ArticleJournal of diabetes science and technology2012
Insulin fibrillation and protein design: topological resistance of single-chain analogs to thermal degradation with application to a pump reservoir.
Article in Journal of diabetes science and technology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 41 citations in OpenAlex.
- Pharmacokinetics and postprandial glycemic excursions following insulin lispro delivered by intradermal microneedle or subcutaneous infusion.Journal of diabetes science and technology · 2012Trial
- Immunomodulatory Effects of Insulin-Derived Fibrils from Infusion Pumps: Role of Phenolic Preservatives in Macrophage Activation.Research square · 2026Article
- Damping amyloid-associated conformational fluctuations in a protein by an engineered diselenide bridge.Protein science : a publication of the Protein Society · 2026Article
- Immunomodulatory Effects of Insulin-Derived Fibrils from Infusion Pumps: Role of Phenolic Preservatives in Macrophage Activation.bioRxiv : the preprint server for biology · 2026Article
- Ultrastable Insulin-Glucagon Fusion Protein Exploits an Endogenous Hepatic Switch to Mitigate Hypoglycemic Risk.ACS pharmacology & translational science · 2025Article
- Stabilization of a protein by a single halogen-based aromatic amplifier.Protein science : a publication of the Protein Society · 2025Article
- Semisynthesis of A6-A11 lactam insulin.Journal of peptide science : an official publication of the European Peptide Society · 2024Article
- Structural basis of insulin fibrillation.Science advances · 2023Article
- Single-chain insulin analogs threaded by the insulin receptor αCT domain.Biophysical journal · 2022Article
- Probing the correlation between insulin activity and structural stability through introduction of the rigid A6-A11 bond.The Journal of biological chemistry · 2018Article
- An ultra-stable single-chain insulin analog resists thermal inactivation and exhibits biological signaling duration equivalent to the native protein.The Journal of biological chemistry · 2018Article
- Pump Users Clamor for Faster Insulin: Is Fast-Acting Insulin Aspart Ready for Them?Journal of diabetes science and technology · 2018Article
- Insulin analogues in type 1 diabetes mellitus: getting better all the time.Nature reviews. Endocrinology · 2017Review
- Moving Toward a Unified Platform for Insulin Delivery and Sensing of Inputs Relevant to an Artificial Pancreas.Journal of diabetes science and technology · 2017Review
- Insulin Formulation Characterization-the Thioflavin T Assays.The AAPS journal · 2017Review
- Pursuit of a perfect insulin.Nature reviews. Drug discovery · 2016Review
- Comparison of rechargeable versus battery-operated insulin pumps: temperature fluctuations.Medical devices (Auckland, N.Z.) · 2016Article
- Analyzing insulin samples by size-exclusion chromatography: a column degradation study.Journal of pharmaceutical sciences · 2015Article
- Protective hinge in insulin opens to enable its receptor engagement.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Design of non-standard insulin analogs for the treatment of diabetes mellitus.Current diabetes reports · 2012Review
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Insulin is susceptible to thermal fibrillation, a misfolding process that leads to nonnative cross-β assembly analogous to pathological amyloid deposition. Pharmaceutical formulations are ordinarily protected from such degradation by sequestration of the susceptible monomer within native protein assemblies. With respect to the safety and efficacy of insulin pumps, however, this strategy imposes an intrinsic trade-off between pharmacokinetic goals (rapid absorption and clearance) and the requisite physical properties of a formulation (prolonged shelf life and stability within the reservoir). Available rapid-acting formulations are suboptimal in both respects; susceptibility to fibrillation is exacerbated even as absorption is delayed relative to the ideal specifications of a closed-loop system. To circumvent this molecular trade-off, we exploited structural models of insulin fibrils and amyloidogenic intermediates to define an alternative protective mechanism. Single-chain insulin (SCI) analogs were shown to be refractory to thermal fibrillation with maintenance of biological activity for more than 3 months under conditions that promote the rapid fibrillation and inactivation of insulin. The essential idea exploits an intrinsic incompatibility between SCI topology and the geometry of cross-β assembly. A peptide tether was thus interposed between the A- and B-chains whose length was (a) sufficiently long to provide the "play" needed for induced fit of the hormone on receptor binding and yet (b) sufficiently short to impose a topological barrier to fibrillation. Our findings suggest that ultrastable monomeric SCI analogs may be formulated without protective self-assembly and so permit simultaneous optimization of pharmacokinetics and reservoir life.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.