[Arg8]-vasopressin (AVP) is involved in the regulation of glucose homeostasis via vasopressin V1A and vasopressin V1B receptor. Our previous studies have demonstrated that vasopressin V1A receptor deficient (V1AR−/−) mice exhibited hyperglycemia, vasopressin V1B receptor deficient (V1BR−/−) mice, in contrast, exhibited hypoglycemia with hypoinsulinemia. These findings indicate that vasopressin V1A receptor deficiency results in decreased insulin sensitivity, whereas vasopressin V1B receptor deficiency results in increased insulin sensitivity. In our previous and present studies, we used the glucose tolerance test to investigate glucose tolerance in mutant mice, lacking either the vasopressinV1A receptor, the vasopressin V1B receptor, or both receptors, that were kept on a high-fat diet. Glucose and insulin levels were lower in V1BR−/− mice than in wild type (WT) mice when both groups were fed the high-fat diet, which indicates that the insulin sensitivity of the V1BR−/− mice was enhanced. V1AR−/− mice on the high-fat diet, on the other hand, exhibited overt obesity, along with an impaired glucose tolerance, while WT mice on the high-fat diet did not. Next, in order to assess the effect of vasopressin V1B receptor deficiency on the development of glucose intolerance caused by vasopressin V1A receptor deficiency, we generated mice that were deficient for both vasopressin V1A receptor and vasopressin V1B receptor (V1ABR−/−), fed them a high-fat diet, and examined their glucose tolerances using the glucose tolerance test. Glucose tolerance was impaired in V1ABR−/− mice, suggesting that the effects of vasopressin V1B receptor deficiency could not influence the development of hyperglycemia promoted by vasopressin V1A receptor deficiency, and that blockade of both receptors could lead to impaired glucose tolerance.