In addition, in human studies, it was found that people who have a variant of AVPR1A which encodes the V1a receptor , had a higher fasting blood glucose level and an increased prevalence of diabetes Roussel et al. He compared the risk of developing diabetes in the future based on current water intake. This observation was made after adjustment for confounding variables. This study proposes that people who drink less water have a greater chance of developing diabetes related to higher AVP levels Patients with Type I diabetes have selective depletion of beta cells.
They have impaired secretion of insulin but have intact secretion of glucagon alpha cells. Not only are the actions of insulin and glucagon antagonistic, but secretion of insulin causes inhibition of the secretion of the glucagon. Therefore, in patients with type 1 diabetes, secretion of glucagon is significantly increased as there is no inhibition by insulin thus elevating the blood glucose level.
Therefore, in Type 1 diabetes, even physiological levels of AVP can cause a profound increase in blood glucose by stimulating glucagon secretion resulting in increased production of glucose by the liver To prove an association between AVP and glucose, Hsu et al. Diabetes in rats was induced by the infusion of streptozotocin. He initially measured basal secretion of glucagon in both groups of rats before AVP was infused.
He then infused AVP and noted that the secretion of glucagon was double in the diabetic rats compared to non-diabetic rats. Thus, the diabetic rat pancreas was more sensitive to AVP in respect to glucagon secretion. They also found that at baseline, before AVP was infused, diabetic rats had a higher concentration of AVP in plasma than non-diabetic rats. This study also showed that a lower concentration of AVP is needed to increase glucagon secretion but a higher concentration of AVP was needed to secrete insulin.
This suggests that alpha cells are more sensitive to AVP than beta cells. AVP thus exerts greater influence on glucagon secretion than insulin secretion at basal levels. Since V1b receptors are involved in the stimulation of glucagon, this study highlights that in the future, a V1b receptor antagonist may play a role in the treatment of diabetes by inhibiting unopposed glucagon secretion Also noteworthy, Dheen et al. It has also been shown that the concentration of AVP in the pancreas of humans and rats is much higher than the concentration present in the serum.
AVP is found in the perivascular compartments of the pancreas and not in islet or acinar cells.
Thus, it is likely that locally formed pancreatic AVP rather than pituitary AVP may play an important role in glucagon production 3 , Finally, Pasquali et al. Thus, AVP has a role in causing hyperglycemia by not only acting on islet cells but through its action on V1b receptors in the pituitary The various cells and receptors that influence blood glucose levels are summarized in Table 2.
Cells, receptors, and the effects of arginine vasopressin on blood glucose levels. Arginine vasopressin has been shown to control fat metabolism by multiple mechanisms. Centrally, it stimulates the sympathetic nervous system which in turn affects lipid metabolism Peripherally, AVP regulates lipid metabolism by regulation of several hormones affecting fat metabolism such as insulin, glucagon, glucocorticoids, and epinephrine.
AVP also affects the glucose level, the substrate needed for fat metabolism 3. Injection of AVP in the lateral ventricle of rat causes stimulation of the sympathetic nervous system by a mechanism not well understood. Sympathetic nervous system stimulation causes the release of epinephrine which in turn causes stimulation of the metabolism of TGs in adipose tissue. Peripheral nerve terminals supply adipose tissue as well as the blood vessels of adipose tissue. It has been shown by various studies that any interruption to these nerve terminals to adipose tissue will affect lipid metabolism.
In human studies, infusion of epinephrine and norepinephrine lead to elevation of free fatty acids FFA which are a byproduct of TG metabolism Hiroyama et al. AVP exerts antilipolytic action by inhibiting tissue lipase thus preventing the breakdown of TG. In his experiment, he infused AVP in V1a-deficient rats and he noted that these rats had increased lipolysis and increased serum levels of glycerol and ketone bodies.
AVP is also known to inhibit the actions of isoproterenol.
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In V1a-deficient mice, isoproterenol was infused and it was noted that in brown adipose tissue BAT , lipolysis was increased threefold Stimulation of lipid metabolism in BAT is known to increase core temperature. Okuno et al. He noted that even in rats with an anterior hypothalamic lesion, the infusion of AVP reduced core body temperature. Thus, he concluded that this effect of AVP was not centrally mediated but was peripheral due to the inhibition of fat metabolism Insulin is the most potent antilipolytic hormone.
Thus, insulin therapy for diabetes causes obesity by inhibiting fat metabolism.
Insulin mediates this action by reducing the level of cyclic AMP in cells. Insulin signaling is done through kinase Akt and p70S6 kinase. These kinases are activated by AVP such that AVP not only causes stimulation of insulin release from islet of Langerhans but also enhances insulin signaling. In V1a-deficient rats, insulin signaling is impaired which in turn causes insulin resistance. Thus, V1a-deficient rats demonstrate increased lipolysis secondary to insulin resistance. AVP can control lipid metabolism by controlling the glucose needed for lipid metabolism.
AVP stimulates glycogenolysis in the liver by stimulating glucagon and epinephrine which in turn cause an increase in glucose levels. Glucose is metabolized in the adipose tissue to TG. Insulin facilitates this conversion V1b receptors are present on the beta cells of the islets of Langerhans. Fujiwara et al. This was due to reduction of insulin release from the islets of Langerhans.
