[Arg(8)]-vasopressin (AVP) plays a crucial role in regulating body fluid retention, which is mediated through the vasopressin V-2 receptor in the kidney. In addition, AVP is involved in the regulation of glucose homeostasis V-1A vasopressin V-1A and vasopressin V-1B receptors. Our previous studies demonstrated that vasopressin V-1A receptor-deficient (V1AR-/-) and V-1B receptor-deficient (V1BR-/-) mice exhibited hyperglycemia and hypoglycemia with hypoinsulinemia, respectively. These findings indicate that vasopressin V-1A receptor deficiency results in decreased insulin sensitivity whereas vasopressin V-1B receptor deficiency results in increased insulin sensitivity. In addition, vasopressin V-1A and vasopressin V-1B receptor double-deficient (V1ABR-/-) mice exhibited impaired glucose tolerance, suggesting that the effects of vasopressin V-1B receptor deficiency do not influence the development of hyperglycemia promoted by vasopressin V-1A receptor deficiency, and that the blockage of both receptors could lead to impaired glucose tolerance. However, the contributions of the entire AVP/vasopressin receptors system to the regulation of blood glucose have not yet been clarified. In this study, to further understand the role of AVP/vasopressin receptors signaling in blood glucose regulation, we assessed the glucose tolerance of AVP-deficient homozygous Brattleboro (di/di) rats using an oral glucose tolerance test (GTT). Plasma glucose and insulin levels were consistently lower in homozygous di/di rats than in heterozygous di/+ rats during the GTT, suggesting that the blockage of all AVP/vasopressin receptors resulting from the AVP deficiency could lead to enhanced glucose tolerance. (c) 2011 Elsevier Inc. All rights reserved.