Chapter 11 — Exercises
Items marked † have worked solutions in Appendix M.
A. Recall
11.1 Name the four people principally associated with the Toronto insulin work and what each contributed.
11.2 † Describe insulin's structure: chains, lengths, and disulfide bonds.
11.3 What kind of receptor does insulin act on, and how does it differ from a GPCR?
11.4 What is GLUT4 and what does insulin do to it?
11.5 † Why does injected insulin cause hypoglycemia when endogenous insulin largely does not?
11.6 What is a hexamer, and why does it matter for rapid-acting insulin?
11.7 What happened in 1982, and why was it significant?
11.8 Name the four analog categories and the problem each solves.
B. The evidence question
11.9 † Insulin was established without randomization. State the general principle governing when randomization is necessary, and apply it to insulin.
11.10 A colleague argues: "insulin proves we over-rely on randomized trials." Respond.
11.11 What would a modern regulator require for a new drug in a uniformly fatal condition with no alternative? What would it not require?
C. Hypoglycemia and counter-regulation
11.12 † Draw or describe the two-lever argument: why endogenous insulin regulation can self-correct and injected insulin cannot.
11.13 Explain hypoglycemia unawareness and why it makes long-standing type 1 diabetes more dangerous rather than less.
11.14 §11.4 argues glycemic targets are not simply "as low as possible." Explain the asymmetry, and describe two patients for whom the right target would differ.
11.15 (Ch 7) Explain why GLP-1 receptor agonists alone rarely cause hypoglycemia. Then explain why they can contribute to it in combination with insulin.
D. Type 1 versus type 2
11.16 † Complete the comparison: core defect, insulin production, and the nature of insulin therapy in each.
11.17 Explain why insulin therapy in type 1 does not lose effectiveness over decades, using the override-versus-replace rule.
11.18 In type 2, insulin overcomes resistance rather than replacing absence. Predict what this implies about dose requirements and about whether the underlying condition is corrected.
11.19 † (Ch 8) Insulin never stops working; GLP-1 agonists' weight effect reverses on discontinuation. Explain both with one rule, and state what the rule predicts for a compound you have not yet met.
E. Engineering
11.20 For each analog strategy — discouraging hexamer formation, protamine complexing, isoelectric shift, fatty acid conjugation, multihexamer chains — state what problem it solves.
11.21 † (Ch 4) Insulin detemir and semaglutide both use fatty acid conjugation for albumin binding. State what each was solving and why the same strategy serves two different purposes.
11.22 Why did recombinant insulin production require solving a folding problem rather than just an expression problem?
11.23 Explain why "smart insulin" would be a genuine solution rather than an incremental improvement. What property would it restore?
F. Devices
11.24 What is a closed-loop system, and why is "artificial pancreas" an overstatement?
11.25 † §11.7 rates closed-loop systems ✅ and notes that this rating is about a device-and-algorithm system rather than a peptide. Does that belong in a book about peptides? Argue a position.
11.26 Name three things closed-loop systems have not solved, and say which you think is most tractable.
G. Pricing
11.27 † State the accurate version of the insulin pricing situation, including at least three complications to the simple story.
11.28 "They sold the patent for a dollar and now it costs hundreds." Identify what is true in this and what the causal account gets wrong.
11.29 Explain why list price versus net price matters, and identify which group is harmed most by high list prices.
11.30 Why has biosimilar competition been slower for insulin than generic competition is for small-molecule drugs? Is that a pricing decision or a regulatory reality?
H. "Explain this to a friend"
11.31 † Explain to someone why a person with type 1 diabetes cannot simply take insulin pills.
11.32 Explain why too much insulin is dangerous within an hour and too little is dangerous over years — and why that shapes the whole therapy.
11.33 Explain the pricing situation without defending anyone and without overstating.
I. Evidence Dossier extension
11.34 † Complete Field 5 at depth for the best-evidenced compound in your dossier, including the "what its history predicts" line.
11.35 For any compound in your dossier, state whether it is a replacement or an override. Then predict, from that alone, whether its effect would persist on discontinuation.
11.36 Insulin's history predicts three things that apply to the GLP-1 drugs, none pharmacological. Name them, and say which you think will matter most in ten years.