Honestly Joe that's a pretty solid analogy. I'd add that one of the interesting things is that turning the GIP key really hard and constantly might actually be similar to breaking the GIP lock in certain tissues — which is the paradox Maria was asking about. But for a quick-and-dirty explanation, your version works great.
Saving this entire thread for my pharmacology seminar presentation next month. This forum is better than half my textbooks tbh.
Thanks for that insight and everyone! 🧬
One additional point worth mentioning: tirzepatide isn't a 1:1 balanced agonist. It has approximately 5x greater affinity for GIPR vs GLP-1R. It's fundamentally a GIP agonist with meaningful GLP-1 activity, not the other way around. This was a deliberate design choice by Lilly's team based on the Finan et al. structure-activity relationship data.
The imbalanced agonism ratio is probably critical to the pharmacology — a perfectly balanced dual agonist might not produce the same results. Biology is about ratios, not just presence/absence.
This kind of rational drug design is what makes tirzepatide such a landmark molecule, regardless of how it compares to future drugs.