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Diagnosis and differential diagnosis of diabetes insipidus: Update
Abstract
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.
... Diabetes mellitus (DM) is a metabolic disorder caused by genetic factors, environment and lifestyle caused by defects in insulin secretion or function. In recent years, the prevalence of DM, the main manifestation of hyperglycemia, has risen sharply, reaching 9.7% [1]. In China, type 2 DM (T2DM) accounts for 90%-95% of in all diabetic patients [2]. ...
... Exclusion criteria for the control group: (1) Now have other endocrine diseases, such as hyperthyroidism, systemic lupus erythematosus, rheumatoid arthritis, etc.; (2) now has diseases that can affect the immune function, such as AIDS, malignant tumor, chronic hepatitis and cirrhosis, chemical, primary renal disease, renal failure, hematological disorders, post-renal transplantation, gastrectomy, etc.; or (3) patients with pulmonary infection, or patients with tuberculosis lesions or suspicious lesions after chest X-ray examination. ...
... Diagnostic criteria for PTB [9]: (1) Clinical symptoms such as cough, expectoration and fever, typical PTB findings combined with chest X-ray and chest computed tomography; (2) tuberculin skin test (PPD) reaction 10 mm; (3) positive TB antibody or γ -interferon release test; (4) positive mycobacterium smear culture; and (5) histopathology consistent with positive tuberculous change and acid fast staining. ...
BACKGROUND
In China, the prevalence of type 2 diabetes mellitus (T2DM) among diabetic patients is estimated to be between 90%-95%. Additionally, China is among the 22 countries burdened by a high number of tuberculosis cases, with approximately 4.5 million individuals affected by active tuberculosis. Notably, T2DM poses a significant risk factor for the development of tuberculosis, as evidenced by the increased incidence of T2DM coexisting with pulmonary tuberculosis (T2DM-PTB), which has risen from 19.3% to 24.1%. It is evident that these two diseases are intricately interconnected and mutually reinforcing in nature.
AIM
To elucidate the clinical features of individuals diagnosed with both T2DM and tuberculosis (T2DM-PTB), as well as to investigate the potential risk factors associated with active tuberculosis in patients with T2DM.
METHODS
T2DM-PTB patients who visited our hospital between January 2020 and January 2023 were selected as the observation group, Simple DM patients presenting to our hospital in the same period were the control group, Controls and case groups were matched 1:2 according to the principle of the same sex, age difference ( ± 3) years and disease duration difference ( ± 5) years, patients were investigated for general demographic characteristics, diabetes-related characteristics, body immune status, lifestyle and behavioral habits, univariate and multivariate analysis of the data using conditional logistic regression, calculate the odds ratio (OR) values and 95%CI of OR values.
RESULTS
A total of 315 study subjects were included in this study, including 105 subjects in the observation group and 210 subjects in the control group. Comparison of the results of both anthropometric and biochemical measures showed that the constitution index, systolic blood pressure, diastolic blood pressure and lymphocyte count were significantly lower in the case group, while fasting blood glucose and high-density lipoprotein cholesterol levels were significantly higher than those in the control group. The results of univariate analysis showed that poor glucose control, hypoproteinemia, lymphopenia, TB contact history, high infection, smoking and alcohol consumption were positively associated with PTB in T2DM patients; married, history of hypertension, treatment of oral hypoglycemic drugs plus insulin, overweight, obesity and regular exercise were negatively associated with PTB in T2DM patients. Results of multivariate stepwise regression analysis found lymphopenia (OR = 17.75, 95%CI: 3.40-92.74), smoking (OR = 12.25, 95%CI: 2.53-59.37), history of TB contact (OR = 6.56, 95%CI: 1.23-35.03) and poor glycemic control (OR = 3.37, 95%CI: 1.11-10.25) was associated with an increased risk of developing PTB in patients with T2DM, While being overweight (OR = 0.23, 95%CI: 0.08-0.72) and obesity (OR = 0.11, 95%CI: 0.02-0.72) was associated with a reduced risk of developing PTB in patients with T2DM.
CONCLUSION
T2DM-PTB patients are prone to worse glycemic control, higher infection frequency, and a higher proportion of people smoking, drinking alcohol, and lack of exercise. Lymphopenia, smoking, history of TB exposure, poor glycemic control were independent risk factors for T2DM-PTB, and overweight and obesity were associated with reduced risk of concurrent PTB in patients with T2DM.
... Ciò nonostante, il test all'ipertonica risultò da subito particolarmente impegnativo dal punto di vista logistico e potenzialmente gravato da effetti collaterali significativi (es., cefalea e nausea), sebbene complessivamente meglio tollerato dai pazienti rispetto al WDT [11]. In tal senso, una recente raccomandazione dello stesso gruppo di ricerca [18] ha quindi suggerito di considerare prudenzialmente un target di natriemia di 147 mmol/L, anziché 150 mmol/L, nella routinaria pratica clinica. Sempre nel tentativo di ovviare a tali limiti, negli ultimi anni sono stati proposti dal gruppo di ricerca svizzero di Basilea, due ulteriori test di stimolo alternativi di tipo non osmotico. ...
... In questo primo lavoro, la somministrazione endovenosa di arginina al 21% 0,5 g/Kg, preceduta da deprivazione idrica di 2 h, ha determinato in 50 adulti sani un significativo aumento dei livelli mediani di copeptina da 5,2 [3,[3][4][5][6][7][8][9][10]9] pmol/L a 9,8 [6,[4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]6] pmol/L durante i primi 60 min dall'inizio dell'infusione [12]. Lo stesso studio ha quindi identificato in una coorte di sviluppo composta da pazienti adulti con SPP (31 PP, 12 DIC completo e 9 parziale) alcuni cut-off di copeptina promettenti sempre a 60 min dall'inizio dell'infusione, successivamente applicati a un'ulteriore coorte di validazione (27 PP, 12 DIC completo e 7 parziale) con risultati di poco inferiori. ...
... In questo secondo lavoro con disegno crossover, condotto su una popolazione più ampia, il cut-off di copeptina di 3,8 pmol/L, precedentemente proposto dallo stesso gruppo di ricerca [12], avrebbe dimostrato un'accuratezza significativamente inferiore rispetto a quella del test all'ipertonica (cut-off 4,9 pmol/L con target di natriemia 149 mmol/L in questa occasione). Gli autori hanno inoltre sottolineato come un cut-off superiore (pari a 5,2 pmol/L), sempre durante test all'arginina, mostrerebbe una buona Sp, nonostante una Se limitata, nell'identificare i casi di PP, conservando quindi un potenziale ruolo di prima linea in uno stepwise approach che riservi l'ipertonica ai casi dubbi, oppure quando questa risulti controindicata (es., scompenso cardiaco cronico, cirrosi epatica, epilessia o gravidanza) [18]. ...
Sommario
Il corretto riconoscimento dei casi di diabete insipido, in particolar modo parziale, rimane tutt’oggi una sfida per l’endocrinologo. Nuovi test di stimolo, osmotici e non, che prevedono la determinazione plasmatica di copeptina, sono stati proposti negli ultimi anni, modificando irreversibilmente le flow-chart diagnostiche. In questa rassegna sono riportate le principali evidenze in merito a tali procedure, con attenzione particolare all’accuratezza e ai limiti intrinseci di ciascuna di esse.
... Diagnosis of DI. We retrieved 11 articles on the diagnosis of DI after pituitary surgery [4,27,[38][39][40][41][42][43][44][45][46]. DI is the most common endocrine complication after pituitary surgery, with an incidence around 10-20%, depending on whether the tumor is confined to the sella or extends beyond it [27]. ...
... We summarize the findings from 3 articles on the approach for patients with suspected DI [27,43,44]. Management of DI depends on the patient's status [43]. ...
... In order to avoid the risk of hyponatremia, patients should be instructed to avoid excessive fluid intake. Similarly, patients should be instructed about the symptoms of hyponatremia such as nausea, vomiting, headache, lethargy and seizures [44]. Most cases of DI after pituitary surgery are transient. ...
Purpose:
Endocrine complications are the most frequent postoperative complications in pituitary surgery. In the absence of guidelines on postoperative care, this article summarizes the available data on the topic.
Method:
We conducted a systematic search of PubMed up to 2021 and updated the search in December 2022.We retrieved 119 articles and included 53 full-text papers.
Results:
Early postoperative care consists is assessment for cortisol deficiency and diabetes insipidus (DI). Experts suggest that all patients should receive a glucocorticoid (GC) stress dose followed by rapid taper. The decision for GC replacement after discharge depends on the morning plasma cortisol level on day 3 after surgery. Experts suggest that patients with morning plasma cortisol < 10 mcg/dl should receive GC replacement at discharge, and those with 10-18 mcg/dl a morning dose only, with formal assessment of the hypothalamic-pituitary-adrenal axis at postoperative week 6. When the cortisol level is > 18 mcg/dl, the patient can be discharged safely off GC, as suggested by observational studies. Postoperative care also includes close monitoring of water balance. In DI, desmopressin is used only in case of uncomfortable polyuria or hypernatremia. Assessment of other hormones is indicated at 3 months postoperatively and beyond.
Conclusion:
Evaluation and treatment of patients following pituitary surgery are based on expert opinion and a few observational studies. Further research is needed to provide additional evidence on the most appropriate approach.
... A thorough medical history, clinical assessment, laboratory evaluation, and radiological tests (e.g., pituitary MRI) can help to indicate the possible etiology of polyuria-polydipsia (PP) syndrome. However, they are insufficient to reach a definitive diagnosis [4]. After secondary causes such as diabetes, hypercalcemia, and hypokalaemia have been ruled out, 24-hour urine collection should be used to confirm the presence of hypotonic polyuria [1]. ...
... The presence of hyponatremia (plasma sodium <135 mmol/L) or low plasma osmolality (<280 mOsm/kg) is highly suspicious for PP, while a high plasma sodium (≥147 mmol/L) and/or plasma osmolality (>300 mOsm/kg) points toward DI. However, most PP patients have sodium and osmolality levels within normal limits, necessitating additional testing [4]. ...
