Exploring the surprising effects of GIP and GLP-1 receptor antagonism in pancreatectomized individuals
Imagine receiving an important text message, but your phone is broken. The message was sent, but it can't be delivered. This is similar to what happens with certain gut hormones in people who have had their pancreas removed. They produce these chemical "messages," but without their pancreas, where do these messages go? What systems do they still affect? This fascinating puzzle is exactly what a team of Scandinavian researchers set out to solve in a groundbreaking 2025 study that reveals just how much we have yet to learn about the hidden languages of our body's hormones.
The term "incretin" was coined in the 1930s to describe gut-derived factors that enhance insulin secretion.
For decades, scientists have known that our gut releases special hormone messengers after we eat that help regulate our metabolism. The two most important ones are called Glucose-dependent Insulinotropic Polypeptide (GIP) and Glucagon-like Peptide-1 (GLP-1). These "incretin" hormones are famous for their ability to stimulate insulin release from the pancreas, but what has remained mysterious is what other jobs they might have beyond this pancreatic function. By studying individuals who have undergone total pancreatectomy (surgical removal of the pancreas), researchers have discovered a remarkable story about how these hormones influence our bodies in ways no one fully appreciated 1 8 .
To understand why this research matters, we need to first meet our key players—the incretin hormones. GIP and GLP-1 are both produced in our gastrointestinal tract in response to food intake. GIP primarily comes from K cells in the upper intestine, while GLP-1 is produced by L cells in the lower intestine 9 .
For years, these hormones were mostly known for their ability to boost insulin secretion from the pancreas in a glucose-dependent manner—meaning they only work when blood sugar is high, preventing dangerous lows.
Studying the isolated effects of these hormones in people with intact pancreases is incredibly difficult because their pancreatic effects are so powerful that they overshadow more subtle actions elsewhere in the body. This is where totally pancreatectomized individuals become invaluable to science.
These individuals have undergone surgical removal of their pancreas, typically due to cancer, severe pancreatitis, or other pancreatic disorders 1 8 .
However, these hormones appear to have job descriptions that extend far beyond insulin regulation. GLP-1 receptors are found throughout the body—in the brain, heart, blood vessels, and even immune cells 2 . This widespread distribution suggests these hormones participate in multiple bodily functions, from controlling appetite to potentially protecting nerves and reducing inflammation. GIP similarly has receptors in various tissues, though its extra-pancreatic functions have been less thoroughly explored 1 .
As a result, they have no pancreatic alpha or beta cells—meaning they cannot produce pancreatic glucagon or insulin. They require insulin therapy to survive, but their guts still produce GIP and GLP-1 after meals 1 8 .
This unique situation creates a natural laboratory for studying what these hormones do when their primary pancreatic targets are absent. As one researcher explained, it's like being able to listen to one instrument in an orchestra by temporarily quieting all the others 7 .
In this pioneering 2025 study published in Diabetes, Obesity and Metabolism, researchers designed an elegant experiment to answer a fundamental question: What happens when we block GIP and GLP-1 receptors in people without a pancreas? 1 8
Participants
Testing Days
Minutes Monitoring
kcal Test Meal
The study followed twelve totally pancreatectomized individuals, each of whom underwent four separate testing days in random order. On each day, they received a different combination of intravenous treatments:
Saline infusion for baseline comparison
GIP(3-30)NH₂ to block GIP receptors
Exendin(9-39)NH₂ to block GLP-1 receptors
Both blockers together
Each session involved drinking a standardized liquid meal (480 kcal), followed by extensive monitoring over 270 minutes. Researchers collected blood samples, measured appetite sensations, heart rate, blood pressure, and even observed how much participants ate when offered an unrestricted buffet afterward 1 8 .
This crossover design (where each participant serves as their own control) and double-blind protocol (where neither researchers nor participants know who's receiving which treatment) represents the gold standard in clinical research, minimizing bias and providing highly reliable results.
When the results were analyzed, the researchers made some surprising discoveries. Contrary to what many expected, blocking GIP and GLP-1 receptors in pancreatectomized individuals did not significantly affect post-meal glucose levels, triglyceride responses, appetite sensations, food intake, heart rate, or blood pressure 1 . This suggests that many well-known effects of these hormones might indeed require the presence of a pancreas.
