(A) Schematic of hexamer disassembly (adapted from mechanism previously described 8). Phenolic ligand (Ph), zinc ion (Zn2+), insulin monomer (triangle). Darker shading indicates the R-state of the hexamer. (B) Structures of the B-chain C-termini of wild-type insulin (ProI) and RAI Aspart (AspI). (C) Chemical structures of L-proline (1), (2S,4S)-hydroxyproline (Hzp; 2), (2S,4R)-hydroxyproline (Hyp; 3). (D) Reduction of blood glucose following subcutaneous injection of 35 µg/kg insulins into streptozotocin-induced diabetic mice. Glucose levels were measured post-injection via tail vein sampling. ProI, AspI, HzpI, HypI or vector were formulated as described 22. Error bars denote one standard deviation (n = 3).