The Lizard Behind Ozempic

Watch

1. Ozempic exists because of a LIZARD!youtube.com/shorts/3CZu2rwL4NQ

Word of the day

Insulin (IN-suh-lin). A polypeptide hormone made by the beta cells of the islets of Langerhans in the pancreas that regulates the metabolism of glucose and other nutrients.

• The insula, a set of folds deep in the brain, takes its name from the same Latin word for island.
• Pepsin, penicillin and aspirin end in the same chemistry ending -in.

Bonus word. Homeostasis, from Greek hómoios, “similar,” and stásis, “a state of standing,” names an organism’s tendency to regulate its internal conditions and hold them stable despite outside change. Hemostasis, the stopping of bleeding, shares stasis.

Predict

1. Natural GLP-1 had a half-life of 28 minutes in pig plasma in a test tube. Deacon’s team swapped GLP-1’s second amino acid, alanine, for glycine, the amino acid exendin-4 carries in that spot. Before you read the paper, take a guess. How many minutes did the glycine version of GLP-1 last in pig plasma? Give your reason in one sentence.

   Hint. DPP-4 removes the first two amino acids of a chain quickly when the second amino acid is alanine or proline.

Read the paper

Deacon and others, “Dipeptidyl peptidase IV resistant analogues of glucagon-like peptide-1 which have extended metabolic stability and improved biological activity,” Diabetologia, 1998. The paper is free to read.

DPP-4, also called dipeptidyl peptidase IV, removes the first two amino acids of GLP-1 and inactivates the hormone. GLP-1’s chain is numbered from 7, which makes position 8 the second amino acid. The team made four versions of GLP-1, each with a different amino acid at position 8. They measured each version’s half-life in pig plasma in a test tube at 37°C, reported in the Results section, and how tightly each version bound the human GLP-1 receptor, reported in Table 3. IC50 is the concentration of a version that displaces half of the labeled GLP-1 from the receptor, and a lower IC50 means tighter binding.

1. Quantitative reasoning To fill in the Times longer column, divide each version’s half-life by natural GLP-1’s half-life of 28.1 minutes. For Aib8, use 6 hours as the shortest possible half-life. How many times longer did each version last than natural GLP-1? And why can you give only a minimum for Aib8?

   Hint. Change 6 hours into minutes first. Deacon’s team saw no breakdown of Aib8 during those 6 hours.

2. Structure and function A medicine based on GLP-1 needs to resist DPP-4 and still bind the GLP-1 receptor. Exendin-4 carries glycine at this spot, and semaglutide, sold as Ozempic, carries Aib. Which version of GLP-1 in the table best meets both needs? And what does the threonine version show about the cost of changing position 8?

   Hint. A lower IC50 means tighter binding. Divide threonine’s IC50 by natural GLP-1’s IC50.

3. Process of science In living pigs, Deacon’s team measured a half-life of 0.9 minutes for intact GLP-1 and 3.3 to 3.9 minutes for the new versions. In the test tube, the half-lives ran from 28 to 197 minutes. Why might the half-lives in living pigs be so much shorter than in the test tube? And what does the gap say about test tube results?

   Hint. A test tube of plasma holds DPP-4. What organs does a living pig have that a test tube lacks?

4. Science and society Deacon’s team included scientists from the University of Copenhagen and from Novo Nordisk, the company that later brought semaglutide to market as Ozempic. The Danish Medical Research Council and the Danish Biotechnology Programme funded the study. What does each partner add to a study like Deacon’s? And what would you check before trusting a study with company co-authors?

   Hint. Think about who makes medicines and who checks results. Then look at the paper’s methods and funding.

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