... In contrast, patients with nephrogenic DI remain below this urine osmolality threshold. The urine osmolality of patients with partial central DI or PP usually rises to 300-800 mOsm/kg [4]. For many years, the gold standard for differential diagnosis has been the standard water deprivation test proposed by Miller et al. [5]. ...
Diabetes insipidus (DI) is a rare disease characterized by hypotonic urine output and polydipsia. We report the case of a 50-year-old male admitted for diabetic ketoacidosis (DKA) in an intensive care unit with sepsis and alcoholic pancreatitis who later developed DI. He had a high copeptin level of >21.4 pmol/L, suggesting DI of nephrogenic origin. At presentation, he had DKA-associated osmotic diuresis. His later finding of elevated copeptin suggesting partial nephrogenic DI created a diagnostic enigma.
... Neurohypophyseal or central diabetes insipidus is characterized by excessive urine production (polyuria) and water intake (polydipsia) that result from deficient or absent Maria Inês Alvelos and Ângela Francisco should be regarded as joint first authors. secretion of vasopressin, also known as antidiuretic hormone (ADH) [1,2]. Most cases are caused by trauma (surgical or accidental), tumors, granulomatous infiltration, autoimmunity, infection, irradiation, or ischemia in the hypothalamic-pituitary region, which result in damage of vasopressin-producing neurons [3]. ...
... The AVP gene (chromosome 20p13) consists of three coding exons and encodes a precursor polypeptide (prepro-vasopressin), which is synthesized in the magnocellular neurons of the supraoptic and paraventricular nuclei of the hypothalamus [5]. The pre-pro-vasopressin is converted to pro-vasopressin, by removal of the signal peptide (amino acids [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] within the endoplasmic reticulum (ER). The pro-vasopressin is packed into secretory granules in the Golgi apparatus and additional processing leads to cleavage of pro-vasopressin into three peptides: the vasopressin hormone (amino acids 20-28), neurophysin II (NPII) (amino acids , which is an intracellular binding protein for vasopressin, and the glycoprotein copeptin (amino acids 126-164). ...
... Vasopressin production decreases gradually and is accompanied by the onset and worsening of polyuria and polydipsia over the years. The loss of vasopressin-producing neurons explains the absence of the characteristic bright spot of the posterior pituitary on magnetic resonance imaging (MRI) [2,9] and the autopsy findings in FNDI patients [10,11]. The expression of the disease is often variable among patients carrying the same mutation, even within the same kindred [12]. ...
Purpose
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.
Methods
Five Portuguese families with autosomal dominant FNDI underwent sequencing of the AVP gene and the identified mutations were functionally characterized by in vitro studies.
Results
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.
Conclusion
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.
... Central Diabetes Insipidus (CDI) results from the inability to produce, transfer or secrete arginine vasopressin (AVP) also known as the anti-diuretic hormone, causing polydipsia, polyuria, and hypernatremia. Acquired CDI can develop following pituitary surgery for sellar masses including pituitary adenomas and craniopharyngioma, head trauma, pituitary metastases, germinomas, disorders affecting the pituitary stalk as Langerhans cell histiocytosis, neurosarcoidosis, hemochromatosis, and hypophysitis [1][2][3][4][5]. CDI rarely develops in patients with large pituitary adenomas preceding surgery [6]. ...
... Diagnosis of idiopathic CDI is established usually after excluding other etiologies. Magnetic resonance imaging (MRI) is performed after confirmation of CDI [3,5]. Imaging can reveal secondary etiologies such as intracranial tumors, pituitary metastases, and infiltrative diseases. ...
Central Diabetes Insipidus (CDI) is mainly associated with structural pathologies of the hypothalamic-pituitary area. Etiologies underlying CDI are identified in most patients, however idiopathic CDI is reported in 13–17% of cases after excluding other etiologies. The Hypopituitarism ENEA Rare Observational Study (HEROS study) retrospectively collected data of patients with idiopathic CDI from 14 pituitary centers in 9 countries. The cohort included 92 patients (59 females 64%), mean age at diagnosis was 35.4 ± 20.7 years, and a mean follow up of 19.1 ± 13.5 years following CDI diagnosis. In 6 women, diagnosis was related to pregnancy. Of 83 patients with available data on pituitary imaging, 40(48%) had normal sellar imaging, and 43(52%) had pathology of the posterior pituitary or the stalk, including loss of the bright spot, posterior pituitary atrophy or stalk enlargement. Anterior pituitary hormone deficiencies at presentation included hypogonadism in 6 (6.5%) patients (5 females), and hypocortisolism in one; during follow-up new anterior pituitary deficiencies developed in 6 patients. Replacement treatment with desmopressin was given to all patients except one, usually with an oral preparation. During follow up, no underlying disease causing CDI was identified in any patient. Patients with idiopathic CDI following investigation at baseline are stable with no specific etiology depicted during long-term follow-up.
... Central Diabetes Insipidus (CDI) results from the inability to produce, transfer or secrete arginine vasopressin (AVP) also known as the anti-diuretic hormone, causing polydipsia, polyuria, and hypernatremia. Acquired CDI can develop following pituitary surgery for sellar masses including pituitary adenomas and craniopharyngioma, head trauma, pituitary metastases, germinomas, disorders affecting the pituitary stalk as Langerhans cell histiocytosis, neurosarcoidosis, hemochromatosis, and hypophysitis (1)(2)(3)(4)(5). CDI rarely develops in patients with large pituitary adenomas preceding surgery(6). ...
... Diagnosis of idiopathic CDI is established usually after excluding other etiologies. Magnetic resonance imaging (MRI) is performed after con rmation of CDI (5,9). Imaging can reveal secondary etiologies such as intracranial tumors, pituitary metastases, and in ltrative diseases. ...
Central Diabetes Insipidus (CDI) is mainly associated with structural pathologies of the hypothalamic-pituitary area. Etiologies underlying CDI are identified in most patients, however idiopathic CDI is reported in 13-17% of cases after excluding other etiologies.
The Hypopituitarism ENEA Rare Observational Study (HEROS study) retrospectively collected data of patients with idiopathic CDI from 14 pituitary centers in 9 countries.
The cohort included 92 patients (59 females), mean age at diagnosis was 35.4±20.7 years, and a mean follow up of 18.2±14.5 years following CDI diagnosis. In 6 women, diagnosis was related to pregnancy. Of 83 patients with available data on pituitary imaging, 40 had normal sellar imaging, and 43 had pathology of the posterior pituitary or the stalk, including loss of the bright spot, posterior pituitary atrophy or stalk enlargement. Anterior pituitary hormone deficiencies at presentation included hypogonadism in 6 patients (5 females), and hypocortisolism in one; during follow-up new anterior pituitary deficiencies developed in 6 patients. Replacement treatment with desmopressin was given to all patients except one, usually with an oral preparation. During follow up, no underlying disease causing CDI was identified in any patient.
Conclusions: patients with idiopathic CDI following investigation at baseline are stable with no specific etiology depicted during long-term follow-up.
... Nephrogenic diabetes insipidus (NDI) is a polyuric condition that results from partial or complete resistance of the late distal tubules and collecting ducts to the actions of arginine vasopressin (AVP). The causes of NDI are listed in table 2 (10,11). Most patients with congenital NDI present with failure to thrive during the first few months of life, whereas those with acquired NDI typically present later in life with polyuria and or polydipsia (10,11).Laboratory evaluation must also include serum osmolality and urine osmolality. ...
... The causes of NDI are listed in table 2 (10,11). Most patients with congenital NDI present with failure to thrive during the first few months of life, whereas those with acquired NDI typically present later in life with polyuria and or polydipsia (10,11).Laboratory evaluation must also include serum osmolality and urine osmolality. NDI is associated with urine that is inappropriately dilute with a urine osmolality less than 300 mOsm/kg in the setting of a serum osmolality greater than 300 mOsm/kg without change in urine osmolality after administration of exogenous vasopressin (12). ...
Hormone resistance is defined as a reduced or absence of target tissues responsiveness to a hormone, where the presentation is related to either a relative lack or excess of hormones. Various disorders of hormone resistance were encountered including, Laron syndrome, nephrogenic diabetes insipidus, thyroid hormone resistance syndrome, pseudohypoparathyroidism, insulin resistance, familial glucocorticoid deficiency, pseudohypoaldosteronism, X linked hypophosphatemic rickets and androgen insensitivity syndrome. The article gives a summary that presents, in concentrated form, what the primary care physicians need to know about recognition, clinical presentation, diagnosis, and management of various hormone resistance in children.
... IgG4-RH is diagnosed using established diagnostic criteria by Takagi et al. [3] and by Leporati et al. [4] Although IgG4-RH may be infrequent, the symptoms show that central diabetes insipidus (CDI) and IgG4-RH generally appear in middle-aged and elderly males and young females [5], with limited reports of pediatric patients. CDI is characterized by an insufficient secretion for AVP production from the hypothalamusneurohypophyseal system after adequate stimulation [6]. There are various causes that can result in CDI, e.g., after pituitary surgery, trauma, and hypophysitis. ...
... There are various causes that can result in CDI, e.g., after pituitary surgery, trauma, and hypophysitis. The symptoms of CDI are a preference for cold drinks, drinking at night, presence of nocturia, polyuria, and polydipsia [6]. CDI due to hypophysitis is a rare condition, and CDI due to IgG4-RH is also rare. ...
