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Diabetes mellitus, widely known to the ancients for polyuria and glycosuria, budded off diabetes insipidus (DI) about 200 years ago, based on the glucose-free polyuria that characterized a subset of patients. In the late 19th century, clinicians identified the posterior pituitary as the site of pathology, and pharmacologists found multiple bioactivities there. Early in the 20th century, the amelioration of the polyuria with extracts of the posterior pituitary inaugurated a new era in therapy and advanced the hypothesis that DI was due to a hormone deficiency. Decades later, a subset of patients with polyuria unresponsive to therapy were recognized, leading to the distinction between central DI and nephrogenic DI, an early example of a hormone-resistant condition. Recognition that the posterior pituitary had 2 hormones was followed by du Vigneaud’s Nobel Prize winning isolation, sequencing, and chemical synthesis of oxytocin and vasopressin. The pure hormones accelerated the development of bioassays and immunoassays that confirmed the hormone deficiency in vasopressin-sensitive DI and abundant levels of hormone in patients with the nephrogenic disorder. With both forms of the disease, acquired and inborn defects were recognized. Emerging concepts of receptors and of genetic analysis led to the recognition of patients with mutations in the genes for 1) arginine vasopressin (AVP), 2) the AVP receptor 2 (AVPR2), and 3) the aquaporin 2 water channel (AQP2). We recount here the multiple skeins of clinical and laboratory research that intersected frequently over the centuries since the first recognition of DI.

On February 24, 1961, in a private animal house on a remote mountain in Vermont, a Long Evans rat gave birth to 17 young. The animal house assistant noticed that in this one cage the water bottle was nearly always empty; some of the young were drinking excessively, and this could be corrected by giving them the antidiuretic hormone, vasopressin. Four of the young were given to Heinz Valtin and Kurt Benerische at Dartmouth Medical School, who bred from them to generate the line that became famous as the Brattleboro rat. With the help of many collaborators, they soon established that this strain had hereditary hypothalamic diabetes insipidus, resulting from a defect in a single gene (1). In 1984, Schmale and Richter (2) showed exactly what the defect was; there was a single base deletion in the sequence encoding neurophysin, part of the vasopressin precursor protein; this gave rise to an open reading frame and hence a greatly altered precursor protein. It turned out that this aberrant precursor, which contains the normal vasopressin sequence, was not secreted but instead accumulates in the cytoplasm of the magnocellular vasopressin neurons in the supraoptic and paraventricular nuclei of the hypothalamus. Despite this, the vasopressin neurons of the Brattleboro rat are in many ways normal. Electrophysiologically, they look very much like normal vasopressin cells, they respond normally to osmotic challenge (3), and indeed the phenotype of the Brattleboro rat can be rescued by adeno-associated viral-mediated gene transfer to restore normal vasopressin expression in the defective vasopressin neurons (4). The Brattleboro rat provided opportunities for fundamental research that were unparalleled in the era before transgenic knockout animals, and these were avidly taken. But as a model for human disease, the Brattleboro rat seemed to be less useful. Diabetes insipidus is a rare disease in humans and can reflect either the absence of vasopressin secretion (central diabetes insipidus) or insensitivity to vasopressin at the level of the kidney (nephrogenic diabetes insipidus). Inpatientswithfamilialdiabetes insipidus(FNDI) of central origin, the genetic defect is usually in the neurophysin-coding region of the vasopressin gene as is the case in the Brattleboro rat (5). However, in affected individuals, severe disease symptoms usually appear only months or years after birth, despite the presence of one normal allele; by contrast, the heterozygous Brattleboro rat never develops symptoms of diabetes insipidus, whereas in the homozygous Brattleboro rat, the defects are present at birth. Many of these mutations that cause FNDI interfere with neurophysin folding and/or dimerization; the mutated precursor cannot be targeting to the regulated neurosecretory granules and is retained in the lumen of the endoplasmic reticulum (ER) (6, 7). In the relatively few cases of human FNDI where autopsy reports are available, neuronal loss is apparent in the magnocellular cells of the hypothalamus; the vasopressin neurons appear to have died, and hence, it has been assumed that the abnormal protein product of the defective allele is toxic to the neurons. As neurons begin to die off, a deficiency in vasopressin secretion is exacerbated, leading to exacerbated osmotic imbalance and increased stimulation of hormone synthesis and hence an increased rate of production of the toxic precursor in the surviving cells, speeding their demise. Thus, at a critical point, this vicious cycle leads to relatively sudden collapse of vasopressin production re

Congenital nephrogenic diabetes insipidus (NDI) is a chronic disorder involving polyuria and polydipsia that results from unresponsiveness of the renal collecting ducts to the antidiuretic hormone vasopressin. Either of the genetic defects in vasopressin V2 receptor or the water channel aquaporin 2 (AQP2) cause the disease, which interfere the water reabsorption at the epithelium of the collecting duct. An unconscious state including a perioperative situation can be life threatening because of the difficulty to regulate their water balance. The Sendai virus (SeV) vector system deleting fusion protein (F) gene (SeV/ΔF) is considered most suitable because of the short replication cycle and nontransmissible character. An animal model for NDI with reduced AQP2 by lithium chloride was used to develop the therapy. When the SeV/ΔF vector carrying a human AQP2 gene (AQP2-SeV/ΔF) was administered retrogradely via ureter to renal pelvis, AQP2 was expressed in the renal collecting duct to reduce urine output and water intake by up to 40%. In combination with the retorograde administration to pelvis, this system could be the cornerstone for the applicable therapies on not only NDI patients but also other diseases associate with the medullary collecting duct.

