The Vasopressin System in the Risk of Diabetes and Cardiorenal Disease, and Hydration as a Potential Lifestyle Intervention

Abstract

Background: Type 2 diabetes, chronic kidney disease (CKD) and its cardiovascular complications are increasing as health problems worldwide. These diseases are interrelated with overlapping occurrence and once diabetes is established, the risk of cardiorenal disease is dramatically elevated. Thus, a search for unifying modifiable risk factors is key for effective prevention. Summary: Elevated fasting plasma concentration of vasopressin, measured with the marker copeptin, predicts new onset type 2 diabetes as well as renal function decline. Furthermore, we recently showed that increased plasma copeptin concentration independently predicts the development of both CKD and other specified kidney diseases. In consequence, high copeptin is an independent risk factor for cardiovascular disease and premature mortality in both diabetes patients and in the general population. Vasopressin is released when plasma osmolality is high, and the easiest way to lower plasma vasopressin and copeptin concentration is to increase water intake. In a human water intervention experiment with 1 week of 3 L/day increased water intake, the one third of the participants with the greatest copeptin reduction (water responders) were those with a phenotype of low water intake (high habitual plasma copeptin and urine osmolality, and low urine volume). The water-responders had a copeptin reduction of 41% after 1 week of increased water intake compared to a control week; in contrast, a 3% reduction occurred in the other two thirds of the study participants. Among water responders, increased water intake also induced a reduction in fasting glucagon concentration. Key Messages: Elevated copeptin, a measure of vasopressin, is a risk marker of metabolic and cardiorenal diseases and may assist in the detection of individuals at higher risk for these diseases. Furthermore, individuals with high copeptin and other signs of low water intake may experience beneficial glucometabolic effects of increased water intake. Future randomized control trials investigating effects of hydration on glucometabolic and renal outcomes should focus on individuals with signs of low water intake including high plasma copeptin concentration.

Elevated copeptin, arterial stiffness, and elevated albumin excretion in adolescents with type 1 diabetes

“…Recent short-term clinical trials have shown that increased water intake can reduce concentrations of plasma copeptin, fasting blood glucose and glucagon in healthy participants. 13,49 Another study also found that increased water consumption resulted in decreased copeptin concentrations in participants with chronic kidney disease, however, no differences in rates of eGFR decline were observed in participants with or without increased water intake. 50 Mechanisms leading to increased AVP, and thus copeptin, in diabetes are also incompletely elucidated.…”

“…The net effect of increased Na + transport is increased renal O 2 consumption, as the majority of oxygen consumed by the kidney is used to support the active reabsorption of Na + . Circulating AVP can also stimulate systemic/renal vasoconstriction, platelet aggregation and hepatic glucose production (V1a receptor) and cortisol secretion (V1b receptor), resulting in hypertension, microalbuminuria, hyperglycemia and insulin resistance, typical features attributed to the development and progression of CVD and worse kidney function . As such, AVP is a potential modifiable risk factor and novel target for future diabetes treatment.…”

“…In contrast to AVP, copeptin is stable for days, easily measured and mimics fluctuations in AVP concentration . Several studies have demonstrated relationships between increased copeptin and the development or worsening of CVD and DKD in cohorts of adults with diabetes . In addition to water reabsorption in the collecting ducts via vasopressin‐2 (V2) receptor activity, AVP stimulates V1a receptor at arterial smooth muscles and the liver as well as V1b receptor at hypothalamus, resulting in vasoconstriction, hepatic glucose production and cortisol secretion, thereby hastening cardiorenal complications in diabetes .…”

“…12 Several studies have demonstrated relationships between increased copeptin and the development or worsening of CVD and DKD in cohorts of adults with diabetes. 10,11,13 In addition to water reabsorption in the collecting ducts via vasopressin-2 (V2) receptor activity, AVP stimulates V1a receptor at arterial smooth muscles and the liver as well as V1b receptor at hypothalamus, resulting in vasoconstriction, hepatic glucose production and cortisol secretion, thereby hastening cardiorenal complications in diabetes. 13 Increased AVP also stimulates the renin-angiotensin-aldosterone system, attenuates natriuresis and thereby increases renal oxygen consumption in experimental animal and human models.…”

“…10,11,13 In addition to water reabsorption in the collecting ducts via vasopressin-2 (V2) receptor activity, AVP stimulates V1a receptor at arterial smooth muscles and the liver as well as V1b receptor at hypothalamus, resulting in vasoconstriction, hepatic glucose production and cortisol secretion, thereby hastening cardiorenal complications in diabetes. 13 Increased AVP also stimulates the renin-angiotensin-aldosterone system, attenuates natriuresis and thereby increases renal oxygen consumption in experimental animal and human models. 14,15 Despite this body of evidence in adult cohorts of patients with diabetes, there are limited data describing the relationships between elevated vasopressin and risk for early CVD and marker of renal dysfunction in adolescents with T1D.…”