title: Biphasic effects of insulin on islet amyloid polypeptide membrane disruption.
abstract: Type II diabetes, in its late stages, is often associated with the formation of extracellular islet amyloid deposits composed of islet amyloid polypeptide (IAPP or amylin). IAPP is stored before secretion at millimolar concentrations within secretory granules inside the β-cells. Of interest, at these same concentrations in vitro, IAPP rapidly aggregates and forms fibrils, yet within secretory granules of healthy individuals, IAPP does not fibrillize. Insulin is also stored within the secretory granules before secretion, and has been shown in vitro to inhibit IAPP fibril formation. Because of insulin's inhibitory effect on IAPP fibrillization, it has been suggested that insulin may also inhibit IAPP-mediated permeabilization of the β-cell plasma membrane in vivo. We show that although insulin is effective at preventing fiber-dependent membrane disruption, it is not effective at stopping the initial phase of membrane disruption before fibrillogenesis, and does not prevent the formation of small IAPP oligomers on the membrane. These results suggest that insulin has a more complicated role in inhibiting IAPP fibrillogenesis, and that other factors, such as the low pH of the secretory granule, may also play a role.
authors.affiliation: Department of Biophysics, University of Michigan, Ann Arbor, Michigan; Department of Chemistry, University of Michigan, Ann Arbor, Michigan.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Brender
authors.affiliation: Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan.
authors.forename: Edgar L
authors.initials: EL
authors.lastname: Lee
authors.affiliation: Department of Biophysics, University of Michigan, Ann Arbor, Michigan; Department of Chemistry, University of Michigan, Ann Arbor, Michigan.
authors.forename: Kevin
authors.initials: K
authors.lastname: Hartman
authors.affiliation: Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan.
authors.forename: Pamela T
authors.initials: PT
authors.lastname: Wong
authors.affiliation: Department of Biophysics, University of Michigan, Ann Arbor, Michigan; Department of Chemistry, University of Michigan, Ann Arbor, Michigan.
authors.forename: Ayyalusamy
authors.initials: A
authors.lastname: Ramamoorthy
authors.affiliation: Department of Biophysics, University of Michigan, Ann Arbor, Michigan; Department of Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, Michigan; Department of Physics, University of Michigan, Ann Arbor, Michigan.
authors.forename: Duncan G
authors.initials: DG
authors.lastname: Steel
authors.affiliation: Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan; Department of Biophysics, University of Michigan, Ann Arbor, Michigan. Electronic address: arigafni@umich.edu.
authors.forename: Ari
authors.initials: A
authors.lastname: Gafni
mesh_terms: D002462:Cell Membrane / Q000187:drug effects*; D002463:Cell Membrane Permeability / Q000187:drug effects; D003432:Cross-Linking Reagents / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D058228:Islet Amyloid Polypeptide / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D020836:Protein Structure, Quaternary; D012996:Solutions; D013997:Time Factors; D053835:Unilamellar Liposomes / Q000378:metabolism
chemical_list: D003432:Cross-Linking Reagents; D007328:Insulin; D058228:Islet Amyloid Polypeptide; D012996:Solutions; D053835:Unilamellar Liposomes