HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 293/6/E1656    most recent 00318.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (14) Citing Articles via Google Scholar Google Scholar Articles by Huang, C.-j. Articles by Butler, P. C. Search for Related Content PubMed PubMed Citation Articles by Huang, C.-j. Articles by Butler, P. C.

Induction of endoplasmic reticulum stress-induced β-cell apoptosis and accumulation of polyubiquitinated proteins by human islet amyloid polypeptide

¹Larry Hillblom Islet Research Center, David Geffen School of Medicine, UCLA, Los Angeles, California; and ²Pfizer Global Research and Development, Pfizer Inc., Groton, Connecticut

Submitted 22 May 2007 ; accepted in final form 26 September 2007

The islet in type 2 diabetes is characterized by an 60% β-cell deficit, increased β-cell apoptosis, and islet amyloid derived from islet amyloid polypeptide (IAPP). Human IAPP (hIAPP) but not rodent IAPP (rIAPP) forms toxic oligomers and amyloid fibrils in an aqueous environment. We previously reported that overexpression of hIAPP in transgenic rats triggered endoplasmic reticulum (ER) stress-induced apoptosis in β-cells. In the present study, we sought to establish whether the cytotoxic effects of hIAPP depend on its propensity to oligomerize, rather than as a consequence of protein overexpression. To accomplish this, we established a novel homozygous mouse model overexpressing rIAPP at a comparable expression rate and, on the same background, as a homozygous transgenic hIAPP mouse model previously reported to develop diabetes associated with β-cell loss. We report that by 10 wk of age hIAPP mice develop diabetes with a deficit in β-cell mass due to increased β-cell apoptosis. The rIAPP transgenic mice counterparts do not develop diabetes or have decreased β-cell mass. Both rIAPP and hIAPP transgenic mice have increased expression of BiP, but only hIAPP transgenic mice have elevated ER stress markers (X-box-binding protein-1, nuclear localized CCAAT/enhancer binding-protein homologous protein, active caspase-12, and accumulation of ubiquitinated proteins). These findings indicate that the β-cell toxic effects of hIAPP depend on the propensity of IAPP to aggregate, but not on the consequence of protein overexpression.

diabetes; ubiquitinated proteins

This article has been cited by other articles:

				A. V. Matveyenko, T. Gurlo, M. Daval, A. E. Butler, and P. C. Butler Successful Versus Failed Adaptation to High-Fat Diet-Induced Insulin Resistance: The Role of IAPP-Induced {beta}-Cell Endoplasmic Reticulum Stress Diabetes, April 1, 2009; 58(4): 906 - 916. [Abstract] [Full Text] [PDF]

				T. Hartley, J. Brumell, and A. Volchuk Emerging roles for the ubiquitin-proteasome system and autophagy in pancreatic {beta}-cells Am J Physiol Endocrinol Metab, January 1, 2009; 296(1): E1 - E10. [Abstract] [Full Text] [PDF]