The spotlight of the Tang Prize in Biopharmaceutical Science this year is on a small 31 amino-acid peptide, called GLP-1 (7-37) (Glucagon-like peptide-1 (7-37)). It is a bioactive hormone with anti-diabetes and anti-obesity functions. The impact of the discoveries of the three laureates is huge, as there are more than 500 million diabetic patients and nearly 1 billion individuals with obesity in the world. In type 2 diabetes, beta-cells of the pancreas do not secret enough insulin and the body does not respond to insulin properly, causing high blood sugar levels which lead to severe eye, foot, kidney, cardiovascular, and other complications. Obesity is regarded as one of the most important global public health issues today since it increases the risk of various health conditions and serious diseases. The number of overweight people worldwide is even larger and is increasing. Fortunately, GLP-1-based therapeutics have recently become blockbuster drugs to treat obesity and diabetes, already benefiting hundreds of millions of users with great future prospects. This is an exemplary story of translating basic research into pharmaceutical success with major impacts on human health.
The journey of the exciting discovery began with the cloning of the anglerfish preproglucagon gene in the early 80s by Dr. Joel Habener from Mass General Hospital/ Harvard Medical School. He discovered this precursor protein contains glucagon and another glucagon-related peptide (GRP). Subsequent cloning of the rat preproglucagon gene showed that it contained glucagon and two additional peptides designated GLP-1 and GLP-2, and that the anglerfish GRP is a GLP-1. Dr. Svetlana Mojsov, working at the Endocrine Unit and head of the HHMI peptide synthesis facility at Mass General Hospital, later identified the active form of intestinal GLP-1 to be GLP-1 (7-37). She collaborated with Dr. Habener to show that GLP-1 (7-37) can induce insulin release from the pancreas rather than the entire GLP-1 (1-37). This is an important discovery that identified the long-sought-after incretin (an intestine-secreted hormone that triggers insulin release) and led to its application as an anti-diabetic strategy. The efforts of Dr. Mojsov in the synthesis of GLP-1 (7-37) and the development of several experimental approaches to detect the GLPs in the intestine were critical. Dr. Habener, Dr. Mojsov, and their collaborators showed in healthy and Type 2 diabetic human subjects that GLP-1 (7-37) is insulinotropic, paving the way for clinical application. Independently at the University of Copenhagen, Denmark, Dr. Jens Juul Holst also isolated and identified GLP-1 (1-37), and subsequently GLP-1 (7-36) amide as an active incretin. His lab characterized the biology and physiology of GLP-1 (7-37), demonstrated its therapeutic potential, and has been actively involved in developing anti-diabetic drugs. These findings of the three scientists together ushered in an era of GLP-based drugs for treating diabetes, with contributions by many from academia and industry. During clinical trials, it was found that patients receiving this type of drug had tendencies of weight loss. Subsequent studies by other groups showed that GLP-1 also has receptors on the hypothalamus and apparently has the ability to suppress appetite and treat obesity. Dr. Holst reported that GLP-1 (7-37) inhibits gastric acid release and slows down gastric emptying. At present, there are at least thirteen GLP-1 RA (GLP-1 receptor agonists) drugs approved by the FDA for treating diabetes and/or obesity. In addition, an emerging oral drug called DPP-4 inhibitors is also widely used in clinics. It blocks the degradation of GLP-1 (7-37) by DPP-4 in the body, thereby prolonging the half-life of GLP-1 (7-37) in promoting insulin secretion and lowering blood sugar.
We are honoring the three brilliant scientists, Dr. Habener, Dr. Mojsov, and Dr. Holst who laid the foundation of this remarkable story with key groundbreaking discoveries. The selection committee acknowledges that from basic discoveries to therapeutic applications is a long journey and many scientists in academia or industry are involved. In particular, Dr. Daniel Drucker, who initiated the GLP research as a postdoctoral fellow at Dr. Habener’s lab, has also contributed significantly to the discovery and application of GLP-based drugs. Following the “3-awardees” guideline, the committee selected the current three laureates as the most deserving ones.
