| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Regular Articles |
From the Division of Endocrinology, Departments of
Medicine*
and Biochemistry & Molecular
Biology,
Mayo Clinic, Rochester, Minnesota
Human islet amyloid polypeptide (hIAPP) is co-secreted with insulin from pancreatic islet ß cells. This peptide spontaneously aggregates in the form of fibrils, and amyloid deposits are associated with dead or degenerating ß cells, a hallmark of noninsulin-dependent diabetes mellitus. We demonstrated that COS-1 cells transfected with vectors expressing hIAPP exhibited intracellular amyloid deposits that were associated with cell death (O'Brien, Butler, Kreutter, Kane, Eberhardt, Am J Pathol 1995, 147:609–616). To establish the mechanism of cell death, we transfected COS-1 cells with vectors expressing amyloidogenic hIAPP or nonamyloidogenic rat IAPP and mutant hIAPP constructs and assayed them for markers characteristic of apoptosis and necrosis by fluorescence-activated cell sorting analysis. Amyloidogenic hIAPP-transfected COS cells contained up to threefold more apoptotic cells present at 96 hours after transfection compared with the nonamyloidogenic vector controls. The hIAPP-induced apoptosis was negligible at 24 and 48 hours after transfection and was maximal at 96 hours which parallels the time course of amyloidogenesis. Immunohistochemical staining and confocal microscopy showed that hIAPP is localized with distinct clustering in the endoplasmic reticulum and Golgi apparatus with no discernable extracellular staining. These experiments provide direct evidence that intracellular hIAPP amyloid causes cell death by triggering apoptotic pathways.
This article has been cited by other articles:
 |
|
 |
|
  M. Apostolidou, S. A. Jayasinghe, and R. Langen Structure of {alpha}-Helical Membrane-bound Human Islet Amyloid Polypeptide and Its Implications for Membrane-mediated Misfolding J. Biol. Chem., June 20, 2008; 283(25): 17205 - 17210. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. F. M. Engel, L. Khemtemourian, C. C. Kleijer, H. J. D. Meeldijk, J. Jacobs, A. J. Verkleij, B. de Kruijff, J. A. Killian, and J. W. M. Hoppener Membrane damage by human islet amyloid polypeptide through fibril growth at the membrane PNAS, April 22, 2008; 105(16): 6033 - 6038. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Marzban, C. J. Rhodes, D. F. Steiner, L. Haataja, P. A. Halban, and C. B. Verchere Impaired NH2-Terminal Processing of Human Proislet Amyloid Polypeptide by the Prohormone Convertase PC2 Leads to Amyloid Formation and Cell Death. Diabetes, August 1, 2006; 55(8): 2192 - 2201. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. F. Paulsson and G. T. Westermark Aberrant Processing of Human Proislet Amyloid Polypeptide Results in Increased Amyloid Formation Diabetes, July 1, 2005; 54(7): 2117 - 2125. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. E. Butler, J. Janson, W. C. Soeller, and P. C. Butler Increased {beta}-Cell Apoptosis Prevents Adaptive Increase in {beta}-Cell Mass in Mouse Model of Type 2 Diabetes: Evidence for Role of Islet Amyloid Formation Rather Than Direct Action of Amyloid Diabetes, September 1, 2003; 52(9): 2304 - 2314. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Sakagashira, H. J. Hiddinga, K. Tateishi, T. Sanke, T. Hanabusa, K. Nanjo, and N. L. Eberhardt S20G Mutant Amylin Exhibits Increased in Vitro Amyloidogenicity and Increased Intracellular Cytotoxicity Compared to Wild-Type Amylin Am. J. Pathol., December 1, 2000; 157(6): 2101 - 2109. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. W.M. Hoppener, B. Ahren, and C. J.M. Lips Islet Amyloid and Type 2 Diabetes Mellitus N. Engl. J. Med., August 10, 2000; 343(6): 411 - 419. [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
