Teacher guide

Predict

The Gila monster is a big orange and black lizard with a venomous bite. Its venom holds a molecule that works like a hormone your body makes after you eat. Could a molecule from lizard venom lead to a medicine for people?

Circle one. Yes / No

Watch

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

Word of the day

Insulin (IN-suh-lin). A hormone that helps move sugar from your blood into your cells. Tiny islands of cells in your pancreas, called islets, make insulin.

• A peninsula is land with water almost all the way around. Peninsula comes from Latin paen-, “almost,” and insula, “island.”
• Insulation in a wall keeps heat from passing through. Insulate comes from Latin for “made into an island.”

Bonus word. Homeostasis (hoh-mee-oh-STAY-sis). Your body keeps the conditions inside it steady, even when conditions outside change. Homeo- means similar, and -stasis means standing. A thermostat keeps a room at a steady temperature in the same way.

Questions

1. Insulin is a hormone, a chemical messenger that travels in your blood. Insulin helps move sugar out of your blood and into your cells. After you eat, your gut makes another hormone called GLP-1, and GLP-1 signals your pancreas to release more insulin. Why does your body release more insulin after you eat?

   Hint. What goes up in your blood after a meal?

2. Your body breaks down GLP-1 in about 2 minutes. A thermostat turns the heat on when a room gets cold and turns the heat off when the room warms up. Why would a GLP-1 signal that shuts off within a few minutes help your body?

   Hint. What could happen to your blood sugar if insulin kept rising long after a meal?

3. Exendin-4 is a molecule from Gila monster venom. Exendin-4 works like GLP-1, but exendin-4 lasts for hours instead of minutes. Why was a molecule that lasts for hours such a big deal for treating high blood sugar?

   Hint. Could a signal that disappears in 2 minutes work as a medicine?

4. Ozempic is the brand name of a medicine called semaglutide. Scientists made semaglutide by changing human GLP-1, and no part of semaglutide comes from lizard venom. Ozempic didn’t come from a lizard. How did Gila monster research still help lead to Ozempic?

   Hint. Exenatide, a lab-made copy of exendin-4, became a medicine in 2005. Ozempic was approved in 2017. Which medicine came first?

Exit ticket

Predict

The Gila monster is a big orange and black lizard with a venomous bite. Its venom holds a molecule that works like a hormone your body makes after you eat. Could a molecule from lizard venom lead to a medicine for people?

Circle one. Yes / No

Watch

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

Word of the day

Insulin (IN-suh-lin). A hormone made by clusters of cells in the pancreas called the islets of Langerhans. Insulin helps cells take in sugar from the blood.

• A peninsula is land almost surrounded by water. Peninsula joins Latin paen-, “almost,” and insula, “island.”
• Pepsin, penicillin and aspirin end in the same chemistry ending -in.

Bonus word. Homeostasis (hoh-mee-oh-STAY-sis) means a living thing keeps its internal conditions steady while conditions outside change. The word joins Greek hómoios, “similar,” and stásis, “standing.” Hemostasis, the stopping of bleeding, ends with the same root.

Questions

1. After a meal, cells in your gut release GLP-1. GLP-1 boosts insulin release when blood sugar is high, and the enzyme DPP-4 in the blood breaks GLP-1 down within about 2 minutes. How do these steps work together as a feedback loop that keeps blood sugar in a steady range?

   Hint. Trace what happens as blood sugar rises after the meal and then falls. When does the insulin boost stop?

2. In 1993, a team that included John Eng tested exendin-4 on insulin-making cells from rats. Exendin-4 pushed labeled GLP-1 off the GLP-1 receptor. Exendin-4 also raised cAMP, a messenger molecule inside the cells, as GLP-1 does, and boosted insulin release when sugar was present. What do the three results show about how exendin-4 acts on insulin-making cells?

   Hint. A receptor is a protein that a hormone binds. What does it mean if exendin-4 can take GLP-1’s place on the receptor and then trigger the same response?

3. Gila monsters make their own GLP-1 in the pancreas and gut. In 1997, Chen and Drucker found that exendin-4 comes from a separate gene, used only in the lizard’s salivary glands. About 53% of exendin-4’s first 30 amino acids match GLP-1. Is exendin-4 the Gila monster’s own GLP-1? Use the gene evidence to back up your answer.

   Hint. Two proteins can look alike and still come from different genes. Which gene makes each protein, and where is each gene used?

4. Semaglutide, sold as Ozempic, shares 94% of its amino acid sequence with human GLP-1. Exendin-4 shares about 53% of its first 30 amino acids with GLP-1. Why do scientists say Ozempic didn’t come from a lizard? And what did the lizard research add on the way to Ozempic?

   Hint. Compare the two percentages. Then compare the years. Exenatide, a lab-made copy of exendin-4, was approved in 2005, and Ozempic in 2017.

Claim, evidence, reasoning

Going further

1. GLP-1 and exendin-4 boost insulin release when sugar is high. Scientists study this boost with insulin-making cells from animal pancreases, kept alive in dishes of liquid with sugar added. Plan an investigation to test whether exendin-4 boosts insulin release only when sugar is high. Name what you change, what you measure, what you keep the same and how many times you repeat each test.

   Hint. You need dishes with low sugar and dishes with high sugar. Decide which dishes get exendin-4.

Exit ticket

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.

Exit ticket