Insulin amyloid polymorphs: implications for iatrogenic cytotoxicity

Yuzu, Keisuke; Lindgren, Mikael; Nyström, Sofie; Zhang, Jun; Mori, Wakako; Kunitomi, Risako; Nagase, Terumasa; Iwaya, Keiichi; Hammarström, Per; Zako, Tamotsu

doi:10.1039/d0ra07742a

Cited by 17 publications

(19 citation statements)

References 30 publications

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“…To confirm the formation of two different types of amyloids from human insulin, the structure and toxicity of incubated insulin samples were evaluated using pFTAA and BTD21, and MTT assays, respectively. pFTAA and BTD21 can be utilized to recognize structural polymorphs of bovine insulin fibrils and filaments in fluorescence assays 19 . Following our previous approach, we carried out the formation of human insulin amyloids without TCEP ((i)-amyloid) or with a reducing reagent, TCEP ((r)-amyloid).…”

Section: Resultsmentioning

confidence: 99%

“…In this study, the minocycline-induced degradation of amyloid formed by insulin preparations was examined by BTD21, BCA, and MTT assays as described above. Since our previous studies showed that the insulin analogs lispro and detemir formed less-toxic amyloids that were detected with BTD21 19 , these analogs were used for further study. The amyloids formed by lispro and detemir were incubated with minocycline and were evaluated based on their fluorescent signal in the BTD21 assay (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Herein, we also demonstrate that human insulin can form toxic amyloid from intact insulin ((i)-amyloid), and less toxic amyloid formed by insulin treated with reducing reagents ((r)-amyloid). Although (r)-amyloid was formed at unphysiological condition, our previous study showed that both types of amyloids were formed from some insulin preparations and also in patients’ insulin ball tissues 19 . Thus, we used these human insulin amyloids as a model of insulin balls.…”

Section: Introductionmentioning

confidence: 90%

“…Previously, we showed that bovine insulin could form two types of amyloids under different solvent conditions: toxic fibrils and less toxic filaments, which formed in the presence of a reducing reagent 15 . Certain amyloid-specific luminescent-conjugated oligothiophenes (LCOs) such as pFTAA, and benzothiadiazole (BTD) derivatives 16 , could discriminate between the two different insulin amyloids 17 – 19 . Herein, we also demonstrate that human insulin can form toxic amyloid from intact insulin ((i)-amyloid), and less toxic amyloid formed by insulin treated with reducing reagents ((r)-amyloid).…”

Section: Introductionmentioning

confidence: 99%

“…Thus, we used these human insulin amyloids as a model of insulin balls. We also used amyloids formed from typical insulin analogs (lispro and detemir) as a model of insulin balls 19 – 21 . Doxycycline has been shown to have a degrading effect on the β2-microglobulin amyloid 22 .…”

Section: Introductionmentioning

confidence: 99%

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Degradation of insulin amyloid by antibiotic minocycline and formation of toxic intermediates

Mori

Yuzu

Lobsiger

et al. 2021

Sci Rep

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Insulin balls, localized insulin amyloids formed at subcutaneous insulin-injection sites in patients with diabetes, cause poor glycemic control owing to impairments in insulin absorption. Our previous study has shown that some insulin balls are cytotoxic, but others are not, implying amyloid polymorphism. Interestingly, the patient with toxic insulin balls had been treated with antibiotic minocycline, suggesting a possible relationship between toxicity of insulin balls and minocycline. However, the direct effect of minocycline on the structure and cytotoxicity of the insulin amyloid is still unclear. Herein, we demonstrated that that minocycline at physiological concentrations induced degradation of insulin amyloids formed from human insulin and insulin drug preparations used for diabetes patients. Interestingly, the process involved the initial appearance of the toxic species, which subsequently changed into less-toxic species. It is also shown that the structure of the toxic species was similar to that of sonicated fragments of human insulin amyloids. Our study shed new light on the clarification of the revelation of insulin balls and the development of the insulin analogs for diabetes therapy.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Degradation of insulin amyloid by antibiotic minocycline and formation of toxic intermediates

Mori

Yuzu

Lobsiger

et al. 2021

Sci Rep

Self Cite

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Spectroscopic Response of Chiral Proteophenes Binding to Two Chiral Insulin Amyloids

Watanabe,

Swaminathan,

Björk

et al. 2024

ChemPhotoChem

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We recently reported on 8 different pentameric oligothiophenes, denoted proteophenes, with different amino acid substitution patterns along the conjugated thiophene backbone. The proteophenes were forming chiral both molecular (solvent dissolved) and self‐assembled nano‐architectonic structures, the latter having approximately 5‐6 times greater ICD responses. Herein, two proteophenes, HS‐84‐E‐E and HS‐84‐K‐K, were further investigated in terms of binding to two chiral variants of insulin amyloid fibrils. Binding curves based on fluorescence revealed strong primary binding sites for both proteophenes and more unspecific secondary binding for especially the latter. Interestingly, their induced circular dichroism (ICD) responses were similar to or stronger than for their solvent form and showed a complicated alteration upon binding suggesting that the microstructure at the binding site governs the helical structure of the ligand. Hyperspectral fluorescence microscopy and FLIM revealed more details on the molecular binding in terms of proteophene emission decay‐times. Vibrational circular dichroism (VCD) analysis showed that VCD signal of amyloid fibrils was enhanced upon binding of proteophenes, suggesting changes in the amyloid microstructures.

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Comparative study of the hydrophobic interaction effect of pH and ionic strength on aggregation/emulsification of Congo red and amyloid fibrillation of insulin

et al. 2022

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Insulin amyloid polymorphs: implications for iatrogenic cytotoxicity

Abstract: Structural polymorphism of insulin amyloids in vivo can be recognized using novel amyloid specific fluorescent probes, pFTAA and BTD21.

Cited by 17 publications

References 30 publications

Degradation of insulin amyloid by antibiotic minocycline and formation of toxic intermediates

Degradation of insulin amyloid by antibiotic minocycline and formation of toxic intermediates

Spectroscopic Response of Chiral Proteophenes Binding to Two Chiral Insulin Amyloids

Comparative study of the hydrophobic interaction effect of pH and ionic strength on aggregation/emulsification of Congo red and amyloid fibrillation of insulin

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