If you have Type II Diabetes or if you need to lose weight, you are probably aware of some hot new drugs, Jardiance, Ozempic, Wegovy, Rybelsus, Mounjaro, and Zepbound. You may also have been besieged by texts, emails, and phone calls about “compounded” versions of these medications.
I thought it might be useful to explain a little about what these medications are, how they are used, and the differences between them.
Recently, I have been discussing the differences between discovery and invention, and how discovery, which comes from basic research, cannot be predicted because we don’t know what we don’t know, and therefore will never be funded by commercial companies. Invention, on the other hand is the fuel that drives commercial companies.
Here’s a little story.
It is about Gila Monsters, Fish, Curiosity and Discovery. It is also about Creativity, Persistence, and Invention.
In 1921 Fred Banting and Charles Best isolated insulin from a dog’s pancreas and injected it into another dog with severe diabetes. The dog lived until they ran out of the extract. A year later a 14-year-old boy, Leonard Thompson was successfully treated with insulin isolated from beef pancreas.
In 1923 Charles Kimball and John Murlin isolated a protein hormone that had the opposite effects as insulin from beef pancreas and named it glucagon.
Now, a little background here. The pancreas is an organ in your body located next to the stomach. It produces enzymes that the body uses to digest food, and it produces two hormones – insulin and glucagon. These two hormones are like the yin and yang of blood sugar. Insulin tells your body to take the sugar in your blood and store it. That sugar is the source of energy for your body, so when you eat a meal and the sugar rises in your blood, insulin is the signal for your body to store that energy. Glucagon is the opposite. When your blood sugar becomes too low, glucagon tells the body to release sugar back into the blood. When these two hormones are working together, they regulate how much sugar is in your blood.
Back to 1906. Researchers in Liverpool had found that an extract from the intestine could lower blood glucose. Later research confirmed that the gut produces hormones similar to what the pancreas produces, chemicals that can affect blood glucose levels; they named these chemicals “incretines”.
In 1986, Joel Habener and Svetlana Mojsov, were investigating incretine proteins, and how the protein hormone glucagon was produced in the intestine.
Proteins are strings of amino acids. Each amino acid is like a unique bead on a chain. There are 20 amino acids and the sequence of those beads on the chain are what gives a protein its activity. The body cannot make amino acids; they have to come from the food that you eat.
You have heard of several of these amino acids such as tryptophan. Tryptophan not only is present as one of the beads in proteins, but it is also a “precursor”, or the chemical that the body uses, to make two other molecules, Melatonin, and Serotonin which affects your mood, sleep, and appetite.
You may also know that vegetarians need to take supplements of certain amino acids like lysine because they are not present in high enough concentrations in plants and vegetables.
Anyway, Habener was interested in how glucagon is produced, and to look at this he looked at the pancreas in fish. Fish? Why fish? As is often the case in basic research, the animal model chosen is based on some particular trait. In this case the problem with looking at the human pancreas is that the cells that he wanted to study are deep inside the pancreas, whereas in fish, those cells exist in a separate organ called the Brockman bodies. Because it is far easier to isolate the cells from these distinct Brockman bodies, fish become a better model.
Habener and Mojsov, at the Mass. General Hospital found that glucagon was made, like insulin, from a precursor molecule called proglucagon that had to be split to become active, and that when it was split, there were other molecules left over. They named these peptides “glucagon-like peptides” or “GLP”. It turns out that the original GLP seen was actually two separate molecules that have now been labeled GLP-1 and GLP-2. Each of these proteins are about 30 amino acids long, and because the chains are so small, they are often referred to as “peptides” rather than “proteins”; the two terms are identical, one just refers to smaller chains.
GLP-1 enhances insulin secretion from the Pancreas, which helps lower your blood sugar. At the same time, it reduces the production of glucagon in your pancreas, which also reduces the signal to release sugar into your blood. It also delays your stomach from emptying, so it makes you feel full faster and longer, helping you reduce your food intake and helps you lose weight.
GLP-2 supports repair and cell growth in your intestine, helping your system’s ability to absorb nutrients.
The basic research in trying to understand how glucagon is produced in the body led to the discovery of intestinally produced proglucagon and the cleavage peptides left over after conversion to glucagon. Studies of these peptides led to the discovery of their functions.
This discovery provided a new channel for applied research, or invention. The pharmaceutical company, Novo Nordisk took that discovery and began to look at how they might use this new discovery.
The problem that Novo Nordisk faced was that the peptide produced from the conversion of proglucagon to glucagon, specifically the GLP-1, was very unstable. When produced in your body, it lasts only a few minutes before it either attaches to another cell and relays its message or is broken up by the enzymes in the stomach and intestine.
The problem for the inventors at Novo Nordisk was to find a way to allow this little messenger to stay around a lot longer. The team at Novo Nordisk used an approach that other chemists at the company had used in the past, they attached a fatty acid piece to the protein which allowed the GLP-1 to bind to the most common protein in the blood – Albumin. This might sound pretty wonky, but think about that chain of 30 beads, the GLP-1 peptide. Picture it like a bracelet. Hanging off of the bracelet is a feather, attached to one of the beads. It turns out that it really matters where that feather is attached.
They tried different places to attach the fatty acid to the GLP-1 and a few different changes in individual amino acids in the chain.
By 2000 they had found a molecule that could last 13 hours. They called this peptide “liraglutide”.
This wasn’t bad, but it wasn’t good enough; so, they went back to the basic research literature. They found some work that had been done in the 1980’s by John Eng. He had been studying the venom from Gila Monsters, which is generally not fatal, but can cause pain and vomiting. Eng was interested if there was a connection between the venom and the GLP’s. He found a molecule that was very similar to GLP-1, but importantly for Novo Nordisk, this molecule had a mutation that extended its life from minutes to over 2 hours. Eng worked with another Pharma company, Amylin and found that this peptide, named Exenatide could be injected twice daily to reduce HbA1c in Type II Diabetics. Exenatide was released in 2004.
Novo Nordisk then tested thousands of different combinations of fatty acids and peptide sequences. The result of all of that experimentation was the development of semaglutide, a molecule that could last for at least a week.
WHEW! So, semaglutide could reduce blood sugar and last for a week before it needed to be replenished. Voila! Ozempic.
In my next post I will talk about the different GLP-1 medications and how they differ from one another.