Acute and chronic hyperglycemic effects of vasopressin in normal rats: involvement of V1A receptors
American Journal of Physiology. Endocrinology and Metabolism
Recent epidemiological studies have revealed novel relationships between low water intake or high vasopressin (AVP) and the risk of hyperglycemia and diabetes. AVP V1A and V1B receptors (R) are expressed in the liver and pancreatic islets, respectively. The present study was designed to determine the impact of different levels of circulating AVP on glucose homeostasis in normal Sprague-Dawley rats, as well as the respective roles of V1AR and V1BR. We showed that acute injection of AVP induces a
... on of AVP induces a dosedependent increase in glycemia. Pretreatment with a selective V 1AR antagonist, but not a V 1BR antagonist, dose-dependently prevented the rise in glycemia. V 1BR antagonism did not modify the hyperinsulinemic response, resulting from AVP-induced hyperglycemia, but enhanced the fall in glucagonemia. Acute administration of selective V 1AR or V1BR agonists confirmed the involvement of V1AR in the hyperglycemic effect of AVP. In chronic experiments, AVP levels were altered in both directions. Sustained AVP infusion through implantable minipumps induced a time-dependent increase in fasting glycemia, whereas lowering endogenous AVP by increasing water intake had no effect. After 4 wk of AVP infusion, the rise in glycemia amounted to 1.1 mmol/l (P Ͻ 0.01) without significant change in insulinemia. This effect was attenuated by cotreatment with a V 1AR antagonist. Similar results were observed in lean Zucker rats. These findings demonstrate for the first time a causal link between chronic high AVP and hyperglycemia through V 1AR activation and, thus, provide a pathophysiological explanation for the relationship observed in human cohorts between the AVP-hydration axis and the risk of diabetes. vasopressin V 1A receptor; vasopressin V1B receptor; glycemia; insulin; glucagon THE NEUROHYPOPHYSIAL HORMONE arginine vasopressin (AVP), via its three receptor types referred as V 1A , V 1B , and V 2 receptors (V 1A R, V 1B R, and V 2 R, respectively), is essential for a wide range of physiological functions, including body fluid homeostasis, cardiovascular homeostasis, and social and stress behavior. In addition, several studies suggest a role of AVP in glucose homeostasis by peripheral effects. AVP has been shown to stimulate hepatic gluconeogenesis and glycogenolysis through the activation of V 1A R, and the secretion of glucagon or insulin through the activation of pancreatic V 1B R (1, 23, 25, 60). Furthermore, AVP acts synergistically with the corticotropin-releasing hormone (CRH) through direct molecular interactions between V 1B R and CRH receptor 1 to regulate ACTH, insulin, and catecholamine release from the pituitary, pancreas, and adrenal medulla, respectively (2, 21, 31, 34, 51) . Whereas acute AVP infusion in the rat and in healthy individuals induces a transient rise in blood glucose concentration (24, 42, 53) , the studies on the role of AVP and AVP receptors on the long-term regulation of blood glucose reported conflicting results. AVP-deficient homozygous Brattleboro rats with central diabetes insipidus show a higher plasma glucose and lower insulin levels than control Long-Evans rats (32), but an enhanced glucose tolerance compared with heterozygous Brattleboro rats (33). On the other hand, genetic inactivation of both V 1A R and V 1B R in mice leads to alterations of glucose tolerance. Mice with genetic inactivation of either V 1A R or V 1B R display opposite phenotypes with either higher or lower fasting glycemia, respectively, than wild type (3, 18). The decreased insulin sensitivity observed in mice lacking V 1A R or lacking both V 1A R and V 1B R suggests a larger contribution to glucose metabolism of V 1A R than V 1B R (32). The present investigation was designed to determine in vivo the acute and long-term impact on glucose homeostasis of various levels of circulating AVP and the respective role of V 1A R and V 1B R in these effects in two strains of normal rats. AVP level was altered chronically in both directions by either AVP infusion or an increase in water intake. Selective pharmacological tools were used to determine the respective role of V 1A R and V 1B R.