Gwynne’s explanation

Ready for a bedtime story? 😆 I’ll try to explain in my imperfect ways how I understand it.

Mounjaro is a molecule built to be like a Lego piece that is “one size fits both” for the body’s GLP-1 and GIP hormone receptors. These are located in a multitude of places around the body. In non-diabetic people (or to be more inclusive, people who don’t have metabolic dysregulations), the hormones that normally tickle or “plug into” these hormone receptors are released by the intestines when food is eaten. A slew of lovely and healthy Metabolic events happen inside the healthy body in response to food when these hormone receptors get tickled.

But in people’s bodies who have diabetes or metabolic dysregulation, this process isn’t working great. So Mounjaro is a molecule that mimics these 2 hormones and when we inject it, it flies around full time for the next week, doing what other people’s bodies tend to naturally, but also only do in response to when they eat food. This injection makes up for the lack our bodies have at running this process on our own with our own hormones. Our own hormones are called “native incretin hormones,” (incretin means digestive) whereas Mounjaro molecules are copycats and called “incretin mimetics.”

One of these hormones that Mounjaro mimics is called the GIP. Here’s what Wikipedia says defines GIP (btw, aptosis means death):

“the function of GIP is to induce insulin secretion, which is stimulated primarily by hyperosmolarity of glucose in the duodenum. After this discovery, some researchers prefer the new name of glucose-dependent insulinotropic peptide, while retaining the acronym “GIP.” The amount of insulin secreted is greater when glucose is administered orally than intravenously.

In addition to its role as an incretin, GIP is known to inhibit apoptosis of the pancreatic beta cells and to promote their proliferation. It also stimulates glucagon secretion and fat accumulation. GIP receptors are expressed in many organs and tissues including the central nervous system enabling GIP to influence hippocampal memory formation and regulation of appetite and satiety.”

First, realize that phrase “glucose-dependent insulinotropic” is saying a lot about the mechanism of action. It means that it doesn’t do its magic unless the glucose situation warrants it: its activity is glucose-dependent. That’s why you don’t get the blood sugar lows. Other medications like Invokana, Jardiance, insulin – these things just have a mechanism of action that’s blunt force. They yank down the blood sugar without intelligent regard for whether it’s a good idea or not (hence the danger of blood sugar lows with these drugs if not watched and managed carefully). The Mounjaro GIP hormone mimic waits until blood glucose is high and then does its thing.

You can see how some of the stuff GIP does sounds clearly good: increases pancreas beta cells buffness and output, for instance. Regulates appetite and influences your sense of fullness? Sounds awesome! But it also says that it increases glucagon secretion and fat accumulation. So it’s like, huh? How’s that good?

Well GIP traits like these are why most diabetes medication manufacturers kinda ignored thinking about creating molecules that would mimic GIP. It seemed like running down the wrong path. Like focusing on GIP might do more harm than good.

So everyone was focusing on the other hormone GLP-1. GLP-1 receptors being activated is what Ozempic does, and Saxenda, and others in that class (daily or weekly injectables). GLP-1 receptor agonists are kind of rock stars at lowering blood sugar, plus they frequently accompany a weight loss effect that exceeds what’s ordinarily considered good enough to label a weight loss drug as effective (5% of total body weight loss – Ozempic typically triggers much more weight loss than this).

Lest we think nothing else was needed, there’s always room for improvement. One trouble with GLP-1 receptor agonists being used all by themselves is that they tend to make you feel pukey. GIP has anti-nausea effects. Eli Lilly, as I understand it, took a creative cool risk and said “So what about if we like, made a cocktail and tried to see what would happen if we made a molecule that tickled both the GLP-1 & GIP receptors? I mean independently, GIP mimicry looks like an unpromising idea, but maybe together, the right amount of tickling ratio of both those hormone receptors will add up to a result that’s more than the sum of its parts. Let’s try and see!”

So like creative chefs, they did, and like a lovely mixed drink, they came upon the right cocktail that exceeded the efficacy of the plain GLP-1 receptor agonists. Kind of like those ingredients you add that kick ass (truffle French fries) but are a little unexpected and wouldn’t have occurred to everyone to try. The studies show the combo gives better overall results for reducing blood sugar and it triggers greater weight loss, and is less likely to create nausea. The cocktail is referred to as dual receptor agonists, or “twincretins.”

Even though the Mounjaro molecule is a one size fits both shaped thing, Mounjaro favors tickling the GIP receptor more than the GLP-1 receptor. This is why folks who used to be on Ozempic feel some weakness in comparison to the experience they were used to. Particularly at the lower doses of Mounjaro, their GLP-1 receptors aren’t getting hit as hard as they were on Ozempic.

As for the night time & Dawn Phenomenon. So our bodies get us ready for the day to like, run from bears at dawn, as if we’re still cave dwellers. And our bodies release a stress hormone, cortisol, some epinephrine, stuff to give us a bit of an adrenaline rush so we’ll wake up. And in response to this stress hormones, our livers reapond by prefueling us with some sugar. This is to enable us to get up & at em without food (since we’ve been fasting in an overnight coma we need to wake up from). This accounts for the Dawn Phenomenon elevated blood sugar numbers.

But then Mounjaro does its GIP-like thing: it kicks in in response to the elevated glucose level and smooshes it back down for us.