oxytocin and Diabetes-Insipidus--Neurogenic

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

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

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

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

Disruptions of the hypothalamic-pituitary axis can cause an arginine vasopressin deficiency, also known as central diabetes insipidus. Patients with this condition are at high risk of additional oxytocin deficiency owing to the close anatomical proximity of oxytocin-producing neurons; however, no conclusive evidence for such a deficiency has been reported. We aimed to use 3,4-methylenedioxymethamphetamine (MDMA, also known as ecstasy), a strong activator of the central oxytocinergic system, as a biochemical and psychoactive provocation test to investigate oxytocin deficiency in patients with arginine vasopressin deficiency (central diabetes insipidus).. This single-centre, case-control study with nested, randomised, double-blind, placebo-controlled crossover trial included patients with arginine vasopressin deficiency (central diabetes insipidus) and healthy controls (matched 1:1 by age, sex, and BMI) and was conducted at the University Hospital Basel, Basel, Switzerland. We used block randomisation to assign participants to receive either a single oral dose of MDMA (100 mg) or placebo in the first experimental session; patients received the opposite treatment at the next session, with a wash-out period of at least 2 weeks between the two sessions. Participants and investigators assessing the outcomes were masked to assignment. Oxytocin concentrations were measured at 0, 90, 120, 150, 180, and 300 min after MDMA or placebo. The primary outcome was the area under the plasma oxytocin concentration curve (AUC) after drug intake. The AUC was compared between groups and conditions using a linear mixed-effects model. Subjective drug effects were assessed throughout the study using ten-point visual analogue scales. Acute adverse effects were assessed before and 360 min after drug intake using a 66-item list of complaints. This trial is registered with ClinicalTrials.gov, NCT04648137.. Between Feb 1, 2021, and May 1, 2022, we recruited 15 patients with arginine vasopressin deficiency (central diabetes insipidus) and 15 healthy controls. All participants completed the study and were included in the analyses. In healthy controls, median plasma oxytocin concentration was 77 pg/mL (IQR 59-94) at baseline and increased by 659 pg/mL (355-914) in response to MDMA, resulting in an AUC of 102 095 pg/mL (41 782-129 565); in patients, baseline oxytocin concentration was 60 pg/mL (51-74) and only slightly increased by 66 pg/mL (16-94) in response to MDMA, resulting in an AUC of 6446 pg/mL (1291-11 577). The effect of MDMA on oxytocin was significantly different between groups: the AUC for oxytocin was 82% (95% CI 70-186) higher in healthy controls than in patients (difference 85 678 pg/mL [95% CI 63 356-108 000], p<0·0001). The increase in oxytocin in healthy controls was associated with typical strong subjective prosocial, empathic, and anxiolytic effects, whereas only minimal subjective effects were observed in patients, in agreement with the lack of increase in oxytocin concentrations. The most frequently reported adverse effects were fatigue (eight [53%] healthy controls and eight [53%] patients), lack of appetite (ten [67%] healthy controls and eight [53%] patients), lack of concentration (eight [53%] healthy controls and seven [47%] patients), and dry mouth (eight [53%] healthy controls and eight [53%] patients). In addition, two (13%) healthy controls and four (27%) patients developed transient mild hypokalaemia.. These findings are highly suggestive of clinically meaningful oxytocin deficiency in patients with arginine vasopressin deficiency (central diabetes insipidus), laying the groundwork for a new hypothalamic-pituitary disease entity.. Swiss National Science Foundation, Swiss Academy of Medical Sciences, and the G&J Bangerter-Rhyner Foundation.

Topics: Arginine; Case-Control Studies; Cross-Over Studies; Diabetes Insipidus, Neurogenic; Diabetes Mellitus; Double-Blind Method; Humans; N-Methyl-3,4-methylenedioxyamphetamine; Oxytocin

Topics: Arginine; Deamino Arginine Vasopressin; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Diabetes Mellitus; Humans; Oxytocin

