pituitrin and Diabetes-Insipidus--Neurogenic

This review focuses on the cellular and molecular aspects underlying familial neurohypophyseal diabetes insipidus (DI), a rare disorder that is usually transmitted in an autosomal-dominant fashion. The disease, manifesting in infancy or early childhood and gradually progressing in severity, is caused by fully penetrant heterozygous mutations in the gene encoding prepro-vasopressin-neurophysin II, the precursor of the antidiuretic hormone arginine vasopressin (AVP). Post mortem studies in affected adults have shown cell degeneration in vasopressinergic hypothalamic nuclei. Studies in cells expressing pathogenic mutants and knock-in rodent models have shown that the mutant precursors are folding incompetent and fail to exit the endoplasmic reticulum (ER), as occurs normally with proteins that have entered the regulated secretory pathway. A portion of these mutants is eliminated via ER-associated degradation (ERAD) by proteasomes after retrotranslocation to the cytosol. Another portion forms large disulfide-linked fibrillar aggregates within the ER, in which wild-type precursor is trapped. Aggregation capacity is independently conferred by two domains of the prohormone, namely the AVP moiety and the C-terminal glycopeptide (copeptin). The same domains are also required for packaging into dense-core secretory granules and regulated secretion, suggesting a disturbed balance between the physiological self-aggregation at the trans-Golgi network and avoiding premature aggregate formation at the ER in the disease. The critical role of ERAD in maintaining physiological water balance has been underscored by experiments in mice expressing wild-type AVP but lacking critical components of the ERAD machinery. These animals also develop DI and show amyloid-like aggregates in the ER lumen. Thus, the capacity of the ERAD is exceeded in autosomal dominant DI, which can be viewed as a neurodegenerative disorder associated with the formation of amyloid ER aggregates. While DI symptoms develop prior to detectable cell death in transgenic DI mice, the eventual loss of vasopressinergic neurons is accompanied by autophagy, but the mechanism leading to cell degeneration in autosomal dominant neurohypophyseal DI still remains unknown.

Topics: Animals; Autophagy; Diabetes Insipidus, Neurogenic; Endoplasmic Reticulum; Glycopeptides; Humans; Neurodegenerative Diseases; Protein Aggregates; Proteolysis; Vasopressins

The antidiuretic hormone vasopressin is synthesized as a longer precursor protein. After folding in the endoplasmic reticulum (ER), provasopressin is transported through the secretory pathway, forms secretory granules in the trans-Golgi network (TGN), is processed, and finally secreted into the circulation. Mutations in provasopressin cause autosomal dominant diabetes insipidus. They prevent native protein folding and cause fibrillar, amyloid-like aggregation in the ER, which eventually results in cell death. Secretory granules of peptide hormones were proposed to constitute functional amyloids and thus might be the cause of amyloid formation of misfolded mutant protein in the ER. Indeed, the same two segments in the precursor-vasopressin and a C-terminal glycopeptide-were found to be responsible for pathological aggregation in the ER and physiological aggregation in granule formation in the TGN. Furthermore, even wild-type provasopressin tends to aggregate in the ER, but is controlled by ER-associated degradation. When essential components thereof, Sel1L or Hrd1, were inactivated, wild-type provasopressin accumulated as fibrillar aggregates in vasopressinergic neurons in mice, causing diabetes insipidus. Evolution of amyloidogenic sequences for granule formation thus made provasopressin dependent on ER quality control mechanisms. These principles may similarly apply to other peptide hormones.

Topics: Amyloid; Animals; Diabetes Insipidus, Neurogenic; Disease Models, Animal; Mice; Protein Aggregates; Vasopressins

The treatment of central diabetes insipidus has not changed significantly in recent decades, and dDAVP and replacement of free water deficit remain the cornerstones of treatment. Oral dDAVP has replaced nasal dDAVP as a more reliable mode of treatment for chronic central diabetes insipidus. Hyponatraemia is a common side effect, occurring in one in four patients, and should be avoided by allowing a regular break from dDAVP to allow a resultant aquaresis. Hypernatraemia is less common, and typically occurs during hospitalization, when access to water is restricted, and in cases of adipsic DI. Management of adipsic DI can be challenging, and requires initial inpatient assessment to establish dose of dDAVP, daily fluid prescription, and eunatraemic weight which can guide day-to-day fluid targets in the long-term.

Topics: Body Weight; Deamino Arginine Vasopressin; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Humans; Hypernatremia; Hyponatremia; Neurophysins; Protein Precursors; Vasopressins

In the pregnant patient, hypotonic polyuria in the setting of elevated serum osmolality and polydipsia should narrow the differential to causes related to diabetes insipidus (DI). Gestational DI, also called transient DI of pregnancy, is a distinct entity, unique from central DI or nephrogenic DI which may both become exacerbated during pregnancy. These three different processes relate to vasopressin, where increased metabolism, decreased production or altered renal sensitivity to this neuropeptide should be considered. Gestational DI involves progressively rising levels of placental vasopressinase throughout pregnancy, resulting in decreased endogenous vasopressin and resulting hypotonic polyuria worsening through the pregnancy. Gestational DI should be distinguished from central and nephrogenic DI that may be seen during pregnancy through use of clinical history, urine and serum osmolality measurements, response to desmopressin and potentially, the newer, emerging copeptin measurement. This review focuses on a brief overview of osmoregulatory and vasopressin physiology in pregnancy and how this relates to the clinical presentation, pathophysiology, diagnosis and management of gestational DI, with comparisons to the other forms of DI during pregnancy. Differentiating the subtypes of DI during pregnancy is critical in order to provide optimal management of DI in pregnancy and avoid dehydration and hypernatremia in this vulnerable population.

Topics: Dehydration; Diabetes Insipidus; Diabetes Insipidus, Nephrogenic; Diabetes Insipidus, Neurogenic; Diagnosis, Differential; Female; Humans; Hypernatremia; Neurophysins; Osmoregulation; Polydipsia; Polyuria; Pregnancy; Pregnancy Complications; Protein Precursors; Vasopressins; Water-Electrolyte Balance

The two main differential diagnoses of central diabetes insipidus are nephrogenic diabetes insipidus and primary polydipsia. Reliable distinction between those entities is essential as treatment differs substantially with the wrong treatment potentially leading to serious complications. Past diagnostic measures using the indirect water deprivation test had several pitfalls, resulting in a low diagnostic accuracy. With the introduction of copeptin, a stable and reliable surrogate marker for arginine vasopressin, diagnosis of diabetes insipidus was new evaluated. While unstimulated basal copeptin measurement reliably diagnoses nephrogenic diabetes insipidus, a stimulation test is needed to differentiate patients with central diabetes insipidus from patients with primary polydipsia. Stimulation can either be achieved through hypertonic saline infusion or arginine infusion. While the former showed high diagnostic accuracy and superiority over the indirect water deprivation test in a recent validation study, the diagnostic accuracy for arginine-stimulated copeptin was slightly lower, but superior in test tolerance. In summary of the recent findings, a new copeptin based diagnostic algorithm is proposed for the reliable diagnosis of diabetes insipidus.

Topics: Biomarkers; Diabetes Insipidus; Diabetes Insipidus, Nephrogenic; Diabetes Insipidus, Neurogenic; Diagnosis, Differential; Diagnostic Techniques, Endocrine; Humans; Neurophysins; Polyuria; Protein Precursors; Vasopressins

Familial neurohypophyseal diabetes insipidus (FNDI) is an autosomal dominant hereditary disorder characterized by severe polydipsia and polyuria that usually presents in early childhood. In this study, we describe a new arginine vasopressin (AVP) gene mutation in an ethnic German family with FNDI and provide an overview of disease-associated AVP-gene mutations that are already described in literature. Three members of a German family with neurohypophyseal diabetes insipidus were studied. Isolated DNA from peripheral blood samples was used for mutation analysis by sequencing the whole coding region of AVP-NPII gene. Furthermore, we searched the electronic databases MEDLINE (Pubmed) as well as HGMD, LOVD-ClinVar, db-SNP and genomAD in order to compare our cases to that of other patients with FNDI. Genetic analysis of the patients revealed a novel heterozygote missense mutation in exon 2 of the AVP gene (c.274T>G), which has not yet been described in literature. We identified reports of more than 90 disease-associated mutations in the AVP gene in literature. The novel mutation of the AVP gene seems to cause FNDI in the presented German family. Similar to our newly detected mutation, most mutations causing FNDI are found in exon 2 of the AVP gene coding for neurophysin II. Clinically, it is important to think of FNDI in young children presenting with polydipsia and polyuria.

Topics: Adult; Diabetes Insipidus, Neurogenic; Female; Genetic Testing; Humans; Male; Middle Aged; Mutation; Neurophysins; Pedigree; Prognosis; Protein Precursors; Vasopressins; Young Adult

In the majority of cases, hereditary neurohypophyseal diabetes insipidus (DI) is a monogenic disorder caused by mutations in the AVP gene. Dominant transmission is by far the most common form. In these patients, symptoms develop gradually at various ages during childhood, progressing with complete penetrance to polyuria and polydipsia that is usually severe. In autosomal dominant neurohypophyseal DI (ADNDI), the mutant prohormone is folding deficient and consequently retained in the ER, where it forms amyloid-like fibrillar aggregates. Degradation by proteasomes occurs, but their clearance capacity appears to be insufficient. Postmortem studies in affected individuals suggest a neurodegenerative process confined to vasopressinergic neurons. Other forms of genetic neurohypophyseal DI include the very rare autosomal recessive type, also caused by mutations in the AVP gene, and complex multiorgan disorders, such as Wolfram syndrome. In all individuals where a congenital form of DI is suspected, including nephrogenic types, genetic analysis should be performed.

Topics: Child; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Diagnosis, Differential; Genetic Predisposition to Disease; Humans; Mutation; Neurophysins; Protein Precursors; Vasopressins

Most cases of acquired central diabetes insipidus are caused by destruction of the neurohypophysis by: 1) anatomic lesions that destroy the vasopressin neurons by pressure or infiltration, 2) damage to the vasopressin neurons by surgery or head trauma, and 3) autoimmune destruction of the vasopressin neurons. Because the vasopressin neurons are located in the hypothalamus, lesions confined to the sella turcica generally do not cause diabetes insipidus because the posterior pituitary is simply the site of the axon terminals that secrete vasopressin into the bloodstream. In addition, the capacity of the neurohypophysis to synthesize vasopressin is greatly in excess of the body's needs, and destruction of 80-90% of the hypothalamic vasopressin neurons is required to produce diabetes insipidus. As a result, even large lesions in the sellar and suprasellar area generally are not associated with impaired water homeostasis until they are surgically resected. Regardless of the etiology of central diabetes insipidus, deficient or absent vasopressin secretion causes impaired urine concentration with resultant polyuria. In most cases, secondary polydipsia is able to maintain water homeostasis at the expense of frequent thirst and drinking. However, destruction of the osmoreceptors in the anterior hypothalamus that regulate vasopressin neuronal activity causes a loss of thirst as well as vasopressin section, leading to severe chronic dehydration and hyperosmolality. Vasopressin deficiency also leads to down-regulation of the synthesis of aquaporin-2 water channels in the kidney collecting duct principal cells, causing a secondary nephrogenic diabetes insipidus. As a result, several days of vasopressin administration are required to achieve maximal urine concentration in patients with CDI. Consequently, the presentation of patients with central diabetes insipidus can vary greatly, depending on the size and location of the lesion, the magnitude of trauma to the neurohypophysis, the degree of destruction of the vasopressin neurons, and the presence of other hormonal deficits from damage to the anterior pituitary.

Topics: Aquaporin 2; Brain Injuries, Traumatic; Diabetes Insipidus, Nephrogenic; Diabetes Insipidus, Neurogenic; Homeostasis; Humans; Neurophysins; Pituitary Diseases; Pituitary Gland, Posterior; Polydipsia; Polyuria; Protein Precursors; Vasopressins; Water-Electrolyte Balance

Familial neurohypophysial diabetes insipidus (FNDI), characterized by delayed-onset progressive polyuria and loss of arginine vasopressin (AVP) neuron, is an autosomal dominant disorder caused by AVP gene mutations. We previously generated a knock-in mouse model for FNDI, which recapitulated the phenotype of human FNDI. To address the mechanisms underlying AVP neuron loss, we subjected FNDI mice to intermittent water deprivation, which accelerated the phenotype and induced AVP neuron loss within a relative short period. Electron microscopic analyses revealed that aggregates were confined to a sub-compartment of the endoplasmic reticulum (ER), ER-associated compartment (ERAC), in AVP neurons of FNDI mice under normal conditions. In contrast, aggregates scattered throughout the dilated ER lumen, and phagophores, autophagosome precursors, emerged and surrounded the ER containing scattered aggregates in FNDI mice subjected to water deprivation for 4 weeks, suggesting that failure of ERAC formation leads to autophagy induction for degradation of aggregates. Furthermore, the cytoplasm was entirely occupied with large vacuoles in AVP neurons of FNDI mice subjected to water deprivation for 12 weeks, at which stage 30-40% of AVP neurons were lost. Our data demonstrated that although autophagy should primarily be a protective mechanism, continuous autophagy leads to gradual loss of organelles including ER, resulting in autophagy-associated cell death of AVP neurons in FNDI mice.

Topics: Animals; Autophagy; Diabetes Insipidus, Neurogenic; Humans; Neurons; Oxytocin; Phenotype; Vasopressins

Diabetes insipidus (DI), be it from central or nephrogenic origin, must be differentiated from secondary forms of hypotonic polyuria such as primary polydipsia. Differentiation is crucial since wrong treatment can have deleterious consequences. Since decades, the gold standard for differentiation has been the water deprivation test, which has limitations leading to an overall unsatisfying diagnostic accuracy. Furthermore, it is cumbersome for patients with a long test duration. Clinical signs and symptoms and MRI characteristics overlap between patients with DI and primary polydipsia. The direct test including vasopressin (AVP) measurement upon osmotic stimulation was meant to overcome these limitations, but failed to enter clinical practice mainly due to technical constraints of the AVP assay. Copeptin is secreted in equimolar amount to AVP but can easily be measured with a sandwich immunoassay. A high correlation between copeptin and AVP has been shown. Accordingly, copeptin mirrors the amount of AVP in the circulation and has led to a 'revival' of the direct test in the differential diagnosis of DI. We have shown that a baseline copeptin, without prior thirsting, unequivocally identifies patients with nephrogenic DI. In contrast, for the differentiation between central DI and primary polydipsia, a stimulated copeptin level of 4.9 pmol/L upon hypertonic saline infusion differentiates these two entities with a high diagnostic accuracy and is superior to the water deprivation test. Close sodium monitoring during the test is a prerequisite. Further new test methods are currently evaluated and might provide an even simpler way of differential diagnosis in the future.

Topics: Awards and Prizes; Diabetes Insipidus, Neurogenic; Diagnosis, Differential; Glycopeptides; Humans; Polydipsia; Polyuria; Saline Solution, Hypertonic; Syndrome; Vasopressins

The aim of this study was to review different animal models of Central Diabetes Insipidus, a neurobiological syndrome characterized by the excretion of copious amounts of diluted urine (polyuria), a consequent water intake (polydipsia), and a rise in the serum sodium concentration (hypernatremia). In rodents, Central Diabetes Insipidus can be caused by genetic disorders (Brattleboro rats) but also by various traumatic/surgical interventions, including neurohypophysectomy, pituitary stalk compression, hypophysectomy, and median eminence lesions. Regardless of its etiology, Central Diabetes Insipidus affects the neuroendocrine system that secretes arginine vasopressin, a neurohormone responsible for antidiuretic functions that acts trough the renal system. However, most Central Diabetes Insipidus models also show disorders in other neurobiological systems, specifically in the secretion of oxytocin, a neurohormone involved in body sodium excretion. Although the hydromineral behaviors shown by the different Central Diabetes Insipidus models have usually been considered as very similar, the present review highlights relevant differences with respect to these behaviors as a function of the individual neurobiological systems affected. Increased understanding of the relationship between the neuroendocrine systems involved and the associated hydromineral behaviors may allow appropriate action to be taken to correct these behavioral neuroendocrine deficits.

