Effect of Environmental Factors on the Kinetics of Insulin Fibril Formation:  Elucidation of the Molecular Mechanism

In the search for the molecular mechanism of insulin fibrillation, the kinetics of insulin fibril formation were studied under different conditions using the fluorescent dye thioflavin T (ThT). The effect of insulin concentration, agitation, pH, ionic strength, anions, seeding, and addition of 1-ani...

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Veröffentlicht in:Biochem.40:6036,2001 2001, 2001-05, Vol.40 (20), p.6036-6046
Hauptverfasser: Nielsen, Liza, Khurana, Ritu, Coats, Alisa, Frokjaer, Sven, Brange, Jens, Vyas, Sandip, Uversky, Vladimir N, Fink, Anthony L
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container_end_page 6046
container_issue 20
container_start_page 6036
container_title Biochem.40:6036,2001
container_volume 40
creator Nielsen, Liza
Khurana, Ritu
Coats, Alisa
Frokjaer, Sven
Brange, Jens
Vyas, Sandip
Uversky, Vladimir N
Fink, Anthony L
description In the search for the molecular mechanism of insulin fibrillation, the kinetics of insulin fibril formation were studied under different conditions using the fluorescent dye thioflavin T (ThT). The effect of insulin concentration, agitation, pH, ionic strength, anions, seeding, and addition of 1-anilinonaphthalene-8-sulfonic acid (ANS), urea, TMAO, sucrose, and ThT on the kinetics of fibrillation was investigated. The kinetics of the fibrillation process could be described by the lag time for formation of stable nuclei (nucleation) and the apparent rate constant for the growth of fibrils (elongation). The addition of seeds eliminated the lag phase. An increase in insulin concentration resulted in shorter lag times and faster growth of fibrils. Shorter lag times and faster growth of fibrils were seen at acidic pH versus neutral pH, whereas an increase in ionic strength resulted in shorter lag times and slower growth of fibrils. There was no clear correlation between the rate of fibril elongation and ionic strength. Agitation during fibril formation attenuated the effects of insulin concentration and ionic strength on both lag times and fibril growth. The addition of ANS increased the lag time and decreased the apparent growth rate for insulin fibril formation. The ANS-induced inhibition appears to reflect the formation of amorphous aggregates. The denaturant, urea, decreased the lag time, whereas the stabilizers, trimethylamine N-oxide dihydrate (TMAO) and sucrose, increased the lag times. The results indicated that both nucleation and fibril growth were controlled by hydrophobic and electrostatic interactions. A kinetic model, involving the association of monomeric partially folded intermediates, whose concentration is stimulated by the air−water interface, leading to formation of the critical nucleus and thence fibrils, is proposed.
doi_str_mv 10.1021/bi002555c
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Shorter lag times and faster growth of fibrils were seen at acidic pH versus neutral pH, whereas an increase in ionic strength resulted in shorter lag times and slower growth of fibrils. There was no clear correlation between the rate of fibril elongation and ionic strength. Agitation during fibril formation attenuated the effects of insulin concentration and ionic strength on both lag times and fibril growth. The addition of ANS increased the lag time and decreased the apparent growth rate for insulin fibril formation. The ANS-induced inhibition appears to reflect the formation of amorphous aggregates. The denaturant, urea, decreased the lag time, whereas the stabilizers, trimethylamine N-oxide dihydrate (TMAO) and sucrose, increased the lag times. The results indicated that both nucleation and fibril growth were controlled by hydrophobic and electrostatic interactions. 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(US)</creatorcontrib><creatorcontrib>Stanford Linear Accelerator Center, Menlo Park, CA (US)</creatorcontrib><title>Effect of Environmental Factors on the Kinetics of Insulin Fibril Formation:  Elucidation of the Molecular Mechanism</title><title>Biochem.40:6036,2001</title><addtitle>Biochemistry</addtitle><description>In the search for the molecular mechanism of insulin fibrillation, the kinetics of insulin fibril formation were studied under different conditions using the fluorescent dye thioflavin T (ThT). The effect of insulin concentration, agitation, pH, ionic strength, anions, seeding, and addition of 1-anilinonaphthalene-8-sulfonic acid (ANS), urea, TMAO, sucrose, and ThT on the kinetics of fibrillation was investigated. The kinetics of the fibrillation process could be described by the lag time for formation of stable nuclei (nucleation) and the apparent rate constant for the growth of fibrils (elongation). The addition of seeds eliminated the lag phase. An increase in insulin concentration resulted in shorter lag times and faster growth of fibrils. Shorter lag times and faster growth of fibrils were seen at acidic pH versus neutral pH, whereas an increase in ionic strength resulted in shorter lag times and slower growth of fibrils. There was no clear correlation between the rate of fibril elongation and ionic strength. Agitation during fibril formation attenuated the effects of insulin concentration and ionic strength on both lag times and fibril growth. The addition of ANS increased the lag time and decreased the apparent growth rate for insulin fibril formation. The ANS-induced inhibition appears to reflect the formation of amorphous aggregates. The denaturant, urea, decreased the lag time, whereas the stabilizers, trimethylamine N-oxide dihydrate (TMAO) and sucrose, increased the lag times. The results indicated that both nucleation and fibril growth were controlled by hydrophobic and electrostatic interactions. 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The kinetics of the fibrillation process could be described by the lag time for formation of stable nuclei (nucleation) and the apparent rate constant for the growth of fibrils (elongation). The addition of seeds eliminated the lag phase. An increase in insulin concentration resulted in shorter lag times and faster growth of fibrils. Shorter lag times and faster growth of fibrils were seen at acidic pH versus neutral pH, whereas an increase in ionic strength resulted in shorter lag times and slower growth of fibrils. There was no clear correlation between the rate of fibril elongation and ionic strength. Agitation during fibril formation attenuated the effects of insulin concentration and ionic strength on both lag times and fibril growth. The addition of ANS increased the lag time and decreased the apparent growth rate for insulin fibril formation. The ANS-induced inhibition appears to reflect the formation of amorphous aggregates. The denaturant, urea, decreased the lag time, whereas the stabilizers, trimethylamine N-oxide dihydrate (TMAO) and sucrose, increased the lag times. The results indicated that both nucleation and fibril growth were controlled by hydrophobic and electrostatic interactions. A kinetic model, involving the association of monomeric partially folded intermediates, whose concentration is stimulated by the air−water interface, leading to formation of the critical nucleus and thence fibrils, is proposed.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>11352739</pmid><doi>10.1021/bi002555c</doi><tpages>11</tpages></addata></record>
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subjects Anilino Naphthalenesulfonates - chemistry
Animals
Anions - chemistry
Cattle
Chemistry, Physical - methods
Excipients - chemistry
Fluorescent Dyes - chemistry
Hydrogen-Ion Concentration
INSULIN
Insulin - chemistry
Insulin - metabolism
KINETICS
Methylamines - chemistry
Models, Chemical
Osmolar Concentration
PARTICLE ACCELERATORS
Protein Denaturation
Salts - chemistry
Sonication
STANFORD LINEAR ACCELERATOR CENTER
STANFORD SYNCHROTRON RADIATION LABORATORY
Sucrose - chemistry
Surface Properties
SYNCHROTRON RADIATION
Thiazoles - chemistry
Urea - chemistry
title Effect of Environmental Factors on the Kinetics of Insulin Fibril Formation:  Elucidation of the Molecular Mechanism
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