Taveau Christopher, Chollet Catherine, Bichet Daniel G, Velho Gilberto, Guillon Gilles, Corbani Maithe, Roussel Ronan, Bankir Lise, Melander Olle, Bouby Nadine
Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers, Paris, France.
Université Pierre et Marie Curie, Paris, France.
Am J Physiol Endocrinol Metab. 2017 Mar 1;312(3):E127-E135. doi: 10.1152/ajpendo.00269.2016. Epub 2016 Dec 20.
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.
近期的流行病学研究揭示了低饮水量或高血管加压素（AVP）与高血糖和糖尿病风险之间的新关系。AVP V1和V2受体（R）分别在肝脏和胰岛中表达。本研究旨在确定不同水平的循环AVP对正常斯普拉格-道利大鼠葡萄糖稳态的影响，以及V1R和V2R各自的作用。我们发现急性注射AVP会导致血糖呈剂量依赖性升高。用选择性V1R拮抗剂而非V2R拮抗剂进行预处理可剂量依赖性地预防血糖升高。V1R拮抗作用并未改变AVP诱导的高血糖所致的高胰岛素反应，但增强了胰高血糖素血症的下降。急性给予选择性V1R或V2R激动剂证实了V1R参与了AVP的高血糖作用。在慢性实验中，AVP水平在两个方向上都发生了改变。通过可植入微型泵持续输注AVP会导致空腹血糖随时间增加，而通过增加饮水量降低内源性AVP则没有效果。输注AVP 4周后，血糖升高达1.1 mmol/L（P<0.01），胰岛素血症无显著变化。这种作用可通过与V1R拮抗剂联合治疗而减弱。在瘦型 Zucker 大鼠中也观察到了类似结果。这些发现首次证明了慢性高AVP通过V1R激活与高血糖之间存在因果联系，并因此为人类队列中观察到的AVP-水合轴与糖尿病风险之间的关系提供了病理生理学解释。