Topics: Animals; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Humans; Models, Animal; Oxytocin; Vasopressins

Neurohypophyseal diabetes insipidus is characterized by polyuria and polydipsia owing to partial or complete deficiency of the antidiuretic hormone, arginine vasopressin (AVP). Although in most patients non-hereditary causes underlie the disorder, genetic forms have long been recognized and studied both in vivo and in vitro. In most affected families, the disease is transmitted in an autosomal dominant manner, whereas autosomal recessive forms are much less frequent. Both phenotypes can be caused by mutations in the vasopressin-neurophysin II (AVP) gene. In transfected cells expressing dominant mutations, the mutated hormone precursor is retained in the endoplasmic reticulum, where it forms fibrillar aggregates. Autopsy studies in humans and a murine knock-in model suggest that the dominant phenotype results from toxicity to vasopressinergic neurons, but the mechanisms leading to cell death remain unclear. Recessive transmission results from AVP with reduced biologic activity or the deletion of the locus. Genetic neurohypophyseal diabetes insipidus occurring in the context of diabetes mellitus, optic atrophy, and deafness is termed DIDMOAD or Wolfram syndrome, a genetically and phenotypically heterogeneous autosomal recessive disorder caused by mutations in the wolframin (WFS 1) gene.

Topics: Animals; Diabetes Insipidus, Neurogenic; Humans; Mutation; Neurophysins; Phenotype; Protein Precursors; Vasopressins

Diabetes insipidus (DI) is a rare complication of pregnancy. It is usually transient, being due to increased placental production of vasopressinase that inactivates circulating vasopressin. Gestational, transient DI occurs late in pregnancy and disappears few days after delivery. Acquired central DI can also occur during pregnancy, for example in a patient with hypophysitis or neuroinfundibulitis during late pregnancy or postpartum. Finally, pre-existing central or nephrogenic DI may occasionally be unmasked by pregnancy. Treatment with dDAVP (desmopressin, Minirin(®)) is very effective on transient DI of pregnancy and also on pre-existing or acquired central DI. Contrary to vasopressin, dDAVP is not degraded by vasopressinase. Nephrogenic DI is insensitive to dDAVP and is therefore more difficult to treat during pregnancy if fluid intake needs to be restricted.

Topics: Deamino Arginine Vasopressin; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Female; Humans; Pregnancy; Pregnancy Complications; Vasopressins

Topics: Aquaporin 2; Biomarkers; Body Water; Diabetes Insipidus, Neurogenic; Education, Medical, Continuing; Humans; Inappropriate ADH Syndrome; Kidney; Polymers; Receptors, Vasopressin; Sodium; Vasopressins; Water-Electrolyte Imbalance

Diabetes insipidus (DI) is a common complication following pituitary surgery and can be transient or permanent. Neurogenic DI occurs following injury to the magnocellular neurons in the hypothalamus that produce and transport arginine vasopressin (AVP) and form the hypothalamo-hypophyseal tract. DI is defined by a constellation of signs and symptoms resulting in dilute high-volume urine output and increasing serum osmolality. The body's inability to concentrate urine leaves the patient dehydrated and leads to metabolic abnormalities that can be life threatening if not recognized and treated in a timely manner with an exogenous AVP analog. The reported incidence of postsurgical central DI varies from 1 to 67%. This wide range likely reflects inconsistencies in the working definition of DI across the literature. Factors affecting the rate of DI include pituitary tumor size, adherence to surrounding structures, surgical approach, and histopathology of pituitary lesion. The likelihood of postoperative DI can be reduced by careful preservation of the neurovascular structures of the hypothalamus, infundibulum, and neurohypophysis. Vigilance and meticulous surgical technique are essential to minimize injury to these critical regions that can lead to postsurgical DI.

Topics: Deamino Arginine Vasopressin; Diabetes Insipidus, Neurogenic; Endoscopy; Humans; Microsurgery; Neurosurgical Procedures; Pituitary Gland; Pituitary Neoplasms; Postoperative Complications; Vasopressins

The hypothalamus and posterior pituitary form a complex neurohumoral system playing a key role in maintaining body fluid homeostasis and reproductive function. We review the pathophysiology mechanisms of posterior pituitary hormones and their implications, beyond water balance and delivery, in social functioning, pair bonding and affiliative behavior. Actual and future treatments for neurohypophysis related disorders are also discussed, particularly focusing on the development of new therapeutic compounds and patents.

Topics: Diabetes Insipidus, Neurogenic; Humans; Hypothalamic Diseases; Models, Anatomic; Oxytocin; Patents as Topic; Vasopressins

Over the past two decades, the genetic and molecular basis of familial forms of diabetes insipidus has been elucidated. Diabetes insipidus is a clinical syndrome characterized by the excretion of abnormally large volumes of diluted urine (polyuria) and increased fluid intake (polydipsia). The most common type of diabetes insipidus is caused by lack of the antidiuretic hormone arginine vasopressin (vasopressin), which is produced in the hypothalamus and secreted by the neurohypophysis. This type of diabetes insipidus is referred to here as neurohypophyseal diabetes insipidus. The syndrome can also result from resistance to the antidiuretic effects of vasopressin on the kidney, either at the level of the vasopressin 2 receptor or the aquaporin 2 water channel (which mediates the re-absorption of water from urine), and is referred to as renal or nephrogenic diabetes insipidus. Differentiation between these two types of diabetes insipidus and primary polydipsia can be difficult owing to the existence of partial as well as complete forms of vasopressin deficiency or resistance. Seven different familial forms of diabetes insipidus are known to exist. The clinical presentation, genetic basis and cellular mechanisms responsible for them vary considerably. This information has led to improved methods of differential diagnosis and could provide the basis of new forms of therapy.

Topics: Animals; Aquaporin 2; Arginine Vasopressin; Deamino Arginine Vasopressin; Diabetes Insipidus; Diabetes Insipidus, Nephrogenic; Diabetes Insipidus, Neurogenic; Diagnosis, Differential; Female; Humans; Male; Mutation; Phenotype; Polydipsia; Polyuria; Receptors, Vasopressin; Vasopressins

Topics: Aquaporin 2; Diabetes Insipidus, Nephrogenic; Diabetes Insipidus, Neurogenic; Humans; Hyponatremia; Hypothalamus; Inappropriate ADH Syndrome; Mutation; Receptors, Vasopressin; Vasopressins

Topics: Administration, Intranasal; Deamino Arginine Vasopressin; Diabetes Insipidus, Neurogenic; Diagnosis, Differential; Humans; Prognosis; Vasopressins

Topics: Animals; Diabetes Insipidus, Neurogenic; Glucocorticoids; Humans; Hypopituitarism; Vasopressins

Topics: Arginine Vasopressin; Body Water; Diabetes Insipidus, Neurogenic; Diagnosis, Differential; Humans; Hyponatremia; Inappropriate ADH Syndrome; Kidney; Kidney Tubules, Collecting; Osmolar Concentration; Vasopressins

The thymus is the unique lymphoid organ responsible for the generation of a diverse repertoire of T lymphocytes that are competent against non self-antigens while being tolerant to self-antigens. A vast repertoire of neuroendocrine-related genes is transcribed in the nonlymphoid cellular compartment of the thymus (thymic epithelial cells, dendritic cells and macrophages). The precursors encoded by these genes engage two types of interactions with developing T cells (thymocytes). First, they are not processed in a classical neuroendocrine way but as the source of self-antigens that are presented to pre-T cells by the major histocompatibility complex proteins of the thymus. This presentation could be responsible for the establishment of central T-cell self-tolerance to neuroendocrine functions. Second, they also deliver signal ligands that are able to bind to neuroendocrine-type receptors expressed by thymocytes. This interaction activates several types of intracellular signalling pathways implicated in the developmental process of T lymphocytes. Several experimental arguments support a role for thymic dysfunction as a crucial factor in the development of organ-specific autoimmune endocrinopathies, such as 'idiopathic' central diabetes insipidus and type 1 diabetes mellitus. The rational use of tolerogenic neuroendocrine self-antigens for the prevention/treatment of autoimmune endocrinopathies is currently under investigation.

Topics: Animals; Cell Differentiation; Diabetes Insipidus, Neurogenic; Diabetes Mellitus, Type 1; Gene Expression Regulation; Humans; Insulin; Oxytocin; Pituitary Hormones; Self Tolerance; T-Lymphocytes; Thymus Gland; Transcription, Genetic; Vasopressins

Diabetes insipidus is a heterogeneous condition characterised by polyuria and polydipsia caused by a lack of secretion of vasopressin, its physiological suppression following excessive water intake, or kidney resistance to its action. The clinical and laboratory diagnosis is confirmed by standard tests, but recent advances in molecular biology and imaging techniques have shed new light on the pathophysiology of this disease. In many patients, central diabetes insipidus is caused by a germinoma or craniopharyngioma; Langerhans' cell histiocytosis and sarcoidosis of the central nervous system; local inflammatory, autoimmune or vascular diseases; trauma from surgery or accident; and, rarely, genetic defects in vasopressin biosynthesis inherited as autosomal dominant or X-linked recessive traits. Thirty to fifty percent of cases are considered idiopathic. Tumour-associated central diabetes insipidus is uncommon in children younger than 5 years old. Biopsy of enlarged pituitary stalk should be reserved for patients with hypothalamic-pituitary mass and progressive thickening of the pituitary stalk since spontaneous recovery may occur. Molecular biology in selected patients may identify those with apparently idiopathic diabetes insipidus carrying the vasopressin-neurophysin II gene mutation.

Topics: Autoimmune Diseases; Brain Neoplasms; Child; Diabetes Insipidus, Neurogenic; Germinoma; Humans; Neurophysins; Vasopressins

The management of central diabetes insipidus has been greatly simplified by the introduction of desmopressin (DDAVP). Its ease of administration, safety and tolerability make DDAVP the first line agent for outpatient treatment of central diabetes insipidus. The major complication of DDAVP therapy is water intoxication and hyponatremia. The risk of hyponatremia can be reduced by careful dose titration when initiating therapy and by close monitoring of serum osmolality when DDAVP is used with other medications affecting water balance. Herein we review the adverse effects of DDAVP and its predecessor, vasopressin, as well as discuss important clinical considerations when using these agents to treat central diabetes insipidus.

Topics: Antidiuretic Agents; Child; Deamino Arginine Vasopressin; Diabetes Insipidus, Neurogenic; Humans; Vasopressins

The central and peripheral mechanisms regulate body water balance near an ideal set point. Osmosensitive neurons in the organum vasculosum lamina terminalis (OVLT) in the anterior hypothalamus play a key role in regulating vasopressin release and drinking behaviour. Patients with OVLT lesions are known to have osmostat fluctuations. Although the brain water channel is suggested to participate in osmoreception, the precise molecular mechanisms of osmoreception and thirst appreciation remain to be clarified. Vasopressin gene mutation is responsible for hereditary central diabetes insipidus. Mutant vasopressin precursors have been reported to impair the secretion of wild-type proteins or cause cellular toxicity. Despite the intact production and secretion of vasopressin, the kidney is unable to concentrate urine in nephrogenic diabetes insipidus (NDI). Most congenital NDI patients have mutations in the G protein-coupled vasopressin V2 receptor gene. V2 receptor mutants are shown not to reach the plasma membrane, not to bind AVP, and not to trigger an intracellular cyclic adenosine-monophosphate signal. Congenital NDI with an autosomal recessive inheritance has mutations of Aquaporin-2 gene, a vasopressin-sensitive water channel in the renal inner medullary collecting duct (IMCD). Aquaporin-2 mutant proteins cannot be expressed at the luminal membrane. The corticopapillary osmotic gradient is necessary for renal sensitivity to vasopressin. The vasopressin-regulated urea transporter in IMCD and the chloride channel (CLC-K1) in the ascending loop of the Henle contribute to the formation of the osmotic gradient. NDI has been shown in mice lacking the CLC-K1. The pathophysiological significance of urea transporter and CLC-K1 has yet to be demonstrated in patients with NDI.

Topics: Animals; Body Water; Diabetes Insipidus, Nephrogenic; Diabetes Insipidus, Neurogenic; Humans; Mice; Rats; Vasopressins; Water-Electrolyte Balance

Topics: Alcohols; Body Water; Central Nervous System Diseases; Child; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Diuresis; Edema; Ethanol; Histiocytosis, Langerhans-Cell; Homeostasis; Humans; Hyponatremia; Infant; Infant, Newborn; Kidney Diseases; Nicotine; Physiology; Pituitary Gland; Pituitary Gland, Posterior; Potassium Deficiency; Prednisone; Pyloric Stenosis; Vasopressins; Water

Topics: Blood; Chlorothiazide; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Diagnosis, Differential; Humans; Permeability; Thirst; Urine; Vasopressins

Melatonin secretion is modulated by the light-dark schedule, mainly through a sympathetic input to the pineal gland. Besides this, arginine vasopressin (AVP) has been found in the pineal glands of several animal species and there is experimental evidence that AVP modulates melatonin secretion in animals. However, the interaction between vasopressin and melatonin secretion in humans has not been systematically investigated. We proposed to study the nocturnal melatonin pattern in patients with central diabetes insipidus (CDI) who lack endogenous secretion of AVP, and the effect on their melatonin secretion of the agonist for V2 type receptors: desmopressin (1-Desamino [8-D Arginine] vasopressin). Plasma melatonin levels were measured in 14 patients with CDI, every 2 h starting from 22:00 h until 06:00 h, following iv injection of saline (day 1) and 3 microg desmopressin (day 2) at 20:00 h. The lights were turned off at 22:30 h and the samples were taken in a dim light. The plasma melatonin secretion pattern was normal in patients with CDI. Desmopressin at a dose 3 times higher than the antidiuretic one did not modify the melatonin levels or the time of the peak secretion. In conclusion melatonin secretion is not modulated by AVP in humans.

Topics: Circadian Rhythm; Deamino Arginine Vasopressin; Diabetes Insipidus, Neurogenic; Drug Administration Schedule; Female; Hormone Replacement Therapy; Humans; Male; Melatonin; Middle Aged; Vasopressins

There have been recent advances assessing copeptin levels in adults with suspected disorders of vasopressin release. Very limited data exits on copeptin levels in children and infants, especially in a critically-ill hospitalized population where hyper- and hypo-natremia are very common. Our objective is to describe the institutional experience assessing copeptin levels in hospitalized infants and children with hyper- or hypo-natremia.. We performed a single-center retrospective case series of all infants, children, and adolescents who had an ultrasensitive plasma copeptin level obtained between 2019-2021.. A total of 29 critically ill patients (6 infants) were identified with 38 % of patients having copeptin levels after neurosurgical procedures for tumors or trauma. Approximately 13/17 children with hypernatremia had central diabetes insipidus (central diabetes insipidus) to diagnose CDI, A copeptin level ≤ 4.9 pmol/L resulted in an 88 % sensitivity (95 % CI 47-99 %), and 66 % specificity (95 % CI 30-93 %). Amongst those with hyponatremia levels were more variable, 8/12 children had syndrome of inappropriate antidiuresis (SIAD) with copeptin levels ranging 4.7-72.6 pmol/L.. While difficult to conclude due to multiple limitations, this case series highlights that typical copeptin cutoffs used to diagnose DI in adults in an ambulatory setting may also translate to a critically-ill pediatric population. Large prospective studies are needed to confirm this observation. In addition, postoperative copeptin levels could potentially be utilized as an additional marker to predict permanent from transient DI, but much larger studies are needed. Further work is needed to establish normative copeptin levels in infants and patients with SIAD.

