Induction of endoplasmic reticulum stress-induced beta-cell apoptosis and accumulation of polyubiquitinated proteins by human islet amyloid polypeptide.
The islet in type 2 diabetes is characterized by an approximately 60% beta-cell deficit, increased beta-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 beta-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 beta-cell loss. We report that by 10 wk of age hIAPP mice develop diabetes with a deficit in beta-cell mass due to increased beta-cell apoptosis. The rIAPP transgenic mice counterparts do not develop diabetes or have decreased beta-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 beta-cell toxic effects of hIAPP depend on the propensity of IAPP to aggregate, but not on the consequence of protein overexpression.
Huang
Chang-Jiang
CJ
Larry Hillblom Islet Research Center, UCLA David Geffen School of Medicine, 900 Weyburn Pl. #A, Los Angeles, CA 90024, USA.
Haataja
Leena
L
Gurlo
Tatyana
T
Butler
Alexandra E
AE
Wu
Xiuju
X
Soeller
Walter C
WC
Butler
Peter C
PC
D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000682:Amyloid / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D053454:Caspase 12 / Q000378:metabolism; D045744:Cell Line, Tumor; D003600:Cytosol / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000502:physiology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D058228:Islet Amyloid Polypeptide; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D025821:Polyubiquitin / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D051381:Rats; D000071701:Regulatory Factor X Transcription Factors; D051742:Transcription Factor CHOP / Q000378:metabolism; D014157:Transcription Factors
D000682:Amyloid; D001786:Blood Glucose; D004268:DNA-Binding Proteins; C497250:Ddit3 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D007328:Insulin; D058228:Islet Amyloid Polypeptide; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D011506:Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D025821:Polyubiquitin; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; C506440:Casp12 protein, mouse; D053454:Caspase 12