Tirzepa-what now?

And an old school tinkering “biohack” (if you can call it that; based on speculation, etc.) (see below)

Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes (Frias et al., 2021)

I shoulda saved “what a time to be alive!” for this post. You thought semaglutide was the greatest progress in managing obesity, right? Say hello to tirzepatide.

Both of these are once weekly subcutaneous injections. Semaglutide is available as a significantly cheaper generic; tirzepatide not yet (to my knowledge).

Weird-looking molecule,,, I bet it tickles more than one receptor…

But that’s neither here nor there for now:

With great power comes great responsibility.

Slightly more side effects in the highest dose tirzepatide group, but not enough to cause massive drop out rates.

Dual GIP and GLP-1 Receptor Agonist Tirzepatide Improves Beta-cell Function and Insulin Sensitivity in Type 2 Diabetes (Thomas et al., 2021)

Damn. All those mouse studies that people like to poo-poo on are starting to pay off.

What does tirzepatide have over GLP-1 agonists like semaglutide?

Both compounds activate GLP-1r signaling. This is beneficial on many levels: reduces hunger, blood glucose, etc. Very effective at that. Tirzepatide also agonizes the GIP receptor. Ultra-processed food (UPF) hack coming.

Incretins (eg, GLP-1 & GIP) power-up first phase insulin secretion in response to meals. It doesn’t work with intravenously administered glucose, because why ever in nature would blood glucose skyrocket without eating something? Sometimes liver chronically overproduces glucose, but this doesn’t constitute a spike that requires taming via robust first phase insulin secretion. That only happens with food and this is a good thing. Robust first phase insulin, that is; it accomplishes the bulk of the work. Prolonged chronic hyperinsulinemia beyond the first phase is relatively useless for glucose disposal and may even be detrimental, promoting insulin resistance in skeletal muscle (and maybe elsewhere).

GLP-1 is good for diabetes and weight management. GIP perhaps not so much. GIP is secreted by nutrients in the upper digestive tract. UPF are more likely to act in the upper GI than lower given that they’re already processed. Whole foods, fibers, intact stuff takes longer to digest, so they’re more likely to be “sensed” lower down in the GI tract, where GLP-1 predominates. This might be, in part, why UPF avoidance works. GIP:GLP-1 balance or something like that.

But tirzepatide also activates GIP signaling! *gasp*

One theory suggests GIP agonism leads to downregulation of GIP signaling, so overall less net GIP activity. This is also why GIP antagonists originally showed some promise acutely. The superior weight loss and weight loss maintenance for upwards of 70 weeks suggests GIP agonism combined with GLP-1 agonism is the winner.

Possible biohack: dissolve 1 acarbose pill and 1 orlistat in a litre of water. Take a sip with each meal. This shifts all the food you eat to a less processed state; not completely inhibiting digestion which could reduce the benefits of GLP-1 (and potentially messy side effects), but still favor the GIP/GLP-1 signaling profile. Non-UPF for thought :)

It takes 2-3 pills of orlistat & acarbose per day to cause bad side effects, but we’re not trying to shut down digestion, just delay it a little bit, like what happens with UPF-free diets.

What do you think?! Am I taking crazy pills or does this seem not unreasonable?

For personalized health consulting services -> email: [email protected].

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calories proper

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