Topics: Adolescent; Child; Critical Illness; Diabetes Insipidus, Neurogenic; Humans; Infant; Retrospective Studies; Vasopressins

Arginine vasopressin (AVP) is an antidiuretic hormone synthesized principally in the hypothalamic supraoptic and paraventricular nuclei. The immunoglobulin heavy chain binding protein (BiP), one of the most abundant endoplasmic reticulum (ER) chaperones, is highly expressed in AVP neurons, even under basal conditions. Moreover, its expression is upregulated in proportion to the increase in AVP expression under dehydration. These data suggest that AVP neurons are constantly exposed to ER stress. BiP knockdown in AVP neurons induces ER stress and autophagy, resulting in AVP neuronal loss, indicating that BiP is pivotal in maintaining the AVP neuron system. Furthermore, inhibition of autophagy after BiP knockdown exacerbates AVP neuronal loss, suggesting that autophagy induced under ER stress is a protective cellular mechanism by which AVP neurons cope with ER stress. Familial neurohypophysial diabetes insipidus (FNDI) is an autosomal dominant disorder caused by mutations in the AVP gene. It is characterized by delayed-onset progressive polyuria and eventual AVP neuronal loss. In AVP neurons of FNDI model mice, mutant protein aggregates are confined to a specific compartment of the ER, called the ER-associated compartment (ERAC). The formation of ERACs contributes to maintaining the function of the remaining intact ER, and mutant protein aggregates in ERACs undergo autophagic-lysosomal degradation without isolation or translocation from the ER, representing a novel protein degradation system in the ER.

Topics: Animals; Arginine Vasopressin; Diabetes Insipidus, Neurogenic; Endoplasmic Reticulum Stress; Mice; Neurons; Protein Aggregates; Vasopressins

Familial neurohypophyseal diabetes insipidus (FNDI) is a degenerative disease of vasopressin (AVP) neurons. Studies in mouse in vivo models indicate that accumulation of mutant AVP prehormone is associated with FNDI pathology. However, studying human FNDI pathology in vivo is technically challenging. Therefore, an in vitro human model needs to be developed. When exogenous signals are minimized in the early phase of differentiation in vitro, mouse embryonic stem cells (ESCs)/induced pluripotent stem cells (iPSCs) differentiate into AVP neurons, whereas human ESCs/iPSCs die. Human ESCs/iPSCs are generally more similar to mouse epiblast stem cells (mEpiSCs) compared to mouse ESCs. In this study, we converted human FNDI-specific iPSCs by the naive conversion kit. Although the conversion was partial, we found improved cell survival under minimal exogenous signals and differentiation into rostral hypothalamic organoids. Overall, this method provides a simple and straightforward differentiation direction, which may improve the efficiency of hypothalamic differentiation.

Topics: Animals; Cell Differentiation; Diabetes Insipidus, Neurogenic; Humans; Hypothalamus; Induced Pluripotent Stem Cells; Mice; Neurons; Vasopressins

A 49-year-old man developed severe hyponatremia associated with transient headache and was diagnosed with syndrome of inappropriate antidiuretic hormone secretion (SIADH). Fluid restriction and sodium supplementation corrected the hyponatremia. However, several days later, the patient exhibited hypernatremia with thirst and polyuria. A detailed examination indicated central diabetes insipidus (CDI) with an intrasellar cystic lesion indicative of Rathke's cleft cyst (RCC). A case of RCC exhibiting headache, hyponatremia, and subsequent hypernatremia has been reported. Our case shows that CDI may appear after SIADH in patients with RCC, especially in those with serum sodium levels that unexpectedly increase rapidly beyond the reference range.

Topics: Central Nervous System Cysts; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Diabetes Mellitus; Humans; Hyponatremia; Inappropriate ADH Syndrome; Male; Middle Aged; Vasopressins

Hypopituitary patients are at risk for bone loss. Hypothalamic-posterior pituitary hormones oxytocin and vasopressin are anabolic and catabolic, respectively, to the skeleton. Patients with hypopituitarism may be at risk for oxytocin deficiency. Whether oxytocin and/or vasopressin contribute to impaired bone homeostasis in hypopituitarism is unknown.. To determine the relationship between plasma oxytocin and vasopressin levels and bone characteristics (bone mineral density [BMD] and hip structural analysis [HSA]) in patients who have anterior pituitary deficiencies only (APD group) or with central diabetes insipidus (CDI group).. This is a cross-sectional study. Subjects included 37 men (17 CDI and 20 APD), aged 20-60 years. Main outcome measures were fasting plasma oxytocin and vasopressin levels, and BMD and HSA using dual X-ray absorptiometry.. Mean BMD and HSA variables did not differ between the CDI and APD groups. Mean BMD Z-scores at most sites were lower in those participants who had fasting oxytocin levels below, rather than above, the median. There were positive associations between fasting oxytocin levels and (1) BMD Z-scores at the spine, femoral neck, total hip, and subtotal body and (2) favorable hip geometry and strength variables at the intertrochanteric region in CDI, but not APD, participants. No associations between vasopressin levels and bone variables were observed in the CDI or ADP groups.. This study provides evidence for a relationship between oxytocin levels and BMD and estimated hip geometry and strength in hypopituitarism with CDI. Future studies will be important to determine whether oxytocin could be used therapeutically to optimize bone health in patients with hypopituitarism.

Topics: Adult; Bone Density; Cross-Sectional Studies; Diabetes Insipidus, Neurogenic; Humans; Hypopituitarism; Male; Middle Aged; Oxytocin; Pelvic Bones; Vasopressins

Central diabetes insipidus is a heterogeneous condition characterized by decreased release of antidiuretic hormone by the neurohypophysis resulting in a urine concentration deficit with variable degrees of polyuria. The most common causes include idiopathic diabetes insipidus, tumors or infiltrative diseases, neurosurgery and trauma. Temozolomide is an oral DNA-alkylating agent capable of crossing the blood-brain barrier and used as chemotherapy primarily to treat glioblastoma and other brain cancers.. Two men (aged 38 and 54 years) suddenly developed polyuria and polydispsia approximately four weeks after the initiation of temozolomide for a glioblastoma. Plasma and urine parameters demonstrated the presence of a urinary concentration defect.. The clinical and laboratory abnormalities completely resolved with intranasal desmopressin therapy, allowing the continuation of temozolomide. The disorder did not relapse after cessation of temozolomide and desmopressin and relapsed in one patient after rechallenge with temozolomide.. Our report highlights the importance of a quick recognition of this exceptional complication, in order to initiate promptly treatment with desmopressin and to maintain therapy with temozolomide.

Topics: Adult; Antineoplastic Agents, Alkylating; Brain Neoplasms; Deamino Arginine Vasopressin; Diabetes Insipidus, Neurogenic; Fatal Outcome; Glioblastoma; Humans; Male; Middle Aged; Temozolomide; Vasopressins

Familial neurohypophyseal diabetes insipidus (FNDI) is a rare disorder characterized by childhood-onset progressive polyuria and polydipsia due to mutations in the arginine vasopressin (AVP) gene. The aim of the study was to describe the clinical and molecular characteristics of families with neurohypophyseal diabetes insipidus.. Five Portuguese families with autosomal dominant FNDI underwent sequencing of the AVP gene and the identified mutations were functionally characterized by in vitro studies.. Three novel and two recurrent heterozygous mutations were identified in the AVP gene. These consisted of one initiation codon mutation in the signal peptide coding region (c.2T > C, p.Met1?), three missense mutations in the neurophysin II (NPII) coding region (c.154T > C, p.Cys52Arg; c.289C > G, p.Arg97Gly; and c.293G > C, p.Cys98Ser), and one nonsense mutation in the NPII coding region (c.343G > T, p.Glu115Ter). In vitro transfection of neuronal cells with expression vectors containing each mutation showed that the mutations resulted in intracellular retention of the vasopressin prohormone. Patients showed progressive symptoms of polyuria and polydipsia, but with wide variability in severity and age at onset. No clear genotype-phenotype correlation was observed.. The intracellular accumulation of mutant vasopressin precursors supports the role of cellular toxicity of the mutant proteins in the etiology of the disorder and explains the progressive onset of the disorder. These findings further expand the AVP mutational spectrum in FNDI and contribute to the understanding of the molecular pathogenic mechanisms involved in FNDI.

Topics: Arginine Vasopressin; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Diabetes Mellitus; Humans; Mutation; Neurophysins; Pedigree; Polydipsia; Polyuria; Vasopressins

Central diabetes insipidus (CDI) is characterized by polyuria and polydipsia caused by impairment of arginine vasopressin (AVP) secretion. In this study, we evaluated plasma AVP concentrations during a hypertonic saline infusion test using a new AVP radioimmunoassay (RIA) which is now available in Japan. Thirteen control subjects, mostly with hypothalamo-pituitary disease but without CDI, and 13 patients with CDI were enrolled in the study. Whether or not subjects had CDI was determined based on the totality of clinical data, which included urine volumes and osmolality. Regression analysis of plasma AVP and serum Na concentrations revealed that the gradient was significantly lower in the CDI group than in the control group. The area under the receiver-operating-characteristic (ROC) curve was 0.99, and the <0.1 gradient cut-off values for the simple regression line to distinguish CDI from control had a 100% sensitivity and a 77% specificity. The ROC analysis with estimated plasma AVP concentrations at a serum Na concentration of 149 mEq/L showed that the area under the ROC curve was 1.0 and the <1.0 pg/mL cut-off values of plasma AVP had a 99% sensitivity and a 95% specificity. We conclude that measurement of AVP by RIA during a hypertonic saline infusion test can differentiate patients with CDI from those without CDI with a high degree of accuracy. Further investigation is required to confirm whether the cut-off values shown in this study are also applicable to a diagnosis of partial CDI or a differential diagnosis between CDI and primary polydipsia.

Topics: Arginine Vasopressin; Diabetes Insipidus, Neurogenic; Female; Humans; Male; Middle Aged; Polyuria; Radioimmunoassay; Saline Solution, Hypertonic; Sodium; Vasopressins

Familial neurohypophyseal diabetes insipidus is a rare disease produced by a deficiency in the secretion of antidiuretic hormone and is caused by mutations in the arginine vasopressin gene.. Clinical, biochemical, and genetic characterization of a group of patients clinically diagnosed with familial neurohypophyseal diabetes insipidus, 1 of the largest cohorts of patients with protein neurophysin II (AVP-NPII) gene alterations studied so far.. The AVP-NPII gene was screened for mutations by PCR followed by direct Sanger sequencing in 15 different unrelated families from Spain.. The 15 probands presented with polyuria and polydipsia as the most important symptoms at the time of diagnosis. In these patients, the disease was diagnosed at a median of 6 years of age. We observed 11 likely pathogenic variants. Importantly, 4 of the AVP-NPII variants were novel (p.(Tyr21Cys), p.(Gly45Ser), p.(Cys75Tyr), p.(Gly88Cys)).. Cytotoxicity seems to be due to consequences common to all the variants found in our cohort, which are not able to fold correctly and pass the quality control of the ER. In concordance, we found autosomal dominant familial neurohypophyseal diabetes insipidus in the 15 families studied.

Topics: Adolescent; Adult; Child; Child, Preschool; Diabetes Insipidus, Neurogenic; Family; Female; Follow-Up Studies; Genetic Predisposition to Disease; Humans; Infant; Male; Middle Aged; Mutation; Neurophysins; Prognosis; Protein Precursors; Vasopressins; Young Adult

There are two forms of diabetes insipidus, central (neurohypophyseal), and nephrogenic, caused by pathogenic variants in the AVP gene and the AVPR2 or AQP2 genes, respectively. We report on a four-generation family, seven individuals had central diabetes insipidus (CDI) and the female index patient seen from age 16 to 26 years had (mild) nephrogenic diabetes insipidus. In her father with CDI, a known pathogenic heterozygous AVP variant c.232_234del p.(Glu78del) was identified, confirming the diagnosis of CDI in him and the other affected family members. In the proband, molecular analysis disclosed a novel heterozygous AVPR2 gene variant, c.962A > T p.(Asn321Ile) and an extremely skewed X-inactivation, confirming X-linked nephrogenic diabetes insipidus (XL-NDI). Whole exome sequencing showed no further causative mutation. This is the first report on the co-existence of CDI and NDI in one family. Our review of symptomatic female AVPR2 heterozygotes includes 23 families with at least one affected female (including this study). There were 21 different causative mutations. Mutation types in females did not differ from those in males. Both severe XL-NDI and mild forms were reported in females. All six females with severe XL-NDI had complete loss-of-function (null) mutations. The remaining 17 female probands had milder XL-NDI caused by 14 missense variants and three null variants of the AVPR2 gene. X-inactivation was studied in nine of these females; all showed extreme or slight skewing. The review underlines that XL-NDI in female AVPR2 heterozygotes is always accompanied by skewed X-inactivation, emphasizing a need for X-inactivation studies in these females.

Topics: Adolescent; Adult; Aquaporin 2; Diabetes Insipidus, Nephrogenic; Diabetes Insipidus, Neurogenic; Diabetes Mellitus; Exome Sequencing; Female; Genes, X-Linked; Humans; Male; Mutation, Missense; Neurophysins; Pedigree; Protein Precursors; Receptors, Vasopressin; Vasopressins; X Chromosome Inactivation; Young Adult

Central diabetes is an infrequent complication reported in the neonatal period.. CDI as a complication of Streptococcus pneumoniae (S. pneumoniae) sepsis and meningitis in a 9-day-old boy is presented. The CDI developed on day 3 after admission and was controlled with nasal vasopressin on the 20th day of admission. Despite antibiotic support, the child died from Acinetobacter sepsis at 4 months of age, but the CDI was well controlled.. Newborns with bacterial meningitis can develop CDI as a sequalae. Treatment of the CDI with nasal vasopressin can be successful in this period. To our knowledge, this is the first newborn of CDI associated with S. pneumoniae meningitis.

Topics: Administration, Intranasal; Antidiuretic Agents; Diabetes Insipidus, Neurogenic; Fatal Outcome; Humans; Infant, Newborn; Male; Meningitis, Pneumococcal; Vasopressins

Autosomal dominant neurohypophyseal diabetes insipidus (adNDI) is caused by arginine vasopressin (AVP) deficiency resulting from mutations in the AVP-NPII gene encoding the AVP preprohormone.. To describe the clinical and molecular features of Italian unrelated families with central diabetes insipidus.. We analyzed AVP-NPII gene in 13 families in whom diabetes insipidus appeared to be segregating.. Twenty-two patients were found to carry a pathogenic AVP-NPII gene mutation. Two novel c.173 G>C (p.Cys58Ser) and c.215 C>A (p.Ala72Glu) missense mutations and additional eight different mutations previously described were identified; nine were missense and one non-sense mutation. Most mutations (eight out of ten) occurred in the region encoding for the NPII moiety; two mutations were detected in exon 1. No mutations were found in exon 3. Median age of onset was 32.5 months with a variability within the same mutation (3 to 360 months). No clear genotype-phenotype correlation has been observed, except for the c.55 G>A (p.Ala19Thr) mutation, which led to a later onset of disease (median age 120 months). Brain magnetic resonance imaging (MRI) revealed the absence of posterior pituitary hyperintensity in 8 out of 15 subjects, hypointense signal in 4 and normal signal in 2. Follow-up MRI showed the disappearance of the posterior pituitary hyperintensity after 6 years in one case.. adNDI is a progressive disease with a variable age of onset. Molecular diagnosis and counseling should be provided to avoid unnecessary investigations and to ensure an early and adequate treatment.

