Three Endocrine Society members have taken home the 2024 Lasker~DeBakey Clinical Medical Research Award. Joel F. Habener, MA, MD, chief of Laboratory of Molecular Endocrinology, Massachusetts General Hospital; Lotte Bjerre Knudsen, DMSc, chief scientific advisor and head of the GLP-1 Centre of Excellence at Novo Nordisk; and Svetlana Mojsov, PhD, research associate professor at Rockefeller University in New York, were honored for their roles in the discovery and development of GLP-1 based drugs that have revolutionized the treatment of obesity.
Habener became interested in how the hormone glucagon fits into the puzzle of how the body regulates blood sugar levels in the 1970s. When Habener cloned the gene for glucagon, he discovered that it encodes not only glucagon itself, but also another molecule that resembles glucagon-like-peptide-1.
“These are diseases with a high morbidity and mortality and are attracting greater research efforts to understand the pathophysiology and to develop effective therapies to combat them,” Habener told Endocrine News in a 2020 interview when he won the Warren Alpert Foundation Prize alongside Daniel J. Drucker, MD. “Obesity and its ensuing constellation of ensuing disorders known as the metabolic syndrome include diabetes, steatohepatitis, hypertension, and even dementia and certain types of cancer.”
Mojsov identified and synthesized the physiologically active form of GLP-1 and developed innovative research methods and reagents that detected GLP-1 in the intestines. Collaborating with other scientists, she drew unambiguous conclusions about essential aspects of GLP-1 biology.
“It will be important for the field of endocrinology to understand how these medicines work in the different disease, and for that to happen it is important to understand that GLP-1RAs have many separate effects that can impact outcomes in different combinations.” – Lotte Bjerre Knudsen, DMSc, chief scientific advisor and head of the GLP-1 Centre of Excellence at Novo Nordisk
“It is a tremendous honor to receive Lasker~DeBakey Clinical Medical Research Award, which recognizes my discovery in the 1980s that GLP-1(7-37) is an incretin with therapeutic potential to treat type 2 diabetes and obesity,” Mojsov says.
Mojsov says that when she was in the Endocrine Unit at Massachusetts General Hospital, she used synthetic chemistry — solid phase peptide synthesis — to obtain large quantities of synthetic GLP-1(7-37) and used it in all studies. First, she developed sensitive and specific radioimmunoassay for GLP-1 and chromatographic methods that allowed her to detect GLP-1(7-37) in rat intestines, a tissue where incretin is secreted.
“I then began a very productive collaboration with Dr. Gordon Weir from the Joslin Diabetes Center in Boston to show that GLP-1(7-37) stimulates insulin release from the perfused rat pancreas at very low picomolar concentration, the same one that is found in blood,” Mojsov says. “My studies at the Endocrine Unit and collaborative studies with Gordon Weir proved that GLP-1(7-37) is the long sought after incretin.”
Mojsov goes on to say that in contrast, experiments in cell lines were inconclusive. For example, she says, GLP-1(7-37) stimulated insulin release from the RIN 1046-38 cells only at very high micromolar concentration. “This is five orders of magnitude higher concentration than the ones in Weir’s experiments. It is not physiological concentration. At very high micromolar concentration glucagon and other peptides in the glucagon family of peptides also stimulate insulin secretion. The biological effect of GLP-1 (7-37) was not specific,” she says. “Collaborative clinical studies with David Nathan at the Massachusetts General Hospital showed that GLP-1(7-37) stimulates insulin release in healthy individuals and patients with type 2 diabetes and established its therapeutic potential.”
Beginning in the 1990s, Knudsen and her team transformed these breakthroughs into treatments to fight diabetes (Ozempic) and obesity (Wegovy), advancing the duration of the drug’s therapeutic effects from a few hours to over a week.
“I’m very happy for GLP-1 to get this incredible recognition, and for me personally I am extremely grateful that the science we do in the pharmaceutical industry, and that I have focused on for 30 years, is recognized in this regard,” Knudsen says.
Knudsen was responsible for inventing the first long-acting GLP-1RA. “I suggested as early as 1996 that it should be prioritized for obesity, based on initial promising animal data, as well as the increasing prevalence of obesity,” she says. “I have continued to lead in obesity with early publications documenting effects on a broad range of neurons involved with both homeostatic and hedonic aspect of energy homeostasis.”
Both Mojsov and Knudsen point to the potential of GLP-1-based drugs beyond obesity and diabetes. “We found that identical GLP-1 receptors exist in the human pancreas, the brain, and the heart, suggesting that the same drug could be used to treat multiple disorders of human health: in the pancreas, in the brain, and in the heart,” Mojsov says.
“Other than diabetes and obesity, then we are witnessing right now unfolding of the GLP-1RA potential in cardiovascular and kidney disease,” Knudsen says. “It will be important for the field of endocrinology to understand how these medicines work in the different disease, and for that to happen it is important to understand that GLP-1RAs have many separate effects that can impact outcomes in different combinations.”
TIME Magazine recognized Habener and Mojsov in its 100 Most Influential People of 2024 earlier this year for their involvement in the development of GLP-1 anti-obesity medications. Through their discoveries and dedicated efforts, Habener, Mojsov, and Knudsen have introduced a new era of weight management, dramatically improving the well-being and health prospects for hundreds of millions. Their work has opened up a burgeoning field of studies about the numerous health benefits seen during GLP-1 therapy, including those related to cardiovascular disease, chronic kidney disorders, fatty liver disease, Alzheimer’s and Parkinson’s diseases, and addiction.
– Derek Bagley
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