1. Job bag number: UK/TB/0214/0025 Date of preparation: May 2014 L-γ-Glu DesB30 insulin Glutamic acid ‘spacer’ DesB30 T T Des(B30) LysB29(γ-Glu Nε-hexadecandioyl) human insulin s s s s A1 B1 A21 ss TYGEECYCCNLQLSISQVINC PT Y YFFFGGGREECCVLLAVLHSLHQ N VK Hexadecandioyl Fatty diacid side chain Insulin degludec: rationally designed, beyond sequence modification

2. Job bag number: UK/TB/0214/0025 Date of preparation: May 2014 Insulin degludec injected Long multihexamer chains assemble [ Phenol; Zn 2+ ] Insulin degludec: immediately after injection Phenol from the vehicle diffuses quickly, and insulin degludec links up via single side-chain contacts Jonassen et al. Pharm Res 2012;29:2104–14

3. Job bag number: UK/TB/0214/0025 Date of preparation: May 2014 Insulin degludec: slow release following injection [ Zn 2+ ] Insulin degludec multihexamers Zinc diffuses slowly causing individual hexamers to disassemble, releasing monomers Subcutaneous depot Monomers are absorbed from the depot into the circulation Jonassen et al. Pharm Res 2012;29:2104–14