Topics: Adolescent; Adult; Child; Child, Preschool; Diabetes Insipidus, Neurogenic; Female; Follow-Up Studies; Humans; Male; Middle Aged; Mutation; Neurophysins; Pedigree; Protein Precursors; Vasopressins; Young Adult

Variability in the severity and age at onset of autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI) may be associated with certain types of variants in the arginine vasopressin (AVP) gene. In this study, we aimed to describe a large family with an apparent predominant female occurrence of polyuria and polydipsia and to determine the underlying cause.. The family members reported their family demography and symptoms. Two subjects were diagnosed by fluid deprivation and dDAVP challenge tests. Eight subjects were tested genetically. The identified variant along with 3 previously identified variants in the AVP gene were investigated by heterologous expression in a human neuronal cell line (SH-SY5Y).. Both subjects investigated clinically had a partial neurohypophyseal diabetes insipidus phenotype. A g.276_278delTCC variant in the AVP gene causing a Ser18del deletion in the signal peptide (SP) of the AVP preprohormone was perfectly co-segregating with the disease. When expressed in SH-SY5Y cells, the Ser18del variant along with 3 other SP variants (g.227G>A, Ser17Phe, and Ala19Thr) resulted in reduced AVP mRNA, impaired AVP secretion, and partial AVP prohormone degradation and retention in the endoplasmic reticulum. Impaired SP cleavage was demonstrated directly in cells expressing the Ser18del, g.227G>A, and Ala19Thr variants, using state-of-the-art mass spectrometry.. Variants affecting the SP of the AVP preprohormone cause adFNDI with variable phenotypes by a mechanism that may involve impaired SP cleavage combined with effects at the mRNA, protein, and cellular level.

Topics: Adult; Cell Line, Tumor; Child; Diabetes Insipidus, Neurogenic; Endoplasmic Reticulum; Family; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Variation; Humans; Male; Neurophysins; Protein Precursors; Proteolysis; RNA, Messenger; Sex Factors; Vasopressins

Central diabetes insipidus can occur after hypothalamic-hypophyseal tract injury. This injury is linked with a deficit in circulating vasopressin and oxytocin, which are produced in the supraoptic nuclei and the hypothalamic paraventricular nuclei. Previous studies indicate that an ectopic neural lobe forms after pituitary stalk lesion in rats, and while the relationship between an ectopic neural lobe and CDI outcomes is unclear, the underlying mechanisms are also unknown. Here, we report that two different CDI characteristics are shown in rats that underwent pituitary stalk electric lesion and are defined by two different groups classified as the recovery group and the no-recovery group. Rats showed an enlarged functional ectopic neural lobe at the lesion site with a low CDI index. Moreover, growth associated protein-43, p-PI3K and p-AKT were up-regulated in the unmyelinated fibers of the ectopic neural lobe. Our findings suggest that the enlarged structure formed a functional ectopic neural lobe after the pituitary stalk lesion, and its regeneration might influence the CDI outcome. This regeneration might be due to an increase in GAP-43 expression through the PI3K/AKT pathway.

Topics: Animals; Diabetes Insipidus, Neurogenic; GAP-43 Protein; Male; Phosphatidylinositol 3-Kinases; Pituitary Gland; Pituitary Gland, Posterior; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Signal Transduction; Up-Regulation; Vasopressins

Autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI) is characterized by severe polyuria and polydipsia and is caused by variations in the gene encoding the AVP prohormone. This study aimed to ascertain a correct diagnosis, to identify the underlying genetic cause of adFNDI in a Swedish family, and to test the hypothesis that the identified synonymous exonic variant in the AVP gene (c.324G>A) causes missplicing and endoplasmic reticulum (ER) retention of the prohormone.. Three affected family members were admitted for fluid deprivation test and dDAVP (1-deamino-8-d-arginine-vasopressin) challenge test. Direct sequencing of the AVP gene was performed in the affected subjects, and genotyping of the identified variant was performed in family members. The variant was examined by expression of AVP minigenes containing the entire coding regions as well as intron 2 of AVP.. Clinical tests revealed significant phenotypical variation with both complete and partial adFNDI phenotype. DNA analysis revealed a synonymous c.324G>A substitution in one allele of the AVP gene in affected family members only. Cellular studies revealed both normally spliced and misspliced pre-mRNA in cells transfected with the AVP c.324G>A minigene. Confocal laser scanning microscopy showed collective localization of the variant prohormone to ER and vesicular structures at the tip of cellular processes.. We identified a synonymous variant affecting the second nucleotide of exon 3 in the AVP gene (c.324G>A) in a family in which adFNDI segregates. Notably, we showed that this variant causes partial missplicing of pre-mRNA, resulting in accumulation of the variant prohormone in ER. Our study suggests that even a small amount of aberrant mRNA might be sufficient to disturb cellular function, resulting in adFNDI.

Topics: Diabetes Insipidus, Neurogenic; Female; Genetic Variation; Humans; Male; Neurophysins; Pedigree; Protein Precursors; Vasopressins

The water deprivation test (WDT) is widely used for the differential diagnosis of the polyuria-polydipsia syndrome (PPS). However, it is inconvenient and may not always be precise in differentiating partial forms of diabetes insipidus (DI) from primary polydipsia (PP). The aim of this study was to evaluate the results of a combined outpatient and inpatient overnight WDT protocol that included an overnight unsupervised period concerning its feasibility and safety.. We performed a retrospective analysis of clinical data and laboratory results of 52 patients with PPS undergoing WDT at a single center.. PP was the most frequent diagnosis, followed by complete central DI (cCDI), partial central DI (pCDI), and nephrogenic DI (NDI). Over 90% of the patients showed an expected increase in serum osmolality at the end of the dehydration period. There were no reports of complications during the overnight deprivation period. Post-dehydration urine osmolality and urine-to-serum osmolality ratio significantly differentiated all the groups ( P<.05), except for cCDI and NDI, which could be differentiated by basal and post-dehydration vasopressin (AVP) levels ( P<.05 for both). Although these measurements were useful for differentiating patients according to their allocation groups, results from WDT and direct AVP levels may often require a comprehensive diagnostic approach, particularly in the challenging groups of PP and pCDI.. A combined outpatient and inpatient overnight WDT protocol is safe and feasible when the test is performed with special care at experienced centers. Newer diagnostic tools are expected to improve the accuracy of PPS diagnosis.. AQP2 = aquaporin-2; AVP = vasopressin; CDI = central diabetes insipidus; cCDI = complete central diabetes insipidus; DDAVP = desmopressin; DI = diabetes insipidus; IQR = interquartile range; MRI = magnetic resonance imaging; Na

Topics: Adolescent; Adult; Aged; Ambulatory Care; Child; Diabetes Insipidus, Nephrogenic; Diabetes Insipidus, Neurogenic; Female; Hospitalization; Humans; Male; Middle Aged; Neurophysins; Osmolar Concentration; Polydipsia; Polydipsia, Psychogenic; Polyuria; Protein Precursors; Retrospective Studies; Syndrome; Vasopressins; Water Deprivation; Young Adult

Familial neurohypophyseal diabetes insipidus (FNDI) is a rare, autosomal dominant, inherited disorder which is characterized by severe polydipsia and polyuria generally presenting in early childhood. In the present study, we aimed to analyze the AVP gene in a Turkish family with FNDI.. Four patients with neurohypophyseal diabetes insipidus and ten healthy members of the family were studied. Diabetes insipidus was diagnosed by the water deprivation test in affected family members. Mutation analysis was performed by sequencing the whole coding region of AVP-NPII gene using DNA isolated from peripheral blood samples.. Urine osmolality was low (<300 mOsm/kg) during water deprivation test, and an increase more than 50 % in urine osmolality and recovery of the symptoms were observed by the administration of desmopressin in all patients. Plasma copeptin levels were lower than expected according to plasma osmolality. Pituitary MRI revealed partial empty sella with a bright spot in index patient and a normal neurohypophysis in the other affected subjects. Genetic screening revealed a novel, heterozygous mutation designated as c.-3A>C in all patients.. c.-3A>C mutation in 5'UTR of AVP gene in this family might lead to the truncation of signal peptide, aggregation of AVP in the cytoplasm instead of targeting in the endoplasmic reticulum, thereby could disrupt AVP secretion without causing neuronal cytotoxicity, which might explain the presence of bright spot. The predicted effect of this mutation should be investigated by further in vitro molecular studies.

Topics: Adult; Case-Control Studies; Diabetes Insipidus, Neurogenic; Family; Female; Follow-Up Studies; Humans; Male; Middle Aged; Mutation; Neurophysins; Pedigree; Prognosis; Protein Precursors; Turkey; Vasopressins; Young Adult

Ultrastructural changes in cells of the renal inner medulla involved in the realization of the antidiuretic effect of vasopressin under conditions of prostaglandin synthesis blockade were studied in the kidneys of Wistar rats and endogenous vasopressin-deficient homozygous Brattleboro rats. The results indicated uniform trend to an increase in the number of clathrincoated vesicles under conditions of hormone treatment combined with prostaglandin synthesis blockade in animals with different neurohypophyseal status. These changes reflected translocation of aquaporins and an increase in the permeability of the collecting tubular epithelium for water. Brattleboro rats, but not Wistar rats, exhibited ultrastructural signs of synthesis activation in the epithelium and widening of the intercellular gaps, which could indicate more intense paracellular water transport.

Topics: Animals; Antidiuretic Agents; Aquaporins; Biological Transport; Clathrin-Coated Vesicles; Diabetes Insipidus, Neurogenic; Diclofenac; Kidney Medulla; Kidney Tubules, Collecting; Microscopy, Electron; Osmolar Concentration; Prostaglandin Antagonists; Prostaglandins; Protein Transport; Rats; Rats, Brattleboro; Rats, Wistar; Vasopressins; Water

Idiopathic early-onset central diabetes insipidus (CDI) might be due to mutations of arginine vasopressin-neurophysin II (AVP-NPII (AVP)) or wolframin (WFS1) genes.. Sequencing of AVP and WFS1 genes was performed in nine children with CDI, aged between 9 and 68 months, and negative family history for polyuria and polydipsia.. Two patients carried a mutation in the AVP gene: a heterozygous G-to-T transition at nucleotide position 322 of exon 2 (c.322G>T) resulting in a stop codon at position 108 (p.Glu108X), and a novel deletion from nucleotide 52 to 54 (c.52_54delTCC) producing a deletion of a serine at position 18 (p.Ser18del) of the AVP pre-prohormone signal peptide. A third patient carried two heterozygous mutations in the WFS1 gene localized on different alleles. The first change was A-to-G transition at nucleotide 997 in exon 8 (c.997A>G), resulting in a valine residue at position 333 in place of isoleucine (p.Ile333Val). The second novel mutation was a 3 bp insertion in exon 8, c.2392_2393insACG causing the addition of an aspartate residue at position 797 and the maintenance of the correct open reading frame (p. Asp797_Val798insAsp). While similar WFS1 protein levels were detected in fibroblasts from healthy subjects and from the patient and his parents, a major sensitivity to staurosporine-induced apoptosis was observed in the patient fibroblasts as well as in patients with Wolfram syndrome.. Early-onset CDI is associated with de novo mutations of the AVP gene and with hereditary WFS1 gene changes. These findings have valuable implications for management and genetic counseling.

Topics: Adolescent; Adult; Age of Onset; Cells, Cultured; Child; Cohort Studies; Diabetes Insipidus, Neurogenic; Female; Genetic Association Studies; Humans; Male; Membrane Proteins; Middle Aged; Mutation, Missense; Neurophysins; Protein Precursors; Vasopressins; Young Adult

Familial central diabetes insipidus (DI), usually an autosomal dominant disorder, is caused by mutations in arginine vasopressin-neurophysin II (AVP-NPII) gene that leads to aberrant preprohormone processing and gradual destruction of AVP-secreting cells.. To determine clinical and molecular characteristics of patients with familial central DI from two different Turkish families.. The diagnosis of central DI was established by 24-h urine collection, water deprivation test, and desmopressin challenge. To confirm the diagnosis of familial central DI, the entire coding region of AVP-NPII gene was amplified and sequenced. A total of eight affected patients and three unaffected healthy relatives from two families were studied.. Genetic analysis revealed a previously reported heterozygous mutation (p.C98X) in family A, and a heterozygous novel mutation (p.G45C) in family B, both detected in exon 2 of AVP-NPII gene. When we compared the clinical characteristics of the two families, it was noticed that as the age of onset of symptoms in family A ranges between 4 and 7 years, it was <1 year in family B. Additionally, pituitary bright spot was present in the affected siblings, but absent in their affected parents.. Familial central DI is a progressive disease, and age of onset of symptoms can differ depending on the mutation. Bright spot on pituitary MRI might be present at onset, but become invisible over time. Genetic testing and appropriate counseling should be given in familial cases of central DI to ensure adequate treatment, and to avoid chronic water deprivation that might result in growth retardation in childhood.

Topics: Adult; Child; Diabetes Insipidus, Neurogenic; Female; Humans; Male; Mutation; Neurophysins; Protein Precursors; Vasopressins

Diabetes insipidus is a disease in which large volumes of dilute urine (polyuria) are excreted due to vasopressin (AVP) deficiency [central diabetes insipidus (CDI)] or to AVP resistance (nephrogenic diabetes insipidus). In the majority of patients, the occurrence of CDI is related to the destruction or degeneration of neurons of the hypothalamic supraoptic and paraventricular nuclei. The most common and well recognized causes include local inflammatory or autoimmune diseases, vascular disorders, Langerhans cell histiocytosis (LCH), sarcoidosis, tumors such as germinoma/craniopharyngioma or metastases, traumatic brain injuries, intracranial surgery, and midline cerebral and cranial malformations. Here we have the opportunity to describe an unusual case of female patient who developed autoimmune CDI following ureaplasma urealyticum infection and to review the literature on this uncommon feature. Moreover, we also discussed the potential mechanisms by which ureaplasma urealyticum might favor the development of autoimmune CDI.

Topics: Arthritis, Reactive; Autoantibodies; Autoimmune Diseases; Diabetes Insipidus, Neurogenic; Female; Humans; Middle Aged; Neurophysins; Protein Precursors; Ureaplasma Infections; Ureaplasma urealyticum; Vasopressins

Central Diabetes Insipidus (CDI) is caused by a deficiency of antidiuretic hormone and characterized by polyuria, polydipsia and inability to concentrate urine. Our objective was to present the results of the molecular analyses of AVP-neurophysin II (AVP-NPII) gene in a large familial neurohypophyseal (central) DI pedigree. A male patient and his family members were analyzed and the prospective clinical data were collected. The proband applied to hospital for eligibility to be a recruit in Armed Forces. The patient had severe polyuria (20 L/day), polydipsia (20.5 L/day), fatique, and deep thirstiness. CDI was confirmed with the water deprivation-desmopressin test according to an increase in urine osmolality from 162 mOsm/kg to 432 mOsm/kg after desmopressin acetate injection. To evaluate the coding regions of AVP-NPII gene, polymerase chain reactions were performed and amplified regions were submitted to direct sequence analysis. We detected a heterozygous three base pair deletion at codon 69-70 (207_209delGGC) in exon 2, which lead to a deletion of the amino acid alanine. A three-dimensional protein structure prediction was shown for the deleted AVP-NPII and compared with the wild type. The three base pair deletion may yield an abnormal AVP precursor in neurophysin moiety, but further functional analyses are needed to understand the function of the deleted protein.