Immunoglobulin G4 (IgG4)-related disorders are characterized by tissue hypertrophy due to IgG4-positive cell infiltration and increased serum IgG4 levels. IgG4-related hypophysitis (IgG4-RH) is characterized by pituitary hypertrophy, IgG4-positive cell infiltration, central diabetes insipidus, and increased serum IgG4 levels. IgG4-RH is diagnosed through diagnostic criteria. A few cases of IgG4-RH in children have been reported. We report a case of CDI with increased serum IgG4 levels that failed to meet the diagnostic criteria of IgG4-RH. The patient developed polyuria and polydipsia at age 11 and was diagnosed as having idiopathic CDI at age 12. The patient was not treated with steroids and is well controlled with antidiuretic hormones. It has been reported that pediatric IgG4-RH differs from that of adults in several respects. We believe that the pediatric IgG4-RH may not fit the diagnostic criteria of adults. There may be also other cases of increased serum IgG4 levels in pediatric patients with idiopathic CDI. We do not know if they are subtypes of IgG4-RH or if serum IgG4 levels are by chance raised in CDI, however, we report them here because IgG4-RH in children may be different from that in adults.
... Central DI is primarily treated with DDAVP or AVP to replace absent AVP hormone due to decreased production of arginine vasopressin [37], with the route of administration being dependent on the clinical setting, whether acutely ill or hospitalized. Clofibrate, chlorpropamide and carbamazepine though ineffective and least preferred in comparison to DDAVP are also administered in Central DI treatment [38]. ...
Diabetes insipidus (DI) is an acquired or hereditary water imbalance disorder characterized by polydipsia and polyuria. It is a condition that involves the excretion of dilute urine in large volumes. The illness can strike at any age, with males and females have identical rates of occurrence of the disease. The two main mechanisms responsible for diabetes insipidus are either insufficient release or production of ADH (antidiuretic hormone) from the hypothalamus (central diabetes insipidus) or ADH resistance in which the kidneys are unable to respond to ADH (nephrogenic diabetes insipidus). Another form of DI is transient diabetes insipidus commonly known as gestational diabetes insipidus that occurs in the second/third trimester of pregnancy due to increased levels of placental vasopressinase that occurs progressively during pregnancy and increases metabolic clearance of vasopressin. The fourth type of DI is primary polydipsia, characterized by elevated levels of water intake that physiologically lower vasopressin and may be psychogenic, iatrogenic or dipsogenic. Signs and symptoms of DI often include water electrolyte-imbalance, excessive or severe thirst, frequent and excessive urination, fatigue, dehydration, and weight loss. Diabetes insipidus (DI) should be distinguished from primary polydipsia, and whether it is caused by a central, nephrogenic, or gestational cause. This distinction is critical since incorrect treatment can result in serious repercussions. Diagnosis of DI includes measurement of plasma sodium and osmolality, baseline copeptin, hypertonic saline stimulation and arginine stimulation test. The treatment for DI includes the use of drugs such as desmopressin, thiazide diuretics, indomethacin and amiloride.
... Moreover, in agreement with other studies [50][51][52], our data demonstrated that the rats in the DM group progressed to severe hyperglycemia, microalbuminuria, polyuria, and polydipsia. Kidney injury was confirmed by functional and structural disturbances at the end of the 11th week. ...
Background
Diabetic nephropathy and hepatopathy are health problems described by specific renal and hepatic structure and function disturbances. The protective effects of the stem cell secretome have been shown in several kidney and liver diseases. The current study aims to evaluate the capability of conditioned media derived from human Wharton’s jelly mesenchymal stem cells (hWJ-MSCs-CM) to alleviate diabetic complications.
Methods
Twenty Sprague Dawley rats were made diabetic through injection of STZ (60 mg/kg, i.p.). At week 8, diabetic rats were divided into two groups: treated [DM + hWJ-MSCs-CM (500 µl/rat for three weeks, i.p.)] and not treated (DM). At the 11th week, three groups (control, DM, and DM + hWJ-MSCs-CM) were kept in metabolic cages, and urine was collected for 24 h. The serum samples were maintained for measuring fasting blood glucose (FBG) and kidney and liver functional analysis. The left kidney and liver parts were kept at -80 °C to assess apelin and transforming growth factor-beta (TGF-β) expression. The right kidney, pancreas, and liver parts were used for histopathologic evaluation.
Results
DM was detected by higher FBG, microalbuminuria, increased albumin/creatinine ratio, and pancreas, renal, and hepatic structural disturbances. Diabetic hepatopathy was determined by increasing liver enzymes and decreasing total bilirubin. The TGF-β gene expression was significantly upregulated in the diabetic kidney and liver tissues. Apelin gene expression was significantly downregulated in the diabetic liver tissue but did not change in kidney tissue. Administration of hWJ-MSCs-CM improved renal and hepatic functional and structural disturbances. Moreover, CM therapy significantly decreased TGF-β expression and enhanced apelin expression in the kidney and liver tissues.
Conclusion
Human WJ-MSCs-CM may have protective effects on diabetic renal and hepatic complications. These effects may happen through the regulation of TGF-β and apelin signaling pathways.
... DN is a very common complication of diabetes, about 30-40% of diabetic patients will progress to DN, and the incidence is increasing year by year (14). DN is an inde-VEGFA, and FGF1 was clearly down-regulated, and the genes ITGB1, CCR4, CXCR3, MMP7, SOX9, and CD163 were clearly up-regulated in DN patients. ...
... Diabetes mellitus (DM), an endocrine disease resulting from the comprehensive intervention of immune factors, pathogenesis, and genetic factors, is also one of the most common chronic diseases globally, with a predilection for the middle-aged and elderly [1]. According to statistics, an average of more than 7 million new cases of DM are diagnosed globally every year, and the accumulated cases are estimated to reach 330 million by 2030 [2]. ...
The objective of this study is to investigate the expression of the carbohydrate response element binding protein (ChREBP) gene in type 2 diabetes mellitus (T2DM) and its correlation with pathological features. For obtaining and exploring the pathological features in patients, sixty T2DM patients (the research group) and thirty healthy controls (the control group) presented to our hospital between January 2019 and June 2019 were selected as the research participants. After DNA extraction from peripheral blood mononuclear cells (PBMCs) and modification of target gene methylation with bisulfite, differences in methylation were verified, and the correlation of ChREBP methylation level with T2DM pathological features and single nucleotide polymorphism (SNP) typing was discussed. According to the prediction results of UCSC Genome Browser Home, there were two CpG islands in the promoter region of the ChREBP gene, and the first exon was selected for research. The ChREBP methylation rate was statistically higher in the research group versus the control group (P < 0.05). Age, FPG, TC, and TG were confirmed by the multiple linear regression analysis to be correlated with the ChREBP methylation rate (P < 0.05). Finally, there was no difference in ChREBP methylation level between CT- and CC-type patients at rs17145750 and rs1051921 loci (P > 0.05). Peripheral blood ChREBP methylation is elevated in T2DM patients and is closely related to age, blood glucose, and blood-lipid level, which is expected to be a new direction for future T2DM diagnosis and treatment.
... In particular, the differential diagnosis in patients with the polyuriapolydipsia syndrome (PPS) is challenging (1). The polyuria of PPS is characterized by a high output of hypotonic urine (2) and includes four conditions: Arginine vasopressin (AVP)-deficiency, nephrogenic diabetes insipidus (NDI), primary polydipsia (PP), and gestational diabetes insipidus. ...
Background:
The diagnosis of the polyuria-polydipsia syndrome is challenging. Copeptin is a robust biomarker of arginine-vasopressin (AVP) secretion. Arginine, which stimulates GH, has been shown also to stimulate copeptin secretion via unknown mechanisms.
Aim:
To investigate copeptin levels in response to three different GH stimulation tests in patients suspected of GH-deficiency.
Methods:
In this cross-sectional study, we measured plasma copeptin levels at baseline and at 60, 105, and 150 minutes in patients undergoing a stimulation test for GH-deficiency with either arginine (n=16), clonidine (n=8) or the insulin tolerance test (ITT) (n=10).
Results:
In patients undergoing the arginine test, the mean age was 9 years, and 10 years for clonidine. The ITT was only performed in adult patients (>18 years) with a mean age of 49 years. Copeptin level increased significantly from baseline to 60 min after arginine (p < 0.01) and ITT (p < 0.01). By contrast, we observed a small non-significant decline in copeptin level after clonidine stimulation (p = 0.14).
Conclusion:
These data support that infusion of arginine increases plasma copeptin levels and reveal a comparable response after an ITT. We hypothesize that the underlying mechanism is abrogation of somatostatin-induced AVP-suppression.
... In recent years, the prevalence of DM, mainly manifested by hyperglycemia, has increased sharply, reaching 9.7%. 1 In China, type 2 diabetes accounts for 90-95% of all diabetic patients. 2 Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis, 3 and most patients with latent TB infection have no obvious clinical symptoms. ...
Objective:
To explore the risk factors of malnutrition in type 2 diabetes mellitus combined with pulmonary tuberculosis (PTB-T2DM) patients and further to provide a clinical research basis for the identification and prevention of malnutrition.
Methods:
From January 2020 to February 2022, 307 adult patients diagnosed with PTB-T2DM were enrolled in this retrospective study. According to whether malnutrition occurred after 6 months of treatment, patients were divided into malnutrition group (n = 123) and non-malnutrition group (n = 184). The nutritional status of patients was evaluated according to the Micro-Nutrition Assessment Scale (MNA). Evaluation of indicators was performed, including general information, disease characteristics of PTB-T2DM and laboratory indicators.
Results:
Univariate logistic regression analysis showed that drinking, divorced, BMI <18.5kg/m2, weight <45kg, waist circumference <79cm, hip circumference <88cm, waist-to-hip ratio <69.99, calf circumference <26kg, grip strength <28kg, NRS score ≥3, Hb <106g/L, Alb <29.00g/L, PA <48.00μmol/L, GHB <3.40%, serum transferrin <1.37 mmol/L, serum potassium <3.18mmol/L, serum sodium <142.95 mmol/L, FEV1 ≥67.90% and RV <2.89% were risk factors for malnutrition in PTB-T2DM patients (all P < 0.05). The results of multivariate logistic regression analysis showed that drinking, divorced, weight <45kg, BMI <18.5kg/m2, NRS score ≥3, Hb <106g/L, Alb <29.00g/L, PA <48.00μmol/L, serum transferrin <1.37mmol/L, FEV1 ≥67.90% and RV <2.89% were independent risk factors for malnutrition in PTB-T2DM patients (all P < 0.05).
