title: 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.affiliation: Diabetes and Obesity Research Program, Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, New South Wales, Australia.
authors.forename: Jeng Yie
authors.initials: JY
authors.lastname: Chan
authors.forename: Jude
authors.initials: J
authors.lastname: Luzuriaga
authors.forename: Mohammed
authors.initials: M
authors.lastname: Bensellam
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Biden
authors.forename: D Ross
authors.initials: DR
authors.lastname: Laybutt
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology* / Q000276:immunology / Q000378:metabolism; D018450:Disease Progression; D004198:Disease Susceptibility; D015536:Down-Regulation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D008820:Mice, Obese; D009765:Obesity / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology*; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism; D010654:Phenylbutyrates / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D046509:Tissue Culture Techniques; D056811:Unfolded Protein Response / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000975:Antioxidants; D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; D007328:Insulin; D010654:Phenylbutyrates; D012333:RNA, Messenger; C075773:4-phenylbutyric acid; D010088:Oxidoreductases