Characterisation of insulin analogues therapeutically available to patients

Handle URI:
http://hdl.handle.net/10754/627494
Title:
Characterisation of insulin analogues therapeutically available to patients
Authors:
Adams, Gary G.; Meal, Andrew; Morgan, Paul S.; Alzahrani, Qushmua E. ( 0000-0001-5305-799X ) ; Zobel, Hanne; Lithgo, Ryan ( 0000-0002-4706-9916 ) ; Kok, M. Samil; Besong, David T. M.; Jiwani, Shahwar I.; Ballance, Simon; Harding, Stephen E.; Chayen, Naomi; Gillis, Richard B. ( 0000-0002-7607-6808 )
Abstract:
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.
KAUST Department:
Functional Nanomaterials Lab, King Abdullah University of Science and Technology (KAUST), Thuwal, Kingdom of Saudi Arabia.
Citation:
Adams GG, Meal A, Morgan PS, Alzahrani QE, Zobel H, et al. (2018) Characterisation of insulin analogues therapeutically available to patients. PLOS ONE 13: e0195010. Available: http://dx.doi.org/10.1371/journal.pone.0195010.
Publisher:
Public Library of Science (PLoS)
Journal:
PLOS ONE
Issue Date:
29-Mar-2018
DOI:
10.1371/journal.pone.0195010
Type:
Article
ISSN:
1932-6203
Sponsors:
Dr. Gary Adams is a non-executive director for the Independent Diabetes Trust and accepts no remuneration for the role. Dr’s Hanne Zobel and Simon Ballance are employees of Nofima AS, however this organisation did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and only provided financial support in the form of authors’ salaries and research materials. The specific roles of these authors are articulated in the ‘author contributions’ section.
Additional Links:
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0195010
Appears in Collections:
Articles

Full metadata record

DC FieldValue Language
dc.contributor.authorAdams, Gary G.en
dc.contributor.authorMeal, Andrewen
dc.contributor.authorMorgan, Paul S.en
dc.contributor.authorAlzahrani, Qushmua E.en
dc.contributor.authorZobel, Hanneen
dc.contributor.authorLithgo, Ryanen
dc.contributor.authorKok, M. Samilen
dc.contributor.authorBesong, David T. M.en
dc.contributor.authorJiwani, Shahwar I.en
dc.contributor.authorBallance, Simonen
dc.contributor.authorHarding, Stephen E.en
dc.contributor.authorChayen, Naomien
dc.contributor.authorGillis, Richard B.en
dc.date.accessioned2018-04-16T11:27:41Z-
dc.date.available2018-04-16T11:27:41Z-
dc.date.issued2018-03-29en
dc.identifier.citationAdams GG, Meal A, Morgan PS, Alzahrani QE, Zobel H, et al. (2018) Characterisation of insulin analogues therapeutically available to patients. PLOS ONE 13: e0195010. Available: http://dx.doi.org/10.1371/journal.pone.0195010.en
dc.identifier.issn1932-6203en
dc.identifier.doi10.1371/journal.pone.0195010en
dc.identifier.urihttp://hdl.handle.net/10754/627494-
dc.description.abstractThe 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.en
dc.description.sponsorshipDr. Gary Adams is a non-executive director for the Independent Diabetes Trust and accepts no remuneration for the role. Dr’s Hanne Zobel and Simon Ballance are employees of Nofima AS, however this organisation did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and only provided financial support in the form of authors’ salaries and research materials. The specific roles of these authors are articulated in the ‘author contributions’ section.en
dc.publisherPublic Library of Science (PLoS)en
dc.relation.urlhttp://journals.plos.org/plosone/article?id=10.1371/journal.pone.0195010en
dc.rightsThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.titleCharacterisation of insulin analogues therapeutically available to patientsen
dc.typeArticleen
dc.contributor.departmentFunctional Nanomaterials Lab, King Abdullah University of Science and Technology (KAUST), Thuwal, Kingdom of Saudi Arabia.en
dc.identifier.journalPLOS ONEen
dc.eprint.versionPublisher's Version/PDFen
dc.contributor.institutionFaculty of Medicine and Health Sciences, University of Nottingham, Queens Medical Centre, Nottingham, NG7 2UH, United Kingdom.en
dc.contributor.institutionNofima AS, Osloveien 1, Ås, Norway.en
dc.contributor.institutionNational Centre for Macromolecular Hydrodynamics, University of Nottingham, School of Biosciences, Sutton Bonington, LE12 5RD, United Kingdom.en
dc.contributor.institutionComputational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, SW7 2AZ, United Kingdom.en
kaust.authorBesong, David T. M.en
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