A 14-year-old girl with newly diagnosed type 1 diabetes is started on a basal-bolus regimen. The physician explains that rapid-acting insulin analogs (lispro, aspart, glulisine) are preferred over regular human insulin for mealtime coverage. The structural basis for their faster onset is:
- A Amino acid substitutions that prevent insulin self-association into dimers and hexamers ✓
- B Addition of zinc to stabilize hexameric forms in the vial
- C Conjugation with fatty acid chains for albumin binding
- D Removal of the C-peptide to reduce molecular weight
Correct answer: A. Amino acid substitutions that prevent insulin self-association into dimers and hexamers
Explanation
Regular insulin self-associates into dimers and hexamers at the injection site, delaying absorption. Rapid-acting analogs (lispro reverses A28-A29; aspart substitutes A28 proline with aspartate; glulisine substitutes A3 asparagine with lysine and A29 lysine with glutamate) prevent hexamer formation, allowing rapid dissociation into monomers and faster absorption. Zinc stabilizes hexamers, the opposite effect.
Reference: Goodman and Gilman's The Pharmacological Basis of Therapeutics, 14th ed.
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