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cJUN N-terminal kinase (JNK) activation mediates islet amyloid-induced beta cell apoptosis in cultured human islet amyloid polypeptide transgenic mouse islets

Subramanian, S. L., Hull, R. L., Zraika, S., Aston-Mourney, K., Udayasankar, J. and Kahn, S. E. 2012, cJUN N-terminal kinase (JNK) activation mediates islet amyloid-induced beta cell apoptosis in cultured human islet amyloid polypeptide transgenic mouse islets, Diabetologia, vol. 55, no. 1, pp. 166-174, doi: 10.1007/s00125-011-2338-7.

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Title cJUN N-terminal kinase (JNK) activation mediates islet amyloid-induced beta cell apoptosis in cultured human islet amyloid polypeptide transgenic mouse islets
Author(s) Subramanian, S. L.
Hull, R. L.
Zraika, S.
Aston-Mourney, K.
Udayasankar, J.
Kahn, S. E.
Journal name Diabetologia
Volume number 55
Issue number 1
Start page 166
End page 174
Total pages 9
Publisher Springer
Place of publication Heidelberg , Germany
Publication date 2012-01
ISSN 0012-186X
1432-0428
Keyword(s) Beta cell apoptosis
JNK activation
Islet amyloid
hIAPP
Summary Aims/hypothesis

Aggregation of human islet amyloid polypeptide (hIAPP) as islet amyloid is associated with increased beta cell apoptosis and reduced beta cell mass in type 2 diabetes. Islet amyloid formation induces oxidative stress, which contributes to beta cell apoptosis. The cJUN N-terminal kinase (JNK) pathway is a critical mediator of beta cell apoptosis in response to stress stimuli including oxidative stress and exogenous application of hIAPP. We determined whether amyloid formation by endogenous hIAPP mediates beta cell apoptosis through JNK activation and downstream signalling pathways.
Methods

hIAPP transgenic and non-transgenic mouse islets were cultured for up to 144 h in 16.7 mmol/l glucose to induce islet amyloid in the presence or absence of the amyloid inhibitor Congo Red or a cell-permeable JNK inhibitor. Amyloid, beta cell apoptosis, JNK signalling and activation of downstream targets in the intrinsic and extrinsic apoptotic pathways were measured.
Results

JNK activation occurred with islet amyloid formation in hIAPP transgenic islets after 48 and 144 h in culture. Neither high glucose nor the hIAPP transgene alone was sufficient to activate JNK independent of islet amyloid. Inhibition of islet amyloid formation with Congo Red reduced beta cell apoptosis and partially decreased JNK activation. JNK inhibitor treatment reduced beta cell apoptosis without affecting islet amyloid. Islet amyloid increased mRNA levels of markers of the extrinsic (Fas, Fadd) and intrinsic (Bim [also known as Bcl2l11]) apoptotic pathways, caspase 3 and the anti-apoptotic molecule Bclxl (also known as Bcl2l1) in a JNK-dependent manner.
Conclusions/interpretation

Islet amyloid formation induces JNK activation, which upregulates predominantly pro-apoptotic signals in both extrinsic and intrinsic pathways, resulting in beta cell apoptosis.
Language eng
DOI 10.1007/s00125-011-2338-7
Field of Research 110199 Medical Biochemistry and Metabolomics not elsewhere classified
Socio Economic Objective 920104 Diabetes
HERDC Research category C1.1 Refereed article in a scholarly journal
Persistent URL http://hdl.handle.net/10536/DRO/DU:30049766

Document type: Journal Article
Collection: School of Medicine
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Created: Fri, 07 Dec 2012, 13:35:54 EST by Kathryn Aston-mourney

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