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.

Abstract

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.

• Authors: Jeng Yie Chan, Jude Luzuriaga, Mohammed Bensellam, Trevor J Biden, D Ross Laybutt
• Journal: Diabetes (Diabetes) Vol. 62 Issue 5 Pg. 1557-68 (May 2013) ISSN: 1939-327X [Electronic] United States
• PMID: 23274897 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• Apoptosis Regulatory Proteins
• Cytokines
• Insulin
• Phenylbutyrates
• RNA, Messenger
• 4-phenylbutyric acid
• Oxidoreductases

Topics

• Animals
• Antioxidants (pharmacology)
• Apoptosis Regulatory Proteins (genetics, metabolism)
• Cytokines (genetics, metabolism)
• Diabetes Mellitus, Type 2 (etiology, immunology, metabolism)
• Disease Progression
• Disease Susceptibility
• Down-Regulation (drug effects)
• Gene Expression Regulation (drug effects)
• Insulin (metabolism)
• Insulin Secretion
• Insulin-Secreting Cells (drug effects, immunology, metabolism)
• Islets of Langerhans (drug effects, immunology, metabolism)
• Mice
• Mice, Mutant Strains
• Mice, Obese
• Obesity (immunology, metabolism, physiopathology)
• Oxidoreductases (genetics, metabolism)
• Phenylbutyrates (pharmacology)
• RNA, Messenger (metabolism)
• Tissue Culture Techniques
• Unfolded Protein Response (drug effects)
• Up-Regulation (drug effects)