Acute and chronic hyperglycemic effects of vasopressin in normal rats: involvement of V_1A receptors

Abstract

Recent epidemiological studies have revealed novel relationships between low water intake or high vasopressin (AVP) and the risk of hyperglycemia and diabetes. AVP V and V 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 VR and VR. We showed that acute injection of AVP induces a dose-dependent increase in glycemia. Pretreatment with a selective VR antagonist, but not a VR antagonist, dose-dependently prevented the rise in glycemia. VR antagonism did not modify the hyperinsulinemic response, resulting from AVP-induced hyperglycemia, but enhanced the fall in glucagonemia. Acute administration of selective VR or VR agonists confirmed the involvement of VR 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 ( < 0.01) without significant change in insulinemia. This effect was attenuated by cotreatment with a VR 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 VR activation and, thus, provide a pathophysiological explanation for the relationship observed in human cohorts between the AVP-hydration axis and the risk of diabetes.

Effects of hydration on plasma copeptin, glycemia and gluco-regulatory hormones: a water intervention in humans

“…VP stimulates glucagon secretion by activation of V1bR in α-cells of pancreatic islets [3] which is concordant with our finding that fasting glucagon concentration was reduced upon water-induced suppression of VP (copeptin). In addition, we recently showed in rodents that during conditions of high VP, selective pharmacological blockade of V1bR with SR149415 resulted in reduction of plasma glucagon [40]. Taken together, our finding that water-induced decrease of copeptin in water-responders is associated with fasting glucagon reduction encourages longterm studies of anti-diabetic effects of water supplementation in subjects with low water intake.…”

Hydration for Health: So What? Ten Advances in Recent Hydration History

“…They also found that specific variants of the AVP gene were also associated with increased risk for hyperglycemia, and that men expressing these variants also had higher plasma copeptin (no association was found in women, who, on average, tend to have lower plasma copeptin than men). This finding is consistent with previous preclinical evidence that AVP contributes to metabolic dysfunction via V1a and V1b receptors expressed in hepatocytes and pancreatic islets, respectively [47][48][49][50].…”

Vasopressin and metabolic disorders: translation from experimental models to clinical use

“…V1bR SSR149415 antagonist did not change the hyperglycaemic response to acute injection AVP, and V1bR agonist d(Leu4, Lys8)VP had no effect on glycaemia. Thus, these results support a major role of V1aR in the humoral control of glycaemia .…”

“…However, whilst V1bR antagonist pretreatment did not change the basal insulinaemia or the insulin response to hyperglycaemia induced by AVP, it enhanced the fall in glucagon secretion after AVP injection . This suggests that endogenous AVP constantly stimulates the glucagon secretion and thus participates in the physiological regulation of glucagon secretion in normal rats.…”

“…We showed that chronic high‐AVP level induced a time‐dependent increase in fasting glycaemia, in two strains of healthy rats, the Sprague Dawley and the lean Zucker rats .…”