Vitenskapelig artikkel

Characterisation of insulin analogues therapeutically available to patients

Adams, Gary G.; Meal, Andrew; Morgan, Paul. S.; Alsahrani, Qushmua E.; Zobel, Hanne Kristine; Lithgo, Ryan; Kok, M. Samil; Besong, David T. M.; Jiwani, Shahwar I.; Ballance, Simon; Harding, Stephen E.; Chayen, Naomi; Gillis, Richard B.

Publikasjonsdetaljer

Tidsskrift: PLOS ONE, vol. 13, p. 1–17, 2018

Utgave: 3

Internasjonale standardnumre:
Trykt: 1932-6203
Elektronisk: 1932-6203

Open Access: gold

Lenker:
ARKIV
DOI

The structure and function of clinical dosage insulin and its analogues were assessed. This
included `native insulins' (human recombinant, bovine, porcine), `fast-acting analogues'
(aspart, glulisine, lispro) and `slow-acting analogues' (glargine, detemir, degludec). Analytical
ultracentrifugation, both sedimentation velocity and equilibrium experiments, were
employed to yield distributions of both molar mass and sedimentation coefficient of all nine
insulins. Size exclusion chromatography, coupled to multi-angle light scattering, was also
used to explore the function of these analogues. On ultracentrifugation analysis, the insulins
under investigation were found to be in numerous conformational states, however the majority
of insulins were present in a primarily hexameric conformation. This was true for all native
insulins and two fast-acting analogues. However, glargine was present as a dimer, detemir
was a multi-hexameric system, degludec was a dodecamer (di-hexamer) and glulisine was
present as a dimer-hexamer-dihexamer system. However, size-exclusion chromatography
showed that the two hexameric fast-acting analogues (aspart and lispro) dissociated into
monomers and dimers due to the lack of zinc in the mobile phase. This comprehensive
study is the first time all nine insulins have been characterised in this way, the first time that
insulin detemir have been studied using analytical ultracentrifugation and the first time that
insulins aspart and glulisine have been studied using sedimentation equilibrium. The structure
and function of these clinically administered insulins is of critical importance and this
research adds novel data to an otherwise complex functional physiological protein.