Glargine and degludec: Solution behaviour of higher dose synthetic insulins

Adams, Gary G.; Alzahrani, Qushmua; Jiwani, Shahwar I.; Meal, Andy; Morgan, Paul S.; Coffey, Frank; Kök, Samil M.; Rowe, Arthur J.; Harding, Stephen E.; Chayen, Naomi E.; Gillis, Richard B.

doi:10.1038/s41598-017-06642-w

Cited by 10 publications

(9 citation statements)

References 33 publications

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“…It is interesting to note that the study of insulins glargine and detemir using AUC (either SV or SE) have been limited or non-existent. IGla was reported by our group [ 3 ] as part of a dosage study involving the single and triple dose forms and similar results are observed in this present investigation. IDet showed interesting multi-hexameric behaviour in AUC-SV, but this was not present in AUC-SE; possibly due to the very high concentration involved (and therefore high signal from the main peak) as well as the low-resolving power from SE analysis.…”

Section: Discussionsupporting

confidence: 92%

“…Although we did not find similar multi-hexameric behaviour in IDeg, we did observe dihexamers. In addition, we found a high degree of non-ideality, confirmed from a previous investigation [ 3 ] to be a result of a lack of buffering salts in the drug preparation. It is possible that the excipient composition in the product prevents the formation of these fibres.…”

Section: Discussionsupporting

confidence: 85%

“…In Diabetes Mellitus (DM), normal physiological processes do not occur and chronic hyperglycaemia is observable, where glycaemic control is severely impaired because of prevailing deficiencies in insulin or its action [ 3 ]. This insufficiency precipitates metabolic and degenerative microvascular and macrovascular complications in multiple organs including the heart, nerves, eyes and kidneys.…”

Section: Introductionmentioning

confidence: 99%

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Characterisation of insulin analogues therapeutically available to patients

et al. 2018

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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.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

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Characterisation of insulin analogues therapeutically available to patients

et al. 2018

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“…PSD for IDeg at 4 • C was approximately 4 nm, which is in agreement with previous studies [38,39]. On Day 1, significant changes were observed in IDeg when it was subjected to increasing temperature (F 1,2 = 375.01, p = 0.03).…”

Section: Particle Size Distributionsupporting

confidence: 91%

Clinically Relevant Insulin Degludec and Its Interaction with Polysaccharides: A Biophysical Examination

et al. 2020

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Protein polysaccharide complexes have been widely studied for multiple industrial applications and are popular due to their biocompatibility. Insulin degludec, an analogue of human insulin, exists as di-hexamer in pharmaceutical formulations and has the potential to form long multi-hexamers in physiological environment, which dissociate into monomers to bind with receptors on the cell membrane. This study involved complexation of two negatively charged bio-polymers xanthan and alginate with clinically-relevant insulin degludec (PIC). The polymeric complexations and interactions were investigated using biophysical methods. Intrinsic viscosity [η] and particle size distribution (PSD) of PIC increased significantly with an increase in temperature, contrary to the individual components indicating possible interactions. [η] trend was X > XA > PIC > A > IDeg. PSD trend was X > A > IDeg > XA > PIC. Zeta (ζ)-potential (with general trend of IDeg < A < XA < X ≈ PIC) revealed stable interaction at lower temperature which gradually changed with an increase in temperature. Likewise, sedimentation velocity indicated stable complexation at lower temperature. With an increase in time and temperature, changes in the number of peaks and area under curve were observed for PIC. Conclusively, stable complexation occurred among the three polymers at 4 • C and 18 • C and the complex dissociated at 37 • C. Therefore, the complex has the potential to be used as a drug delivery vehicle.Polymers 2020, 12, 390 2 of 15 Alginates (A) are linear polymers of 1,4-linked β-D-mannuronic acid residues and 1,4-linked α-L-guluronic residues, containing homo-polymeric sequences [7]. Xanthan (X) is composed of D-glucosyl, D-mannosyl, and D-glucuronyl acid residues in a 2:2:1 molar ratio and variable proportions of O-acetyl and pyruvyl residues. Its main chain consists of β-D-glucose units linked at the 1 and 4 positions. Side-chains consist of a tri-saccharide composed of mannose (β-1,4) glucuronic acid and (β-1,2) mannose, attached to alternate glucose residues in the backbone by α-1,3 linkages [8,9].Xanthan gum and alginate complexes (XA) have been studied previously [10] and used for functional foods [11], tissue engineering [3,12,13] and drug delivery. As negatively charged polymers, xanthan [14][15][16][17] and alginate [18][19][20] have been used separately, and in combination with positively charged polymers such as chitosan, as potential vehicles for insulin delivery.Interactions among different types of protein-polysaccharide complexes (PPCs) have been previously investigated using a variety of methods [21,22]. The formation and dissociation of PPCs and their solubility depend on many factors such as surface charge, pH, temperature and ionic strength of the solvent [23]. These factors greatly influence non-covalent interactions such as electrostatic, H-bonding, hydrophobic, and steric interactions, as well as covalent interactions [24]. Conjugation of polysaccharides with therapeutic proteins is a well-established phenomenon [25]. In particul...

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“…The solution structure of degludec has been studied by both small-angle X-ray scattering (SAXS; Steensgaard et al, 2013) and analytical ultracentrifugation (Adams et al, 2017(Adams et al, , 2018Steensgaard et al, 2013). While there is general agreement that degludec is found as a dihexamer in phenol-containing solutions, different crystal forms show ambiguous intermolecular contacts (Steensgaard et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Solution structures of long-acting insulin analogues and their complexes with albumin

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Sønderby

Barrientos

et al. 2019

Acta Cryst Sect D Struct Biol

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The lipidation of peptide drugs is one strategy to obtain extended half-lives, enabling once-daily or even less frequent injections for patients. The half-life extension results from a combination of self-association and association with human serum albumin (albumin). The self-association and association with albumin of two insulin analogues, insulin detemir and insulin degludec, were investigated by small-angle X-ray scattering (SAXS) and dynamic light scattering (DLS) in phenolic buffers. Detemir shows concentration-dependent self-association, with an equilibrium between hexamer, dihexamer, trihexamer and larger species, while degludec appears as a dihexamer independent of concentration. The solution structure of the detemir trihexamer has a bent shape. The stoichiometry of the association with albumin was studied using DLS. For albumin-detemir the molar stoichiometry was determined to be 1:6 (albumin:detemir ratio) and for albumin-degludec it was between 1:6 and 1:12 (albumin:degludec ratio). Batch SAXS measurements of a 1:6 albumin:detemir concentration series revealed a concentration dependence of complex formation. The data allowed the modelling of a complex between albumin and a detemir hexamer and a complex consisting of two albumins binding to opposite ends of a detemir dihexamer. Measurements of size-exclusion chromatography coupled to SAXS revealed a complex between a degludec dihexamer and albumin. Based on the results, equilibria for the albumin-detemir and albumin-degludec mixtures are proposed.

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Glargine and degludec: Solution behaviour of higher dose synthetic insulins

Cited by 10 publications

References 33 publications

Characterisation of insulin analogues therapeutically available to patients

Characterisation of insulin analogues therapeutically available to patients

Clinically Relevant Insulin Degludec and Its Interaction with Polysaccharides: A Biophysical Examination

Solution structures of long-acting insulin analogues and their complexes with albumin

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