We investigated the effects of hyperosmolality, chronic treatment with lithium chloride (LiCl), and the addition of LiCl in vitro on vasopressin-sensitive (VP) adenylate cyclase (AdC) and cAMP phosphodiesterase (cAMP-PDIE) activities in the medullary thick ascending limb of Henle's loop (MAL) and medullary collecting tubule (MCT) microdissected from the outer medulla of the rat kidney. A hyperosmolar medium (800 mosmol) markedly enhanced AdC activity stimulated by 10(-6) M VP specifically in MCT, while having little effect or slightly decreasing VP-stimulated AdC in MAL, compared to activities under standard isotonic conditions. Hyperosmolality decreased cAMP-PDIE activity to about the same degree in MAL and MCT. Inclusion of LiCl in the incubation medium (15-20 mM) caused a significant dose-dependent inhibition of VP-stimulated AdC activity in both MAL and MCT, but had no effect on CAMP-PDIE in either segment. AdC and cAMP-PDIE activities in MAL and MCT from chronic LiCl-treated polyuric rats did not differ from controls when assayed under standard isotonic conditions. However, when assayed in a hyperosmolar (800 mosmol) medium, VP-sensitive AdC activity was significantly lower (P < 0.01) in MCT from LiCl-treated rats compared to control levels, while VP-sensitive AdC in MAL did not differ in LiCl-treated and control rats. The present results suggest that lowered VP-sensitive AdC activity in MCT of LiCl-treated polyuric rats may contribute to the observed lower concentrating ability and collecting tubule resistance to VP. Inhibition of VP-sensitive AdC in MAL as well as MCT by the acute addition of LiCl in vitro may explain the decreased urinary diluting ability observed with acute infusions of Li salts in vivo in the rat.

THE FACT that adrenalectomy reduces markedly the diuretic responseto water and increases the susceptibility to water intoxicationhas generally been attributed exclusively to adrenal cortical and notmedullary deficiency. Eversole, Edelmann and Gaunt (1940) notedsome deficiency in handling water in rats with one adrenal removedand the second demedullated, but since this was easily repaired bycortical extract, it was taken as evidence of a slight functional incapacityof this single regenerated cortical gland. Other evidence isavailable that one adrenal cannot maintain animals during stress aswell as two (Horvath, Hitchcock and Hartman, 1938; Ingle, 1940). It is known, however, that epinephrine injections affect renal circulation (Richards and Plant, 1922 a, b; Chasis, Ranges, Goldring and Smith, 1938). Both polyuria (Richards and Plant) and oliguria (Rydin and Verney, 1938; Chasis, et al.) have been reported to follow the use of epinephrine, and according to Toth (1938) which result is seen depends upon dosa...

It is a well known fact that in diabetes mellitus the clinical pictures may be dominated by polyuria and polydipsia. It is also well known that in diabetes insipidus the same symptoms are observed and the question arises whether a relation exists between the two diseases. This question has been often raised and has given rise to a rather extensive literature. That a relation exists is made probable by certain cases that have been described, in which one disease changed into the other [Senator (1), Lewin (2)]. On the other hand, Naunyn (3) denies any relation between diabetes mellitus and insipidus, and Umber (4) states that it has never been proved that in a case of polyuria and glyeosuria a real diabetes insipidus existed. Nevertheless, it is remarkable that patients with diabetes insipidus not seldom give a family history of diabetes mellitus. Trousseau (5) considered this fact important enough that he prefaced his clinical treatise on polydipsia with the words

Pituitary stalk lesions produce a triphasic disturbance in water metabolism. A short-lasting polyuria is followed by an oliguric period of 3 days' duration, which then merges into a manifest diabetes insipidus. During the oliguric phase ADH content of the degenerating posterior lobe considerably declines. The activity of the pituitary-adrenal system during the 3 phases of the diabetes insipidus remains at a constant basal level. The system is unresponsive to noxious stimuli and only partially responsive to lysine vasopressin (LVP). During the oliguric interphase neither LVP nor a crude median eminence extract was capable of releasing ACTH. Since adrenal sensitivity to ACTH of rats with stalk lesions was normal and ACTH content of their anterior pituitaries, although temporarily diminished, was enough to stimulate the adrenals if released, the results are interpreted to indicate that the pituitary of rats with stalk lesions is at least temporarily isolated and rendered unresponsive to corticotrophin releas...

Anatomically the hypophysis cerebri is divided into three portions, the pars anterior, the pars intermedia and the pars posterior. Clinically, however, the pars intermedia and the pars posterior can not well be separated, as the extract of the pars posterior also contains that of the pars intermedia. The hormone of the pars anterior affects chiefly the osseous and the genital systems, hypersecretion producing gigantism early in life and acromegaly after growth has ceased, with secondary effects on the dermal system, temperature, pulse, blood pressure and mental function. The hormone of the pars posterior chiefly affects metabolism; hyposecretion produces increased carbohydrate tolerance and adiposity; hypersecretion, decreased carbohydrate tolerance with polyuria; it also causes contraction of the unstriped muscle. I am interested chiefly in the relation of carbohydrate metabolism to variations in pituitary activity and therefore shall deal merely with this phase of the subject. Engelbach (1) found that h...

