Diabetes Insipidus

NF-E2-related factor-2 (Nrf2) regulates cellular responses to oxidative and electrophilic stress. Loss of Keap1 increases Nrf2 protein levels, and Keap1-null mice die of oesophageal hyperkeratosis because of Nrf2 hyperactivation. Here we show that deletion of oesophageal Nrf2 in Keap1-null mice allows survival until adulthood, but the animals develop polyuria with low osmolality and bilateral hydronephrosis. This phenotype is caused by defects in water reabsorption that are the result of reduced aquaporin 2 levels in the kidney. Renal tubular deletion of Keap1 promotes nephrogenic diabetes insipidus features, confirming that Nrf2 activation in developing tubular cells causes a water reabsorption defect. These findings suggest that Nrf2 activity should be tightly controlled during development in order to maintain renal homeostasis. In addition, tissue-specific ablation of Nrf2 in Keap1-null mice might create useful animal models to uncover novel physiological functions of Nrf2.

We developed a variant database for diabetes syndrome genes, using the Leiden Open Variation Database platform, containing observed phenotypes matched to the genetic variations. We populated it with 628 published disease-associated variants (December 2016) for: WFS1 (n = 309), CISD2 (n = 3), ALMS1 (n = 268), and SLC19A2 (n = 48) for Wolfram type 1, Wolfram type 2, Alström, and Thiamine-responsive megaloblastic anemia syndromes, respectively; and included 23 previously unpublished novel germline variants in WFS1 and 17 variants in ALMS1. We then investigated genotype-phenotype relations for the WFS1 gene. The presence of biallelic loss-of-function variants predicted Wolfram syndrome defined by insulin-dependent diabetes and optic atrophy, with a sensitivity of 79% (95% CI 75%-83%) and specificity of 92% (83%-97%). The presence of minor loss-of-function variants in WFS1 predicted isolated diabetes, isolated deafness, or isolated congenital cataracts without development of the full syndrome (sensitivity 100% [93%-100%]; specificity 78% [73%-82%]). The ability to provide a prognostic prediction based on genotype will lead to improvements in patient care and counseling. The development of the database as a repository for monogenic diabetes gene variants will allow prognostic predictions for other diabetes syndromes as next-generation sequencing expands the repertoire of genotypes and phenotypes. The database is publicly available online at https://lovd.euro-wabb.org.

PurposeAlthough transient diabetes insipidus (DI) is the most common complication of pituitary surgery, there is no consensus on its definition. Polyuria is the most overt symptoms of DI, but can also reflect several physiological adaptive mechanisms in the postoperative phase. These may be difficult to distinguish from and might coincide with DI. The difficulty to distinguish DI from other causes of postoperative polyuria might explain the high variation in incidence rates. This limits interpretation of outcomes, in particular complication rates between centers, and may lead to unnecessary treatment. Aim of this review is to determine a pathophysiologically sound and practical definition of DI for uniform outcome evaluations and treatment recommendations.MethodsThis study incorporates actual data and the experience of our center and combines this with a review of literature on pathophysiological mechanisms and definitions used in clinical studies reporting of postoperative DI.ResultsThe occurrence of excessive thirst and/or hyperosmolality or hypernatremia are the best indicators to discriminate between pathophysiological symptoms and signs of DI and other causes. Urine osmolality distinguishes DI from osmotic diuresis.ConclusionsTo improve reliability and comparability we propose the following definition for postoperative DI: polyuria (urine production > 300 ml/hour for 3 h) accompanied by a urine specific gravity (USG) 300 mosmol/kg, or serum sodium > 145 mmol/L. To prevent unnecessary treatment with desmopressin, we present an algorithm for the diagnosis and treatment of postoperative DI.

The hypothalamo-neurohypophysial system consists of specialized neurons in the supraoptic and paraventricular nuclei that project to the central nervous system and the posterior pituitary, where they secrete arginine vasopressin (AVP) and oxytocin (OXT) into the systemic circulation. AVP is the key endocrine regulator of water balance via V2 receptor-mediated aquaporin-2 insertion in renal collecting ducts and modulates vascular tone via V1 receptors. OXT plays a central role in labor and lactation, but also influences metabolism, social behavior, emotional processing, and stress regulation. AVP deficiency (formerly central diabetes insipidus) results from hypothalamic-posterior pituitary disruptions or injury due to surgery, trauma, tumors, infiltrative or autoimmune disease, vascular events, or genetic causes. It is characterized by hypotonic polyuria, polydipsia, and dehydration risk, and is diagnosed by distinguishing it from AVP resistance and primary polydipsia, with copeptin-based tests providing high diagnostic accuracy. Treatment relies on desmopressin and careful education to prevent both dehydration and hyponatremia. In contrast, OXT deficiency has only recently been recognized as a potential clinical entity, particularly in patients with hypothalamic-pituitary disruptions or injury and concurrent AVP deficiency. Emerging evidence links it to social dysfunction, anxiety, and reduced quality of life. Diagnosis remains challenging due to unreliable basal OXT levels and limited stimulation tests; novel approaches, including 3,4-methylenedioxymethamphetamine (MDMA) challenge and neurophysin I as a surrogate marker, are under investigation. Preliminary studies suggest intranasal OXT may improve socioemotional outcomes, but robust evidence from randomized controlled trials is needed.