Design of Insulin Variants for Improved Treatment of Diabetes - Peptide and Protein Design for Biopharmaceutical Applications - page 260

potency in humans (15-30 %) [103], but this problem was corrected by
adjusting the dose and redefining the unit for this particular insulin.
Levemir was fully developed and market-introduced in 2005. Levemir
provides a flat and reproducible profile with coverage for up to
24 hours. Once-daily dosing is the most common regime [104], but
some patients need twice-daily dosing for full basal coverage. The
mechanism of protraction is based on binding to albumin [105-108],
an endogenous protein of 66 kDa, which is present in both subcutis and
the circulation.
Increased oligomerization of acylated insulin, and binding of acylated
insulin dimer to two albumins have been suggested to participate in the
prolonged drug residence in subcutis [109,110]. Detemir-albumin bind-
ing in the circulation advantageously provides an insulin-buffering effect,
which seemingly protects against insulin spikes, which could otherwise
lead to hypoglycaemia [111,112]. Detemir is based on desB30 human
insulin, because acylated desB30 insulin gave stronger binding to albumin
compared to full-chain insulin [96].
Levemir cannot be mixed with regular insulin, because the fast-acting
insulin would be partially retained in the Levemir depot (blunting of
individual profiles by formation of mixed hexamers).
Initiation of insulin therapy typically leads to weight gain, especially in
type 2 diabetes. However, Levemir turns out be weight-neutral,
i.e. patients retain their weight after initiation of Levemir therapy
[113]. It is not fully understood why this is the case [114], but the
increased hydrophobicity of the myristyl insulin relative to other insulins
or the albumin-binding property could be partly involved. Alternatively,
since Levemir provides a more predictable profile relative to other basal
insulins, the generally more stable blood sugar may lead to less influence
on appetite and thus less snacking by patients.
Apart from fatty acids, other albumin-binding ligands have been inves-
tigated in pursuit of protraction of soluble insulin. Fatty diacids have been
used, and these can provide very long insulin effect due to increased
albumin binding [109,115], but in some cases these compounds seem to
suffer from low potency [115].
Bile acid derivatives of insulin bind to albumin, but these insulins are in
some cases longer acting than should be expected from the albumin bind-
ing alone. Studies by size-exclusion chromatography (SEC), among other
methods, have revealed that bile acid insulins can form high-molecular-
weight self-assemblies (multihexamers) at the site of injection [116,117].
As long as phenol is present (in the vial), the insulin is in R-fold, and as
shown by SEC, the R-fold does not give rise to the high-molecular-weight