The case here reported is unique in that there is a clinical history of disturbed function of the thyroid, pancreas, adrenal and probably hypophysis. Autopsy showed caseous tuberculosis peculiarly limited to all the endocrine glands. The history follows. Mr. E. A. O'C, aged 28, a logger, had been married six years and had four healthy children. He was first seen February 9, 1917, saying that sugar had been found in the urine. For about a month he had noticed increased thirst and some polyuria. He was certain that in March, 1916, no sugar was found when he was examined. Family History: His father died at 62 of pernicious anemia “following malaria” and was alcoholic. His mother died at 45 of tuberculosis. Two brothers were alive and well, although one had a goiter. Patient's History: The patient had typhoid at 10 and articular rheumatism in 1903 and again in 1919, when he was confined to his bed for four months.

A SUSPENSION of pitressin tannate in oil1 (PTO) has proved effective in controlling the polydipsia and polyuria of experimental and clinical diabetes insipidus (Blotner, 1942; Court & Taylor, 1943; Greene & January, 1940 & Thorn & Stein, 1941). The effect of a single intramuscular injection persists for a period of 24 to 96 hours in contrast to the evanescent action (3 to 6 hours) of the aqueous preparation (Blotner, 1942). The prolonged action of pitressin tannate is probably due primarily to its slow absorption from the site of injection. As far as we are aware, there has been but one report dealing with the activity of successive injections of pitressin tannate on normal animals, rabbits (Dexter and Weiss, 1941). This communication presents some studies on the effect of PTO on the water exchange and renal concentrating power of normal dogs and in addition, its effects are compared with those produced by a prolonged period of water limitation.

THE FEEDING of large doses of desiccated thyroid to animals with diabetes Tinsipidus is known to produce an exaggeration of the polyuria already present (Fisher and Ingram, 1936; White, et al., 1938; Bruhn, 1939; Hare, 1940; Clarke, 1940). Conversely, thyroidectomy reduces the urine volume in diabetes insipidus (Fisher and Ingram, 1936; Blotner and Cutler 1941; Hare, 1940). In animal experiments the reduction of the polyuria amounted to as much as 25 to 50 per cent, but the urine volume under these conditions was still 1 to 4 times the volume in normal cats. The specific role of the thyroid gland in the maintenance of the full polyuria of diabetes insipidus is not known. No studies of renal physiology i n such animals after thyroidectomy have been reported. The diuretic effect of thyroid feeding appears to be associated with the metabolism-Stimulating factor (Bruhn, 1939), although the administration of such substances as dinitrophenol and dinitroorthocresol has no effect on water exchange in animals with...

On the basis of Engelbach’s (1) conclusions that hypopituitarism suggests an increased carbohydrate tolerance, John (2) has diagnosed from the blood sugar curve test a co-existing diabetes mellitus or prediabetic state in five women with clinical pituitary dystrophy; characteristic findings were a high renal threshold for glucose. However, Howard (3) has postulated “a decreased sugar tolerance in pituitary disease except in the later stages when the pars intermedia has been destroyed by pressure or invasion when increased sugar tolerance is to be expected.” Janney and Henderson (4) and more recently Major (5) regard an abnormal sugar tolerance curve solely as an indication of endocrine disturbance. Since certified cases of pituitary tumor associated with long continued polyuria show the posterior lobe of the pituitary gland to be invariably involved by the process (Kennaway and Mottram, 6), characteristic disturbances of sugar metabolism might be expected in diabetes insipidus. Accordingly, we have studie...

ALL the recent evidence indicates that diabetes insipidus is due to underfunction of the pars intermedia of the hypophysis cerebri rather than to hyperpituitarism as was formerly thought. One of the most brilliant instances of the beneficial effects of a substitution-therapy that we have is the control of the polyuria (and polydipsia) with increase of the concentration of the urine in diabetes insipidus now possible by means of subcutaneous injections of the posterior lobe (and pars intermedia) of the hypophysis cerebri. A number of cases are now on record in which the patients were kept comfortable and excreting a urine of normal amount and of normal specific gravity by injecting ‘Pituitrin’ or ‘Pituitary Liquid’. Until a much larger body of material has been made available for study and for critical judgment, it would seem desirable, for the present, that all syndromes and especially all endocrinopathies associated with diabetes insipidus be reported, especially if a pituitrin-therapy is applied.

THE amount of I131 collected by the thyroid is proportional to the concentration of I131 in the blood. Hence, if thyroid function remains at a constant level, the amount of I131 accumulated by the thyroid will be determined in part by factors which may influence its concentration in the blood. Such factors would include ability of the kidneys to excrete iodide, changes in blood volume, extracellular fluid volume or other alterations of the iodide space. The thyroid of the hypophysectomized rat collects about one eighth as much radioiodine as does that of the normal animal (Randall and Albert, 1951). It is assumed that this depression denotes a diminution of thyroid function resulting from the loss of thyrotropin. However, it is conceivable that the lowered accumulation of I131 could be due to some extrathyroidal mechanism. Because of the marked polyuria which occurs during the first few days following hypophysectomy, it was thought worth while to determine the effect of hypophysectomy on the renal clearan...

