The 2024 Lasker-DeBakey Clinical Medical Research Award has been presented to Svetlana Mojsov, PhD, Joel Habener, MD, and Lotte Bjerre Knudsen, DMSc, for the discovery of glucagon-like peptide 1 for the treatment of obesity.
The regulation of glucose metabolism by pancreatic and intestinal peptides was a subject of intense research as early as the 1960s and 1970s, fueled by the discovery of incretins, substances secreted in the intestines that stimulate insulin release from the pancreas in response to oral glucose. A parallel line of research during this period was focused on understanding glucagon biology, and one approach to studying glucagon biology was to chemically synthesize glucagon agonists and antagonists; the solid phase synthesis protocol developed in the 1960s by R. Bruce Merrifield, PhD, was the method of choice.
My doctoral research focused on developing a more efficient synthetic strategy for the synthesis of glucagon and glucagon analogues. Using newly developed techniques, I synthesized crystalline glucagon that was as potent in stimulating blood glucose levels in rabbits as natural glucagon. I developed a second synthetic strategy for the solid phase synthesis of glucagon that was even more efficient.
Others, including Bell and colleagues, pursued a molecular biology approach to study glucagon biology. They reported that mammalian glucagon is synthesized as part of a larger protein, preproglucagon, that contained 2 additional peptides that Bell and colleagues named glucagon-like peptides 1 and 2 (GLP-1 and GLP-2). Based on the predicted amino acid sequence encoded in the gene, Bell and colleagues proposed that cleavage of 2 pairs of basic residues flanking GLP-1 would release a 37-amino-acid-long peptide from the polyprotein.
In the early 1980s, working as an independent investigator at the Endocrine Unit at Massachusetts General Hospital in Boston, I analyzed the amino acid sequence published by Bell and colleagues and noticed the presence of a basic arginine amino acid at position 6 in the GLP-1 sequence that could undergo enzymatic cleavage to release a 31-amino-acid GLP-1 (7-37) (Figure). My critical scientific insight was that the shorter GLP-1 (7-37) showed perfect alignment with amino acids present in glucagon that were known to be important for glucagon's biological activity. Other investigators in the field focused on the longer 37-amino-acid GLP-1 (1-37) in their studies.
Based on extensive homology with glucagon, I predicted that GLP-1 (7-37) was the biologically active incretin. To prove this hypothesis, I synthesized large quantities of GLP-1 (7-37) by the solid phase method using the same synthetic strategy developed earlier for the improved synthesis of glucagon. The synthesis was essential for all subsequent experiments that I conducted with my collaborators.
At the same time, Gerhard Heinrich, MD, working independently in the group of Joel Habener, MD, found that preproglucagon messenger RNAs exist in the rat colon and pancreas. However, the northern blot method used by Heinrich to detect these messenger RNAs could not distinguish between GLP-1 (1-37) and GLP-1 (7-37).
To prove the hypothesis that GLP-1 (7-37) was the biologically active incretin, I needed to find a way to identify GLP-1 (7-37) among the large numbers of peptides present in rat intestinal extracts. To do this, I developed highly specific antibodies against GLP-1, a sensitive radioimmunoassay, and, most importantly, high-pressure ion exchange chromatography to separate GLP-1 (1-37) from GLP-1 (7-37). Using these newly developed methods, I found GLP-1 (7-37) in rat intestines and, to a smaller degree, in rat pancreas. Most importantly, my analytical methods, including high-pressure ion exchange chromatography, enabled detection and resolution of the different forms of GLP-1, including GLP-1 (7-37), in rat intestines.
To determine the biological activity of the GLP peptides, Habener and I collaborated with Gordon Weir, MD, to perform experiments in his perfused rat pancreas model and showed that synthetic GLP-1 (7-37) stimulated insulin release at low picomolar concentrations like those found in the blood. Of equal importance was the finding that GLP-1 (1-37) was inactive in the perfused rat pancreas even at high nonphysiological micromolar concentrations. Thus, by early 1987, Habener and I, together with our collaborators, established that GLP-1 (7-37) is an incretin at physiologically relevant concentrations in animal models. Subsequently we established that GLP-1 (7-37) stimulation of insulin secretion is glucose dependent.
