In This Article
The blockbuster drugs of today are the result of 50 years of biochemical detective work. We cover:
- The 1960s Mystery: The "Incretin Effect"
- 1970s: The discovery of GIP (The First Hormone)
- 1980s: Sequencing GLP-1 from Proglucagon
- The Gila Monster Connection: Solving the Half-Life Problem
- The Renaissance: Why GIP made a comeback with Tirzepatide
Medications like Semaglutide (Ozempic/Wegovy) and Tirzepatide (Mounjaro/Zepbound) seem to have appeared overnight to revolutionize metabolic health. In reality, they are the culmination of a scientific saga that began half a century ago.
The story involves a physiological puzzle known as the "Incretin Effect," a rebranding of a gastric hormone, and an unlikely contribution from the venom of a lizard found in the American Southwest. To understand where biotechnology is going, we must look at the molecular origins of GLP-1 and GIP.
The 1960s: The Incretin Effect
Before scientists found the specific hormones, they found a phenomenon. In the mid-1960s, researchers (Elrick et al. and McIntyre et al.) conducted a simple yet profound experiment.
The Experiment
They measured insulin levels in patients after administering glucose in two different ways:
- Intravenously (IV): Glucose injected directly into the blood.
- Orally: Glucose consumed by mouth.
The Result: Even when blood sugar levels were identical, the oral glucose triggered a significantly higher insulin release (up to 70% more) than the IV glucose.
They concluded that the gut must signal the pancreas to prepare for sugar before it even enters the bloodstream. They called these theoretical gut signals "Incretins."
1970s: The Discovery of GIP
The hunt for the specific molecule responsible for this effect led first to GIP.
Isolated in 1971 by Brown and Pederson, it was originally named Gastric Inhibitory Polypeptide because it appeared to inhibit stomach acid secretion in dogs. However, researchers later realized its primary role in humans was stimulating insulin secretion in a glucose-dependent manner.
Consequently, it was renamed Glucose-dependent Insulinotropic Polypeptide (keeping the acronym GIP). While GIP explained part of the incretin effect, it didn't explain all of it—especially in Type 2 Diabetics, where GIP seemed to lose its effectiveness. The search continued.
1980s: Finding GLP-1
In the early 1980s, the focus shifted to the proglucagon gene. By cloning this gene, researchers discovered that it encoded not just glucagon, but two other peptide sequences: GLP-1 and GLP-2.
Glucagon-like Peptide-1 (GLP-1) was identified as the second, more potent incretin. Unlike GIP, GLP-1 retained its ability to stimulate insulin (and suppress glucagon) even in diabetic patients.
The DPP-4 Hurdle
Discovery did not immediately lead to a drug. The problem was DPP-4 (Dipeptidyl peptidase-4), an enzyme in the body that breaks down native GLP-1 in less than 2 minutes. You cannot put native GLP-1 in a pill or a standard injection; it vanishes before it can work.
The Lizard and the Breakthrough
To create a viable medicine, scientists needed a version of GLP-1 that could resist the DPP-4 enzyme. The breakthrough came from Dr. John Eng in the early 1990s, who was studying the venom of the Gila Monster (Heloderma suspectum).
Dr. Eng discovered a peptide in the lizard's venom called Exendin-4. It was remarkably similar to human GLP-1 but had a critical structural difference that made it immune to DPP-4 degradation.
This lizard peptide became Exenatide (Byetta), the first FDA-approved GLP-1 agonist in 2005. This paved the way for Liraglutide (Victoza) and eventually Semaglutide (Ozempic), which were chemically modified human GLP-1 chains rather than lizard derivatives.
The Return of GIP: Mounjaro
For years, GIP was ignored in therapeutics because it doesn't lower blood sugar well on its own in diabetics. However, recent biotech engineering revealed a synergy.
Tirzepatide (Mounjaro) represents the next evolution. It is a single molecule that activates both the GLP-1 and GIP receptors.
- GLP-1: Drives satiety and insulin secretion.
- GIP: Enhances the insulin response and, critically, improves lipid metabolism and fat storage regulation in white adipose tissue.
By stacking these mechanisms (and chemically modifying the peptide to last 5+ days in the blood), we have entered the era of the "Twincretin."
Biotech is Just Getting Started
From lizard venom to dual-agonist peptides, the history of metabolic health is fascinating. Stay ahead of the next breakthrough—like Triple Agonists (Retatrutide)—by joining the Great Meets community.