Experimental lesions in the hypothalamus in eats have been found in this laboratory (Fisher, Ingram and Ranson, 1934) to be associated with permanent polyuria only when the lesions are placed so as to interrupt the tractus supraoptico-hypophyseus, which courses down the infundibular stalk to the pars posterior and pars intermedia of the hypophysis. Animals with permanent polyuria show marked atrophy of the supraoptic nucleus and of the posterior lobe. The polyuria resulting from such lesions occurs in two phases: a transient phase lasting one to four days after operation, and a permanent phase which comes on after a latent period of 8 to 15 days. The permanent polyuria seems to be a deficiency phenomenon, but it is not unlikely that the transient diuresis may be due to irritation, possibly of one of the lobes of the hypophysis. It will be recalled that Weed, Cushing and Jacobson (1913) observed diuresis and glycosuria in catheterized rabbits and cats following stimulation of the hypophysis and after stimu...

The writer has had the opportunity to observe closely an individual diagnosed as having idiopathic diabetes insipidus, with the following briefly summarized findings: The patient is a male, aged 22, without subjective complaints other than polydipsia and polyuria. The condition appeared suddenly at 5 years of age, without known injury or antecedent illness. There is no familial record of the disease. Physical examination reveals no abnormality excepting a resting blood pressure of 100/65 mm. Hg. Basal metabolic records are well within normal limits. The sella turcica gives no suggestion of abnormality in x-ray negatives. There is no suggestion of hemianopsia. The eye grounds evidence no abnormality. The blood contains cellular elements in normal proportion. The following chemical findings were obtained on analysis of the blood

Genital hypoplasia may be limited to the sex organs, but usually it is accompanied by more general manifestations. These not only involve aberrations in physique but may, especially in older patients, lead to feelings of inferiority or inadequacy, neurasthenic behavior, and occasionally to actual reactive depressions. Since attempts to correct the physical defects may merely therefore prove inadequate, a series of cases is presented here which portray the clinical and therapeutic features involved in the treatment of such conditions. Case 1. M. S., a white male, now 14 years of age, was first seen in June 1933 because of the absence of testes. His family history was non-contributory. He was a full-term child who was delivered by high forceps with a birth weight of 8½ lbs. He was always obese and was troubled with polydypsia, polyuria and enuresis since early childhood.

Diabetes insipidus occurs chiefly in the early stages of life. In a book published by one of the authors of the present paper (Maranon, 1920) we reported statistics of 35 cases observed personally, of which 75 per cent showed commencement of the process before the patients were 10 years old. Since then we have seen 15 more cases which maintain the same proportion. Within this period the most favorable age for commencement of polyuria is that of the years immediately preceding the coming of puberty. It is very uncommon that this process begins in the first two years of a child’s life and it is this circumstance which induces us to publish the case referred to in this paper. Deluca (1915) has recently reported a case of diabetes insipidus which started at three months; we understand that this is the earliest mentioned in the literature. Delafield and Rachel (quoted by Rathery, 1912) mention a case in a child of six months; Variot speaks of one of seventeen months (quoted by Rathery) and Pincherle and Magni ...

Since Kamm (1) and his co-workers succeeded in separating the extract of the posterior pituitary body into two almost pure fractions, the oxytocic and pressor, renewed interest in the physiology of this organ has been stimulated. These authors observed in rabbits that the diuretic action of pituitary gland extractswas limited to the pressor principle. Gargle et al. (2) studied the effect of the oxytocic and pressor principles on water diuresis in four normal subjects and on thirst and polyuria in two cases of diabetes insipidus. They also found that the antidiuretic effect was possessed by the pressor principle alone. Recently, I had occasion to observe the effect of the oxytocic and pressor principles of the pituitary gland on water diuresis in a group of healthy adult male medical students. The materials employed were supplied by the manufacturers, Parke, Davis & Company, under their trade names, Oxytocin and Vasopressin.

THE CAUSE of the diabetes insipidus (d.i.) following removal of the po′terior hypophysis or hypothalamic lesions is still in many points o′ scure. At the presentmoment, the theory is widely held that it is a renal phenomenon. In the first place, in some species the operation is followed first by a polyuria and subsequently by a polydipsia (1,2,). Also, by removing the kidneys (or ureteral ligation), Richter (1, 3) has shown that in the rat the polyuria of d.i. is primary to the polydipsia, since this operation abolished the animals’ excessive thirst. By employing various other methods in the d.i. cat, Fisher, Ingram and Ranson (a) have come to the same conclusion. The renal defect in d.i. isthought to be due to the lack of secretion of the antidiuretic hormone following the operations (4, 5). In turn, this causes a defective renal tubular resorption of water (6, 7).

A married white woman of 41 came to the Diabetic Clinic of The Lankenau Hospital for the relief of distressing occipital headaches preceding and immediately following the menstrual period. These came on, as a rule, in the mornings and lasted several hours. The menstrual cycle was regular each month, lasted five days and was followed by a period of lassitude and weakness. The patient further complained of an excessive and eccentric appetite, polyuria, with some burning, and also of constipation. Her past history indicated susceptibility to infections in the upper respiratory tract, causing frequent severe colds, sore throat, and tonsillitis.

DIFFERENT authors have shown that the injection of renin produces polyuria in rabbits (Pickering, 1940; Brandt et al., 1948; Hughes, et al., 1949); and in rats (Addis et al., 1949; Masson et at., 1950; Sellers et al., 1951; Croxatto et al., 1951). The polyuric effect of renin is abolished by adrenalectomy in rats maintained on 1% NaCl drinking solution (Croxatto et al., 1952). The different behavior of renin in normal and adrenalectomized rats is observed both in animals normally hydrated with free intake of water and in water-loaded animals. Whether the adrenal factor involved in the action of renin arose from the cortex or medulla and whether or not it involved interaction with either the anterior or posterior pituitaries are questions left unanswered by past work. The present experiments were designed to provide such answers. materials and methods Pig renin was prepared according to the method of Braun Menendez (1943).

