The Right Chemistry: How the Gila monster assisted weight-loss research

Glucagon-like peptide-1 agonists are all the rage right now. But how did we get here?

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“Glucagon-like peptide-1 agonist.” Sounds like a mouthful, but such substances may actually keep you from filling your mouth. Ozempic and Wegovy, the GLP-1 agonists that have recently been basking in the spotlight, may be the long-awaited medications that can help win the battle against obesity. “May,” though, is an important qualifier.

The use of GLP-1 agonists for weight control is often described over-enthusiastically as a “breakthrough” or “giant leap forward.” History teaches us that science rarely progresses by giant leaps; discoveries are the result of a series of small steps. However, the story of  GLP-1 agonists does indeed begin with a giant leap, one that was taken in 1902 by physiologists Ernest Starling and William Bayliss at London’s University College.

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“On January 16th, 1902, a bitch of about 6 kilos weight” is the epic beginning to Starling and Bayliss’s description of their “critical experiment” in the September issue of that year’s Journal of Physiology. That experiment involved severing all nerves of the female dog around the pancreas and the duodenum, the beginning of the small intestine and then injecting a small amount of acid, such as that produced by the stomach during digestion, into the duodenum.

Remarkably, this stimulated secretion of pancreatic juices despite there being no connection via nerves. Perhaps even more remarkable was the observation that intravenous injection of an extract of the intestinal mucosa mimicked the action of the acid. Clearly, some chemical secreted in the intestines was able to send a message to the pancreas through the bloodstream.

Starling and Bayliss named this substance “secretin” and coined the term “hormone,” from the Greek for “stir into action,” for substances produced in one part of the body capable of stimulating action elsewhere by travelling through the bloodstream. This was the beginning of the field of endocrinology, from the Greek terms “endo,” meaning within, and “krine,” meaning to secrete.

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Their seminal paper stimulated research into duodenal secretions and by the 1970s, a number of details emerged. Introducing glucose into the intestine sent a message to the pancreas to release insulin into the bloodstream. That message was in the form of two hormones, glucose-dependent insulinotrophic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). An obvious corollary to this discovery was the potential of these hormones to treat Type 2 diabetes.

In a landmark 1987 paper, Dr. Daniel Drucker, now at the University of Toronto, identified GLP-1 as a peptide consisting of 30 amino acids, but its use as a treatment presented a big challenge. GLP-1 had a very short half-life in the blood, meaning that a diabetic patient would have to inject it every few minutes. This was obviously not practical and the search was on to find a way to modify the molecular structure of GLP-1 with an aim of retaining its insulin-boosting effect while extending its survival in the blood.

It is at this point that science got a monstrous boost from an unlikely source, a foot-long lizard found mainly in Arizona and New Mexico.

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The Gila monster eats only once or twice a year, a phenomenon that interested Jean-Pierre Raufman, a gastroenterologist at the National Institutes of Health. He found that the lizard’s saliva contains biologically active molecules that caused inflammation of the pancreas in test animals. This intrigued John Eng, an endocrinologist at the Veterans Administration Medical Center in New York, who had trained under Rosalyn Yalow, recipient of the 1977 Nobel Prize in Physiology or Medicine for the development of radioimmunoassay. This technique allows for the measurement of tiny amounts of biological substances in blood, such as insulin. In 1992, following up on Raufman’s work, Eng discovered that a compound in the lizard’s saliva, which he named “exendin-4,” was a peptide that had an amino acid sequence similar to that of GLP-1. He wondered whether it could be of some use in the treatment of diabetes.

Indeed, exendin-4 stimulated insulin release and, importantly, it did not get degraded as quickly in the blood as GLP-1.

Eng patented exendin-4 as a drug and in 1996 licensed it to Amylin, a pharmaceutical company that partnered with Eli-Lilly to introduce exenatide — a synthetic version of exendin-4 — as Byetta for the treatment of Type 2 diabetes. A twice-daily injection stimulated insulin secretion whenever glucose entered the intestines and, unlike drugs that boost insulin secretion indiscriminately, had a reduced risk of causing low blood sugar. And there was another benefit. The drug reduced appetite and resulted in weight loss.

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Parallel to the development of exenatide, Danish pharmaceutical company Novo Nordisk was tackling the problem of GLP-1 breakdown.

The idea was to link the peptide to another molecule that could ferry it around the bloodstream and prevent contact with enzymes that would degrade it. Extensive trials resulted in exchanging a few amino acids in GLP-1 and joining the modified version to human serum albumin, a protein naturally produced in the liver by means of a link formulated with an array of glutamate and fatty acid molecules in a proprietary fashion.

This “GLP-1 agonist,” so-called because of its fit into receptors on pancreatic cells just like the natural hormone, went on the market as the diabetes treatment liraglutide and was subsequently approved for obesity. Further adjustments in molecular structure led to semaglutide, requiring only a weekly injection. It was approved for diabetes as Ozempic, and at a slightly higher dose for obesity as Wegovy. Tirzepatide (Mounjaro) is the newest kid on the block and promises to be even more effective at weight control, since it mimics not only GLP-1, but GIP.

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There are some caveats to be considered before anointing these drugs as the Holy Grail of weight control.

At around $1,000 a month, they are expensive, and use has to be continuous because weight is regained if they are stopped. Long-term effects are unknown and there have been hints of possible adverse impact on the thyroid and pancreas — but these have to be weighed against the very significant benefits of reducing obesity, a risk factor for multiple conditions.

GLP-1 agonists may not exactly be a giant leap in the battle against obesity, but they may well be a large step.

Joe Schwarcz is director of McGill University’s Office for Science & Society ( He hosts The Dr. Joe Show on CJAD Radio 800 AM every Sunday from 3 to 4 p.m.

[email protected] 

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