The quest for effective treatments for diabetes and obesity has led to remarkable advancements in understanding the role of gut hormones, particularly glucagon-like peptide-1 (GLP-1). These advances have culminated in the development of GLP-1-based drugs, which are currently making waves for their ability to manage blood sugar, promote significant weight loss, and potentially offer benefits for cardiovascular health and addiction treatment. As the Karolinska Institutet prepares to award the 2023 Nobel Prize for Physiology or Medicine, the spotlight is on the groundbreaking research and collaborative efforts that paved the way for these transformative medications. This article delves into the fascinating history of GLP-1 research, highlighting the key discoveries, the scientists involved, and the scientific challenges overcome in developing these "blockbuster drugs."
The Dawn of Molecular Biology and the Discovery of GLP-1
The story of GLP-1 begins in the late 1970s and early 1980s with the advent of recombinant DNA technology, a revolutionary set of techniques that allowed scientists to isolate genes and understand how they function. This new technology enabled researchers to convert mRNA into DNA, sequence it, and even splice it into bacteria to create biomolecular factories.
Richard Goodman, then a young doctor, utilized these techniques to study the hormone somatostatin. His research led him to the pancreas, where he sought to isolate the gene for somatostatin. P. Kay Lund, a new postdoc, joined Goodman's lab and used his anglerfish DNA-containing bacterial library to identify the genetic sequence for the precursor to glucagon, a hormone that increases blood sugar.
Their research, published in 1982, revealed that the glucagon precursor gene contained the code for three peptides: glucagon and two novel hormones expressed in the gut. This discovery marked the initial identification of GLP-1, although its significance was not immediately recognized.
Unraveling the Structure and Function of GLP-1
In 1983, Svetlana Mojsov, a chemist with expertise in glucagon, joined Mass General's endocrine unit, with an interest in GLP-1. Mojsov hypothesized that the active structure of GLP-1 was a smaller fragment of the full molecule, a truncated version she called GLP-1(7-37).
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Meanwhile, researchers had observed that oral sugar intake led to higher insulin levels compared to intravenous sugar administration, suggesting the gut secreted an insulin-stimulating substance in response to meals. Mojsov began supplying peptides and reagents to Dan Drucker, another Habener postdoc, who was also working to unravel the GLP-1 mystery. Drucker also found GLP-1 (7-37) in experiments in cell lines.
In February 1987, Mojsov, Weir, and Habener published a paper demonstrating that GLP-1(7-37) stimulated insulin secretion in rat pancreases. Drucker's data were published a few months later, in May.
The Missing Incretin and the Therapeutic Potential of GLP-1
Jens Juul Holst, a gastrointestinal surgeon, had been searching for the missing incretin for over a decade. He had observed that bariatric surgery patients experienced surges in insulin and crashing blood sugar due to alterations in their gut.
Holst's team initially struggled to replicate the insulin-stimulating effect of GLP-1. However, with the help of Thue Schwartz, they discovered the correct cleavage pattern for GLP-1, specifically the 7-37 version. This breakthrough revealed the potential of GLP-1 to treat diabetes by increasing glucose-dependent insulin secretion.
In the summer of 1987, Holst conducted experiments on seven healthy volunteers, infusing them with a solution of GLP-1. The results provided immediate proof-of-concept that GLP-1 could be a viable therapeutic agent.
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The Short Life of GLP-1 and the Quest for Long-Acting Analogs
Researchers soon discovered that GLP-1 has a very short half-life in the bloodstream, as enzymes rapidly degrade it. This limitation spurred the search for ways to prolong its activity.
The discovery of exendin-4, a peptide found in the venom of Gila monsters, provided a crucial breakthrough. Jean-Pierre Raufman, a young gastroenterologist, was studying the effects of various substances on pancreatic cells when he observed that Gila monster venom spurred a significant spike in amylase secretion.
John Eng, a research fellow, isolated and determined the structure of exendin-4. It was remarkably similar to GLP-1, but it lasted much longer in the bloodstream. Despite its potential, major pharmaceutical companies initially dismissed exendin-4.
Amylin Pharmaceuticals, a small biotech startup, recognized the potential of exendin-4 and licensed Eng's lizard peptide in 1996. They developed a synthetic version called exenatide, which received FDA approval in 2005 as Byetta, a treatment for diabetes.
GLP-1 and Weight Loss: An Unexpected Benefit
Users of exenatide reported not only improved blood sugar control but also significant weight loss. While Holst and other GLP-1 researchers considered the weight loss effects of exenatide to be modest, it demonstrated that GLP-1 receptor agonists could be a viable approach for treating diabetes.
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Inspired by these findings, Novo Nordisk began clinical trials of its own GLP-1 receptor agonist, liraglutide. Lotte Bjerre Knudsen, a Novo Nordisk researcher, discovered that GLP-1 could suppress appetite in addition to stimulating insulin secretion.
Knudsen's team developed a technology to make GLP-1 long-acting by adding long fatty acid chains that bind to albumin, protecting it from degradation. The resulting molecule, liraglutide, entered clinical testing in 2000 and was approved by the FDA as Victoza in 2010.
The Brain-Gut Connection and the Mechanism of Weight Loss
Researchers discovered GLP-1 receptors in various locations outside the pancreas, including the vagal nerve, which connects the gut to the brain. Bloom's team at Hammersmith found that injecting GLP-1 into the brains of rats suppressed their appetite.
Clinical trials with Victoza confirmed that liraglutide not only controlled blood sugar but also promoted weight loss. Studies tracing the drug's path through the bodies of mice revealed that liraglutide could access circumventricular organs in the brain, suggesting that its weight loss effects were mediated through the brain.
Subsequent research has provided compelling evidence that the weight loss effects of GLP-1 agonists are primarily mediated through the brain, independent of their impact on blood glucose.
The Nobel Prize and the Recognition of GLP-1 Research
The development of GLP-1-based drugs represents a remarkable achievement in biomedical research, with the potential to transform the treatment of diabetes, obesity, and other related conditions. The Nobel Prize Assembly faces the challenge of recognizing the contributions of numerous individuals who played crucial roles in this scientific journey.
Randy Seeley, director of the Michigan Nutrition Obesity Research Center, emphasizes that all the steps, from discovering the hormone to the translational work to making the drugs, were necessary to reach the current state.
The Nobel Prize often leans toward honoring basic research, but the translational work and drug development aspects are also essential. The discovery that targeting GLP-1 receptors could lead to substantial weight loss was a crucial turning point, but assigning credit for that discovery is challenging.