THE PARTICIPATION of the pars nervosa of the hypophysis in water metabolism has been abundantly demonstrated in various animals (3). Its ablation or its degeneration sequent to denervation is followed by a pronounced polyuria and polydipsia. Since the antidiuretic hormone that it secretes, probably pituitrin, is generally thought to act by controlling renal tubular absorption (4), and since this absorptive process is intimately connected with salt metabolism, it is not surprising that salt has been found to affect these experimental diabetes. Oehme and Oehme (5) reported that sodium chloride exerted a polyuric action on diabetes insipidus, and this has been experimentally verified by Bailey and Bremer (6), Curtis (7), Fisher, Ingram and Ransom (3), and Bellows (8). In this study, the effects not only of NaCl but also of other common salts on experimental diabetes insipidus are reported.

These experiments were designed to test the possibilities that the estrogen inhibition of the polyuria-polydipsia of food-deprived male rabbits may be due to an effect on: 1) renal hemodynamics or renal tubular handling of water, and/ or 2) water ingestion. Glomerular nitration rates (CCr) and renal plasma flows (CPAH) were determined on trained rabbits during: 1) control (fed), 2) polyuric-polydipsic (food-deprived) and 3) inhibited polyuric-polydipsic (receiving 400 μg estradiol benzoate, EB) periods. To assess renal water handling, the response to a water load was studied. To evaluate changes in fluid ingestion, the 3-hr drinking response was measured following administration of 10% NaCl, by gavage. Estradiol was administered in varying doses 2 hr prior to the test. The timed drinking (6 hr) of food deprived rabbits with and without estrogen treatment was measured. The polyuria-polydipsia was not accompanied by changes in CCCr or PAH, nor did the estrogen alter these parameters while inhibiting the pol...

Recently there came under our observation a patient who had developed intense thirst and polyuria, which seemed to be associated with the appearance of malignant metastases in the bones of the skull. The case would seem to be of sufficient importance to put on record. ANAMNESIS The patient, who was brought to us for consultation by her family physician, was a woman of 58 years, the wife of a well-to-do business man. She complained chiefly of excessive thirst, of very frequent urination, of weakness, of peculiar morning vomiting and of marked disability in the lower part of the back. The family history was negative except that one sister had died of metastases of a cancer of the breast. The patient herself had ordinarily been well except for chronic constipation. She had had four children and three miscarriages, and had passed the menopause at 43 with no remarkable symptoms. At 48 the left breast was removed by a competent surgeon because of a tumor

Earlier investigations had shown that chronic overdosage with mineralo-corticoids, such as desoxycorticosterone acetate (DCA), can produce a syndrome of “hyalinosis.” Its manifestations differ somewhat in various species. In the rat, the animal most commonly used for this kind of study, hyalinosis is characterized by nephrosclerosis (glomerular and arteriolar hyalinization, hyalin casts), a “rheumatic-like” myocarditis (partially hyalinized granulomatous nodules in the heart) and periarteritis nodosa (with hyalinization and inflammation, especially in the mesenteric and cerebral vessels). These morphologic changes are accompanied by hypertension and polyuria. Although, with prolonged and heavy DCA overdosage, this syndrome can be elicited even in the intact rat on a normal diet, its development is greatly accelerated by the “conditioning” effect of unilateral nephrectomy and a high NaCl intake. The hypothesis has been advanced that excess production of, or unusual sensitization to, endogenous mineralo-cor...

SINCE 1931 every case of glycosuria found on routine examination of stU 'dents at the University of Minnesota Students' Health Service has been further studied by means of a glucose tolerance test. This report covers an analysis of 583 such cases studied from 1931 to 1937, inclusive. Determination of presence of glycosuria. A positive reaction to the standard Bene'diet qualitative test was taken as evidence of glycosuria. No known diabetics were included in this study. History and physical examinations. All individuals presenting themselves for glucose tolerance tests because of glycosuria were questioned regarding the following. (a) Presence or absence of family history of diabetes. (b) Frequency of urination, e.g., polyuria and nocturia. (c) Increased thirst and appetite or rapid gain or loss of weight. (d) History of fatigue, acute or chronic infections, boils, carbuncles and previous glycosuria. (e) The type of diet the patient was eating previous to finding of glycosuria.

THE PARTICIPATION of the thyroid gland in water metabolism has long been suspected because of the well-known polyuria of hyperthyroidism and the oliguria of hypothyroidism. This has been further related to the hypophysis through the thyrotropic hormone. Barnes, Regan and Bueno (2) showed that the polyuria caused by injections of anterior hypophyseal extracts was prevented by thyroidectomy; the theory followed that the so-called ‘diuretic’ hormone of the anterior lobe was probably the thyrotropic hormone. This caused diuresis by stimulating the thyroid and hence a hyperthyroid diuresis followed. This phenomenon was, furthermore, related to the diuresis following the placement of a silver clip on the infundibulum of dogs. Mahoney and Sheehan (3) reported this operation to result in a considerable diuresis which could be prevented by a thyroidectomy.

