title: Inhibition of insulin amyloid fibril formation by cyclodextrins.
abstract: Localized insulin-derived amyloid masses occasionally form at the site of repeated insulin injections in patients with insulin-dependent diabetes and cause subcutaneous insulin resistance. Various kinds of insulin including porcine insulin, human insulin, and insulin analogues reportedly formed amyloid fibrils in vitro and in vivo, but the impact of the amino acid replacement in insulin molecules on amyloidogenicity is largely unknown. In the present study, we demonstrated the difference in amyloid fibril formation kinetics of human insulin and insulin analogues, which suggests an important role of the C-terminal domain of the insulin B chain in nuclear formation of amyloid fibrils. Furthermore, we determined that cyclodextrins, which are widely used as drug carriers in the pharmaceutical field, had an inhibitory effect on the nuclear formation of insulin amyloid fibrils. These findings have significant implications for the mechanism underlying insulin amyloid fibril formation and for developing optimal additives to prevent this subcutaneous adverse effect.
authors.affiliation: a Department of Neurology , Graduate School of Medical Sciences, Kumamoto University , Kumamoto , Japan .
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kitagawa
authors.forename: Yohei
authors.initials: Y
authors.lastname: Misumi
authors.forename: Mitsuharu
authors.initials: M
authors.lastname: Ueda
authors.forename: Yuya
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Tasaki
authors.forename: Konen
authors.initials: K
authors.lastname: Obayashi
authors.forename: Taro
authors.initials: T
authors.lastname: Yamashita
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Jono
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Arima
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ando
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000737:chemistry; D052160:Benzothiazoles; D003505:Cyclodextrins / Q000737:chemistry*; D005456:Fluorescent Dyes; D006801:Humans; D007328:Insulin / Q000737:chemistry*; D061267:Insulin Aspart / Q000737:chemistry*; D000069057:Insulin Detemir / Q000737:chemistry*; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011994:Recombinant Proteins / Q000737:chemistry; D012996:Solutions; D013050:Spectrometry, Fluorescence; D013844:Thiazoles
chemical_list: D000682:Amyloid; D052160:Benzothiazoles; D003505:Cyclodextrins; D005456:Fluorescent Dyes; D007328:Insulin; D011994:Recombinant Proteins; D012996:Solutions; D013844:Thiazoles; C009462:thioflavin T; D000069057:Insulin Detemir; D061267:Insulin Aspart
keywords: Amyloid; cyclodextrins; insulin; insulin analogue; insulin ball