He also noted that these mice had increased insulin sensitivity which probably acts as a compensatory response to low serum insulin levels. Also, in these mice, lipolysis was impaired since V1b receptor deficiency may stimulate lipogenesis by increasing insulin sensitivity It has been shown that on a day-to-day basis, AVP does not play a significant role in the maintenance of BP Landry et al. Black people have a higher incidence of hypertension than white people. The level of AVP has also been shown to be higher in black individuals.
Urine volume was lower in blacks compared to whites and urine concentration was higher in black people compared to whites especially in the daytime. Also, studies found that even when BP was in the normal range, pulse pressure was higher in black individuals. There was a strong statistical association between higher urine concentration and high pulse pressure in black men. Black men and women were compared with each other regarding urine volume and urine concentrating ability and it was shown that men had a higher ability to retain salt and concentrate urine than women.
Increased conservation of sodium caused less nocturnal dipping of BP in black men and increased conservation of sodium in day time resulted in a higher BP at night Choukroun et al. Bankir et al. The results showed that urine sodium excretion was independent of urine flow rate as long as urine flow was higher than 1 L but once urine flow was less than 1 L, sodium excretion decreased.
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This suggests that a higher level of vasopressin is required for sodium conservation and sodium is absorbed only when the AVP level reaches a certain threshold. A higher vasopressin level in black people compared to whites could be due to a change in the set point of the hypothalamic osmostat to lower levels of serum osmolality.
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This higher AVP could be a survival advantage in black people for facilitating water conservation in adverse drought and famine conditions. This adaptation could cause decreased sodium excretion. In black people, RAAS activity is low. This may explain why ACE inhibitors are not as effective in black hypertensive patients It has also been shown in humans that acute stimulation of V2 receptors in men by DDAVP not only reduced urine volume but that AVP causes an increase in the capacity of epithelial sodium channel ENaC receptors in the distal nephron to absorb sodium.
This effect is solute-specific as the excretion of potassium and creatinine did not change. The retention of sodium or impaired sodium excretion can cause hypertension.
Vasopressin is synthesized in the hypothalamus and secreted from the pituitary gland
Thus, hypertension in black individuals is thought to be salt-sensitive as an increase in salt intake will result in retention of sodium. AVP may also play a significant role in salt-sensitive hypertension in chronic kidney disease CKD patients due to a higher level of AVP causing activation of preglomerular V1a receptors and V2 receptors in collecting tubule Further it has been demonstrated that AVP, at levels much higher than needed to maintain an antidiuretic response, can cause smooth muscle contraction by acting on V1a receptors.
However, this response is rapidly buffered by an intact autonomic nervous system and intact cardiovascular reflexes causing activation of the vagus nerve and bradycardia.
It has been demonstrated in dogs that if the autonomic nervous system is disrupted, acute infusion of AVP will significantly elevate the mean arterial pressure MAP. Mohring et al. The results revealed that to increase MAP by 10 mm Hg, a times higher concentration of AVP was needed in normal subjects than in those with automatic insufficiency. These data suggest that a higher level of AVP in primary hypertension in humans can have significant impact on the cardiovascular system if the autonomic nervous system is disrupted In summary, the complex interrelationships of AVP, sodium, water, and other hormones in relation to the control of BP are of great interest and should continue to be the object of study.
Traditional risk factors for CKD progression such as diabetes, hypertension, and albuminuria are well described. We know that water intake and vasopressin levels are inversely related. Low 24 h urine volume and low water intake has been correlated with worsening CKD and is known to be associated with high AVP levels. Elevated urinary osmolality is not only associated with worsening CKD but also associated with initiation of dialysis after 72 months In humans, the retrospective MDRD trial has confirmed this association and this has been supported by experimental studies in rats.
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On the contrary, when V2 receptors were selectively blocked, the outcome was opposite. Further, elevated copeptin levels, a surrogate marker for AVP, are associated with albuminuria and decreasing glomerular filtration rate GFR in kidney transplant patients Such observations support the hypothesis that V2 receptor stimulation is associated with worsening CKD.
Alcohol and tobacco exert opposite influences on GFR. Alcohol blocks the V2 receptor and tobacco stimulates the V2 receptor. Arginine vasopressin may also cause worsening CKD by stimulating the renin angiotensin system. AVP interacts with V2 receptors causing direct stimulation of renin and indirectly it increases renin activity by reducing sodium load to the macula densa.
Increased RAAS activity causes constriction of efferent arteriole which causes hyperfiltration and glomerular damage with worsening proteinuria Arginine vasopressin is also known to affect GFR. Anderson et al. Hyperfiltration may induce glomerulosclerosis, proteinuria, and worsening kidney disease. This effect may be more relevant with high protein intake, male gender, and black race In another study, a comparison was done between diabetic rats that have normal vasopressin secretion and rats with no vasopressin secretion.
DM was generated by causing destruction of islets of Langerhans cells by infusing streptozotocin. Over time, rats that had diabetes and no vasopressin secretion had none of the signs of early diabetic nephropathy compared to rats with diabetes with intact vasopressin secretion. Also, urinary albumin excretion UAE occurred to a much lesser extent in diabetic vasopressin-deficient rats Bardoux et al. Desmopressin when infused in healthy people not only increased urine osmolality but also significantly increased UAE.