Topics: Alanine; Diabetes Insipidus, Neurogenic; Female; Humans; Male; Models, Molecular; Neurophysins; Pedigree; Protein Conformation; Protein Precursors; Sequence Deletion; Vasopressins; Young Adult

The immunoglobulin heavy chain binding protein (BiP) is an endoplasmic reticulum (ER) chaperone, which binds to newly synthesized secretory and transmembrane proteins to facilitate protein folding. BiP mRNA is expressed in the arginine vasopressin (AVP) neurons in the supraoptic nucleus of wild-type mice even in basal conditions, and the expression levels increase in response to dehydration. These data suggest that AVP neurons are subjected to ER stress. Familial neurohypophysial diabetes insipidus (FNDI) is caused by mutations in the gene locus of AVP. The mutant proteins could accumulate in the ER and possibly increase ER stress in the AVP neurons. We bred mice possessing a mutation causing FNDI, which manifested progressive polyuria, as do the patients with FNDI. Electron microscopic analyses demonstrated that aggregates accumulated in the ER of AVP neurons in FNDI mice. Despite polyuria, which could potentially induce dehydration, AVP mRNA expression was decreased in the supraoptic nucleus, and the AVP mRNA poly(A) tail length was shortened in FNDI mice compared with wild-type mice. Incubation of hypothalamic explants of wild-type mice with ER stressors caused shortening of the poly(A) tail length of AVP mRNA, accompanied by decreases in the expression. These data revealed a mechanism by which ER stress decreases poly(A) tail length of AVP mRNA, and this reduces the load of unfolded proteins that form the aggregates in ER of the AVP neurons in FNDI mice.

Topics: Animals; Diabetes Insipidus, Neurogenic; Disease Models, Animal; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Humans; Hypothalamus; Mice; Neurons; Protein Folding; RNA, Messenger; Vasopressins

Autosomal dominant familial diabetes insipidus (FNDI) is a rare disease characterized by polydipsia and polyuria due to deficiency of the antidiuretic hormone, arginine vasopressin (AVP). We report the first Slovak family with the disease. Noteworthy is the concordantly belated debut of the disease symptoms in two monozygotic twin proband girls in the age of 17 years. Because of inconclusive results of water deprivation test consistent with partial diabetes insipidus (DI), missing "bright spot" of posterior pituitary gland in T1-weighted magnetic resonance imaging and family occurrence of polyuria and polydipsia on anamnestic evaluation.. Molecular genetic testing of the AVP gene was proceeded, because of the inconclusive results of water deprivation test consistent with partial diabetes insipidus, missing "bright spot" of posterior pituitary gland in T1-weighted magnetic resonance imaging and family occurrence of polyuria and polydipsia on anamnestic evaluation.. Genetic analysis revealed a heterozygous g.279G>A substitution that predicts a p.Ala19Thr substitution in the signal peptide of the AVP prohormone. The wide intrafamiliar variations (3 to 17 years) in disease onset together with the concordantly delayed debut of polyuria in two monozygotic twin girls suggest that individual differences in genetic influences family environmental factors may modify the penetrance of the mutation of the AVP gene.. The present paper supports the notion that molecular genetic evaluation should be performed in all patients with familial occurrence of DI regardless of the clinical results.

Topics: Adolescent; Diabetes Insipidus, Neurogenic; Family Health; Female; Humans; Male; Mutation, Missense; Neurophysins; Pedigree; Protein Precursors; Slovakia; Twins, Monozygotic; Vasopressins

Familial neurohypophyseal diabetes insipidus (FNDI) typically presents with age-dependent penetrance and autosomal dominant inheritance caused by missense variations in one allele of the AVP gene encoding the arginine vasopressin (AVP) prohormone. We present the molecular genetic characteristics underlying an unusual form of FNDI occurring with very early onset and seemingly autosomal recessive inheritance. By DNA amplification and sequencing, we identified a novel variant allele of the AVP gene carrying a 10,396 base pair deletion involving the majority of the AVP gene as well as its regulatory sequences in the intergenic region between the AVP and the OXT gene, encoding the oxytocin prohormone. We found two chromosomes carrying the deletion in affected family members and one in unaffected family members suspected to transmit the deleted allele. Whole-genome array analysis confirmed the results and excluded the presence of any additional major pathogenic abnormalities. The deletion is predicted to abolish the transcription of the AVP gene, thus the fact that family members heterozygous for the deletion remain healthy argues, in general, against haploinsufficiency as the pathogenic mechanism FNDI. Accordingly, our data is strong support to the prevailing idea that dominant inheritance of FNDI is due to a dominant-negative effect exerted by variant AVP prohormone.

Topics: Age of Onset; Alleles; Diabetes Insipidus, Neurogenic; Female; Genes, Recessive; Heterozygote; Humans; Infant; Infant, Newborn; Male; Mutation; Neurophysins; Pedigree; Pregnancy; Protein Precursors; Sequence Deletion; Vasopressins

Familial neurohypophyseal diabetes insipidus (FNDI) is mostly an autosomal dominant inherited disorder presenting with severe polydipsia and polyuria typically in early childhood. To date, 69 different variations in the AVP gene encoding the AVP prohormone have been identified in autosomal dominant FNDI (adFNDI). In this study we present a family of seven generations, in which a novel variation in the AVP gene seems to cause adFNDI. Clinical assessment by 24 h urine collection, water deprivation test, desmopressin (dDAVP) challenge, and magnetic resonance imaging (MRI) of the posterior pituitary are presented. The diagnosis of adFNDI was confirmed by direct DNA sequence analysis of the AVP gene. Inheritance pattern and clinical history clearly pointed towards adFNDI. Inability of concentrating urine upon dehydration was demonstrated by a water deprivation test, and neurohypophyseal diabetes insipidus was strongly suspected after dDAVP administration, during which renal concentration ability quadrupled. MRI revealed a very weak pituitary "bright spot" in each of six subjects and a further reduction in the size of the neurohypophysis in a 7-year follow-up MRI scan in one subject. DNA sequence analysis revealed heterozygousity for a novel g.1785T > C gene variation predicting a p.Leu63Pro substitution in four affected subjects. Genetic testing in the diagnostic evaluation of families in which diabetes insipidus segregates is highly recommended in that interpretation of clinical assessments can be difficult. Furthermore, presymptomatic diagnosis can ease the parental concern of the carrier status of their offspring, and also avoid unnecessary surveillance of those being unaffected.

Topics: Diabetes Insipidus, Neurogenic; Female; Heterozygote; Humans; Italy; Magnetic Resonance Imaging; Male; Neurophysins; Pedigree; Protein Precursors; Sequence Analysis, DNA; Vasopressins

Surgical manipulation of the pituitary stalk, neurohypophysis or the hypothalamus may disturb control of the plasma sodium level. The factors that might predict the risk of postoperative sodium imbalance are not clear, and were investigated in this study.. A retrospective survey of 129 surgical records for the occurrence of plasma sodium levels outside the normal range, following transsphenoidal procedures. Median patient age was 49 (range 20-78) years, 65 female. 73 of the operated lesions were non-functioning pituitary adenomas. Patients were considered to have impaired plasma sodium balance if the range of 135-145 mmol/L was not maintained.. Of all 129 surgical cases, 68 (53%) experienced an imbalance in sodium levels. Severe sodium imbalance (≥ 149 or ≤ 131 mmol/L) was observed in 28 patients (22%). 13 showed hypernatraemia (median day 1), and 15 hyponatraemia (median day 6). Tumour size was associated with an increased incidence of sodium imbalance, particularly in patients younger than 49 years; surgery resulted in sodium imbalance in 38% of young patients operated on for tumours < 22 mm and in 76% of young patients, operated on for tumours ≥ 22 mm. Overall, tumour size increased with patients' age, and tumour size was less predictive for sodium disturbances in elderly patients. Median time in hospital was 5 days for patients without sodium imbalance, 6 days for patients with hypernatraemia and 11 days for patients with hyponatraemia.. Following pituitary surgery, patients with large tumours, in particular those of young age, are at higher risk for losing control of their plasma sodium level. Increased ADH secretion (hyponatraemia), but not transient diabetes insipidus was associated with a prolonged hospital stay. Postoperative follow-up of patients with sellar tumours should include careful monitoring of plasma sodium levels within the first two postoperative weeks and clear patients' instructions.

Topics: Adenoma; Adult; Aged; Analysis of Variance; Diabetes Insipidus, Neurogenic; Female; Homeostasis; Humans; Hypernatremia; Hyponatremia; Male; Middle Aged; Pituitary Neoplasms; Postoperative Complications; Retrospective Studies; Sella Turcica; Sodium; Tumor Burden; Vasopressins; Young Adult

Central diabetes insipidus (CDI) is caused by deficient secretion of antidiuretic hormone (ADH) due to different conditions that can affect the hypothalamic neurons. It results in an inability to retain normal quantities of free water, which leads to polyuria, including at night, and polydipsia. In adults, it is mostly due to the "idiopathic" form or present after pituitary surgery or a traumatic brain injury. In rare cases, an underlying systemic disease is found. The diagnosis of CDI is based on the water deprivation test. Pituitary MRI and specific clinical and biological work-up are recommended to precise etiology. Treatment of choice is desmopressin, a synthetic analogue of the endogenous ADH hormone. A multidisciplinary team generally provides management and monitoring of CDI.

Topics: Adult; Antidiuretic Agents; Deamino Arginine Vasopressin; Diabetes Insipidus, Neurogenic; Humans; Magnetic Resonance Imaging; Patient Care Team; Polydipsia; Polyuria; Vasopressins; Water Deprivation

Autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI), a disorder caused by mutations in the vasopressin (AVP)-neurophysin II (NPII) gene, manifests gradually during early childhood with progressive polyuria and polydipsia. Patients are usually treated with synthetic AVP analog. If unlimited access to water is provided, prognosis is usually good even in the absence of specific treatment. In this study, we describe three families with adFNDI, in which growth failure was a prominent complaint, on the clinical and molecular level.. Histories from affected and unaffected family members were taken. Height and weight of index patients were recorded longitudinally. Patients underwent water deprivation tests, magnetic resonance imaging, and genetic analysis. One mutant was studied by heterologous expression in cell culture.. A total of ten affected individuals were studied. In two of the three pedigrees, a novel mutation in the AVP-NPII gene was found. The index children in each pedigree showed growth retardation, which was the reason for referral in two. In these cases, water intake was tightly restricted by the parents in an attempt to overcome suspected psychogenic polydipsia and to improve appetite. Once the children were treated by hormone replacement, they rapidly caught up to normal weight and height.. Genetic testing and appropriate parent counseling should be enforced in adFNDI families to ensure adequate treatment and avoid chronic water deprivation, which causes failure to thrive.

Topics: Child; Child, Preschool; Diabetes Insipidus, Neurogenic; Female; Growth Disorders; Humans; Infant; Magnetic Resonance Imaging; Male; Mutation; Neurophysins; Pedigree; Polyuria; Vasopressins; Water Deprivation

Familial neurohypophysial diabetes insipidus (FNDI) is a rare disease that is inherited in an autosomal dominant manner. In a previous study, we made a mouse model for FNDI, which showed progressive polyuria accompanied by inclusion bodies in the arginine vasopressin (AVP) neurons formed by aggregates in the endoplasmic reticulum. The present study was conducted to determine whether the activities of AVP neurons are related to the phenotype progression in the FNDI model. In the first experiment, female heterozygous mice were administered either desmopressin (dDAVP) or a vehicle (control) subcutaneously with osmotic minipumps for 30 days. The dDAVP treatment significantly decreased the urine volume, AVP mRNA expression, and inclusion bodies in the AVP neurons. Urine volume in the dDAVP group remained significantly less than the control for 14 days even after the minipumps were removed. In the second experiment, the males were fed either a 0.2% Na or 2.0% Na diet for 6 mo. Urine AVP excretion was significantly increased in the 2.0% Na group compared with the 0.2% Na group for the first 2 mo but gradually decreased thereafter. Throughout the experiments, urine volume increased progressively in the 2.0% Na group but not in the 0.2% Na group. Immunohistochemical analyses revealed that inclusion bodies in the AVP cells had significantly increased in the 2.0% Na compared with the 0.2% Na group. These data demonstrated that activation of AVP neurons could accelerate the aggregate formation as well as the progression of the polyuria in the FNDI model mice.

Topics: Animals; Deamino Arginine Vasopressin; Diabetes Insipidus, Neurogenic; Disease Progression; Drinking; Hematocrit; Hypoglycemic Agents; Immunohistochemistry; In Situ Hybridization; Male; Mice; Mice, Inbred C57BL; Neurons; Osmolar Concentration; Phenotype; Pituitary Gland, Posterior; Sodium, Dietary; Urodynamics; Vasopressins

The particularities of urine osmotic concentration depending on hormonal background of vasopressin were studied in rats. It was found that WAG and Brattleboro lines of rats characterized respectively by normal level and absence of endogenous vasopressin, possess interline correlation of urine osmolality (p = 0.86) in various conditions between the extreme hydrating and dehydratation. Concentrating level of WAG rats varies from 747 +/- 94 to 2936 +/- 128 mOsm/kg, but that of Brattleboro rats changes more within the 160 +/- 9 being twice lower as isotonicity to 1305 +/- 142 mOcm/kg. Urine concentrating goes up to 1391 +/- 76 mOcm/kg in Brattleboro rats already on the day of the action of exogenous vasopressin secreted from ALZET minipump, however, in spite of constant work of this minipump during 4 hrs a week, further increasing of urine osmolality was not observed in Brattleboro rats.

Topics: Animals; Antidiuretic Agents; Diabetes Insipidus, Neurogenic; Hypothalamus; Rats; Rats, Brattleboro; Species Specificity; Time Factors; Vasopressins

Central diabetes insipidus (DI) characterized by polyuria, polydipsia and inability to concentrate urine, has different etiologies including genetic, autoimmune, post-traumatic, among other causes. Autosomal dominant central DI presents the clinical feature of a progressive decline of arginine-vasopressin (AVP) secretion.. In this study, we characterized the clinical features and sequenced the AVP-NPII gene of seven long-term follow-up patients with idiopathic central DI in an attempt to determine whether a genetic cause would be involved.. The diagnosis of central DI was established by fluid deprivation test and hyper-tonic saline infusion. For molecular analysis, genomic DNA was extracted and the AVP-NPII gene was amplified by polymerase chain reaction and sequenced.. Sequencing analysis revealed a homozygous guanine insertion in the intron 2 (IVS2 +28 InsG) of the AVP-NPII gene in four patients, which represents an alternative gene assembly. No mutation in the code region of the AVP-NPII gene was found.. The homozygous guanine insertion in intron 2 (IVS2 +28 InsG) is unlikely to contribute to the AVP-NPII gene modulation in DI. In addition, the etiology of idiopathic central DI in children may not be apparent even after long-term follow-up, and requires continuous etiological surveillance.