In a series of papers dealing with the experimental production of polyuria in cats and monkeys (1, 2, 3) evidence has been presented to show that permanent polyuria as produced in such forms is associated with lesions interrupting the nervous pathway extending from the nucleus supraopticus to the posterior hypophysis. In these cases there is atrophy of the supraoptic nuclei and of the pars nervosa of the hypophysis, and such atrophic glands have been found to be deficient in content of antidiuretic, pressor and oxytocic principles (4). It has been further shown that polyuria may occur in cats following direct removal of the posterior lobe including the stalk, providing functional anterior lobe tissue is left (5). Cats with diabetes insipidus, or even a latent tendency that way due to partial interference with the supraoptico-hypophyseal system, are unusually sensitive to the diuretic effects of thyroid and salt feeding, but thyroidectomy, while diminishing the intensity of the polyuria, has not in our exp...

The purpose of this investigation was to determine which components of the anterior pituitary gland possess diabetogenic activity. The production of diabetes in intact dogs by the administration of the extracts was taken as the index of this activity. The growth-promoting and adrenocorticotrophic activities of the various fractions were also determined. This study was aided greatly by the application of the methods of Wilhelmi, Fishman and Russell (1948) which made possible the preparation of a sufficient quantity of purified growth hormone. Purified adrenocorticotrophic hormone (ACTH) was prepared, and also three fractions, namely, APE and SC (which are diabetogenic) and APP (which produces fat mobilization). The production of definite hyperglycaemia, glycosuria and polyuria in intact dogs in 2 to 4 days following the first injection of the extract was the criterion of diabetogenic activity. In our experience, about 60 per cent of normal dogs are sensitive to the diabetogenic factors of the anterior pitu...

IT WAS shown by Selye, Hall and Rowley (1943) that treatment with desoxycorticosterone acetate (DCA) of unilaterally nephrectomized rats given a high sodium intake resulted in a syndrome of which the main characteristics were hypertension, polyuria, nephrosclerosis, cardiac nodules and periarteritis nodosa. Some of these changes are so similar to those of ltypertension in man that the assumption was made (Selye, Hall and Rowley, 1943) that mineralo-corticoids could be involved in human hypertension. This hypothesis has received additional support from recent work on the so-called meta-corticoid hypertension (Friedman and Friedman, 1949, 1951; Prado, 1950; Green, Saunders, Wahlgren and Craig, 1952; Salgado, 1953). A number of measures have been reported to inhibit the development of the syndrome induced by DCA; we have found that hypophysectomy before or even during the hormonal treatment can inhibit some of the toxic manifestations of DCA overdosage (Salgado and Selye, 1952; Salgado and Selye, 1953).

Insulin is a true internal secretion derived from the ductless glands (islands of Langerhans) of the pancreas. Like other glands of internal secretions, i. e., the thyroid, the suprarenals, the pituitary bodies, etc., the islet cells of the pancreas, because of various functional or pathological changes, may function excessively or deficiently. The part which the internal secretion of the pancreas (insulin) plays in carbohydrate metabolism is well known. When there is a deficiency of insulin with defective carbohydrate metabolism there accumulates in the blood an excess of sugar (hyperglycemia), a part of which is excreted by the kidneys (glycosuria). Tradition tells us that the ancients observed bees swarming around the “sweet” urine of patients who also had the syndrome of polyuria, thirst, hunger and emaciation, and they called the disease diabetes mellitus. If diabetes had been discovered since our present nosology of disease has been accepted it would be called hypoinsulinism, because that name ident...

In recent years, notably before the War, we have carried out a series of researches on the pituitary body. These researches, undertaken without any preconceived idea, have furnished some results which have for the most part been published in various journals. It is of these results that we wish now to offer a succinct review. We must consider in succession the relation of polyuria to the removal of the pituitary body, the relation of polyuria to the lesions of the base of the brain, the site of the lesions which lead to polyuria, the interrelation of polyuria and polydipsia and the question of the regulation of water retention in the body.

IT is ESTABLISHED that some patients with Addison’s disease given large doses of desoxycorticosterone acetate develop cardiac dilatation and signs of circulatory failure (I). Similar doses in normal dogs cause marked polydipsia and polyuria and result inperiodic muscular weakness associated with very low serum potassium levels (2). The present study is concerned with the effects of prolonged administration of this drug in albinorats. In a preliminary experiment the treated rats failed to show effects similar to those seen in the human patient or in the dogs but changes in the weight of the testes and pituitary glands directed attention to the endocrine organs in subsequent groups. Group I. Due to the striking effect of the drug on serum potassium levels of human patients and dogs, the first group of rats was maintained on a low K diet (3) throughout theperiod of observation.

DIABETES INSIPIDUS is generally considered to be the result of a disturbance in the production or release of an antidiuretic hormone by the pars nervosa of the pituitary gland. The condition may be produced experimentally in the following ways: (1) destruction of the supraoptic nuclei of the hypothalamus by electrolytic lesions, (2) transection of the pituitary stalk, which interrupts the nerve supply to the posterior lobe, and (3) removal of the pars nervosa. The polyuria begins immediately after this last procedure and usually continues throughout the life of the subject. The onset of the permanent polyuria after the first and second procedure is more complex. The normal course of events following interruption of the supraoptico hypophysial tract may be divided into three characteristic phases (Fisher, Ingram and Ranson, 1938): (1) Transient phase which begins soon after the operation and lasts 1 to 7 days.

