Two adiponectin receptors were recently identified, AdipoR1 and R2. AdipoR1 expression was increased approximately 2.5-fold in muscle tissues from insulin-deficient diabetic mice, but normalized with insulin administration. AdipoR1 expression was decreased by 44% in insulin-resistant obese, as compared to lean, mice. These results indicate AdipoR1 expression to correlate inversely with plasma insulin levels. Insulin treatment for 24 h decreased AdipoR1 expression by approximately 60% in C2C12 myocytes. In addition, this effect was mediated by the phosphatidylinositol-3 kinase/Foxo 1 dependent pathway. In contrast, AdipoR2 expression was not significantly altered in diabetic states. Our results indicate that regulation of AdipoR1, but not AdipoR2, may be involved in glucose and lipid metabolism in diabetic states.