Conclusion:
Drinking, divorced, weight <45kg, BMI <18.5kg/m2, NRS score ≥3, Hb <106g/L, Alb <29.00g/L, PA <48.00μmol/L, serum transferrin <1.37mmol/L, FEV1 ≥67.90% and RV <2.89% may be independent risk factors for malnutrition in PTB-T2DM patients, and timely identification of high-risk groups could improve the prognosis of PTB-T2DM patients.
... Diabetes is a metabolic disease that causes high blood sugar to cause many chronic health problems, such as cardiovascular diseases, vision damage, and kidney disease [58]. In two transcriptome datasets (GSE9006 [59] and GSE19420 [60]) for diabetes, VTP values were significantly greater in patients than in normal controls (P < 0:05) (Figure 8(a)). ...
Background: Although transcriptomic data have been widely applied to explore various diseases, few studies have investigated the association between transcriptomic perturbations and disease development in a wide variety of diseases.
Methods: Based on a previously developed algorithm for quantifying intratumor heterogeneity at the transcriptomic level, we defined the variation of transcriptomic perturbations (VTP) of a disease relative to the health status. Based on publicly available transcriptome datasets, we compared VTP values between the disease and health status and analyzed correlations between VTP values and disease progression or severity in various diseases, including neurological disorders, infectious diseases, cardiovascular diseases, respiratory diseases, liver diseases, kidney diseases, digestive diseases, and endocrine diseases. We also identified the genes and pathways whose expression perturbations correlated positively with VTP across diverse diseases.
Results: VTP values were upregulated in various diseases relative to their normal controls. VTP values were significantly greater in define than in possible or probable Alzheimer’s disease. VTP values were significantly larger in intensive care unit (ICU) COVID-19 patients than in non-ICU patients, and in COVID-19 patients requiring mechanical ventilatory support (MVS) than in those not requiring MVS. VTP correlated positively with viral loads in acquired immune deficiency syndrome (AIDS) patients. Moreover, the AIDS patients treated with abacavir or zidovudine had lower VTP values than those without such therapies. In pulmonary tuberculosis (TB) patients, VTP values followed the pattern: active TB > latent TB > normal controls. VTP values were greater in clinically apparent than in presymptomatic malaria. VTP correlated negatively with the cardiac index of left ventricular ejection fraction (LVEF). In chronic obstructive pulmonary disease (COPD), VTP showed a negative correlation with forced expiratory volume in the first second (FEV1). VTP values increased with H. pylori infection and were upregulated in atrophic gastritis caused by H. pylori infection. The genes and pathways whose expression perturbations correlated positively with VTP scores across diseases were mainly involved in the regulation of immune, metabolic, and cellular activities.
Conclusions: VTP is upregulated in the disease versus health status, and its upregulation is associated with disease progression and severity in various diseases. Thus, VTP has potential clinical implications for disease diagnosis and prognosis.
... 3e6 Diabetes is a metabolic disease characterized by elevated blood glucose levels. 7,8 Impaired metabolism of glucose, lipids and proteins can lead to changes in circulation of macrovessels and microvessels, thus increasing the risk of multiple complications in diabetic patients, including retinopathy, neuropathy, nephropathy, cardiovascular complications and delayed wound healing. 9,10 A large amount of evidence indicates that there is a relationship between diabetes and periodontal disease. ...
Background
/purpose: Periodontal disease is a chronic inflammatory disease that occurs in the tissues that support and attach teeth. There is considerable evidence of a relationship between diabetes and periodontal disease. Emerging studies have reported that myeloid-derived growth factor (MYDGF) can inhibit apoptosis and inflammation. The purpose of this study was to investigate whether MYDGF mediates the role of hyperglycemia in fibroblasts in periodontitis tissues.
Materials and methods
Fibroblasts were isolated and cultured from normal gums. Gene expression levels were detected by RT-PCR. The protein level was detected by western blotting. Cell viability was determined by MTT assay. To investigate the role of MYDGF, the plasmid was transfected into fibroblasts. The expression levels of cytokines were determined by ELISA.
Results
High glucose can down-regulate the expression of MYDGF in human gingival fibroblasts in a time-dependent manner, and decrease the fibroblast activity. SOD level was decreased and MDA level was increased in gingival fibroblasts by high glucose. High glucose up-regulates pro-apoptotic indicator Bax, down-regulates anti-apototic indicator Bcl-2, and increased endoplasmic reticulum stress related indicators Nox 2, GRP78, ATF6, and PERK. In addition, high glucose increased TNF-α, IL-1β, IL-8 and CXCL1 protein levels in fibroblasts. Our study also found that high glucose inhibits the AKT signaling pathway and activates the nuclear factor κB (NF-κB) pathway. Interestingly, overexpression of MYDGF reversed these effects.
Conclusion
MYDGF is down-regulated in gingival fibroblasts induced by high glucose. Overexpression of MYDGF inhibits apoptosis induced by high glucose, inhibits oxidative stress and cytokine secretion of gingival fibroblasts induced by high glucose, and induces AKT pathway activation and NF-κB pathway inhibition.
... Necukrinis diabetas yra vienas iš vandens apykaitos homeostazės sutrikimų, kai padidėja jo sekrecija per inkstus [1]. Padidėjusi šlapimo sekrecija (arba poliurija) apibrėžiama kaip >50 ml/kg per 24 h išskiriamo šlapimo kiekiu [2,3]. Liga tradiciškai pavadinta necukriniu diabetu, nes dėl padidėjusio vandens netekimo pacientai nuolat jaučia padidėjusį troškulį, kuris yra vienas iš cukrinio diabeto simptomų [4]. ...
Necukrinis diabetas pagal patogenezę skirstomas į centrinį ir nefrogeninį. Centrinio necukrinio diabeto priežastis – sutrikusi vazopresiną sekretuojančių neuronų funkcija, kurią sukelia AVP geno mutacijos, anatominiai pogumburio ar kankorėžinės liaukos pakitimai, infekcijos, onkologiniai, autoimuniniai procesai, infiltracinės galvos smegenų ligos. Nefrogeninį necukrinį diabetą sukelia mutacijos, kurių poveikyje sintetinami nefunkcionalūs vazopresino receptoriai ar akvaporinų baltymai, arba tam tikrų vaistų (amfotericino, cisplatinos, ciklofosfamido, ličio ir kt.) vartojimas lėtinio inkstų nepakankamumo metu, sergant policistine inkstų liga. Centrinio necukrinio diabeto gydymas iš esmės nepasikeitė – pagrindinis vaistas yra desmopresinas. Nefrogeninis necukrinis diabetas gydomas dieta, ribojančia natrio kiekį, skiriama tiazidinių diuretikų, amilorido ir nesteroidinių vaistų nuo uždegimo. Literatūroje daugėja informacijos apie galimą fosfodiesterazės inhibitorių, statinų, prostaglandinų, metformino panaudojimą, tačiau reikalingi tolesni išsamesni tyrimai, kurie patvirtintų jų efektyvumą klinikinėje praktikoje.
... Establishing the presence of hypotonic polyuria is the essential irst step, as 15% of referral cases have normal urine volume; urinary frequency, secondary to infection, prostatism, or irritable bladder, is often misdiagnosed as polyuria (32). The clinical de initions of polyuria are inconsistent in the literature; polyuria has been de ined on 24-hour urine collection as urine output in excess of 50 mL/kg body weight in adults (33) and has also been arbitrarily de ined as >3 L/day (34). These de initions are widely different, and re lect the lack of a consensus statement from the endocrine societies on the diagnosis of diabetes insipidus. ...
Central diabetes insipidus (CDI) is a clinical syndrome which results from loss or impaired function of vasopressinergic neurones in the hypothalamus/posterior pituitary, resulting in impaired synthesis and/or secretion of arginine vasopressin (AVP). AVP deficiency leads to the inability to concentrate urine and excessive renal water losses, resulting in a clinical syndrome of hypotonic polyuria with compensatory thirst. CDI is caused by diverse aetiologies, although it typically develops due to neoplastic, traumatic or autoimmune destruction of AVP synthesizing/secreting neurones.
This review focuses on the diagnosis and management of CDI, providing insights into the physiological disturbances underpinning the syndrome. Recent developments in diagnostic techniques, particularly the development of the copeptin assay, have improved accuracy and acceptability of the diagnostic approach to the hypotonic polyuria syndrome. We discuss the management of CDI with particular emphasis on management of fluid intake and pharmacological replacement of AVP. Specific clinical syndromes such as adipsic diabetes insipidus and diabetes insipidus in pregnancy as well as management of the perioperative patient with diabetes insipidus are also discussed.
... Establishing the presence of hypotonic polyuria is the essential irst step, as 15% of referral cases have normal urine volume; urinary frequency, secondary to infection, prostatism, or irritable bladder, is often misdiagnosed as polyuria (32). The clinical de initions of polyuria are inconsistent in the literature; polyuria has been de ined on 24-hour urine collection as urine output in excess of 50 mL/kg body weight in adults (33) and has also been arbitrarily de ined as >3 L/day (34). These de initions are widely different, and re lect the lack of a consensus statement from the endocrine societies on the diagnosis of diabetes insipidus. ...
Hyponatremia is the most common electrolyte disturbance seen in clinical practice, affecting up to 30% of acute hospital admissions, and is associated with significant adverse clinical outcomes. Acute or severe symptomatic hyponatremia carries a high risk of neurological morbidity and mortality. In contrast, chronic hyponatremia is associated with significant morbidity including increased risk of falls, osteoporosis, fractures, gait instability and cognitive decline, prolonged hospital admissions and aetiology-specific increase in mortality.
