The prevalence of obesity and T2DM, have been increasing at an alarming rate, creating a need for new therapeutic strategies. Dietary blueberry consumption has been associated with numerous health benefits, including improved blood sugar regulation. Specifically, previous studies report that blueberry consumption improves blood sugar concentrations both in obese human subjects and in rodent models of obesity. However, the mechanisms by which this occurs remain poorly defined. Interestingly, we have preliminary data demonstrating that chronic whole blueberry consumption preserves pancreatic islet morphology in a prediabetic rat model. Islets contain β-cells which are responsible for the production of insulin, a key hormone responsible for regulation of blood sugar levels. Previous work has reported that dietary blueberry consumption decreases inflammation and oxidative stress, which are critical contributors to the development of type 2 diabetes through the promotion of insulin resistance and β-cell dysfunction and death. Furthermore, oxidative stress and inflammation both promote endoplasmic reticulum (ER) stress which contributes to the development of insulin resistance and β-cell death. Therefore, we will use male high fat diet-fed diet induced obese (DIO) mice to investigate the role of oxidative stress, inflammation and ER stress in blueberry-mediated improvements in blood sugar regulation. We expect blueberry-treated mice to exhibit improved blood sugar regulation and islet function, as reported in previous studies. Consistent with our preliminary data, we expect blueberry-treated mice to exhibit preservation of β-cell morphology. We expect blueberry-induced improvements in β-cell morphology to be associated with reductions in β-cell inflammation, oxidative stress and ER stress. We also expect these three pathways to be ameliorated in liver, resulting in improved insulin sensitivity in this metabolically important organ. The proposed in depth assessment of oxidative stress, inflammation and ER stress will provide highly novel and comprehensive data on the β-cell protective and insulin sensitizing effects ofchronic whole blu eberry consumption. This study will provide compelling evidence to support the health promoting benefits of greater incorporation of whole blueberries in the diet. In particular, the identification and development of therapeutics that can protect β-cells has been notoriously difficult. Therefore, the β-cell protective effect of chronic whole blueberry consumption has the potential to transform the dietary management of the prediabetic state.