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. The current knowledge of the molecular differences between resistant and susceptible β-cells is very poor. Here, we investigated the time-dependent islet gene expression changes in mouse models of obesity with opposing diabetes disposition in order to study the mechanisms of β-cell compensation (diabetes-resistant ob/ob mice) and failure (diabetes-prone db/db mice). Islets were isolated from pre-diabetic (6-week-old) and diabetic (16-week-old) db/db and non-diabetic ob/ob mice, and their respective age-matched control mice, and RNA was analysed by RT-PCR. Unexpectedly, expressions of the adaptive unfolded protein response (UPR) genes were induced in 6-week-old db/db and ob/ob mouse islets. This indicates that ER stress precedes diabetes in susceptible β-cells, but also that it is present in robust islets. With time, adaptive 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 anti-oxidant genes displayed time-dependent upregulation in db/db islets, but were unchanged in ob/ob islets. Treatment of db/db mouse islets ex vivo with the chemical chaperone 4-phenylbutyric acid (PBA) for 24 h partially restored changes in several β-cell function genes and transcription factors, but did not affect inflammation or anti-oxidant gene expressions. 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.