In this ‘Approach to the patient’ we review and compare the current recommendations, guidelines and literature for diagnosis and treatment options for both acute and chronic hyponatremia, illustrated by two illustrative case studies. Particular focus is concentrated on the diagnosis and management of the syndrome of inappropriate antidiuresis. An understanding of the pathophysiology of hyponatremia, along with a synthesis of the duration of hyponatremia, biochemical severity, symptomatology, and blood volume status, forms the structure to guide the appropriate and timely management of hyponatremia.
We present 2 illustrative cases which represent common presentations with hyponatremia and discuss the approach to management of these and other causes of hyponatremia.
... Both nephrogenic and CDI will have urine osmolarity below 300 mosm/kg after water deprivation. 13 Although the indirect water deprivation test was not officially performed for this patient, after fourteen hours of fasting, she was noted to have urine osmolarity of 93 mosm/kg. The response to desmopressin differentiates nephrogenic DI and CDI. ...
Postoperative polyuria due to diabetes insipidus (DI) is commonly reported complication of pituitary surgery. However, central DI postabdominal surgery is rare and related to unmasking of pre‐existing DI or prolonged surgery with significant intraoperative blood loss. A thorough workup needs to be performed to exclude central DI in such patients. Diabetes insipidus due to posterior pituitary insufficiency should be a crucial differential diagnosis in postoperative polyuria. Although commonly reported in pituitary surgeries, it can occur in prolonged abdominal surgeries as well.
... Para aquellas situaciones intermedias en las que todavía no pueda diferenciarse entre DIC y polidipsia primaria, puede plantearse la realización de un test salino hipertónico al 3%. De esta forma, si la cifra de copeptina es mayor de 4,9 pmol/L con una natremia ≥150 mEq/L, el diagnóstico de polidipsia primaria es altamente probable (3,11,12) . También se está trabajando en el establecimiento de puntos de corte tras test de estímulo con arginina: Este test parece ser más sencillo de implementar y con menos efectos adversos que el test salino hipertónico. ...
Diabetes insípida. Enfoque diagnóstico y terapéutico Diabetes insipidus. Diagnostic and therapeutic approach Resumen La diabetes insípida es un trastorno del metabolismo del agua caracterizado por la presencia de poliuria y polidipsia, que se clasifica en central (DIC) o nefrogé-nica (DIN) en función de si existe alteración en la sínte-sis o en la acción de la hormona vasopresina. Se trata de una enfermedad rara con mayor prevalencia de la DIC que de la DIN. Tanto en la DIC como en la DIN podemos observar etiología genética y adquirida. El diagnóstico diferencial se plantea fundamentalmente con la polidipsia primaria. Desde el punto de vista bio-químico, la DI se caracteriza por Na ≥145 mEq/L, os-molaridad sanguínea ≥295 mOsm/kg y osmolaridad urinaria <300 mOsm/kg. En ocasiones, es necesario recurrir al test de restricción hídrica para poder acla-rar el diagnóstico. La determinación basal del péptido copeptina puede resultar de utilidad en el diagnóstico diferencial de la diabetes insípida. La realización de RM craneal y del área hipotálamo-hipofisaria valoran-do el tamaño del tallo hipofisario es mandatorio en pa-cientes con DIC, tanto para el diagnóstico como para el seguimiento posterior. Los estudios genéticos se centrarán en pacientes con antecedentes familiares y en formas idiopáticas de inicio temprano. El pilar del tratamiento de la DIC lo constituye la desmopresina en sus distintas formas de presentación. Abstract Diabetes insipidus is a water metabolism disorder characterized by the presence of polyuria and polydip-sia. It is classified as central (DIC) or nephrogenic (DIN) depending on whether there is a disturbance in the synthesis or action of the hormone vasopressin. It is a rare disease with higher prevalence of DIC compared to DIN. In both DIC and DIN we can observe genetic and acquired etiology. The differential diagnosis is mainly raised with primary polydipsia. From a biochemical point of view, DI is characterized by Na ≥145 mEq/L, serum osmolarity ≥295 mOsm/kg, and urine osmolarity <300 mOsm/kg. Sometimes, it is necessary to perform a water deprivation test to clarify the diagnosis. Baseline determination of copeptin may be useful in the differential diagnosis of diabetes insipi-dus. Brain and hypothalamic area MRI assessing the size of the pituitary stalk is mandatory in patients with DIC at the time of diagnosis and for the subsequent follow-up. Genetic studies will focus on patients with a family history and patients with idiopathic early-onset clinical presentation. The mainstay of DIC treatment is desmopressin in its different forms of presentation. Introducción La diabetes insípida (DI) es un trastorno del metabolis-mo del agua caracterizado por un incremento notable de la diuresis (poliuria) junto con una disminución de la capacidad de concentración de la orina (hipostenuria) que como consecuencia produce un aumento considerable de la ingesta hídrica (polidipsia) (1-3). Cuando se evidencia un volumen urinario superior a 2 L/m 2 /24 horas a cualquier edad hablamos de poliuria. A continuación, se muestran otros criterios de poliuria en función de la edad: a. >150 mL/kg/día en el periodo neonatal; b. >100-110 mL/kg/día hasta los dos años; c. >40-50 mL/kg/día a partir de los dos años (2). Tras la exclusión de trastornos de la diuresis osmótica, como la diabetes mellitus, el diagnóstico diferencial de la DI comprende formas primarias y secundarias de poliuria. Dentro de las formas primarias nos encon-tramos la DI central (DIC) y la DI nefrogénica (DIN). La DIC es debida a una alteración de la síntesis y/o secreción de la hormona arginina vasopresina (AVP) en el sistema hipotálamo-neurohipófisis en respuesta a un incremento de la osmolaridad. A diferencia de la
... The response to DDAVP differentiates nephrogenic and central DI. After DDAVP, urine osmolality will increase >50% for CDI and <50% for NDI [25]. However, the indirect water deprivation test is limited due to its 70% diagnostic accuracy [1]. ...
Diabetes insipidus (DI) is an endocrine condition involving the posterior pituitary peptide hormone, antidiuretic hormone (ADH). ADH exerts its effects on the distal convoluted tubule and collecting duct of the nephron by upregulating aquaporin-2 channels (AQP2) on the cellular apical membrane surface. DI is marked by expelling excessive quantities of highly dilute urine, extreme thirst, and craving for cold water. The two main classifications of DI are central diabetes insipidus (CDI), characterized by a deficiency of the posterior pituitary gland to release ADH, and nephrogenic diabetes insipidus (NDI), characterized by the terminal distal convoluted tubule and collecting duct resistance to ADH. The two less common classifications include dipsogenic DI, characterized by excessive thirst due to a low osmotic threshold, and gestational DI, characterized by increased concentration of placental vasopressinase during pregnancy. Treatment of DI is dependent on the disease classification, but severe complications may arise if not tended to appropriately. The most important step in symptom management is maintaining fluid intake ahead of fluid loss with emphasis placed on preserving the quality of life. The most common treatment of CDI and gestational DI is the administration of synthetic ADH, desmopressin (DDAVP). Nephrogenic treatment, although more challenging, requires discontinuation of medications as well as maintaining a renal-friendly diet to prevent hypernatremia. Treatment of dipsogenic DI is mainly focused on behavioral therapy aimed at regulating water intake and/or administration of antipsychotic pharmaceutical therapy. Central and nephrogenic subtypes of DI share a paradoxical treatment in thiazide diuretics.
... Central diabetes insipidus (CDI) is characterized by the insufficient synthesis or inadequate secretion of arginine vasopressin (AVP; also called antidiuretic hormones or ADHs), resulting in varying degrees of polyuria [4]. AVP is a neuropeptide produced by magnocellular neurons of the paraventricular and supraoptic nuclei [5]. ...
Damage to the hypothalamus may result from direct surgical injury or from hemorrhage and ischemia caused by the procedure. Patients with hypothalamus damage can be comatose and exhibit hyperthermia. Here, we present a patient whose hypothalamus was directly damaged by a drainage catheter. His clinical manifestations included diabetes insipidus, hyperthermia and adrenocorticotropic hormone (ACTH) deficiency. The patient was a 48-year-old male and had a body weight of 95 kg. He was admitted to the hospital on August 31, 2019 for memory impairment and nonspecific dizziness that persisted for four months. A magnetic resonance image of the head showed an intraventricular mass attached to the anterior third of the septum pellucidum and Monro's foramen and enlargement of the left lateral ventricle. This intraventricular cystic tumor was 1.9 cm in diameter, without gadolinium enhancement. The tumor resection was performed without complications and with less bleeding than expected. The patient developed central diabetes insipidus within just two hours after the operation and presented with hyperthermia within six hours after the operation. ACTH deficiency was evident on day 1 after surgery. After we removed the catheter 19 hours after the operation, the patient never developed polyuria or high fever again. Two months later, his ACTH level was normal and never needed to take prednisone again. This unusual complication should be taken into account in patients who need external ventricular drains. Much attention should be paid to ensure that the length of the drainage catheter beneath the brain surface does not exceed 5 cm.
Objetivo: determinar la prevalencia de Gingivitis en pacientes diabéticos del hospital IEES período diciembre 2022- febrero 2023. Método: Descriptiva observacional. Resultados y conclusión: Se encontró una prevalencia del 98,6% de gingivitis en los pacientes analizados. Asimismo, se determinó que la hemoglobina glicosilada si tiene que ver con la presencia de gingivitis. Existiendo una prevalencia del 51,6% en mujeres y el 48,3% en hombres, siendo más frecuente en mujeres. Se evidencia que el 10% de mayores de 65 años presentan gingivitis y el 90% menores de 65 años presentan gingivitis.
