Table 2.

Modifications of insulin analogs and their impact on the absorption of insulin.

Analog	Type of Insulin Analog	Modification	Impacts on the Absorption of Insulin
Lispro	Bolus	Reversal of the insulin’s B28 (proline) and B29 (lysine)	The designed modifications prevent formation of a dimer/hexamer or self-association, resulting in faster absorption of insulin monomers when injected subcutaneously.
Aspart	Bolus	Substitution of B28 proline with aspartic acid	Reduce monomer–monomer interaction. Enhance repulsion between charged aspartic acid and nearby glutamic acid B21, causing rapid insulin hexamer dissociation into monomers.
Glulisine	Bolus	Two modifications: Asparagine at position B3 substituted for lysine Lysine at position B29 substituted for glutamic acid.	These modifications change the isoelectric point from 5.5 (native insulin) to 5.1, improving the solubility of insulin after subcutaneous injection. This enhances stable dimers and monomers at pharmaceutical concentrations in zinc-free buffer.
Glargine	Basal	B-chain C-terminal extension with two arginine residues A-chain position 21 substitution of glycine for asparagine	The isoelectric point increases to 6.7 to enhance the solubility of insulin. The glycine substitution prevents the deamidation effect of asparagine, causing a more stable insulin aggregation for long-term release.
Detemir	Basal	Acylation of myristic acid to lysine at B-chain position 29	Detemir binds to albumin and forms a reversible bond, resulting in slow release and prolonged action.
Degludec	Basal	Deletion of B-chain position 30 threonine Conjugation of hexadecenoic diacid—B-chain position 29 lysine via glutamate linker	Degludec establishes an insulin depot via insulin multi-hexamer formation in the subcutaneous layer with highly predictable gradual dissociation, resulting in long-term release and action.
Icodec	Basal	C20 fatty diacid-containing side chain Three amino acid substitutions (A14E, B16H, and B25H)	The C20 fatty diacid-containing side chain enforces strong, reversible albumin binding and the gradual release of icodec from albumin. The substituted amino acids result in a slower receptor-mediated clearance, prolonging its half-life.