Topics: Child; Child, Preschool; Diabetes Insipidus, Neurogenic; Female; Follow-Up Studies; Humans; Infant; Introns; Male; Mutagenesis, Insertional; Neurophysins; Protein Precursors; Vasopressins

One of the synthetic analogues of antidiuretic hormone-desmopressin is used in patients with central diabetes insipidus and in those with coagulation disorders. However, its effects on bile secretion are not fully defined. We investigated the effect of desmopressin on bile formation and determined the role of V1a vasopressin receptors in the action of desmopressin on choleresis. Rats were injected intraportally with a bolus of desmopressin; the changes of bile flow, the content of free and conjugated cholates were compared with control animal group. Selective antagonist of V1a receptors was injected 10 minutes before desmopressin treatment and the findings were compared with the results after desmopressin injection alone. Desmopressin increased bile flow, secretion of total cholates like amino acids conjugated, while diminished free bile acids content. Secreted bile volume and conjugated bile acids content were reduced in V1a receptors antagonist+desmopressin-treated rats. In contrast, free bile acids content was more than the results in desmopressin-treated rats. Desmopressin at concentrations nearly equal to physiological concentrations of natural hormone in blood shows its choleretic effect. Antagonist of V1a vasopressin receptors modulates desmopressin action. This certifies the role of these receptors in the action of desmopressin on different processes of bile formation.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Bile; Bile Acids and Salts; Cholagogues and Choleretics; Deamino Arginine Vasopressin; Diabetes Insipidus, Neurogenic; Humans; Male; Rats; Rats, Wistar; Receptors, Vasopressin; Vasopressins

Autosomal dominant neurohypophyseal diabetes insipidus results from mutations in the precursor protein of the antidiuretic hormone arginine vasopressin. Mutant prohormone is retained in the endoplasmic reticulum of vasopressinergic neurons and causes their progressive degeneration by an unknown mechanism. Here, we show that several dominant pro-vasopressin mutants form disulfide-linked homo-oligomers and develop large aggregations visible by immunofluorescence and immunogold electron microscopy, both in a fibroblast and a neuronal cell line. Double-labeling showed the pro-vasopressin aggregates to colocalize with the chaperone calreticulin, indicating that they originated from the endoplasmic reticulum. The aggregates revealed a remarkable fibrillar substructure. Bacterially expressed and purified mutant pro-vasopressin spontaneously formed fibrils under oxidizing conditions. Mutagenesis experiments showed that the presence of cysteines, but no specific single cysteine, is essential for disulfide oligomerization and aggregation in vivo. Our findings assign autosomal dominant diabetes insipidus to the group of neurodegenerative diseases associated with the formation of fibrillar protein aggregates.

Topics: Animals; Chlorocebus aethiops; COS Cells; Diabetes Insipidus, Neurogenic; Disulfides; Endoplasmic Reticulum; Humans; Mutation; Protein Conformation; Protein Folding; Protein Precursors; Vasopressins

It has been reported that various types of axonal injury of hypothalamo-neurohypophyseal tract can result in degeneration of the magnocellular neurons (MCNs) in hypothalamus and development of central diabetes insipidus (CDI). However, the mechanism of the degeneration and death of MCNs after hypophysectomy in vivo is still unclear. This present study was aimed to disclose it and to figure out the dynamic change of central diabetes insipidus after hypophysectomy.. The analysis on the dynamic change of daily water consumption (DWC), daily urine volume(DUV), specific gravity of urine(USG) and plasma vasopressin concentration showed that the change pattern of them was triphasic and neuron counting showed that the degeneration of vasopressin neurons began at 10 d, aggravated at 20 d and then stabilized at 30 d after hypophysectomy. There was marked upregulation of cleaved Caspase-3 expression of vasopressin neurons in hypophysectomy rats. A "ladder" pattern of migration of DNA internucleosomal fragments was detected and apoptotic ultrastructure was found in these neurons. There was time correlation among the occurrence of diabetes insipidus, the changes of plasma vasopressin concentration and the degeneration of vasopressin neurons after hypophysectomy.. This study firstly demonstrated that apoptosis was involved in degeneration of supraoptic vasopressin neurons after hypophysectomy in vivo and development of CDI. Our study on time course and correlations among water metabolism, degeneration and apoptosis of vasopressin neurons suggested that there should be an efficient therapeutic window in which irreversible CDI might be prevented by anti-apoptosis.

Topics: Animals; Apoptosis; Caspase 3; Cell Count; Diabetes Insipidus, Neurogenic; Drinking; Hypophysectomy; Male; Nerve Degeneration; Neurons; Rats; Rats, Sprague-Dawley; Supraoptic Nucleus; Urine; Vasopressins

Topics: Codon, Nonsense; Diabetes Insipidus, Neurogenic; Humans; Molecular Sequence Data; Mutation, Missense; Neurophysins; Protein Precursors; Vasopressins

The autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI) is caused by diverse mutations in one allele of the gene that encodes the arginine vasopressin (AVP) precursor protein, AVP-neurophysin II (AVP-NP II). Most of the mutations identified so far are located in either the signal peptide or NP II moiety. Two recently published mutations in the AVP gene identified in kindreds with adFNDI predict a substitution of histidine for tyrosine at position 2 and a deletion of phenylalanine at position 3 in AVP. They are unique among adFNDI mutations in that they are the only adFNDI mutations that affect amino acid residues in the AVP moiety of the pro-hormone. Here, we report a novel heterozygous missense mutation in the AVP moiety of the AVP-NP II gene in a Japanese person with neurohypophyseal diabetes insipidus (DI). This mutation occurs at position 2 in AVP and predicts a substitution of serine for tyrosine (Y21S). It is expected to interfere with normal binding of AVP with NP II, and thus result in misfolding of the precursor proteins. The data of this study support the notion that mutations affecting the AVP moiety can result in the initiation of the pathological processes.

Topics: Aged, 80 and over; Amino Acid Sequence; Arginine Vasopressin; Base Sequence; Diabetes Insipidus, Neurogenic; Heterozygote; Humans; Hypothalamus; Japan; Magnetic Resonance Imaging; Male; Mutation, Missense; Neurophysins; Pedigree; Pituitary Gland; Protein Precursors; Vasopressins

Up to 21% of severe cases of malaria tropica are associated with polyuria and are life-threatening. We describe a 39-yr-old man with malaria tropica who developed disseminated intravascular coagulation, polyuria, and a pituitary lesion. Empiric treatment with vasopressin improved the polyuria. This is the first case of malaria tropica in which central diabetes insipidus has been documented.

Topics: Adrenal Insufficiency; Adult; Diabetes Insipidus, Neurogenic; Disseminated Intravascular Coagulation; Humans; Hydrocortisone; Magnetic Resonance Imaging; Malaria, Falciparum; Male; Natriuresis; Pituitary Gland, Posterior; Polyuria; Pulmonary Embolism; Renal Insufficiency; Vasopressins

Topics: Amino Acid Substitution; Child; Diabetes Insipidus, Neurogenic; Humans; Mutation, Missense; Netherlands; Neurophysins; Protein Precursors; Vasopressins

Topics: Amino Acid Substitution; Child; Diabetes Insipidus, Neurogenic; Humans; Mutation, Missense; Netherlands; Neurophysins; Protein Precursors; Vasopressins

Topics: Amino Acid Substitution; Child; Diabetes Insipidus, Neurogenic; France; Humans; Mutation, Missense; Neurophysins; Protein Precursors; Vasopressins

Topics: Amino Acid Substitution; Child; Diabetes Insipidus, Neurogenic; Humans; Mutation, Missense; Neurophysins; Protein Precursors; Vasopressins; Wales

We describe a child who has congenital nasal pyriform aperture stenosis with single maxillary central incisor, holoprosencephaly and central diabetes insipidus without any apparent anterior pituitary dysfunction. Conservative management of the congenital nasal pyriform aperture stenosis is adopted and management of diabetes insipidus is described. A literature review is undertaken.

Topics: Abnormalities, Multiple; Bronchoscopy; Deamino Arginine Vasopressin; Diabetes Insipidus, Neurogenic; Enteral Nutrition; Female; Holoprosencephaly; Humans; Infant, Newborn; Intubation, Intratracheal; Magnetic Resonance Imaging; Nasal Cavity; Nasal Obstruction; Renal Agents; Tomography, X-Ray Computed; Vasopressins

Prostaglandins have an important role in renal salt and water reabsorption. PGE2 is the main kidney prostaglandin and is thought to be mainly produced in the kidney inner medulla (IM). There are indications that PGE2 synthesis in nephrogenic (NDI) and central (CDI) diabetes insipidus is altered. We hypothesize that the expression of the major PGE2 synthesis enzymes cyclooxygenases 1 and 2 (COX-1, COX-2) and membrane-associated PGE2 synthase (mPGES) is altered in the kidneys of rats with NDI and CDI. Wistar rats treated with lithium for 4 wk were used as the NDI model. One-half of the NDI model rats were additionally dehydrated for 48 h. Brattleboro (BB) rats that lack endogenous antidiuretic hormone were used as the CDI model. Expression and localization of COX-1, COX-2, and mPGES in IM, inner stripe of outer medulla (ISOM), and cortex were determined by immunoblotting and immunohistochemistry. In lithium-induced NDI, expression of COX-1, COX-2, and mPGES was markedly decreased in IM. In ISOM and cortex, COX-1 expression was marginally reduced and mPGES expression was unaltered. COX-2 expression was undetected in ISOM and marginally increased in cortex. Consistent with this, the density of COX-2-expressing cells in macula densa was significantly increased, indicating differential regulation of COX-2 in IM and cortex. Dehydration of NDI rats resulted in a marked increase in COX-2 immunolabeling in IM interstitial cells, and there was no significant change in COX-1 and mPGES expression in any kidney zone. Treatment of DDAVP in BB rats for 6 days resulted in a markedly increased expression of COX-1, COX-2, and mPGES in IM. In the cortex, there were no changes in the expression of COX-1 and mPGES, whereas COX-2 expression was decreased. These results identify markedly reduced expression of COX-1, COX-2, and mPGES in IM in lithium-induced NDI. Furthermore, there were major changes in the expression of COX-1, COX-2, and mPGES in rats with CDI.

Topics: Animals; Cyclooxygenase 1; Cyclooxygenase 2; Deamino Arginine Vasopressin; Dehydration; Diabetes Insipidus, Nephrogenic; Diabetes Insipidus, Neurogenic; Dinoprostone; Intramolecular Oxidoreductases; Kidney Concentrating Ability; Kidney Cortex; Kidney Medulla; Lithium; Male; Membrane Proteins; Polyuria; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Brattleboro; Rats, Wistar; Renal Agents; Vasopressins; Water Deprivation

Mutations in the human gene encoding the antidiuretic hormone vasopressin (VP) cause autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI), a rare inherited disorder that presents as polydipsia and polyuria as a consequence of a loss of secretion of VP from posterior pituitary nerve terminals. Work from our laboratories has shown that adFNDI, like other neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's, is associated with autophagy. We have recently shown that the activation of autophagy in mouse neuroblastoma Neuro2a cells after adenoviral vector-mediated delivery of an adFNDI mutant VP transgene (Cys67stop) is a cell survival mechanism; its inhibition induces apoptosis. We now show that expression of Cys67stop sensitizes Neuro2a cells to the lethal effects of dopamine. This mode of cell death exhibits features typically associated with classical apoptosis. Yet inhibition of autophagy reversed these effects and rescued cell viability. We propose that autophagy-mediated cell death is a "two-hit" process: Following the cellular stress of the accumulation of a misfolded mutant protein, autophagy is prosurvival. However, a second insult triggers an autophagy-dependent apoptosis.

Topics: Adenoviridae; Animals; Autophagy; Cadaverine; Caspases; Cell Death; Cell Line, Tumor; Cell Survival; Codon, Terminator; Cysteine; Diabetes Insipidus, Neurogenic; Disease Models, Animal; Dopamine; Fluorescent Dyes; Gene Expression; Genetic Vectors; Mice; Mutation; Neuroblastoma; Phagosomes; Transfection; Transgenes; Vacuoles; Vasopressins

Autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI) is a progressive, inherited neurodegenerative disorder that presents as polydipsia and polyuria as a consequence of a loss of secretion of the antidiuretic hormone vasopressin (VP) from posterior pituitary nerve terminals. VP gene mutations cause adFNDI. Rats expressing an adFNDI VP transgene (Cys67stop) show a neuronal pathology characterized by autophagic structures in the cell body. adFNDI has thus been added to the list of protein aggregation diseases, along with Alzheimer's, Parkinson's and Huntington's, which are associated with autophagy, a bulk process that delivers regions of cytosol to lysosomes for degradation. However, the role of autophagy in these diseases is unclear. To address the relationships between mutant protein accumulation, autophagy, cell survival, and cell death, we have developed a novel and tractable in vitro system. We have constructed adenoviral vectors (Ads) that express structural genes encoding either the Cys67stop mutant protein (Ad-VCAT-Cys67stop) or an epitope-tagged wild-type VP precursor (Ad-VCAT). After infection of mouse neuroblastoma Neuro2a cells, Ad-VCAT encoded material enters neurite processes and accumulates in terminals, while the Cys67stop protein is confined to enlarged vesicles in the cell body. Similar to the intracellular derangements seen in the Cys67stop rats, these structures are of ER origin, and colocalize with markers of autophagy. Neither Ad-VCAT-Cys67stop nor Ad-VCAT expression affected cell viability. However, inhibition of autophagy or lysosomal protein degradation, while having no effect on Ad-VCAT-expressing cells, significantly increased apoptotic cell death following Ad-VCAT-Cys67stop expression. These data suggest that activation of autophagy by the stress of the expression of an adFNDI mutant protein is a prosurvival mechanism.

Topics: Acridine Orange; Adenoviridae; Animals; Animals, Genetically Modified; Autophagy; Blotting, Western; Cadaverine; Cathepsin D; Cell Line, Tumor; Codon, Terminator; Cysteine; Diabetes Insipidus, Neurogenic; Fluorescent Antibody Technique; Fluorescent Dyes; Gene Expression; Genetic Vectors; Hydrogen-Ion Concentration; Lysosomes; Mutation; Neurites; Neuroblastoma; Neurons; Organelles; Rats; Recombinant Proteins; Transfection; Transgenes; Vacuoles; Vasopressins

Autosomal dominant neurohypophyseal diabetes insipidus (ADNDI) has been known as a rare disorder transmitted as an autosomal dominant trait, characterized by polyuria and polydipsia, and caused by deficient neurosecretion of arginine vasopressin precursor (AVP-NPII). We reported an ADNDI family with linkage to chromosome 20p13 but without mutations in the AVP-NPII gene.. The objective of this study was to identify the corresponding locus responsible for ADNDI in a family without AVP-NP II gene mutations.. Two families with ADNDI were diagnosed by water deprivation test. The AVP-NPII gene was amplified by PCR and sequenced. A genomewide scan was performed in one family using 400 microsatellite markers covering 22 autosomes.. A 3-bp deletion (1827-1829delAGG) of AVP-NPII gene was identified in the affected individuals in one family. Although no mutations could be detected in the coding, the promoter, and intronic regions of AVP-NPII gene in the other family, a maximum LOD score of 1.202999 (theta = 0.00) was obtained at marker D20S889 by genomewide scan, and a 7-cM interval on chromosome 20p13 was defined by fine mapping with markers D20S199-D20S849. Furthermore, the intragenic region that regulates AVP-NPII and oxytocin expression as an enhancer element and the UBCE7IP5 gene that participates in prohormone degradation were sequenced. No alterations could be detected either.. The corresponding locus responsible for ADNDI is possibly heterogeneous regarding the slightly different clinical features in these two families.