The impacts of natural plant extracts, including Lycium barbarum polysaccharides (LBP), mulberry leaf flavonoids (MLF), and ginkgo leaf flavonoids (GLF), on high glucose (HG)-induced injury in HBZY-1 mesangial cells were analyzed. LBP, MLF, and GLF were individually extracted, and their purities were determined. HBZY-1 cells cultured in low glucose (LG) served as the Normal group (NG), while HG culture represented the HG group. Subsequently, HBZY-1 cells in the HG group were treated with 300 μ g/mL of LBP, MLF, and GLF, resulting in the HG+LBP, HG+MLF, and HG+GLF groups, respectively. Cell viability (CV) was assessed using the MTT assay, and cellular morphological changes were observed through HE staining. Meanwhile, lactate dehydrogenase (LDH) and nitric oxide (NO) levels were examined using the microplate method. Furthermore, malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) levels were detected by ELISA. mRNA levels in IL-6, IL-1 β , and TNF- α were assessed using real-time quantitative polymerase chain reaction (rt-qPCR), and Collagen IV was examined using immunofluorescence. The results revealed that the polysaccharide content in the LBP extract was 63.57%, the flavonoid contents in the MLF and GLF extracts were 55.40% and 48.62%, respectively. Based on the NG group, HG group exhibited decreased CV, increased LDH and MDA, decreased NO, SOD, and GSH-Px, elevated mRNA levels in IL-6, IL-1 β , and TNF- α , and reduced Collagen IV, showing great differences ( P < 0.05). Based on the HG group, the HG+LBP, HG+MLF, and HG+GLF groups demonstrated increased CV, decreased LDH and MDA levels, increased NO, SOD, and GSH-Px levels, decreased mRNA levels in IL-6, IL-1 β , and TNF- α , and increased Collagen IV, presenting obvious differences ( P < 0.05). Comparing to the HG+LBP group, the HG+MLF and HG+GLF groups exhibited enhanced CV, downshifted LDH and MDA, elevated NO, SOD, and GSH-Px, downregulated mRNA in IL-6, IL-1 β , and TNF- α , and increased Collagen IV ( P < 0.05). No significant changes in CV, LDH, MDA, NO, SOD, GSH-Px, IL-6, IL-1 β , TNF- α , or Collagen IV were observed in the HG+MLF and HG+GLF groups to the NG group ( P >0.05). In conclusion, natural plant extracts such as LBP, MLF, and GLF exerted protective effects against injury in HBZY-1 mesangial cells caused by HG and possessed significant anti-inflammatory, antioxidant stress, and antifibrotic damage properties.
Aim
The liver is an important metabolic organ that governs glucolipid metabolism, and its dysfunction may cause non‐alcoholic fatty liver disease, type 2 diabetes mellitus, dyslipidaemia, etc. We aimed use systematic investigation of the key factors related to hepatic glucose metabolism, which may be beneficial for understanding the underlying pathogenic mechanisms for obesity and diabetes mellitus.
Materials and methods
Oral glucose tolerance test (OGTT) phenotypes and liver transcriptomes of BXD mice under chow and high‐fat diet conditions were collected from GeneNetwork. QTL mapping was conducted to pinpoint genomic regions associated with glucose homeostasis. Candidate genes were further nominated using a multi‐criteria approach and in vitro validated to confirm their functional relevance.
Results
Our results showed that plasma glucose levels in the oral glucose tolerance test were significantly affected by both diet and genetic background. To identify further the candidate genes associated with hepatic glucose metabolism, the results revealed nine genetic regulating loci on chromosomes 1, 4, 7 and 11, respectively, by quantitative trait loci mapping. Moreover, TEA Domain Transcription Factor 1 (TEAD1), myosin VIIA (MYO7A) and NADH:ubiquinone oxidoreductase subunit C2 (NDUFC2) were identified as the candidate functional genes. Functionally, siRNA‐mediated TEAD1, MYO7A and NDUFC2 significantly decreased glucose uptake. Reverse transcription‐polymerase chain reaction assays confirmed that the downregulation of those three candidates inhibited the transcription of genes related to insulin and glucose metabolism pathways.
Conclusions
Our study contributes novel insights to the understanding of hepatic glucose metabolish, demonstrating the impact of TEAD1, MYO7A and NDUFC2 on mitochondrial function in the liver and their regulatory role in maintaining in glucose homeostasis.
This study investigates the application effectiveness of combined serum C-peptide and glycated hemoglobin testing in the clinical diagnosis of diabetes. The research involved 80 diabetic patients treated at our hospital between January 2022 and January 2023, meeting the inclusion criteria. Additionally, 80 individuals undergoing health examinations during the same period constituted the healthy control group. Blood glucose indicators were measured in both groups, and complications were recorded. Serum C-peptide and glycated hemoglobin were individually and jointly tested, with an analysis of sensitivity, specificity, and other diagnostic indicators for diabetes. General participant data in the patient and healthy control groups were comparable ( P > 0.05). In the patient group, C-peptide (C-PR), fasting blood glucose (FBG), and 2-hour postprandial blood glucose (2 h PBG) levels were higher than those in the control group, while glycated hemoglobin (HbA1c) levels were lower ( P < 0.05). Those in the patient group with low C-PR levels and HbA1c levels >7.5% showed a higher incidence of complications ( P < 0.05). The combined test of serum C-peptide and glycated hemoglobin in the patient group demonstrated higher accuracy, sensitivity, and specificity compared to individual diagnostic tests ( P < 0.05). The combined test proves to be effective in the clinical diagnosis of diabetes, offering elevated accuracy, sensitivity, and specificity compared to singleindicator testing. This approach bears substantial clinical significance.
The liver is an important metabolic organ that governs glucolipid metabolism, and its dysfunction may cause Non-alcoholic fatty liver disease, type 2 diabetes mellitus, dyslipidemia, etc. Systematic investigation of the key factors related to hepatic glucose metabolism may be beneficial for understanding the underlying pathogenic mechanisms for obesity and diabetes mellitus. Here, we quantified oral glucose tolerance test (OGTT) phenotypes and liver transcriptomes in BXD mice under chow and high-fat diet conditions. Our results demonstrated that plasma glucose levels in OGTT were significantly affected by both diet and genetic background. To further identify the candidate genes associated with hepatic glucose metabolism, and the results revealed 9 genetic regulating loci on chromosomes 1, 4, 7 and 11, respectively by QTL mapping. Moreover, TEAD1, MYO7A and NDUFC2 were identified as the candidate functional genes. Functionally, siRNA-mediated TEAD1, MYO7A and NDUFC2 significantly decreased the glucose uptake. RT-PCR assays confirmed that the down-regulation of those three candidates inhibited the transcription of genes related to insulin and glucose metabolism pathways. Consequently, our study uncovered the role of TEAD1, MYO7A and NDUFC2 that influenced the mitochondrial function in to regulate glucose homeostasis and provided novel targets for the diagnosis, treatment, and prognosis of glucose metabolism-related diseases.
Antidiuretic hormone is released by the pituitary gland, and is responsible for regulating water absorption at the distal nephron level, specifically in the renal collecting tubule. This occurs by binding to its type 2 receptor which generates the induction of aqueous channels towards the basolateral membrane of the main cells of the kidney. When diabetes insipidus occurs, patients have a state of decreased secretion or peripheral resistance of this hormone in its receptor, so that water is not reabsorbed, it is abundantly eliminated and this generates hydroelectrolyte imbalances. This article will review the biology of the antidiuretic hormone, physiology, hydroelectrolytic alterations and based on the understanding of the altered mechanisms, its association with the management of diabetes insipidus.
Insulin is one of the most important drugs in the clinical treatment of diabetes. There is growing interest in oral insulin administration as it mimics the physiological pathway and potentially reduces side effects associated with subcutaneous injection. In this study, a nanoparticulate system was developed using acetylated cashew gum (ACG) and chitosan by the polyelectrolyte complexation method, for oral administration of insulin. The nanoparticles were characterized by size, zeta potential and encapsulation efficiency (EE%). And they had a particle size of 460 ± 11.0 nm, PDI of 0.2 ± 0.021, zeta potential of 30.6 ± 0.48 mV, and an EE% of 52.5 %. Cytotoxicity assays were performed for HT-29 cell lines. It was observed that ACG and nanoparticles did not have a significant effect on cell viability, verifying their biocompatibility. Hypoglycemic effects of the formulation were analyzed in vivo, noting that the nanoparticles reduced blood glucose by 51.0 % of baseline levels after 12 h, not inducing signs of toxicity or death. Biochemical and hematological profiles were not clinically modified. Histological study indicated no signs of toxicity. Results showed that the nanostructured system presented itself as a potential vehicle for oral insulin release.
Serum sodium disorders are generally a marker of water balance in the body. Thus, hypernatremia is most often caused by an overall deficit of total body water. Other unique circumstances may lead to excess salt, without an impact on the body's total water volume. Hypernatremia is commonly acquired in both the hospital and community. As hypernatremia is associated with increased morbidity and mortality, treatment should be initiated promptly. In this review, we will discuss the pathophysiology and management of the main types of hypernatremia, which can be categorized as either a loss of water or gain of sodium that can be mediated by renal or extrarenal mechanisms.
Aim:
To investigate the relationship of the lipoprotein(a), albuminuria, myostatin with sarcopenia in elderly patients with type 2 diabetes (T2D).
Methods:
A total of 461 elderly patients with T2D who were admitted to our hospital were selected as the research subjects. There were 34 cases in line with Asian sarcopenia diagnosis (group A), and 427 patients had no such symptoms as the control group (group C). The levels of lipoprotein(a), albuminuria, myostatin in each group were compared, and the effect factors of muscle loss in elderly patients with T2D were analyzed by univariate/multivariate logistic regression.
