Chan, Jeng Yie
[Diabetes and Metabolism Division, Garvan Institute of Medical Research]
Luzuriaga, Jude
[Diabetes and Metabolism Division, Garvan Institute of Medical Research]
Bensellam, Mohammed
[UCL]
Biden, Trevor J
[Diabetes and Metabolism Division, Garvan Institute of Medical Research]
Laybutt, D Ross
[Diabetes and Metabolism Division, Garvan Institute of Medical Research]
The normal β-cell response to obesity-associated insulin resistance is hypersecretion of insulin. Type 2 diabetes develops in subjects with β-cells that are susceptible to failure. Here, we investigated the time-dependent gene expression changes in islets of diabetes-prone db/db and diabetes-resistant ob/ob mice. The expressions of adaptive unfolded protein response (UPR) genes were progressively induced in islets of ob/ob mice, whereas they declined in diabetic db/db mice. Genes important for β-cell function and maintenance of the islet phenotype were reduced with time in db/db mice, whereas they were preserved in ob/ob mice. Inflammation and antioxidant genes displayed time-dependent upregulation in db/db islets but were unchanged in ob/ob islets. Treatment of db/db mouse islets with the chemical chaperone 4-phenylbutyric acid partially restored the changes in several β-cell function genes and transcription factors but did not affect inflammation or antioxidant gene expression. These data suggest that the maintenance (or suppression) of the adaptive UPR is associated with β-cell compensation (or failure) in obese mice. Inflammation, oxidative stress, and a progressive loss of β-cell differentiation accompany diabetes progression. The ability to maintain the adaptive UPR in islets may protect against the gene expression changes that underlie diabetes development in obese mice.
Bibliographic reference |
Chan, Jeng Yie ; Luzuriaga, Jude ; Bensellam, Mohammed ; Biden, Trevor J ; Laybutt, D Ross. Failure of the adaptive unfolded protein response in islets of obese mice is linked with abnormalities in β-cell gene expression and progression to diabetes.. In: Diabetes, Vol. 62, p. 1557-68 (2013) |
Permanent URL |
http://hdl.handle.net/2078/192292 |