Diabetes Insipidus: Pathogenesis, Diagnosis, and Clinical Management

Introduction and background

Diabetes insipidus (DI) is a rare disorder, affecting roughly 1 in 25,000 people or about 0.004% of the global population [1]. Due to the rare occurrence in the population, the various forms of DI can be relatively neglected in medical education as well as in a research setting for improving clinical management [1]. Although DI is an uncommon endocrine disorder the outcome for untreated disease can negatively impact the quality of life for the patient. Epidemiologically, DI does not show a predilection for males or females and it can develop at any age with hereditary forms developing earlier in life [1]. DI can be classified into four major categories which include central, nephrogenic, dipsogenic, or gestational [1]. DI is most commonly defined as a urine volume of more than 3-3.5 liters in a 24-hour period in adults with a urine osmolality of less than 300 mOsmol/kg. In most cases of DI, urine volume far exceeds 3-3.5 liters in a 24-hour period [2]. The principal hormone of diabetes insipidus is the posterior pituitary hormone ADH, which is one of the main determinants regarding water homeostasis within the body. antidiuretic hormone (ADH) acts on its target organ, the kidney, to increase urine osmolality [3]. Osmoregulation and baroregulation are the two principal negative feedback mechanisms that control the secretion of ADH [4]. Ever so slight changes, even that of less than 1% in plasma osmolality, are detected by the osmoreceptors of the hypothalamus. This detection of an increase in osmolality leads to the release of ADH from the posterior pituitary gland. A similar response can be examined with respect to baroreceptors stimulated by a decrease in blood volume. The deviation in blood volume requires approximately a 5%-10% difference in volume [2]. Upon release with its transport protein carrier, neurohypophysin II (NPII) from the hypothalamus, ADH travels to the posterior pituitary where it is stored until released. Once stimulated a change in plasma osmolality or stimulation of baroreceptors, ADH is released into the bloodstream as a water-soluble peptide hormone and acts on its target by binding to the aquaporin-2 receptors (AQP2) in the basolateral membrane of the collecting duct (see Figure ​Figure1).1). Once bound to the receptor, it activates the Gs-adenylyl cyclase system pathway, leading to an increase in intracellular levels of cAMP. This increase in cAMP levels activates protein kinase A, finally leading to the phosphorylation of preformed AQP2 channels. The phosphorylation leads to the insertion of AQP2 into the apical membrane surface of the cell (see Figure ​Figure2).2). It has been established that without this insertion of AQP2 the renal collecting duct would remain essentially impermeable to water. The purpose of AQP2 is to remove water from the renal filtrate and concentrate the urine. In the case of DI, water is unable to move freely from the lumen of the nephron into the cells of the collecting duct along an osmotic gradient, which in turn leads to the excretion of diluted urine. ADH can increase urine osmolality to about 1,200 mOsmol/kg and reduce urine output to 0.5 ml/min or about 700-800 ml/day. Upon establishing water balance within the body, levels of circulating ADH drop and the amount of inserted AQP2 channel proteins in the apical plasma membrane are down-regulated [2,3].

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About the Author: Tung Chi