Results:
The incidence of sarcopenia in 461 elderly patients with T2D in this study was 7.37 % (34/461). However, the levels of appendicular skeletal muscle mass index (ASMI, kg/m2), albumin and epidermal growth factor receptor (eGFR) in group A were lower than those in group C (P < 0.05). The levels of lipoprotein(a), albuminuria, myostatin in group A were higher those in group C (P < 0.05). Additionally, group A had a higher morbidity in diabetic retinopathy and neuropathy. Univariate logistic regression analysis revealed that the risk factors of muscle loss are ASMI, lipoprotein(a), albuminuria, myostatin, diabetic retinopathy and neuropathy. Multivariate Logistic regression analysis showed that the risk factors of muscle loss in elderly patients with T2D were lipoprotein(a), albuminuria, myostatin and diabetic neuropathy.
Conclusion:
The lipoprotein(a), albuminuria, myostatin and diabetic neuropathy are closely related to the occurrence and development of muscle loss in elderly patients with T2D.
Nephrogenic diabetes insipidus is defined as an inability to concentrate urine due to a complete or partial alteration of the renal tubular response to arginine vasopressin hormone, resulting in excessive diluted urine excretion. Hereditary forms are caused by molecular defects in the genes encoding either of the two main renal effectors of the arginine vasopressin pathway: the AVPR2 gene, which encodes for the type 2 vasopressin receptor, or the AQP2 gene, which encodes for the water channel aquaporin-2. About 90% of cases of nephrogenic diabetes insipidus result from loss-of-function variants in the AVPR2 gene, which are inherited in a X-linked recessive manner. The remaining 10% of cases result from loss-of-function variants in the AQP2 gene, which can be inherited in either a recessive or a dominant manner. The main symptoms of the disease are polyuria, chronic dehydration and hypernatremia. These symptoms usually occur in the first year of life, although some patients present later. Diagnosis is based on abnormal response in urinary osmolality after water restriction and/or administration of exogenous vasopressin. Treatment involves ensuring adequate water intake on demand, possibly combined with thiazide diuretics, non-steroidal anti-inflammatory drugs, and a low-salt and protein diet. In this review, we provide an update on current understanding of the molecular basis of inherited nephrogenic insipidus diabetes.
Background
Diabetes is a common metabolic disease that is associated with gut microbiota dysbiosis and iron metabolism. Salidroside (SAL) is the main ingredient of the traditional Chinese herb Rhodiola, previous studies have shown that SAL could reshape the gut microbiota and limit iron accumulation. Therefore, it is possible that SAL can act as an alternative therapy for diabetes, and its underlying mechanism is worth exploring.
Methods
SAL was used to treat diabetic db/db mice. Serum glucose and iron levels and the histopathology of myocardial fibres were evaluated. The gut microbiota composition was determined by 16S rRNA Illumina sequencing technology.
Results
Treatment with SAL significantly reduced blood glucose and ameliorated diabetic cardiomyopathy in diabetic db/db mice, which was accompanied by inhibited ferroptosis and iron accumulation. Furthermore, the 16S rRNA sequencing results showed that SAL induced a change in the gut microbiota composition. Overall, SAL could increase the proportion of probiotic bacteria and decrease Lactobacillus to improve gut microbiota. Specifically, SAL increased the ratio of Bacteroidetes to Firmicutes in diabetic mice. The most significant biomarker was the genus Lactobacillus between the MD group and the SAL group. In addition, COG and KEGG analyses suggested that SAL mainly participated in nutrient metabolism, among them iron metabolism was associated with the abundance of Lactobacillus.
Conclusions
SAL could reduce the glucose level and protect against diabetic cardiomyopathy in diabetic mice, which might be mediated by the change in the gut microbiota and the regulation of iron metabolism. The findings suggested that SAL was a promising complementary option for diabetes therapy.
Objective
This study provided a rough estimate incidence of primary pediatric central diabetes insipidus (CDI) and examines the diagnostic factors between pediatric CDI and primary polydipsia (PP).
Methods
We collected 27 patients with chief complaints of polyuria and/or polydipsia from January 2014 to December 2018 in the Department of Pediatrics, Our University Hospital.
Results
We diagnosed type 1 diabetes mellitus (T1DM) in 16 patients, CDI in 5, PP in 5, and nocturnal enuresis in 1. The rough estimate incidence rate of pediatric CDI was 0.71/100,000/year. The diagnostic factors were a body mass index (BMI), urine gravity in the morning, urine volume and intake volume over 24 h, and bright spots in the posterior pituitary in a magnetic resonance image (MRI). The cutoff value of urine gravity in the morning for CDI was <1.010, with a sensitivity of 100 % and specificity of 100 %. The cutoff value of urine volume over 24 h for CDI was >2299 mL/m², with a sensitivity of 100 % and specificity of 85.7 %. No pediatric CDI patients had the bright spot in the posterior pituitary of their MRI, using a type 1–weighted image; however, only 1 out of 4 PP patients did not show the bright spot.
Conclusion
The rough estimate incidence of pediatric CDI with polydipsia and polyuria under the limited condition was 0.71/100,000/year, which was very low. Distinguishable factors between CDI patients and PP patients were BMI, urine and intake volumes over 24 h, and a bright spot on an MRI. Further studies with multiple institutes and more patients are required to confirm these findings.
Optimal fluid management is a cornerstone of pediatric neuroanesthesia. The primary aims of fluid therapy in pediatric neurosurgery are to maintain euvolemia and hemodynamic stability while avoiding dyselectrolytemia and imbalances in glucose and metabolic homeostasis. Hypervolemia, hypovolemia, dyselectrolytemia, and metabolic derangement can lead to significant morbidities in children. Fluid management requires careful consideration of the preoperative hydration and electrolyte status of the child, the nature of the surgery, potential for major blood loss, the need for osmotic diuretics, and the overall fluid balance. Isotonic crystalloids are the mainstay of fluid therapy in pediatric neurosurgical procedures. Intraoperative supplementation of dextrose-containing fluids is only required in some special circumstances. The volume and choice of osmotic fluids are guided by the specific needs of the surgery, institutional practice, and hemodynamic and biochemical parameters of the child.
Red blood cell (RBC) transfusions are a frequent intervention in critically ill patients, including those with traumatic brain injury. Indeed, anemia is frequent in these patients and is associated with an increased risk of poor outcome; transfusions are often given to try and improve oxygen delivery and tissue oxygenation. The pathophysiology of anemia in patients with traumatic brain injury is multifactorial, including primary blood loss because of bleeding and secondary loss related to minor procedures or phlebotomy, hemodilution secondary to fluid resuscitation, and altered RBC production. The aim of RBC transfusion in patients with traumatic brain injury is essentially to increase cerebral oxygenation, but it is not clear whether RBC transfusion has a beneficial effect on oxygenation in patients with moderate anemia. Moreover, complications of transfusion, including transfusion-associated circulatory overload and transfusion-related acute lung injury, may offset its potential benefits. The optimal hemoglobin level that could be used to trigger RBC transfusion in patients with traumatic brain injury is undefined. In this chapter, we summarize recent data on the effects of anemia and RBC transfusion on cerebral oxygenation and on outcomes in patients with traumatic brain injury and suggest how best to optimize transfusion management in these patients.
Diabetes insipidus (DI) is a disorder characterized by excretion of large amounts of hypotonic urine. Central DI results from a deficiency of the hormone arginine vasopressin (AVP) in the pituitary gland or the hypothalamus, whereas nephrogenic DI results from resistance to AVP in the kidneys. Central and nephrogenic DI are usually acquired, but genetic causes must be evaluated, especially if symptoms occur in early childhood. Central or nephrogenic DI must be differentiated from primary polydipsia, which involves excessive intake of large amounts of water despite normal AVP secretion and action. Primary polydipsia is most common in psychiatric patients and health enthusiasts but the polydipsia in a small subgroup of patients seems to be due to an abnormally low thirst threshold, a condition termed dipsogenic DI. Distinguishing between the different types of DI can be challenging and is done either by a water deprivation test or by hypertonic saline stimulation together with copeptin (or AVP) measurement. Furthermore, a detailed medical history, physical examination and imaging studies are needed to ensure an accurate DI diagnosis. Treatment of DI or primary polydipsia depends on the underlying aetiology and differs in central DI, nephrogenic DI and primary polydipsia.
Background
Several studies have investigated copeptin as a prognostic marker of different acute diseases and as a diagnostic marker in disorders of water and salt homeostasis. However, no data of the normal circadian rhythm of copeptin in healthy subjects are available.
Aim
To investigate the circadian rhythm of copeptin in healthy subjects under standardized conditions.
Methods
19 healthy volunteers aged 18 to 53 years, male and female, were studied in a prospective observational study. In all 19 participants, blood samples for copeptin were taken in regular intervals of 30 minutes for 24 hours after a fasting period of minimum 8 hours.
Results
The mean values of copeptin showed a circadian rhythm, similar to that described for AVP release, with a trend towards higher levels (5.9 ± 1 pmol/L) at night and early morning between 4 am and 6 am and lowest levels (2.3 ± 0.2 pmol/L) in the late afternoon between 5 pm and 7 pm. This finding was only observed in individuals with initial higher copeptin levels, whereas in individuals with lower basal copeptin levels no circadian rhythm was observed.
Conclusion
There is evidence for a circadian rhythm in copeptin release during 24 hours, however, of minor extent. These findings suggest that copeptin levels can be determined irrespectively of the time of the day.
PurposeThis publication reviews the accepted knowledges and the findings still discussed on several features of autoimmune hypophysitis, including the most recently described forms, such as IgG4 and cancer immunotherapy- related hypophysitis. Methods
The most characteristic findings and the pending controversies were derived from a literature review and previous personal experiences. A single paragraph focused on some atypical examples of the disease presenting under confounding pretences. ResultsHeadache, visual field alterations and impaired pituitary secretion are the most frequent clinical findings of the disease. Pituitary biopsy, still considered the gold diagnostic standard, does not always receive consent from the patients. The role of magnetic resonance imaging is limited, as this disease may generate images similar to those of other diseases. The role of antipituitary and antihypothalamus antibodies is still discussed owing to methodological difficulties and also because the findings on the true pituitary antigen(s) are still debated. However, the low sensitivity and specificity of immunofluorescence, one of the more widely employed methods to detect these antibodies, may be improved, considering a predetermined cut-off titre and a particular kind of immunostaining. Conclusion
Autoimmune hypophysitis is a multifaceted disease, which may certainly be diagnosed by pituitary biopsy. However, the possible different clinical, laboratory and imaging features must be considered by the physician to avoid a misdiagnosis when examining a possibly affected patient. Therapeutic choice has to be made taking into account the clinical conditions and the degree of hypothalamic-pituitary involvement, but also considering that spontaneous remissions can occur.