I also synthesized GLP-2 and a second amidated form of GLP-1, GLP-1 (7-36)amide, and detected both in rat intestinal extracts and GLP-1 (7-36)amide to a smaller degree in the rat pancreas. Again, in collaboration with Weir, Habener and I showed that GLP-1 (7-37) and GLP-1 (7-36)amide were equally potent in stimulating insulin release from the perfused rat pancreas at low physiological concentrations.
Clinical studies were rapidly initiated by several groups, including Bernhard Kreymann, MD, and colleagues, as well as David Nathan, MD, working with Habener and I. Kreymann and colleagues confirmed the results obtained in the rat pancreas model in humans in 1987 (doi:10.1016/S0140-6736(87)91194-9), namely that GLP-1 (7-36) infusion leads to an increase in insulin secretion. With Nathan and Habener, we established the therapeutic potential of GLP-1 (7-37) in individuals with type 2 diabetes, finding that GLP1 (7-37) infusion at physiological concentrations increased insulin secretion and lowered blood glucose in people with diabetes.
The effects of GLP-1 on weight loss were initially suggested by experiments by Turton and colleagues (doi:10.1038/379069a0), who reported that synthetic GLP-1 (7-36)amide administered directly to the hypothalamus of fasted rats inhibited appetite. These observations were extended in clinical studies that found that administration of GLP-1 (7-36)amide led to significant weight loss (US patent 6,583111B1.2003). Their results were consistent with observations I had made earlier with Yang Wei, MS, that, in addition to pancreas, GLP-1 receptors are also expressed in the human brain, suggesting that GLP-1 agonists could be developed to treat both diabetes and obesity.
Based on my experiments with Habener, Massachusetts General Hospital obtained patents for use of GLP-1 (7-37) and GLP-1 (7-36)amide for treatment of type 2 diabetes in 1992 and in 1996, and they were licensed to Novo Nordisk in the mid-1990s.
Lotte Bjerre Knudsen, DMSc, led a team at Novo Nordisk that developed 2 injectable GLP-1 agonists with prolonged half-life in circulation, liraglutide and semaglutide, by conjugating long chains of lipids to GLP-1 (7-37). Liraglutide, which is administered once a day, was approved for type 2 diabetes in 2010 and for weight loss in 2014. Semaglutide, which is administered once a week, was approved for type 2 diabetes in 2017 and for obesity in 2021. Individuals taking semaglutide lose up to 15% of their body weight.
Recently, a new once-weekly injectable peptide, tirzepatide, that is even more effective in reducing body weight than semaglutide, was approved for treatment of type 2 diabetes and obesity. Tirzepatide is a novel molecule where gastric inhibitory polypeptide (GIP) coagonism was inspired by the work of Richard DiMarchi, PhD, and Matthias Tschöp, MD. It combines the sequences of GLP-1 (7-37) with GIP. Individuals receiving the new combination drug can lose more than 20% of their body weight.
The discovery almost 40 years ago that GLP-1 is an incretin led to the development of effective GLP-1 analogues for treating diabetes and obesity and opened up a new frontier for the development of peptide-based therapeutics for obesity treatment.
Corresponding Author: Svetlana Mojsov, PhD, Rockefeller University, 1230 York Ave, New York, NY 10121 ([email protected]).
Published Online: September 19, 2024. doi:10.1001/jama.2024.17571
Conflict of Interest Disclosures: Dr Mojsov is a co-inventor on the patents licensed by Massachusetts General Hospital to Novo Nordisk and received royalties from 2010 to 2012.
Additional Contributions: I thank Michel Nussenzweig, MD, PhD, HHMI, Rockefeller University, for critical review of a previous draft of the manuscript (not compensated).