Topics: Adolescent; Adult; Chromosomes, Human, Pair 20; Diabetes Insipidus, Neurogenic; Genes, Dominant; Genetic Linkage; Haplotypes; Humans; Male; Middle Aged; Mutation; Neurophysins; Polymerase Chain Reaction; Protein Precursors; Vasopressins

Central diabetes insipidus, characterized by severe polyuria and polydipsia, is a disorder resulting from deficient secretion of the small neuropeptide hormone vasopressin in the neurohypophysis. The standard therapy is daily and life-long administration of vasopressin analog (desmopressin acetate), but gene therapy is potentially alternative to the conventional replacement therapy. To obtain the therapeutic neuropeptide more feasibly, we tried to express vasopressin in nonneuronal tissues using nonviral gene transfer techniques. We found that the unprocessed large precursor form, provasopressin, was predominantly produced in nonendocrine cells transfected with the wild-type vasopressin gene, because of the lack of neuroendocrine cell-specific endopeptidases. In sharp contrast, appropriately processed bioactive vasopressin can be efficiently produced even in nonendocrine cells with a modified vasopressin gene containing a ubiquitous endoprotease furin cleavage site. We also succeeded in maintaining a long-term antidiuretic effect on vasopressin-deficient (Brattleboro) rats by direct introduction of the furin-processible gene into skeletal muscle by electroporation. Altogether, our data clearly show that skeletal muscle is a useful target tissue for continuous delivery of bioactive neuropeptide. Furthermore, our strategies may be applicable to future gene therapies for central diabetes insipidus and other peptide hormone deficiencies.

Topics: Animals; COS Cells; Diabetes Insipidus, Neurogenic; Diuresis; Furin; Genetic Therapy; LLC-PK1 Cells; Male; Muscle, Skeletal; Myoblasts; Neurosecretory Systems; Rats; Rats, Brattleboro; Swine; Transfection; Vasopressins

Autosomal dominant neurohypophyseal diabetes insipidus (ADNDI) is a defect in free water conservation caused by mutations in the single gene that encodes both vasopressin (VP) and its binding protein, neurophysin II (NP II). Most of the human mutations in this gene have been in the portion encoding the NP molecule; the resultant abnormal gene products are believed to cause cellular toxicity as improperly folded precursor molecules accumulate in the endoplasmic reticulum. We identified a new American kindred with ADNDI and found a novel mutation in the VP molecule. A 78-yr-old man was noted to have hypotonic polyuria and plasma hyperosmolarity; the urinary concentration defect was reversed by administration of VP. His symptomatology dated to childhood, and his family history was consistent with autosomal transmission of the polyuric syndrome, with affected members in three generations, including several females. Affected individuals were found to be heterozygous for a 3-bp deletion in exon 1 of arginine VP (AVP)-NP II, predicting a deletion of phenylalanine 3 (known to be critical for receptor binding) in the VP nonapeptide. Neuro 2A cells stably transfected with the mutant AVP-NP construct showed increased rates of apoptosis as assessed by flow cytometric methods. These observations support the concept that cellular toxicity of abnormal AVP-NP gene products underlies the development of ADNDI, and the data further demonstrate that mutations affecting the AVP moiety can result in initiation of these pathological processes.

Topics: Aged; Apoptosis; Base Sequence; Diabetes Insipidus, Neurogenic; Flow Cytometry; Gene Deletion; Genes, Dominant; Heterozygote; Humans; Male; Molecular Sequence Data; Mutation; Neurophysins; Pedigree; Polyuria; Protein Precursors; Vasopressins

Topics: Adult; Cyclophosphamide; Dermatomyositis; Diabetes Insipidus, Neurogenic; Female; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Magnetic Resonance Imaging; Vasopressins

An unusual mutation in the arginine vasopressin (AVP) gene, predicting a P26L amino acid substitution of the AVP prohormone, is associated with autosomal recessive familial neurohypophyseal diabetes insipidus (FNDI). To investigate whether the cellular handling of the P26L prohormone differed from that of the Y21H prohormone associated with autosomal dominant inheritance of FNDI, the mutations were examined by heterologous expression in cell lines. Immunoprecipitation demonstrated retarded processing and secretion of the Y21H prohormone, whereas the secretion of the P26L prohormone seemed to be unaffected. Confocal laser scanning microscopy showed accumulation of the Y21H prohormone in the endoplasmic reticulum, whereas the P26L prohormone and/or processed products were localized in secretory granules in the cellular processes. RIA analysis showed reduced amounts of immunoreactive Y21H-AVP and P26L-AVP in the cell culture medium. Thus, the recessive mutation does not seem to affect the intracellular trafficking but rather the final processing of the prohormone. Our results provide an important negative control in support of the hypothesis that autosomal dominant inheritance of FNDI is caused by mutations in the AVP gene that alter amino acid residues important for folding and/or dimerization of the neurophysin II moiety of the AVP prohormone and subsequent transport from the endoplasmic reticulum.

Topics: Arginine Vasopressin; Cells, Cultured; Diabetes Insipidus, Neurogenic; Humans; Microscopy, Confocal; Mutation; Neurophysins; Precipitin Tests; Vasopressins

We describe a novel missense mutant of arginine vasopressin (AVP)-dependent neurohypophyseal diabetes insipidus in an autosomal dominant family. A 54-year-old woman was admitted to our hospital because of thyroidectomy for thyroid cancer. After thyroidectomy she was found to have hypernatremia and polyuria and polydipsia both of which had been present from childhood. She had no obstructive hydronephrosis. Her father, father's younger sister and her third son also had polyuria and polydipsia. Basal plasma AVP concentration at normal plasma osmolality was normal but did not respond to increased plasma osmolality despite hyperosmolality during infusion of hypertonic saline infusion, indicating that plasma AVP secretion was impaired. Sodium concentration in urine and urine osmolality were low and increased after nasal administration of DDAVP. There was a diminished but bright signal of pituitary posterior gland on magnetic resonance T1 weighted image. Molecular genetic analysis demonstrated that the patient and her son had a single heterozygous missense mutation (G-->A) at nucleotide 1829 in 1 AVP allele, yielding an abnormal AVP precursor with lacking Glu-47 in its neurophysin II moiety. The abnormal AVP precursor may be related to the impaired AVP secretion.

Topics: Adult; Base Sequence; Deamino Arginine Vasopressin; Diabetes Insipidus, Neurogenic; Female; Humans; Hyponatremia; Male; Middle Aged; Molecular Sequence Data; Mutation, Missense; Neurophysins; Pedigree; Polyuria; Protein Precursors; Sequence Analysis, DNA; Vasopressins

We report a case of central diabetes insipidus (CDI) in a patient with AIDS due to cytomegalovirus (CMV) infection of the vasopressin-producing areas of the hypothalamus. The clinical diagnosis is established by definitive clinical and laboratory evidence of CDI. Detailed histopathological and immunohistochemical studies establish CMV as the causative agent and demonstrate the deficit of vasopressin in the synthesizing neurons. Physicians caring for patients with AIDS should be aware of CDI and adipsic hypernatremia as potential complications of CMV infection. The case also demonstrates that patients with diabetes insipidus do not have polyuria when glucocorticoid deficiency coexists.

Topics: Acquired Immunodeficiency Syndrome; Adult; Cytomegalovirus Infections; Diabetes Insipidus, Neurogenic; Fatal Outcome; Humans; Hypothalamus; Immunohistochemistry; Male; Vasopressins

A 38-year-old woman was admitted with severe thirst and polyuria at 31 weeks' gestation. The plasma concentration of vasopressin (AVP) was very low (0.73 pg/ml) under conditions of high plasma osmolality (316 mOsm/ kg). T1-weighted magnetic resonance (MR) images revealed enlargement of the pituitary posterior lobe with absence of the hyperintense signal. After delivery, restoration of the hyperintense signal was demonstrated. This depletion-repletion process, which reflects the decrease and increase in amount of neurosecretory granules, is recognized in the case of transient central diabetes insipidus during pregnancy. We consider that an increase in cystine-aminopeptidase (CAP) activity is implicated in the pathogenesis.

Topics: Adult; Diabetes Insipidus, Neurogenic; Female; Follow-Up Studies; Humans; Hyperplasia; Magnetic Resonance Imaging; Pituitary Gland, Posterior; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pregnancy Trimester, Third; Remission, Spontaneous; Risk Assessment; Vasopressins

Familial autosomal dominant neurohypophyseal diabetes insipidus (FNDI) is a rare form of central diabetes insipidus (DI), which is caused by mutations in the vasopressin-neurophysin II (AVP-NPII) gene. The present study evaluated the AVP secretion over time and analysed the structure of the AVP-NPII gene in a Brazilian family with FNDI.. Four affected members and one nonaffected member from one Brazilian family with FNDI were studied. The diagnosis of central DI was established by fluid deprivation test and hypertonic saline infusion. Two affected members were assessed twice within a 6-year interval. For molecular analysis, genomic DNA was extracted and the AVP-NPII gene was amplified by polymerase chain reaction.. The functional assessment of patients with FNDI over time confirmed a progressive loss in AVP secretion. Two patients were first diagnosed as partial central DI and, several years later, they developed severe central DI. Sequencing analysis revealed a heterozygous new point mutation in the nucleotide 1892 in the coding sequence for neurophysin-II of the AVP-NPII gene (1892G>C) predicting an amino acid substitution (A68P) in all affected members.. Our data demonstrate a gradual vasopressinergic deficiency due to a novel mutation in the AVP-NPII gene in a Brazilian family with FNDI. The accumulation of A68P mutated precursor might have a cytotoxicity effect, leading to a gradual death of magnocellular neurones, and a progressive decline in AVP secretion.

Topics: Adult; Child; Diabetes Insipidus, Neurogenic; Exons; Female; Humans; Male; Neurophysins; Pedigree; Point Mutation; Polymerase Chain Reaction; Radioimmunoassay; Vasopressins

We have tested the hypothesis that familial neurohypophysial diabetes insipidus (FNDI) is initiated by a process of autophagy. FNDI is a dominant, progressive inherited disorder characterized by pronounced drinking and urination caused by loss of secretion of antidiuretic hormone (vasopressin). In rats expressing an FNDI mutant transgene (Cys67stop) in vasopressin magnocellular neurones, the mutant protein fails to enter the regulated secretory pathway, and accumulates in a swollen and distended endoplasmic reticulum (ER) that also contains wild-type, endogenous vasopressin. Transmission electron microscopy suggested that these are autophagic vesicles. We have now examined the expression of vesicular markers in our transgenic rats, and demonstrate that activation of autolysosomal processes is a consequence of the expression of Cys67stop. Swollen vesicles containing Cys67stop are immunoreactive for cathepsin D (a lysosomal protease), endolyn (a marker of late endosomes) and lysosomal associated membrane protein 1, suggesting that they may be degradative autolysosomes. In addition, there is an up-regulation of lysosomal markers specifically in cells expressing Cys67stop. The expression of Cys67stop affects neither the trans-Golgi network nor early endosomes. These data support the proposal that Cys67stop mutant protein aggregates within the ER, which is targeted for lysosomal degradation by autophagy.

Topics: Animals; Animals, Genetically Modified; Antigens, CD; Autophagy; Blotting, Western; Diabetes Insipidus, Neurogenic; Endoplasmic Reticulum; Endosomes; Hypothalamus; Immunohistochemistry; Lysosomal Membrane Proteins; Lysosomes; Mutation; Neurons; Protein Transport; Rats; Transgenes; Vasopressins

Diagnosis of autoimmune central diabetes insipidus (CDI) is based on the presence of autoantibodies to AVP-secreting cells (AVPcAb) or the coexistence of other autoimmune polyendocrine syndromes; moreover, it can be also suggested by the presence of lymphocytic infundibulo-neurohypophysitis, evidenced by biopsy of pituitary stalk and/or by pituitary stalk thickening on magnetic resonance imaging (MRI). However, so far, in clinical CDI patients with lymphocytic infundibulo-neurohypophysitis, AVPcAb have not been investigated and in those with or without autoimmune polyendocrine syndromes (APS), longitudinal studies on the behavior of AVPcAb alone, or of both AVPcAb and hypothalamic pituitary imaging on MRI are lacking. Aim of this work was to investigate in these patients the occurrence of AVPcAb (by indirect immunofluorescence) and of pituitary stalk thickening (by MRI) and their longitudinal changes during a follow-up period. We studied 22 patients, aged 29-53, with APS and complete CDI, grouped as follows: 10 with recent onset (< or =1.5 yr) of CDI (group 1a) and 12 with CDI of long-term duration (> or = 7 yr) (group 1b); moreover, a group of 13 patients with apparent idiopathic CDI of recent onset (<1.5 yr) were studied. They were divided, on the basis of the detection of AVPcAb as follows: 5 AVPcAb positive patients (aged 19-26) classified as isolated autoimmune CDI (group 2) and 8 AVPcAb negative patients (aged 21-26), classified as true idiopathic CDI (group 3). All patients were evaluated yearly, along 5 yr, for AVPcAb and for hypothalamic-pituitary region imaging. At study entry, 8/10 (80%) of patients in group 1a and 7/12 (58.3%) in group 1b were positive for AVPcAb and persisted positive subsequently, during all the follow-up period, even if at lower titers. All patients in group 2 were positive and all those in group 3 were negative for AVPcAb and persisted positive and negative, respectively, for all the follow-up study. Among the AVPcAb-positive patients, only 5 in group 1a and 2 in group 2 showed also pituitary stalk thickening at the first observations, which however spontaneously disappeared subsequently indicating a possible lymphocytic infundibulo-neurohypophysitis. All patients in the studied groups showed loss of the hyperintense signal of the neurohypophysis on MRI at entry and during all the follow-up period. Results of this longitudinal study suggest: 1) AVPcAb, frequently present at high titers in recent phases of CDI, persist subs

Topics: Adult; Autoantibodies; Autoimmune Diseases of the Nervous System; Diabetes Insipidus, Neurogenic; Female; Follow-Up Studies; Humans; Hypothalamo-Hypophyseal System; Immunoglobulin G; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Vasopressins

Postmortem examinations of the hypothalamus of patients with autosomal dominant neurohypophyseal diabetes insipidus (adNDI), which have been reported only on persons dying between the ages of 37-87 yr, reveal the presence of the arginine vasopressin (AVP)-producing parvocellular neurons but the absence of 95% of the expected AVP-producing magnocellular neurons. To determine whether the clinical course of adNDI is compatible with the hypothesis that the neuropathologic findings are attributable to a progressive loss of magnocellular neurons beginning in early life, we performed posterior pituitary magnetic resonance imaging and water deprivation tests, including plasma ACTH measurements, on 17 affected members of a kindred with the deltaE47 neurophysin mutation whose ages ranged from 3 months to 54 yr. Nine adult nonaffected members (ages, 20-56 yr) underwent these tests as controls. All six children undergoing magnetic resonance imaging demonstrated a posterior pituitary hyperintense signal (PPHS). Eight of nine affected adults showed an absent or barely visible PPHS, whereas eight of nine age-matched nonaffected adults produced a normal size PPHS. During water deprivation tests, infants concentrated their urine normally, and a 3-month-old infant produced a high plasma AVP level of 15.7 pmol/liter. By school age, affected children were no longer able to concentrate their urine or prevent hypernatremia. Affected adults became dehydrated; their median plasma AVP level was less than 1.0 pmol/liter, but their median fasting plasma ACTH was 2-fold greater than the level of nonaffected adults (10.0 vs. 5.0 pmol/liter; P = 0.008). These results suggest that adNDI is a progressive disease associated with chronic loss of the magnocellular neurons that supply AVP to the posterior pituitary but preservation of the parvocellular neurons that supply AVP and CRH to the median eminence and stimulate ACTH production during hypernatremia.

