Adiponectin, a metabolically-active cytokine secreted from adipose tissue, is reported to have anti-apoptotic effects on β-cells as well as anti-hyperglycemic effects through adiponectin receptor signaling. However, the anti-apoptotic effects of adiponectin on β-cells have not been confirmed in established diabetic models, and the anti-hyperglycemic effects and their associated signal cascades remain controversial. To investigate the effects of adiponectin on β-cell protection and its down-stream signaling events, we have generated β-cell-specific rat insulin promoter (RIP)-AdipoR1 transgenic mice (AdipoR1 mice), in which the adiponectin receptor, AdipoR1, is overexpressed in β-cells in a manner synchronous with insulin demand. AdipoR1 mice were then mated with Akita mice, a diabetes model in which β-cell apoptosis results from endoplasmic reticulum (ER) stress. AdipoR1 protein expression and localization in islets from AdipoR1 mice as well as in an AdipoR1-transfected mouse insulinoma cell line were confirmed, as was the activation of both AMPK and Akt in AdipoR1 mice by adiponectin. Nevertheless, there were no significant differences in Ad lib feed and fasting blood glucose levels, or in glucose tolerance tests, between Akita mice [Ins2Akita (C96Y) +/- mouse model] and AdipoR1/Akita and from 4 weeks to 10 weeks of age. Similarly, pancreatic insulin contents of AdipoR1/Akita mice were not significantly different from those in Akita mice from 15 to 20 weeks of age, but they were significantly lower than in wild-type mice. Immunostaining for insulin and subsequent electron microscopy showed that β-cell destruction in AdipoR1/Akita mice was not markedly improved in comparison with that in Akita mice. Serum adiponectin concentrations were confirmed to be extremely high (> 30 μg / ml) compared with the Kd value (0.06 μg / ml) in all mouse groups at 15 to 20 weeks of age. Therefore, although the physiological levels of adiponectin are sufficient to activate AMPK and Akt when AdipoR1 is overexpressed in β-cells, yet adiponectin cannot protect β-cells in Akita mice from ER stress-induced destruction.