It has been quite conclusively shown that pituitary extract—posterior lobe—is effective in controlling the polydipsia and polyuria of diabetes insipidus. It has, however, been necessary in practically every case to administer the extract by intramuscular injection. As a rule one injection per day, regardless of the size of the dose, is not sufficient to relieve the patient. Usually two or three injections of 1 cc. each are required to keep down both the day and the night intake and output. Since, in most cases, this treatment has to be continued indefinitely a great financial and physical burden must be endured by the patient. The present price of the liquid extract is about 25 cents per 1 cc. ampoule. Since it usually requires three injections per day the cost to the patient would be $0.75 per day for the extract, alone. To this is to be added the physician’s charge for giving the injections

OCCASIONALLY there occur unexplained isolated lesions of the brain which, if investigated carefully from a clinical and pathological point of view, often aid materially in the understanding and the augmenting of the current knowledge concerning certain important functions of the human nervous system. Such discrete, well-placed lesions are often difficult or even impossible to reproduce experimentally because of their location and because of the associated tissue reac tions which usually accompany surgical procedures. Investigation of such human cases often allows for a better understanding and interpretation of the results ob-tained from experimental studies. C. L. (H. N. 611653) was an 18-year-old female. Her history indicated that her birth was attended with little difficulty. She had been healthy when born, began to walk at 10 months and talk at one year of age. She developed fairly normally, although it was noticed even in early childhood that the child was small in stature and had a moderate polyuria...

Injection of a synthetic progesterone, medroxyprogesterone acetate (MPA or Depo-ProveraR), a widely used contraceptive, into Chinese hamsters (Cricetulus griseus) induced a profound polyuria with daily output of dilute urine equal to about 50% body weight of the hamster. However, relatively normal ability for renal urine concentration was demonstrated by administration of exogenous vasopressin. Body weight did not increase during onset of MPA-induced polyuria or during interval of vasopressin-induced oliguria, suggesting that primary polydipsia was not etiologic. Administration of this steroid to Chinese hamsters was nontoxic, although these polyuric animals were unusually sensitive to water deprivation. This polyuria was not observed when progesterone alone was injected into Chinese hamsters or when MPA was given to other related hamster species (Armenian, Syrian, Turkish or Djzungarian). The MPA-injected Chinese hamster represents a unique model of vasopressin sensitive diabetes insipidus induced by a steroid in a species-specific fashion.

In the horse, a syndrome of hirsutism, hyperglycemia, glucosuria, polydipsia, polyuria, polyphagia, and progressive debilitation has been recognized. Most often the syndrome has been associated with adenomas of the pars intermedia of the pituitary and bilateral adrenal hyperplasia or nodular hyperplasia involving primarily the zona fasciculata. Previously, the syndrome has been ascribed to compression of the hypothalamus by an expanding but functionally inactive pituitary neoplasm. In the present case, with RIA determination of plasma ACTH concentrations, the syndrome was ascribed to pituitary ACTH-dependent hyperadrenocorticism and likened to human Cushing's disease.

Experimental obesity produced in rats by stereotaxic lesions of the ventromedial hypothalamus (VMH) resulted in hyperphagia, polydipsia, polyuria, decreased urine osmolality, and enhanced excretion of total solute and urea. A 24-h water deprivation test revealed the inability of VMH-lesioned rats to increase urine antidiuretic hormone (ADH) excretion. Thus, destruction of the VMH area appears to be accompanied by impairment of ADH secretion, resulting in a diabetes insipidus syndrome that is partially masked by food restriction and improved by treatment with exogenous ADH.

The early development of diabetes insipidus passes through 3 phases in rats on constant diet after electrolytic interruption of the supraoptic tracts in the hypothalamus. Immediately postoperatively, there is a burst of overdrinking with rapid weight gain and polyuria. The interphase then supervenes: weight is lost, the urine becomes more concentrated and scant. The large discrepancy between fluid intake and urine output characteristic of the first phase narrows. Approximately six days postoperatively, water turnover rises abruptly, weight gain resumes, and water intake exceeds urine volume by a value roughly twice that of the intact animal. Total solute excretion decreases during the initial burst of polyuria and rises to a peak at the end of the interphase. These fluctuations appear to parallel urea output. The changes in water turnover are unaccompanied by major alterations in the ratio between urinary potassium and sodium, can be suppressed by vasopressin, are unaltered by ACTH administration and pers...

Daily measurements of body weight, water and food intakes and urinary Na+, K+, Cl-, osmolarity and volume were made during 7 days of ad lib. feeding, followed by 7 days of food deprivation in normal male, and normal and ovariectomized female rabbits. Male rabbits deprived of food show a marked increase in fluid intake and urine output which is associated with an enhanced Na+ excretion. In contrast, female rabbits display a diminished or even depressed fluid exchange during food withdrawal; the onset of the increased Na+ excretion, although present as in the male, is delayed. Ovariectomy converts the female type of response to that of the male, i.e., a polyuria and polydipsia. Diethylstilbestrol (100 μg/day) or estradiol (100 μg/ day) given to the male on the 3rd and 4th days of food deprivation results in a significantly reduced water intake and urine output and increased urinary osmolar concentration; similar results are obtained in estradioltreated ovariectomized rabbits. Possible mechanisms of this est...

