Chapter 7 — Exercises

Items marked † have worked solutions in Appendix M.

A. Recall

7.1 Describe the experiment that demonstrates the incretin effect. What must be matched between the two conditions?

7.2 † Which cell makes GLP-1? Which makes GIP? Where in the gut is each concentrated?

7.3 From what precursor is GLP-1 cut? What other hormone comes from the same precursor, and in which tissue?

7.4 † List GLP-1's four actions and the tissue each acts on.

7.5 What does DPP-4 do to GLP-1, and what is the resulting half-life?

7.6 Name three brain regions with GLP-1 receptors, and state what is special about the area postrema.

7.7 What is the ileal brake?

7.8 † Define glucose-dependence and state its principal safety consequence.

B. Mechanism

7.9 Explain why GLP-1's action is described as "amplifying" rather than "triggering" insulin release, and why the distinction matters clinically.

7.10 † GLP-1 agonists alone rarely cause hypoglycemia, but can contribute to it in combination therapy. Explain both facts using §7.4.

7.11 DPP-4 removes two residues from GLP-1's N-terminus. Using §7.3's Molecule callout, explain why this is more damaging than removing two residues from the C-terminus would be.

7.12 Explain the "ileal brake" and propose how it might relate to the metabolic effects of bariatric surgery. State what would make your proposal testable.

7.13 † §7.6 raises a puzzle: if most GLP-1 is destroyed before it circulates, how does it act systemically? State the proposed resolution and explain what it implies about injected agonists.

C. GIP

7.14 Why was GIP largely dismissed as a therapeutic target for two decades? Give two distinct reasons.

7.15 † Adding GIP receptor agonism to GLP-1 agonism improves outcomes, despite GIP's blunted insulin effect in diabetes and its apparent fat-storage role. State the four proposed explanations and say which you find most and least plausible, with reasons.

7.16 Both GIP agonists and GIP antagonists are being pursued for obesity. What does that state of affairs indicate? Is it evidence that the field is confused, or evidence that it is working properly?

7.17 Using Chapter 2 §2.7 and Chapter 3 §3.5, explain how sustained agonism at a receptor could produce an effect resembling antagonism.

D. Applying earlier chapters

7.18 † (Ch 3) Explain why GLP-1 receptor agonists do not suppress endogenous GLP-1, while exogenous growth hormone suppresses endogenous GH. Name the architectural difference and state the general rule.

7.19 (Ch 2) GLP-1-induced nausea typically fades over weeks; the metabolic effects persist. Explain using Chapter 2's termination mechanisms, and state the general principle about tolerance.

7.20 (Ch 4) Native GLP-1 is rated ❌ as a therapy despite confirmed physiological activity. Explain what makes this rating unusual and what it demonstrates about the rating system.

7.21 † (Ch 5) "Food noise" is a patient-derived report of quieted preoccupation with food. Place it on the evidence ladder, state what would be required to study it properly, and explain why dismissing it would be both rude and scientifically wrong.

E. "Explain this to a friend"

7.22 † Explain the incretin effect in three sentences to someone who has never heard of it.

7.23 Your friend asks why Ozempic makes people nauseated. Explain it in a way that makes clear the nausea is connected to how the drug works rather than being a random side effect.

7.24 Explain to someone why these drugs don't cause the dangerous low blood sugar that insulin does.

F. Judgment and limits

7.25 §7.9 states the incretin system does not explain why obesity happens. Explain why a drug working on a system is not evidence that the system caused the disease. Connect to Chapter 5's CAST case.

7.26 † §7.6 and §7.7 suggest injected agonists may act through different routes than endogenous GLP-1. Identify at least two claims commonly made about these drugs that this should make you more cautious about.

7.27 The incretin story is a forty-year publicly funded basic-science investment that produced a major drug class. Chapter 6 described a very different information pipeline. Compare the two, and say what makes them different.

G. Evidence Dossier extension

7.28 † Deepen Field 3 for every peptide in your dossier, adding tissues, actions, load-bearing action, routes, and what is not known.

7.29 For at least one peptide, identify the load-bearing action for the specific claim you care about. If a source describes several actions and then asserts a benefit without saying which action produces it, note that.

7.30 For every peptide in your dossier, write the "what is NOT known" mechanistic line. Compare across your entries: is the length of this line related to how much evidence exists?