Vasopressin and hydration play a major role in the development of glucose intolerance and hepatic steatosis in obese rats

Diabetologia Vasopressin and hydration play a major role in the development of glucose intolerance and hepatic steatosis in obese rats Christopher Taveau 1 2 3 4 Catherine Chollet 1 2 3 4 Ludovic Waeckel 1 2 3 4 Dorinne Desposito 1 2 3 4 Daniel G. Bichet 1 2 3 4 Marie-Françoise Arthus 1 2 3 4 Christophe Magnan 1 2 3 4 Erwann Philippe 1 2 3 4 Valerie Paradis 1 2 3 4 Fabienne Foufelle 1 2 3 4 Isabelle Hainault 1 2 3 4 Sofia Enhorning 1 2 3 4 Gilberto Velho 1 2 3 4 Ronan Roussel 1 2 3 4 Lise Bankir 1 2 3 4 Olle Melander 1 2 3 4 Nadine Bouby 1 2 3 4 0 ) Inserm U1138, Centre de Recherche des Cordeliers, 15 rue de l'Ecole de Medecine , 75006 Paris , France 1 R. Roussel Department of Diabetology-Endocrinology-Nutrition, DHU FIRE, Bichat Hospital, AP-HP , Paris , France 2 S. Enhorning 3 V. Paradis Anatomy and Pathology Department, Beaujon Hospital , Paris , France 4 D. G. Bichet Aims/hypothesis High plasma copeptin, a marker of vasopressin (VP) secretion, has been shown to be associated with the metabolic syndrome and development of type 2 diabetes in humans. The present study was designed to determine the long-term influence of plasma VP concentration in a rodent model prone to metabolic dysfunction. Methods Obese Zucker rats and their lean counterparts were submitted for 4 weeks to one of three protocols inducing different levels of VP. Circulating VP was either reduced by increasing the daily water intake (low-VP), or increased by a chronic i.p. infusion of VP (high-VP). The control rats had normal VP levels that depended on their own regulation of water intake and VP secretion. - Conclusion/interpretation These findings show a causal relationship between the VP–hydration axis and the metabolic risk. Therapeutic perspectives include diet recommendations regarding hydration, but also potential pharmacological interventions targeting the VP V1aR. Abbreviations IR Insulin resistance ITT Insulin tolerance test Norm-VP Normal vasopressin V1aR Vasopressin V1a receptor V1bR Vasopressin V1b receptor VP Vasopressin Introduction Although it has been known for several decades that plasma vasopressin (VP) is increased in patients with type 1 or with type 2 diabetes mellitus [ 1 ] and in animal models of diabetes [ 2, 3 ], only recently has the VP–hydration axis emerged as a risk factor for impaired glucose homeostasis and diabetes. An increasing body of data suggests that VP may play a part in glucose homeostasis, besides its well-defined role in urine concentration and body water homeostasis. Acute VP infusion in the rat and in healthy individuals was shown to induce a transient rise in blood glucose concentration [ 4–6 ]. Ex vivo studies showed that VP stimulates gluconeogenesis and glycogenolysis through the activation of hepatic arginine VP receptor 1A (V1aR), and the release of either glucagon or insulin, depending on concomitant extracellular glucose levels, through the activation of arginine vasopressin receptor 1B (V1bR) in pancreatic islets [ 7–9 ]. Furthermore, VP stimulates adrenocorticotropin hormone release through the activation of pituitary V1bR [ 10, 11 ]. The finding that mice with deleted V1aR and/or V1bR exhibit metabolic disorders [ 12–15 ] has prompted several epidemiological investigations in humans. Plasma copeptin, a stable surrogate marker for VP derived from the same preprohormone [ 16 ], has been shown to be associated with insulin resistance, metabolic syndrome and obesity [ 17 ]. High plasma copeptin predicted future diabetes mellitus independently of known risk factors [ 18 ]. The secretion of VP and copeptin strongly depends on the level of hydration. We reported that water intake was inversely and independently associated with the risk of developing hyperglycaemia in a cohort of the general French population [ 19 ]. Additionally, VP was shown to contribute to albuminuria and to diabetes-induced nephropathy in animal models [ 20, 21 ]. Epidemiological studies in humans are consistent with these findings [ 21–23 ]. These observations suggest that a high level of circulating VP has adverse consequences on glucose metabolism, although a causal link between a sustained high level of VP and disorders of glucose homeostasis has not been established. The present investigation was designed to evaluate the longterm impact on glucose homeostasis of various levels of circulating VP. The experiments were performed in obese Zucker rats, a genetic model of insulin resistance, and in their lean controls. VP level was altered chronically in both directions, by either VP infusion or an increase in water intake. We showed that VP impaired tolerance to a glucose load, but also induced a marked rise in plasma glucose after pyruvate administration. Blockade of V1aR reduced glucose intolerance. Unexpectedly, a reduction in plasma VP led to improvement of hepatic lipid metabolism and liver steatosis. Methods Animals and treatments All animal procedures were conducted in accordanc (...truncated)