Metabolic balance studies were made on rats with permanent diabetes insipidus produced by placing electrolytic lesions in the median eminence of the tuber cinereum. Daily water, food, Na and K intakes, urine volume and osmolality, and Na and K excretion were measured for periods up to 6 months. Following lesion, the rats showed the characteristic signs of diabetes insipidus, i.e., polyuria and polydipsia. Among the additional observations made in this study, 3 were most striking. 1) Food intake increased significantly above the control value. This increased food consumption was due in part to the marked increase in water exchange. 2) Although these rats continuously excreted hypotonic urine, when challenged by water deprivation, they were able to concentrate their urine to nearly control levels. 3) These animals altered water intake and urine volume, but not urine osmolality, when deprived of food or fed sucrose. This is in contrast to control rats, which showed marked reductions in urine osmolality and n...

No disruption of menstrual cycles or ovulation was observed in baboons exposed to constant light. Adult cycling female rats as a reference animal were exposed to the same constant light, and persistent vaginal cornification and follicular ovaries devoid of corpora lutea developed. It is inferred that a difference exists between baboons and rats for sensitivity to light as a regulator of gonadotrophin secretion. When baboons were exposed to this constant light, polydipsia and polyuria were observed, suggesting that other disorders of neural activity did develop. ? (Endocrinology 89: 1322, 1971) HE ROLE of light in the neuroendocrine system with respect to the function of the gonad has been reviewed from studies limited to rodents (1-2). In the rhesus monkey infertility and/or menstrual irregularities occur during the summer season both in northern and southern hemispheres (3). However, gonadotrophic function of the rhesus monkey has proved refractory to alternation in light-dark stimulation in the laboratory (4). In the baboon we have observed few menstrual irregularities during the summer season under outdoor conditions. It suggests that the environmental conditions, such as light or temperature may affect reproductive cycles in the baboons as in rats. Therefore, the Received October 2, 1970. influence of constant light on the menstrual cycles of the baboons has been investigated, using rats exposed to the same constant light for

Rats deprived of food but allowed water show an increased urine volume with a high spontaneous water intake. Adrenalectomized rats maintained with deoxycorticosterone acetate and deprived of food void a significantly lower volume of a more concentrated urine and have about half the water intake of deprived controls. The adrenalectomized rats, with this lower water turnover, show the same body weight changes and eliminate the same total solute load as the deprived controls. These results suggest that the spontaneous responses of the adrenal cortex to food deprivation affect water exchange by influencing the regulation of water intake. (Endocrinology 80: 835, 1967)

Several groups of workers have established that chlorpropamide, an oral hypoglycemic agent, reduces urine flow in some individuals with diabetes insipidus (DI). The present study was designed to examine the effectiveness of this agent in rats with total hypothalamic diabetes insipidus (Brattleboro strain). In the first type of experiment chlorpropamide was administered ip to DI rats after appropriate control urine collections. No effect was found on urine volume, osmolality, sodium concentration, or potassium concentration. In the second group of experiments the DI rats were pretreated with chlorpropamide 2 hr before the administration of a minimally effective dose of arginine-vasopressin. In these experiments the urine osmolality was increased, urine volume decreased, and both sodium and potassium concentrations of the urine were increased significantly compared to control animals not given chlorpropamide. In the next set of experiments similar results were found with chronically administered chlorpropam...

These experiments were undertaken to determine the involvement of the adrenocortical hormones in the inhibition by estrogens of the polyuric-polydipsic syndrome induced by salt deficiency in the male rabbit. Daily measurements were made of body weight, water intake and urinary volume, Na† and K† during 10 consecutive days of food deprivation in normal and adrenalectomized male rabbits receiving 17β-estradiol (100 µg/day) and/or hydrocortisone acetate (Fac, 2.5 mg/day) for the first 5 days. Normal males, when deprived of food, developed the typical polyuria and polydipsia which were accompanied by a marked rise in urinary Na†. The administration of Fac further enhanced significantly the fluid exchange during the first 5 days. The administration of estradiol completely inhibited the polyuriapolydipsia, and this effect per sisted into the second 5 days. Estradiol administration to the Fac treated rabbits not only abolished the enhancement due to Fac but depressed water intake and urine volume to values less ...

Prolonged inhibition of 11β-hydroxylation in the adrenal cortex has been produced in 8 normal dogs by means of mepyrapone (Metopirone; Su-4885). Physiologic changes which occurred consisted of blood pressure elevation, hypokalemia, polyuria, a decrease in urinary specific gravity, and an increase in urinary excretion of 17- ketosteroids. Many of these changes, including the blood pressure elevation, were reversed by administration of dexamethasone. Adrenal hyperplasia was noted in several of the animals. These changes are thought to be similar to those occurring in the hypertensive form of congenital adrenal hyperplasia. Additional evidence is thus provided for the theory of 11β-hydroxylase deficiency as the cause of this disease. An experimental model has been described which may aid in further study of the physiologic changes resulting from this enzymatic abnormality. (Endocrinology 78: 511, 1966)

F. S. (240446), colored, male, fifty years old, occupation butcher, was admitted to the medical service of the University Hospifal, Sept. 24, 1923. His chief complaint upon admission wasfdizziness and polyuria. AHis family history was essentially irrelevant. He had been a heavy user of alcoholics during his entire adult life. During March, 1923, he cut his finger while butchering. Following this he developed a gangrene which necessitated the amputation of the finger by his family physician. During the summer prior to his admission he noticed that he drank great quantities of water in an attempt to satisfy his thirst, that he had a ravenous appetite and an excessive excretion) of urine. His polyuria developed to the point that he dribued urine between his frequent urinations. He also noted some Vdeina of the feet, body andface, which was transient. He was informed that he was suffering from diabetes mellitus and advised to enter the hospital.