Chapter 7 — Quiz

Twenty-two questions.

Multiple choice

1. The incretin effect is demonstrated by comparing insulin responses to: a) glucose versus fat b) oral versus intravenous glucose at matched blood glucose c) fasting versus fed states d) diabetic versus non-diabetic subjects

2. GLP-1 is produced by: a) pancreatic beta cells b) intestinal L cells c) hepatocytes d) gastric parietal cells

3. GLP-1 and glucagon are both cut from: a) insulin b) proglucagon c) proinsulin d) somatostatin

4. Which is NOT one of GLP-1's four actions? a) enhances glucose-dependent insulin secretion b) suppresses glucagon c) slows gastric emptying d) increases hepatic glucose production

5. GLP-1's nausea arises primarily from: a) direct gastric irritation b) slowed gastric emptying plus hindbrain receptor activation c) insulin release d) glucagon suppression

6. Glucose-dependence means GLP-1: a) requires glucose to be absorbed b) amplifies insulin release that glucose is already driving, rather than forcing it c) only works after meals d) converts glucose to glycogen

7. Native GLP-1's circulating half-life is approximately: a) 1–2 minutes b) 1–2 hours c) 13 hours d) 1 week

8. DPP-4 cleaves GLP-1: a) at the C-terminus b) two residues from the N-terminus, removing the activating region c) in the middle d) only in the liver

9. GIP is produced by: a) L cells b) K cells c) beta cells d) alpha cells

10. GIP was largely dismissed as a drug target because: a) it does not exist in humans b) its insulinotropic effect is blunted in type 2 diabetes and it appears to promote fat storage c) it cannot be synthesized d) it causes hypoglycemia

11. The area postrema is significant because: a) it produces GLP-1 b) it has an incomplete blood-brain barrier, allowing circulating peptides to act on neurons directly c) it controls insulin secretion d) it is where DPP-4 is made

12. L cells are concentrated: a) in the stomach b) in the upper duodenum c) distally, in the ileum and colon d) in the pancreas

13. DPP-4 inhibitors produce effects that are, compared with GLP-1 receptor agonists: a) larger b) identical c) modest, because they can only preserve physiological GLP-1 levels d) unrelated

14. In type 2 diabetes, the incretin effect is: a) enhanced b) unchanged c) substantially reduced d) reversed

15. GLP-1 receptors are found in all of the following EXCEPT: a) pancreatic beta cells b) heart and kidney c) hindbrain d) red blood cells

16. "Food noise" refers to: a) gastrointestinal sounds b) intrusive background preoccupation with food c) a measurement artifact d) noise in appetite study data

Short answer

17. Explain why GLP-1 receptor agonists do not suppress endogenous GLP-1, and state the general rule for predicting suppression.

18. Explain the puzzle raised in §7.6 — if most GLP-1 is destroyed before it circulates, how does it act systemically? — and its proposed resolution.

19. State the four proposed explanations for why adding GIP agonism helps despite GIP's apparently unhelpful profile.

20. State three things the incretin system does NOT explain.

Applying the rating discipline

21. Native GLP-1 as a therapy is rated ❌. Explain what makes this rating unusual and what it teaches about what a rating attaches to.

22. A source states that GLP-1 drugs "restore your body's natural satiety signaling." Using §7.6 and §7.7, identify what is misleading in this, and state what would have to be true for it to be accurate.

Answer key **1.** b. **2.** b. **3.** b. **4.** d. **5.** b. **6.** b. **7.** a. **8.** b. **9.** b. **10.** b. **11.** b. **12.** c. **13.** c. **14.** c. **15.** d. **16.** b. **17.** GLP-1 release is triggered by **nutrients arriving in the gut**, not by a sensor measuring circulating GLP-1 against a set point. There is no upstream tier detecting total GLP-1 and turning itself down, so an exogenous agonist does not produce classical axis suppression. **The general rule (Ch 3):** expect feedback suppression where there is an upstream sensor comparing total circulating hormone against a set point — and do not assume one exists. Pituitary hormones and sex steroids have one; gut hormones largely do not. **18.** **The puzzle:** DPP-4 is abundant on capillary endothelium in the gut wall itself, so much GLP-1 is inactivated before it even leaves the intestinal circulation, and hepatic first-pass extraction removes much of the rest. Very little intact GLP-1 reaches systemic circulation. **The proposed resolution:** much of endogenous GLP-1's action may be **local** — activating receptors on vagal afferent nerve endings in the gut wall a very short distance from the L cell, with the vagus then relaying the signal neurally to the hindbrain. The hormone may function more as a paracrine signal with a neural relay than as a classical endocrine one. **Why this matters:** an injected long-acting agonist produces sustained systemic exposure and reaches receptors directly, including in brain regions with a leaky blood-brain barrier. **It may not be the same signal**, which is a candidate explanation for why the drug effect so far exceeds anything endogenous GLP-1 produces. **19.** (1) GIP receptor agonism in the brain may contribute to appetite reduction independently of peripheral metabolic effects; (2) the blunted insulin response in diabetes may be restored once glucose control improves, so GIP agonism becomes useful after GLP-1 agonism has acted; (3) sustained GIP receptor agonism may **desensitize** the receptor so that a chronic agonist behaves functionally like an antagonist; (4) the peripheral fat-storage effect may simply be outweighed. **None is established**, and the fact that both GIP agonists and antagonists are being pursued is an honest indication of that. **20.** Any three of: why obesity happens; the magnitude of the drug effect compared with endogenous signaling; why weight returns on discontinuation (predicted in principle by the override-vs-replace rule, but not explained in detail); the non-metabolic benefits and whether they are downstream of weight, glucose, direct receptor effects, or inflammation; and who should take these drugs, which is a clinical judgment rather than a physiological question. **21.** It is unusual because **the ❌ is awarded on delivery grounds rather than efficacy grounds.** Native GLP-1's physiological activity is confirmed — continuous intravenous infusion in humans demonstrably lowers glucose and reduces food intake. It fails as a therapy because a one-to-two-minute half-life cannot be delivered outside a hospital. **What it teaches:** a rating attaches to a **claim**, and the claim "is this a viable treatment" requires that the compound can be delivered, not merely that the biology is real. It also demonstrates the distinction the rating system exists to preserve: "the mechanism doesn't work" and "this cannot be delivered" are different failures with different remedies — and in this case the remedy was found by *not using the native peptide*. **22.** **What is misleading:** the word "restore." Three problems. First, endogenous GLP-1 acts largely **locally** through vagal afferents at concentrations and in a temporal pattern that an injected weekly agonist does not reproduce — so the drug is not delivering more of the same signal, it is delivering a different one through partly different routes. Second, the magnitude is not physiological: sustained supraphysiological receptor agonism produces weight loss that endogenous GLP-1 never achieves, which is the opposite of restoration. Third, "restore" implies a prior deficiency, and whether people with obesity have a GLP-1 deficiency that the drug corrects is not established. **What would have to be true:** that people receiving the drug had demonstrably subnormal GLP-1 signaling, that the drug returned it to a normal range rather than exceeding it, and that it did so through the same routes at the same times. None of those has been shown, and the third is probably false.