The standout finding—and arguably the most important discovery from this study—involved bone metabolism. The researchers found that when they blocked GIP receptors (either alone or in combination with GLP-1 blockade), it significantly reduced the meal-induced suppression of bone resorption (bone breakdown) 1 8 .
| Experimental Condition | CTX Reduction (% of baseline) | Interpretation |
|---|---|---|
| Placebo infusion | 64% ± 15% | Normal meal-induced bone protection |
| GIP receptor blockade | 84% ± 9% | Significantly reduced bone protection |
| GLP-1 receptor blockade | Similar to placebo | Minimal effect on bone response |
| Combined blockade | 85% ± 8% | Similar to GIP blockade alone |
To understand this finding, it helps to know that eating normally temporarily slows down the natural process of bone breakdown. The marker CTX (carboxy-terminal collagen crosslinks) in the blood indicates how much bone is being broken down—lower CTX means less bone loss. The study revealed that GIP plays a crucial role in this protective post-meal bone effect, even in people without a pancreas 1 6 .
This discovery builds on earlier research that had suggested GIP might influence bone health. Special cells called osteoclasts that break down bone tissue have been found to contain GIP receptors. When GIP activates these receptors, it appears to put the brakes on osteoclast activity, thus protecting our skeleton 1 .
GIP reduces osteoclast activity by up to 64% after meals
While bone metabolism emerged as the clear story, the researchers made other interesting observations. When they blocked GLP-1 receptors, they noted that circulating GLP-1 levels increased 1 8 . This makes biological sense—when you block a hormone's receptor, the body often compensates by producing more of the hormone.
The absence of effects on other systems was itself informative. The finding that appetite and food intake weren't affected by blocking these hormones in pancreatectomized people suggests that the well-documented appetite-suppressing effects of GLP-1-based drugs (like semaglutide) might work through different mechanisms or require an intact pancreas 1 .
| Parameter Measured | Finding | Potential Interpretation |
|---|---|---|
| Postprandial glucose | No significant changes | Pancreas required for glycemic effects |
| Triglycerides | No significant changes | Lipid effects may need pancreatic input |
| Appetite sensations | No differences | Famous appetite effects may work differently |
| Food intake (ad libitum) | No changes | Pancreas may be needed for satiety signals |
| Heart rate & blood pressure | No effects | Cardiovascular influences may be indirect |
| Reagent/Tool | Function in Study |
|---|---|
| GIP(3-30)NH₂ | Selective GIP receptor blocker that prevents GIP from activating its receptors |
| Exendin(9-39)NH₂ | Selective GLP-1 receptor blocker that prevents GLP-1 from activating its receptors |
| Liquid mixed meal test | Standardized nutrient challenge to stimulate natural hormone release |
| Carboxy-terminal collagen crosslinks (CTX) | Biochemical marker of bone breakdown activity |
| Appetite visual analog scales | Structured self-reporting tool to quantify hunger and fullness sensations |
This research fundamentally expands our understanding of how incretin hormones work in the human body. The discovery that GIP regulates bone metabolism independently of pancreatic function reveals what scientists call an "extrapancreatic effect"—an action that occurs outside the traditional pancreas-centered view.
This has important implications for how we think about designing medications that target these hormone systems. Most existing GLP-1-based drugs (like those used for diabetes and weight loss) were developed with the pancreas as the primary target. Understanding the extrapancreatic effects might help researchers develop more selective medications that target specific benefits while minimizing side effects 2 9 .
The bone-protective effect of GIP is particularly intriguing for future drug development. Conditions like osteoporosis affect millions worldwide, and a natural hormone that protects bone health could point toward novel treatment approaches. Similarly, the fact that these hormones work through receptors in the brain suggests possibilities for managing appetite and weight, though the exact mechanisms require further exploration 5 .
The broader field of incretin research is rapidly expanding. As noted in a comprehensive 2024 review, GLP-1 receptor agonists show promise for conditions ranging from neurodegenerative diseases like Alzheimer's and Parkinson's to cardiovascular disorders and even certain inflammatory conditions 2 . Understanding exactly how these hormones work—both with and without a pancreas—will be crucial for unlocking their full therapeutic potential.
This innovative study in pancreatectomized individuals reminds us that the human body speaks many biochemical languages simultaneously. By temporarily blocking specific hormonal messages in people without a pancreas, researchers discovered that GIP plays a previously underappreciated role in protecting our bones—a finding that transcends the traditional pancreas-centered view of incretin biology.
As research continues to decode these complex hormonal conversations, we gain not only deeper understanding of human physiology but also new pathways for treating disease. The hidden lives of our gut hormones continue to surprise us, revealing that even well-studied biological messengers can have secret jobs that we're only beginning to understand.
What other hidden functions might our hormones perform? As this research shows, sometimes to answer the biggest questions in science, we need to study the remarkable people who teach us what happens when standard body parts are missing, revealing the incredible adaptability and complexity of human physiology.