Topics: Adult; Aging; Child; Child, Preschool; Diabetes Insipidus, Neurogenic; Female; Genes, Dominant; Humans; Infant; Magnetic Resonance Imaging; Male; Middle Aged; Mutation; Neurophysins; Pedigree; Pituitary Gland, Posterior; Vasopressins; Water Deprivation

The autosomal dominant form of familial neurohypophyseal diabetes insipidus (adFNDI) has been linked to 40 different mutations of the gene encoding the vasopressin-neurophysin II (AVP-NPII) precursor. All of these mutations have been located in either the signal peptide or neurophysin II moiety. We now report a three-generation Turkish kindred in which severe adFNDI cosegregates with a novel missense mutation in the part of the AVP-NPII gene encoding the AVP moiety. This mutation (T-->C at position 285 in the genomic sequence) was found in only one allele and predicts a substitution of histidine for tyrosine at position 2 in AVP. Like other adFNDI mutations, this substitution is expected to impair folding and processing of the precursor, in this case by interfering with normal binding of the AVP and NPII moieties. It is associated clinically with inability to concentrate urine during fluid deprivation, a greater than 80% deficiency of AVP secretion, and absence of the posterior pituitary bright spot on magnetic resonance imaging. These findings are consistent with the hypothesis that mutations in the AVP-NPII gene cause adFNDI by directing the production of a folding incompetent precursor that prevents the expression of the normal allele via a cytotoxic effect on the magnocellular neurons.

Topics: Adolescent; Adult; Amino Acid Substitution; Diabetes Insipidus, Neurogenic; Female; Genes, Dominant; Histidine; Humans; Male; Middle Aged; Mutation; Neurophysins; Pedigree; Protein Precursors; Tyrosine; Vasopressins

Five patients with well-controlled, long-standing, central diabetes insipidus had acute development of dehydration, hyponatremia, and inappropriate natriuresis in the setting of polyuria resistant to exogenous antidiuretic hormone. Hyponatremia and dehydration worsened with fluid restriction or use of exogenous antidiuretic hormone. We discuss the challenges in diagnosis and management of probable salt wasting in children with central diabetes insipidus.

Topics: Adolescent; Adult; Child; Child, Preschool; Diabetes Insipidus, Neurogenic; Female; Humans; Hyponatremia; Male; Polyuria; Sodium Chloride; Vasopressins

Topics: Animals; Diabetes Insipidus, Neurogenic; Endoplasmic Reticulum; Humans; Hypothalamus; Mutation; Neurons; Rats; Transgenes; Vasopressins

Over 20 mutations affecting the neurophysin moiety of the vasopressin prohormone, have been identified in families suffering from familial neurohypophysial diabetes insipidus (FNDI). Only one of these, NP87E-->stop, is located outside the central conserved domain implicated in sorting of the vasopressin prohormone. To obtain clues about the mechanism of induction of FNDI by this atypical mutant we stably expressed wild type and NP87E-->stop vasopressin prohormones in (neuro)endocrine cell lines. Metabolic labeling and immunoprecipitation demonstrated reduced processing of the mutant prohormone to neurophysin. In addition, evoked secretion of neurophysin and vasopressin was diminished, suggesting that part of the mutant is retained in another intracellular compartment than the secretory granules. Indeed, immunofluorescence demonstrated accumulation of the truncated vasopressin prohormone in the endoplasmic reticulum. We conclude that the presence of the vasopressin moiety and the central conserved core of the neurophysin domain suffices for sorting and processing, but not for efficient endoplasmic reticulum exit of the vasopressin-neurophysin molecule.

Topics: Animals; Diabetes Insipidus, Neurogenic; Electrophoresis, Polyacrylamide Gel; Endoplasmic Reticulum; Humans; Immunohistochemistry; Mice; Microscopy, Confocal; Mutation; Neurophysins; PC12 Cells; Pituitary Neoplasms; Plasmids; Protein Precursors; Protein Processing, Post-Translational; Protein Transport; Rats; Transfection; Tumor Cells, Cultured; Vasopressins

Topics: Chemical Phenomena; Chemistry, Physical; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Genetics; Hypothalamus; Pharmacology; Physiology; Rats; Research; Urine; Vasopressins

Frequent errors in the diagnosis of diabetes insipidus arise from (1) failure to produce an adequate stimulus for release of antidiuretic hormone, and (2) failure to appreciate acute or chronic changes in renal function that may obscure test results. Properly timed determination of body weight, urine volume and serum and urine osmolarity during the course of water deprivation, and comparison of these values with those obtained after administration of exogenous vasopressin, eliminates most diagnostic errors. In four patients who had experienced local and systemic reactions to other exogenous forms of vasopressin, diabetes insipidus was satisfactorily controlled by administration of synthetic lysine-8 vasopressin in nasal spray. A fifth patient was also treated satisfactorily with this preparation.

Topics: Aerosols; Arginine Vasopressin; Biological Transport; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Humans; Lypressin; Lysine; Patient Discharge; Vasopressins; Water Deprivation

Topics: Arginine Vasopressin; Child; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Humans; Infant; Pharmacology; Vasopressins; Water-Electrolyte Balance

Topics: Aerosols; Benzothiadiazines; Child; Chlorothiazide; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Drug Therapy; Humans; Quinazolines; Sulfonamides; Vasopressins

Topics: Brain; Carbon Isotopes; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Hypothalamus; Inulin; Kidney Tubules; Microinjections; Permeability; Pharmacology; Rats; Research; Tritium; Vasopressins; Water

Topics: Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Diagnosis, Differential; Humans; Infusions, Parenteral; Pharmacology; Psychotic Disorders; Sodium Chloride; Thirst; Vasopressins; Water

Topics: Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Genetics; Hypothalamus; Metabolism; Rats; Research; Stress, Physiological; Urine; Vasopressins; Water-Electrolyte Balance

Topics: Arginine Vasopressin; Calcium; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Humans; Hyponatremia; Magnesium; Physiology; Potassium; Sodium; Vasopressins; Water-Electrolyte Balance

Topics: Chlorothiazide; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Diagnosis; Diagnosis, Differential; Diuretics; Humans; Hydrochlorothiazide; Physiology; Polyuria; Syndrome; Thirst; Vasopressins

Topics: Acetazolamide; Adolescent; Chlorthalidone; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Diuretics; Hydrochlorothiazide; Kidney Function Tests; Pharmacology; Spironolactone; Vasopressins; Water-Electrolyte Balance

Topics: Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Diarrhea; Diarrhea, Infantile; Humans; Infant; Kidney Diseases; Vasopressins; Water-Electrolyte Balance

Topics: Autopsy; Bone Marrow Examination; Busulfan; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Humans; Leukemia; Leukemia, Myeloid; Mercaptopurine; Polyuria; Prednisone; Vasopressins

Topics: Arginine Vasopressin; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Humans; Hypertension; Lysine; Obesity; Vasopressins

Topics: Angiotensin II; Angiotensins; Biomedical Research; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Kidney; Metabolism; Pharmacology; Sodium; Urine; Vasopressins; Water

Topics: Acute Kidney Injury; Atropine; Biomedical Research; Blood Volume; Convalescence; Dehydration; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Edema; Epinephrine; Female; Heart Failure; Hemorrhage; Humans; Hypertonic Solutions; Menstruation; Pharmacology; Placebos; Pregnancy; Renal Insufficiency; Salivation; Sweating; Uremia; Vasopressins; Water-Electrolyte Balance

Synthetic 8-lysine vasopressin administered as a nasal spray to three patients with diabetes insipidus resulted in excellent control in one. In the other two it was of some value as therapy supplemental to pitressin tannate in oil. The patient who was adequately controlled with "spray therapy" alone required the sprays every three hours during the day, but none during the night.

Topics: Aerosols; Arginine Vasopressin; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Drug Therapy; Humans; Lypressin; Lysine; Nasal Sprays; Pharmaceutical Solutions; Pituitary Hormones, Posterior; Respiratory Therapy; Vasopressins

Topics: Aerosols; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Diabetes Mellitus; Female; Humans; Hypersensitivity; Lypressin; Lysine; Pregnancy; Pregnancy in Diabetics; Toxicology; Vasopressins; Water Intoxication

Topics: Angiotensins; Aortic Diseases; Brain; Brain Damage, Chronic; Dehydration; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Hexamethonium Compounds; Humans; Infant; Infant, Newborn; Infant, Newborn, Diseases; Kidney Function Tests; Norepinephrine; Physiology; Renal Artery Obstruction; Vasopressins; Water-Electrolyte Balance

Topics: Child; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Dilatation; Enuresis; Humans; Hydronephrosis; Polyuria; Surgical Procedures, Operative; Urinary Bladder Neck Obstruction; Urography; Vasopressins

Topics: Adolescent; Arginine Vasopressin; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Drug Therapy; Humans; Hydrochlorothiazide; Spironolactone; Vasopressins; Wounds and Injuries

Topics: Arginine Vasopressin; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Drug Therapy; Hepatitis; Humans; Hydrocortisone; Vasopressins

Topics: Adrenocorticotropic Hormone; Cushing Syndrome; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Diabetic Nephropathies; Endocrine Glands; Endocrine System Diseases; Hormones; Humans; Hypercalcemia; Hypothyroidism; Liver Diseases; Lung Neoplasms; Neoplasms; Nephrosis; Polycythemia; Pseudopseudohypoparathyroidism; Vasopressins

Topics: Antidiuretic Agents; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Diuresis; Humans; Insulin; Vasopressins

Topics: Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Dwarfism; Humans; Hydronephrosis; Vasopressins

Topics: Arginine Vasopressin; Diabetes Insipidus; Diabetes Insipidus, Nephrogenic; Diabetes Insipidus, Neurogenic; Humans; Vasopressins

Topics: Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Humans; Polyuria; Syndrome; Thirst; Vasopressins

Topics: Arginine Vasopressin; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Vasopressins

Topics: Animals; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Hypophysectomy; Hypothalamus; Pituitary Gland; Rats; Vasopressins; Water

Topics: Bendroflumethiazide; Child; Diabetes Insipidus; Diabetes Insipidus, Nephrogenic; Diabetes Insipidus, Neurogenic; Diet, Sodium-Restricted; Electrolytes; Humans; Hydronephrosis; Infant; Intellectual Disability; Spironolactone; Vasopressins; Water-Electrolyte Balance

Topics: Addison Disease; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Diuresis; Diuretics; Humans; Hyperglycemia; Kidney Tubules; Osmosis; Physiology; Polyuria; Syndrome; Vasopressins

Topics: Aerosols; Arginine Vasopressin; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Humans; Lysine; Nasal Sprays; Vasopressins

Topics: Central Nervous System Diseases; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Humans; Infant; Infant Nutrition Disorders; Kidney Function Tests; Metabolism; Potassium Deficiency; Sodium; Urine; Vasopressins; Water

Topics: Adolescent; Child; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Diabetes Mellitus; Female; Genetics, Medical; Humans; Siblings; Vasopressins

Topics: Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Growth; Growth Hormone; Humans; Hypothalamus; Vasopressins

Topics: Chlorothiazide; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Growth; Hypophysectomy; Hypothalamus; Nutritional Physiological Phenomena; Nutritional Sciences; Rats; Toxicology; Vasopressins

Topics: Acidosis; Antidiuretic Agents; Blood Chemical Analysis; Blood Glucose; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Diabetes Mellitus; Diabetic Ketoacidosis; Humans; Vasopressins; Water-Electrolyte Balance

Topics: Adolescent; Bendroflumethiazide; Child; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Diuresis; Humans; Hydroflumethiazide; Kidney Function Tests; Potassium; Sodium Chloride; Spironolactone; Vasopressins

Topics: Angiotensin Amide; Angiotensin II; Arginine Vasopressin; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Humans; Kidney; Valine; Vasopressins

Topics: Arginine Vasopressin; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Humans; Procaine; Vasopressins

Topics: Alcohols; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Diuresis; Ethanol; Humans; Hydrocortisone; Hypopituitarism; Vasopressins

Topics: Adrenalectomy; Aldosterone; Animals; Arginine Vasopressin; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Hypophysectomy; Potassium; Rats; Sodium; Vasopressins; Water-Electrolyte Balance

Topics: Arginine Vasopressin; Chlorothiazide; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Humans; Vasopressins

Topics: Arginine Vasopressin; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Vasopressins

Topics: Arginine Vasopressin; Chlorothiazide; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Humans; Hyaluronoglucosaminidase; Vasopressins

Topics: Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Disease; Humans; Medical Records; Myxedema; Pituitary Gland; Pituitary Gland, Anterior; Thyroid Gland; Vasopressins

Topics: Arginine Vasopressin; Bicarbonates; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Humans; Sodium Bicarbonate; Vasopressins

Topics: Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Humans; Incidence; Vasopressins

Topics: Brain; Brain Injuries; Craniocerebral Trauma; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Humans; Vasopressins

Topics: Chlorothiazide; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Vasopressins

Topics: Arginine Vasopressin; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Humans; Vasopressins

Topics: Arginine Vasopressin; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Humans; Prognosis; Vasopressins

Topics: Carcinoma; Carcinoma, Bronchogenic; Diabetes Insipidus, Neurogenic; Humans; Hyponatremia; Kidney; Sodium; Vasopressins

Topics: Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Humans; Thirst; Vasopressins

Topics: Arginine Vasopressin; Diabetes Insipidus; Diabetes Insipidus, Nephrogenic; Diabetes Insipidus, Neurogenic; Humans; Medical Records; Vasopressins

Topics: Alcohols; Arginine Vasopressin; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Ethanol; Female; Humans; Mental Disorders; Pregnancy; Vasopressins

Topics: Arginine Vasopressin; Child; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Humans; Infant; Vasopressins

Topics: Arginine Vasopressin; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Humans; Vasopressins

Topics: Arginine Vasopressin; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Humans; Vasopressins

Topics: Arginine Vasopressin; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Humans; Vasopressins

Topics: Arginine Vasopressin; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Vasopressins

Topics: Arginine Vasopressin; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Vasopressins

Topics: Arginine Vasopressin; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Hepatitis; Vasopressins

Topics: Arginine Vasopressin; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Diuresis; Diuretics; Humans; Pituitary Gland, Posterior; Vasopressins

Topics: Arginine Vasopressin; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Humans; Vasopressins

Topics: Administration, Buccal; Arginine Vasopressin; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Humans; Vasopressins

Topics: Arginine Vasopressin; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Humans; Vasopressins

Topics: Arginine Vasopressin; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Humans; Medical Records; Vasopressins

Topics: Body Fluids; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Humans; Kidney; Vasopressins

Topics: Child; Diabetes Insipidus; Diabetes Insipidus, Nephrogenic; Diabetes Insipidus, Neurogenic; Humans; Infant; Kidney Diseases; Vasopressins

Topics: Arginine Vasopressin; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Humans; Vasopressins

Topics: Addison Disease; Adrenal Cortex; Adrenal Cortex Hormones; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Humans; Hydrocortisone; Vasopressins

Topics: Adrenal Cortex; Adrenal Cortex Hormones; Adrenocorticotropic Hormone; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Humans; Neoplasms; Pituitary Gland; Pituitary Neoplasms; Vasopressins

Topics: Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Heredity; Humans; Vasopressins

Topics: Child; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Humans; Infant; Vasopressins

Topics: Arginine Vasopressin; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Heredity; Humans; Vasopressins

Topics: Cataract; Child; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Diabetes Mellitus; Eosinophilia; Humans; Infant; Infant, Newborn; Infant, Newborn, Diseases; Toxoplasmosis; Toxoplasmosis, Congenital; Vasopressins

Topics: Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Heredity; Hormones; Humans; Pituitary Gland; Pituitary Gland, Posterior; Vasopressins

Topics: Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Hormones; Humans; Pituitary Gland; Pituitary Gland, Posterior; Vasopressins

Topics: Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Humans; Kidney; Vasopressins

Topics: Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Humans; Oxytocin; Pituitary Hormones; Vasopressins

Topics: Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Diabetes Mellitus; Vasopressins

Topics: Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Vasopressins