Design of Insulin Variants for Improved Treatment of Diabetes

Høeg-Jensen, Thomas

doi:10.1002/9780470749708.ch7

Cited by 5 publications

(3 citation statements)

References 166 publications

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“…During treatment of diabetes, an insulin preparation is injected subcutaneously. After injection, the insulin is believed to possibly take the form of higher-order oligomers and over time dissociate into monomeric insulin, which enters the bloodstream and is biologically active. , The dissociation rate of the injected insulin has a profound effect on the bloodstream insulin level and, consequently, the glucose level and well-being of the diabetes patient . Too high blood glucose, hyperglycemia, can result in micro- and macrovascular damage, and too low, hypoglycemia, can result in coma or death. , Thus, failure to mimic the blood insulin levels of healthy individuals can have severe consequences for the diabetes patient, and one of the long-standing goals of research into insulin-based diabetes treatment has been to imitate the glucose level driven release of insulin present in healthy humans .…”

Section: Introductionmentioning

confidence: 99%

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Structural Insight into the Self-Assembly of a Pharmaceutically Optimized Insulin Analogue Obtained by Small-Angle X-ray Scattering

et al. 2020

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B29Nε-lithocholyl-γ-l-βGlu-desB30 human insulin [NN344] belongs to a group of insulins with fatty acid or sterol modifications. These insulin analogues have been found to form subcutaneous depots upon injection and hereby have a protracted release profile in vivo. In the present study, B29Nε-lithocholyl-γ-l-Glu-desB30 human insulin was investigated using in-solution small-angle X-ray scattering (SAXS) at chemical conditions designed to mimic three stages during treatment in vivo: in-vial/pen, postinjection, and longer times after injection. We found that the specific insulin analogue formed a mixture of mono- and dihexamers under in-vial/pen conditions of low salt and stabilizing phenol. At postinjection, conditions mimicking a subcutaneous depot, B29Nε-lithocholyl-γ-l-Glu-desB30 human insulin, formed very long straight soluble hexamer-based rods stacked along the Zn(II)-axis. The self-assembly was triggered by an increase in salt concentration when going from vial to physiological conditions. Mimicking longer times after injection and the additional removal of phenol caused the length of the rods to decrease significantly. Finally, we found that the self-assembly could be controlled by varying the amount of modification at the interaction interface by making mixed hexamers of B29Nε-lithocholyl-γ-l-Glu-desB30 and desB30 human insulin. This opens extra possibilities for controlling the release profile of very-long-acting insulins.

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Section: Introductionmentioning

confidence: 99%

“…The second class is the long-acting insulin analogues. These are engineered to have a much slower release profile, and hereby mimic the basal insulin level in the blood present between food intake . This kind of delayed release can, for example, be achieved by inducing nanoscale oligomerization of the hexamers into larger structures.…”

Section: Introductionmentioning

confidence: 99%

Structural Insight into the Self-Assembly of a Pharmaceutically Optimized Insulin Analogue Obtained by Small-Angle X-ray Scattering

et al. 2020

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“…In a healthy individual, pancreatic β-cells continuously excrete insulin to maintain plasma glucose levels around 4-6 mM. In patients diagnosed with diabetes mellitus this mechanism is impaired and tight glucose control is imperative to reduce the risks of hypoglycaemic and hyperglycaemic episodes [12]. However, studies have shown that normal human insulin (as well as porcine and bovine insulins) and intermediate-acting insulins like NPH have high variability in terms of pharmacodynamic and pharmacokinetic behaviour in vivo preceding poor glycaemic control [11,23].…”

Section: Introductionmentioning

confidence: 99%

Exploration of temperature and shelf-life dependency of the therapeutically available Insulin Detemir

Beji

Gillis

Dinu

et al. 2020

European Journal of Pharmaceutics and Biopharmaceutics

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Purpose: Insulin, in typical use, undergoes multiple changes in temperature; from refrigerator, to room temperature, to body temperature. Although long-term storage temperature has been well-studied, the short term changes to insulin are yet to be determined. Insulin detemir (IDet) is a clinically available, slow-acting, synthetic analogue characterised by the conjugation of a C14 fatty acid. The function of this modification is to cause the insulin to form multi-hexameric species, thus retarding the pharmacokinetic rate of action. In this investigation, the temperature dependence properties of this synthetic analogue is probed, as well as expiration. Methods: Dynamic light scattering (DLS) and viscometry were employed to assess the effect of temperature upon IDet. Mass spectrometry was also used to probe the impact of shelf-life and the presence of certain excipients. Results: IDet was compared with eight other insulins, including human recombinant, three fast-acting analogues and two other slow-acting analogues. Of all nine insulins, IDet was the only analogue to show temperature dependent behaviour, between 20°C and 37°C, when probed with non-invasive backscatter dynamic light scattering. Upon further investigation, IDet observed significant changes in size related to temperature, direction of temperature (heated/cooled) and expiration with cross-correlation observed amongst all 4 parameters. Conclusions: These findings are critical to our understanding of the behaviour of this particular clinically relevant drug, as it will allow the development of future generations of peptide-based therapies with greater clinical efficacy.

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The ABC of Insulin: The Organic Chemistry of a Small Protein

Østergaard

Mishra

Jensen

2020

Chemistry A European J

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Insulin is a small protein crucial for regulating the blood glucose level in all animals. Since 1922 it has been used for the treatment of patients with diabetes. Despite consisting of just 51 amino acids, insulin contains 17 of the proteinogenic amino acids, A‐ and B‐chains, three disulfide bridges, and it folds with 3 α‐helices and a short β‐sheet segment. Insulin associates into dimers and further into hexamers with stabilization by Zn2+ and phenolic ligands. Selective chemical modification of proteins is at the forefront of developments in chemical biology and biopharmaceuticals. Insulin's structure has made it amenable to organic and inorganic chemical reactions. This Review provides a synthetic organic chemistry perspective on this small protein. It gives an overview of key chemical and physico‐chemical aspects of the insulin molecule, with a focus on chemoselective reactions. This includes N‐acylations at the N‐termini or at LysB29 by pH control, introduction of protecting groups on insulin, binding of metal ions, ligands to control the nano‐scale assembly of insulin, and more.

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Design of Insulin Variants for Improved Treatment of Diabetes

Cited by 5 publications

References 166 publications

Structural Insight into the Self-Assembly of a Pharmaceutically Optimized Insulin Analogue Obtained by Small-Angle X-ray Scattering

Structural Insight into the Self-Assembly of a Pharmaceutically Optimized Insulin Analogue Obtained by Small-Angle X-ray Scattering

Exploration of temperature and shelf-life dependency of the therapeutically available Insulin Detemir

The ABC of Insulin: The Organic Chemistry of a Small Protein

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