How a Gut Hormone Became a Breakthrough Medicine

GLP-1 started as a curiosity in the lab—a hormone that helps control blood sugar. Today, medicines based on GLP-1 are transforming care for millions of people with diabetes and obesity. This review traces decades of research published in the Journal of Clinical Investigation, showing how basic science discoveries about how our bodies manage food and energy led to drugs that reduce heart attacks, strokes, and death. Understanding this journey reveals how patient scientific work creates real-world medical breakthroughs.

Study Relevance

Dr. Daniel Drucker from the University of Toronto reviewed decades of GLP-1 research published in the Journal of Clinical Investigation for the journal's 100th anniversary. GLP-1 (glucagon-like peptide 1) is made in the gut after eating and signals the pancreas to release insulin. What makes this molecule special is that it also tells the brain when we're full.

The first incretin hormone—a gut hormone that triggers insulin release—was found in the 1970s. But GLP-1 turned out to work better in people with type 2 diabetes than other similar hormones, making it an ideal drug target. This review explains how scientists figured out what GLP-1 does in the body and how those discoveries led to medicines now used worldwide.

Key Findings Across Decades of Research

How GLP-1 Controls Blood Sugar

Studies in mice bred without GLP-1 receptors showed these animals couldn't properly release insulin when blood sugar rose. When researchers gave healthy people a GLP-1-blocking drug called exendin(9-39), their insulin dropped and their glucagon (a hormone that raises blood sugar) increased. This proved GLP-1 naturally helps control both hormones in humans.

One puzzle: GLP-1 drugs work well in diabetic patients, but a similar hormone called GIP doesn't work as well in diabetes. Research published in 2020 found that when blood sugar stays high too long, pancreas cells switch which signals they respond to. GLP-1 can activate two different signaling pathways (called Gq and Gs), while GIP only activates one (Gs). This switching explains why GLP-1 keeps working in diabetes when GIP fails.

How GLP-1 Reduces Appetite

When researchers infused GLP-1 directly into human volunteers' brains in the 1990s, people felt fuller and ate less at their next meal. Later work showed GLP-1 receptors sit on specific neurons in the hypothalamus and brainstem—brain regions that control hunger.

Interestingly, when scientists deleted GLP-1 receptors from mouse brains, the mice ate and weighed the same as normal mice. But when those same mice received GLP-1 drugs, they didn't lose weight. This means natural GLP-1 plays only a small role in daily eating, but GLP-1 drugs can powerfully override hunger signals when given at higher doses.

A 2023 study identified specific neurons that have both GLP-1 and leptin (another appetite hormone) receptors. Activating these neurons prevented obesity in mice, even on high-fat diets. This helps explain why GLP-1 drugs cause such dramatic weight loss.

Benefits Beyond Blood Sugar and Weight

GLP-1 affects more than metabolism. Research in 2002 showed GLP-1 raises blood pressure and heart rate in animals by activating the autonomic nervous system. Yet paradoxically, starting in 2016, large clinical trials found that long-acting GLP-1 drugs reduced heart attacks, strokes, cardiovascular death, and overall mortality in people with type 2 diabetes. Recent trials extended these benefits to people with obesity and heart failure.

GLP-1 drugs also show promise for brain diseases. A 2013 trial gave exenatide (a GLP-1 drug) to 44 people with Parkinson's disease for 12 months. Patients showed modest improvements in movement and thinking tests, though the small study size limits firm conclusions.

Critical Analysis

Strengths:

• This review synthesizes decades of rigorous research published in a top-tier journal
• Findings come from multiple study types: gene knockout mice, human infusion studies, and large clinical trials
• Mechanisms are tested at multiple levels—from molecules to cells to whole organisms
• Clinical trials included thousands of patients and showed consistent benefits

Limitations:

• The Parkinson's trial studied only 44 people (20 received active drug), limiting statistical power
• Some mechanisms involve mouse studies that may not fully translate to humans
• The review doesn't quantify effect sizes from clinical trials or provide detailed statistical analysis
• Long-term safety beyond current trial durations remains to be established
• Most mechanistic work focuses on pharmacological doses, which are much higher than natural GLP-1 levels

Real-World Implications

GLP-1 drugs are now first-line treatments for type 2 diabetes and obesity. Medications like semaglutide (Ozempic, Wegovy) and liraglutide (Victoza, Saxenda) help millions manage conditions that were previously difficult to treat.

The cardiovascular benefits mean these aren't just diabetes drugs—they prevent heart attacks and strokes. For someone with diabetes and heart disease, a GLP-1 drug might be as important as blood pressure or cholesterol medication.

Newer approaches combine GLP-1 with GIP (the other incretin hormone) in a single injection. Tirzepatide (Mounjaro, Zepbound) produces even greater weight loss and is now approved for obesity. Oral GLP-1 drugs are in late-stage testing, which could make treatment more convenient.

The fact that these drugs help with heart failure, kidney disease, and potentially brain disorders suggests GLP-1 affects many body systems. Ongoing trials are testing GLP-1 drugs for fatty liver disease, peripheral artery disease, and Alzheimer's disease.

Perspective and Future Directions

The GLP-1 story demonstrates how fundamental research pays dividends across decades. Scientists who isolated incretin hormones in the 1970s couldn't have predicted that this work would lead to drugs preventing heart attacks and strokes in 2024.

Several questions remain open: Can we develop GLP-1 drugs that protect neurons without affecting appetite? Why do some people respond better to these drugs than others? Can understanding exactly which brain circuits mediate weight loss lead to better treatments with fewer side effects?

The next wave of multi-hormone drugs—combining GLP-1 with other peptides—may prove even more effective. Small molecule drugs that activate the GLP-1 receptor are being developed, which could offer easier manufacturing and potentially oral administration.

As trials expand into new disease areas, we may discover that GLP-1's effects extend even further than currently known. Each new application requires careful study to ensure benefits outweigh risks in each specific patient population.

LifeiQ Commentary

What makes the GLP-1 story remarkable isn't just the scientific discoveries—it's the patience required. Four decades separated the first incretin experiments from cardiovascular outcome trials. This timeline underscores a truth often lost in our fast-moving world: transformative medicine emerges from sustained, methodical inquiry. As we watch GLP-1 drugs expand into neurology, cardiology, and hepatology, we're reminded that today's basic research seeds tomorrow's clinical breakthroughs. The question isn't whether to invest in fundamental science, but whether we have the institutional patience to see it through.

References

Drucker, D.J. (2024). The GLP-1 journey: from discovery science to therapeutic impact. Journal of Clinical Investigation, 134(2):e175634. https://doi.org/10.1172/JCI175634