 7:07
  SPEAKER_01: You can't tune a balance you can't trust.
• 7:09
  SPEAKER_00: Not honestly.
• 7:10
  SPEAKER_01: Let me pull it together.
• 7:12
  SPEAKER_01: A receptor is a lock on a cell, and a molecule that fits and turns it is a key.
• 7:17
  SPEAKER_01: Right.
• 7:17
  SPEAKER_01: And the first compounds in this family carried one key, GLP1, and everything it does sits on the incoming side, so turning it up just did that half louder.
• 7:28
  SPEAKER_00: That's the ceiling.
• 7:29
  SPEAKER_01: So researchers added a second meal messenger, GIP, and then a third signal that works the other direction entirely, glucagon, the spending side.
• 7:38
  SPEAKER_01: That's the sequence.
• 7:39
  SPEAKER_01: And the catch is that arms interact, so more isn't automatically better.
• 7:44
  SPEAKER_01: It has to be balanced.
• 7:45
  SPEAKER_00: That's a fair summary.
• 7:47
  SPEAKER_00: Oh, and one last thing that's easy to overlook.
• 7:50
  SPEAKER_00: Everybody hears three and files it under bigger.
• 7:53
  SPEAKER_00: It isn't bigger, it's wider.
• 7:55
  SPEAKER_00: And the next compound out of this field almost certainly won't be four signals, it'll be whichever three make the right shape.
• 8:02
  SPEAKER_00: Nobody's collecting locks, they're looking for a chord.
• 8:05
  SPEAKER_01: Oh, I see.
• 8:06
  SPEAKER_01: It was never about the size of the sound.
• 8:08
  SPEAKER_01: If you want to go slower, there's a plain English write-up on the GLP compounds at peptidesearch.us.
• 8:14
  SPEAKER_01: The peptide research section is where I'd start.
• 8:17
  SPEAKER_01: And if today's breakdown was useful, follow the show.
• 8:20
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• 8:25
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• 8:27
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• 8:37
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• 8:42
  SPEAKER_01: That's our show.
• 8:43
  SPEAKER_01: Go put a second lamp in the corner.