The Incretin Everyone Wrote Off: The Strange Career of GIP and How It Came Back

Biology is full of molecules that were famous, then dismissed, then rediscovered. Few have had as dramatic a swing as GIP. For a decade or two it was a footnote. Today it sits at the center of one of the most active areas of metabolic research. Understanding why requires following three plot twists.

Act one: the gut hormone that was misnamed

The story starts in the 1960s and 70s, with a puzzle called the incretin effect. Researchers noticed that glucose taken by mouth triggers a much larger insulin release than the same amount of glucose given intravenously. Something released from the gut after eating was telling the pancreas to prepare. That something was named an incretin, and finding it became a chase.

In 1970, John Brown and colleagues at the University of British Columbia purified a 42-amino-acid peptide from pig intestine. Its activity in their assay was that it inhibited gastric acid secretion, so they named it gastric inhibitory polypeptide, GIP. For a while this seemed like its job.

Then, in 1973, research by Dupré and colleagues demonstrated that GIP also stimulates insulin release in a glucose-dependent manner, meaning it works when blood sugar is elevated and fades when it is not. The name no longer fit, and the acronym was retained while the words were changed to glucose-dependent insulinotropic polypeptide. It was one of the two major incretins, alongside GLP-1, which was identified in the 1980s.

Act two: the disappointment

When researchers looked at people with type 2 diabetes, the picture turned unflattering for GIP. In a series of experiments in the early 1990s, including work by Michael Nauck and colleagues, infusing GIP in patients with type 2 diabetes produced a much weaker insulin response than in healthy volunteers, whereas GLP-1 retained its effect. The incretin effect as a whole is blunted in type 2 diabetes, and GIP seemed to be the part that failed most completely.

The natural conclusion was that GIP was a poor drug target. Pharmaceutical effort shifted decisively to GLP-1, which led to exenatide, liraglutide and later compounds. GIP receded from the spotlight.

An extra twist: the obesity data

Complicating things further, experiments in mice in the early 2000s suggested that blocking GIP signaling might protect against diet-induced obesity. Mice lacking the GIP receptor gained less weight on a high-fat diet. This led some laboratories to develop GIP receptor antagonists as potential anti-obesity agents, the exact opposite of using GIP to boost incretin action.

By the 2010s the field was split in an uncomfortable way. One camp wanted to block the GIP receptor. Another was about to stimulate it.

Act three: the dual-agonist idea

Several observations began to shift the argument.

• Blunted does not mean absent. The weak response in type 2 diabetes appeared to be partly a consequence of chronically high blood sugar, and there was evidence that the response to GIP could be partially restored when glucose was brought under control.
• Unimolecular co-agonists worked in animals. In 2009, a team including Richard DiMarchi and Matthias Tschöp published work showing that a single peptide engineered to activate two receptors, the glucagon receptor and the GLP-1 receptor, could produce larger effects on body weight in rodents than a single-receptor agonist. It proved the concept of one molecule acting on multiple targets.
• GIP’s role in fat tissue and in the brain became clearer, hinting that it contributes to energy balance beyond the pancreas.
• Chronic stimulation versus acute stimulation. Prolonged activation of the GIP receptor can cause the receptor to desensitize, effectively behaving like an antagonist, which may explain some of the apparent paradox between “agonist” and “antagonist” results.

Out of this milieu came a design: a single peptide based on the GIP sequence but engineered to also activate the GLP-1 receptor, with a fatty acid chain attached so that it binds albumin in blood and persists for days. That molecule is tirzepatide, reported by researchers at Eli Lilly in 2018 as an imbalanced dual agonist, with a stronger effect on the GIP receptor than on the GLP-1 receptor. Phase 3 programs followed.

What remains unsettled

It would be a mistake to treat the story as finished. Several questions are still open in the research literature.

1. Is the benefit of the dual agonist due to the GIP component, the GLP-1 component, or an interaction? Comparisons with GLP-1 agonists alone suggest additional effects, but separating them is hard because the molecules differ in many ways beyond receptor profile.
2. Does GIP agonism or antagonism matter more for weight? Both have been argued, and the reconciliation, via receptor desensitization or tissue-specific effects, is still debated.
3. Which tissues mediate the effect? The brain, adipose tissue and pancreas all express the GIP receptor, and their relative contributions are being unpicked with tissue-specific knockouts.

A lesson in not over-reading single experiments

The GIP story is a cautionary tale about declaring a pathway dead from one kind of experiment. The weak insulin response in diabetes was real, but it did not mean what it was first taken to mean. The obesity phenotype in knockout mice was real, but it did not mean that agonism was futile. Context, timing and receptor biology all matter.

For researchers studying dual-incretin pharmacology, specifications and batch documentation are on the GLP2TZ (Tirzepatide) 20mg product page.

All Lucid Aminos products are sold strictly for laboratory research use. They are not drugs, dietary supplements or food, and they are not for human or veterinary use. This article is a historical and educational account of published research and is not medical advice.