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 characterised by arginine vasopressin deficiency. Oxytocin is structurally related to vasopressin and is synthesised in the same hypothalamic nuclei, thus we hypothesised that patients with acquired central diabetes insipidus and anterior hypopituitarism would display an oxytocin deficiency. Moreover, psychological research has demonstrated that oxytocin influences social and emotional behaviours, particularly empathic behaviour. We therefore further hypothesised that central diabetes insipidus patients would perform worse on empathy-related tasks, compared to age-matched and gender-matched clinical control (clinical control-isolated anterior hypopituitarism) and healthy control groups.. Fifty-six participants (age 46.54 ± 16.30 yrs; central diabetes insipidus: n = 20, 8 males; clinical control: n = 15, 6 males; healthy control: n = 20, 7 males) provided two saliva samples which were analysed for oxytocin and completed two empathy tasks.. Hypopituitary patients (both central diabetes insipidus and clinical control groups) had significantly lower oxytocin concentrations compared to healthy control participants. Hypopituitary patients also performed significantly worse on both the reading the mind in the eyes task and the facial expression recognition task compared to healthy control participants. Regression analyses further revealed that central diabetes insipidus patients' oxytocin concentrations significantly predicted their performance on easy items of the reading the mind in the eyes task.. Hypopituitarism may therefore be associated with reduced oxytocin concentrations and impaired empathic ability. While further studies are needed to replicate these findings, our data suggest that oxytocin replacement may offer a therapeutic approach to improve psychological well-being in patients with hypopituitarism.

Topics: Adult; Diabetes Insipidus, Neurogenic; Empathy; Facial Recognition; Female; Humans; Hypopituitarism; Male; Middle Aged; Oxytocin; Personality

Familial neurohypophysial diabetes insipidus (FNDI) is caused by mutations in the gene locus of arginine vasopressin (AVP), an antidiuretic hormone. Although the carriers are normal at birth, polyuria and polydipsia appear several months or years later. Previously, we made mice possessing a mutation causing FNDI and reported that the mice manifested progressive polyuria as do the patients with FNDI. Here, we report that decreases in AVP mRNA expression in the supraoptic nucleus were accompanied by shortening of the AVP mRNA poly(A) tail length in the FNDI mice, a case in which aggregates accumulated in the endoplasmic reticulum (ER) of the hypothalamic AVP neurons. Expression levels of AVP heteronuclear RNA in the supraoptic nucleus, a sensitive indicator for gene transcription, were not significantly different between FNDI and wild-type mice. Incubation of hypothalamic explants of wild-type mice with ER stressors (thapsigargin and tunicamycin) caused shortening of the poly(A) tail length of AVP and oxytocin mRNA, accompanied by decreases in their expression. On the other hand, an ER stress-reducing molecule (tauroursodeoxycholate) increased the poly(A) tail length as well as the expression levels of AVP and oxytocin mRNA. These data reveal a novel mechanism by which ER stress decreases poly(A) tail length of neurohypophysial hormones, probably to reduce the load of unfolded proteins.

Topics: Animals; Arginine Vasopressin; Diabetes Insipidus, Neurogenic; Endoplasmic Reticulum Stress; Mice; Oxytocin; Pituitary Hormones, Posterior; Poly A; RNA, Messenger; Supraoptic Nucleus

Most mutations of the arginine vasopressin-neurophysin II (AVP-NPII) gene cause autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI). Such mutations are predicted to alter the three-dimensional structure of the prohormone, which accumulates in the cell body, ultimately leading to neuronal degeneration and hormonal deficit. In this study we describe the case of a 26-year-old female reporting a long-lasting history of polyuria/polydipsia. The father of the patient was affected by diabetes insipidus and was under desmopressin treatment until the time of his death. Nevertheless, the patient had never been subjected to endocrine evaluation.. Clinical and genetic studies were performed. An 8-h fluid deprivation test plus desmopressin challenge and a 5% saline solution test were performed, in order to confirm the diagnosis. DNA was extracted from peripheral blood lymphocytes and subjected to direct sequencing of the entire coding region of the AVP-NPII gene.. Clinical assessment of the patient confirmed the diagnosis of neurohypophyseal diabetes insipidus. Desmopressin treatment was started, which effectively reversed the polyuria/ polydipsia syndrome. Genetic analysis revealed a novel mutation (1665T>A) in exon 2 of the AVP-NPII gene, disrupting one of the disulfide bonds present in the NPII moiety which play a fundamental role in determining the proper folding of the molecule. In summary, in the present study we have described a novel mutation of the AVP-NPII gene, which is consistent with the malfolding/toxicity hypothesis underlying the pathogenesis of adFNDI.

Topics: Adult; Arginine Vasopressin; Base Sequence; Deamino Arginine Vasopressin; Diabetes Insipidus, Neurogenic; Drinking Behavior; Female; Humans; Molecular Structure; Mutation; Neurophysins; Oxytocin; Pedigree; Polyuria; Protein Precursors; Renal Agents

Topics: Animals; Body Fluids; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Dogs; Oxytocics; Oxytocin

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