Healthy kidneys maintain fluid and electrolyte homoeostasis by adjusting urine volume and composition according to physiological needs. The final urine composition is determined in the last tubular segment: the collecting duct. Water permeability in the collecting duct is regulated by arginine vasopressin (AVP). Secretion of AVP from the neurohypophysis is regulated by a complex signalling network that involves osmosensors, barosensors and volume sensors. AVP facilitates aquaporin (AQP)-mediated water reabsorption via activation of the vasopressin V2 receptor (AVPR2) in the collecting duct, thus enabling concentration of urine. In nephrogenic diabetes insipidus (NDI), inability of the kidneys to respond to AVP results in functional AQP deficiency. Consequently, affected patients have constant diuresis, resulting in large volumes of dilute urine. Primary forms of NDI result from mutations in the genes that encode the key proteins AVPR2 and AQP2, whereas secondary forms are associated with biochemical abnormalities, obstructive uropathy or the use of certain medications, particularly lithium. Treatment of the disease is informed by identification of the underlying cause. Here we review the clinical aspects and diagnosis of NDI, the various aetiologies, current treatment options and potential future developments.
The polyuria-polydipsia syndrome comprises primary polydipsia (PP) and central and nephrogenic diabetes insipidus (DI). Correctly discriminating these entities is mandatory, since inadequate treatment causes serious complications. The diagnostic "gold standard" is the water deprivation test with assessment of arginine vasopressin (AVP) activity. However, test interpretation and AVP measurement are challenging.
Evaluate accuracy of copeptin, a stable peptide stoichiometrically co-secreted with AVP, in the differential diagnosis of polyuria-polydipsia syndrome.
Prospective multicenter observational cohort study.
Four Swiss or German tertiary referral centers.
Adults >18 years old with history of polyuria and polydipsia.
Standardized combined water deprivation/3% saline infusion test, terminated when serum sodium exceeded 147 mmol/L; circulating copeptin and AVP levels; final diagnosis based on water deprivation/saline infusion test results, clinical information, and treatment response.
Fifty-five patients were enrolled (11 complete central DI, 16 partial central DI, 18 PP, 10 nephrogenic DI). Without prior thirsting, a single baseline copeptin level >21.4 pmol/L differentiated nephrogenic DI from other etiologies with 100% sensitivity and specificity, rendering water deprivation testing unnecessary in such cases. Stimulated copeptin >4.9 pmol/L (at sodium levels >147 mmol/L) differentiated between patients with PP and patients with partial central DI with 94.0% specificity and 94.4% sensitivity; stimulated AVP >1.8 pg/ml differentiated between these same categories with 93.0% specificity and 83.0% sensitivity.
Incorporation bias from including AVP levels as a diagnostic criterion.
Copeptin is a promising new tool in the differential diagnosis of the polyuria-polydipsia syndrome, and a valid surrogate marker for AVP. Primary funding sources: Swiss National Science Foundation, University of Basel.
Context:
Central diabetes insipidus (CDI) is considered idiopathic in 20% to 50% of affected subjects.
Objective:
The purpose of this study was to determine whether a systematic diagnostic workup could achieve better etiologic diagnosis in children and adolescents presenting with polyuria and polydipsia.
Design and setting:
This is a prospective study conducted at a tertiary referral center. Patients underwent clinical and endocrine evaluations every 6 months and neuroimaging every 6 months for 2 years and yearly for 3 years. Endocrine function and neuroimaging were also reassessed after adult height achievement.
Participants:
A total of 85 consecutive patients with CDI were enrolled at a median age of 7.5 years; those with idiopathic CDI were stratified based on pituitary stalk thickness.
Main outcome measures:
To establish the etiology of CDI, we determined the time lag between its onset and the specific diagnosis, the long-term impact on pituitary function, and the overall long-term outcomes.
Results:
Of the subjects, 24 (28.2%) received an etiologic diagnosis at presentation and 11 (13%) within 2.5 years (n = 7 germinomas and n = 4 Langerhans cell histiocytosis), 7 (8.2%) were lost to follow-up, and 43 (50.6%) were considered to have idiopathic disease and were followed until the median age of 17.3 years. Neuroimaging identified 40 of 43 patients with self-limited inflammatory/autoimmune pituitary stalk thickness within the first 6 months, the severity of which was significantly correlated to pituitary dysfunction. The probability of >10-year-survival without an anterior pituitary defect was related to the severity of pituitary stalk thickness, and 53% showed permanent anterior pituitary defects. Three patients developed Langerhans cell histiocytosis and 1 developed Hodgkin lymphoma after a median of 9 and 13 years, respectively.
Conclusions:
A diagnostic etiology was achieved in 96% of patients with CDI. Risk stratification based on the degree of pituitary stalk thickness is of prognostic value for long-term outcomes including permanent pituitary dysfunction. New guidance is provided for the management of these patients.
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.
Posterior pituitary function in patients with suspected diabetes insipidus is usually assessed by a water deprivation test. Alternatively, a nonosmotic stimulus such as hypoglycemia may be used to stimulate vasopressin [arginine vasopressin (AVP)] secretion. Plasma AVP measurement may aid in the diagnosis and, especially, differential diagnosis of diabetes insipidus and polydipsia. However, AVP measurement is cumbersome. Copeptin, the stable C-terminal glycopeptide of the AVP prohormone, is stoichiometrically secreted from the posterior pituitary.
The aim was to study the value of copeptin levels in the diagnosis of diabetes insipidus during insulin-induced hypoglycemia.
A total of 38 patients were studied during insulin-induced hypoglycemia as part of a combined pituitary function test for possible anterior pituitary disease. There were 29 patients who had normal posterior pituitary function, and nine had central diabetes insipidus. Blood sampling was done before and 30, 45, and 90 min after iv insulin injection. Copeptin was measured with a new sandwich immunoassay.
Patients with intact posterior pituitary function had basal copeptin levels of 3.7 +/- 1.5 pm, with a maximal increase to 11.1 +/- 4.6 pm 45 min after insulin injection. Copeptin levels in patients with diabetes insipidus were 2.4 +/- 0.5 pm before insulin injection, with a maximum increase to 3.7 +/- 0.7 pm. Both basal and stimulated copeptin levels were lower in patients with diabetes insipidus as compared with patients with intact posterior pituitary function. A stimulated copeptin level 45 min after insulin injection of less than 4.75 pm had an optimal diagnostic accuracy to detect diabetes insipidus.
Copeptin measurement may be used to assess posterior together with anterior pituitary function during insulin-induced hypoglycemia.
Stress is defined as anything that throws the body out of homeostatic balance; for example an acute illness. Any stressor which activates the hypothalamo-pituitary-adrenal (HPA) axis leads to an increase in concentrations of the adrenal stress hormone, cortisol. One of the major hypothalamic stress hormones, which is stimulated by different stressors, is vasopressin (AVP). However, measurement of circulating AVP levels is challenging because it is released in a pulsatile pattern, it is unstable and is rapidly cleared from plasma. AVP derives from a larger precursor peptide (pre-provasopressin) along with copeptin which is released in an equimolar ratio to AVP and is more stable in the circulation and easy to determine. Copeptin levels were found to closely mirror the production of AVP. We have shown that copeptin more subtly mirrors the individual stress level compared to cortisol. Due to the positive association of copeptin with the severity of illness and outcome, copeptin has been proposed as a prognostic marker in acute illness. The prognostic accuracy of copeptin has been analysed in sepsis, pneumonia, lower respiratory tract infections, stroke and other acute illnesses. Thereby, copeptin was found to accurately mirror disease severity and to discriminate patients with unfavourable outcomes from patients with favourable outcomes. Copeptin improves the prognostic information provided by commonly used clinical scoring instruments. Importantly, interpretation of copeptin levels must always consider the clinical setting. An accurate prognostic assessment has the potential to guide interventions and effectively plan and monitor rehabilitation and, thus optimise the management of individual patients and the allocation of limited health care resources. Future intervention studies must prove the value of copeptin in clinical decision making and in improving the overall medical management of patients with acute illnesses.
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.
Transient polyuria and polydipsia during pregnancy are rare, and their cause is not entirely clear. Possible explanations include the exacerbation of preexisting abnormalities in the secretion or action of vasopressin and abnormally large increases in plasma vasopressinase activity.
We studied two women in whom overt polyuria and polydipsia developed during the third trimester of pregnancy and disappeared after delivery. The secretion and action of vasopressin were studied both when the women had polyuria and polydipsia and later, when their water intake and urine volume were normal.
One patient had partial nephrogenic diabetes insipidus. She had little increase in urine osmolality in response to water deprivation, hypertonic-saline infusion, and vasopressin injection and no response to desmopressin acetate (1-deamino-8-D-arginine vasopressin) during the immediate postpartum period. Her basal and stimulated plasma vasopressin concentrations were high (16.5 to 203.4 pmol per liter) before and during hypertonic-saline infusion 30 months post partum. The other patient had partial neurogenic diabetes insipidus. She had subnormal basal plasma vasopressin concentrations, a subnormal increase in the plasma vasopressin level and a subnormal decrease in urine flow in response to the administration of vasopressin, and a normal response to desmopressin. After pregnancy, when her urine volume was normal, she had no increase in plasma vasopressin in response to hypertonic-saline infusion, but she had a normal rise in the plasma vasopressin level and a normal renal response to vasopressin administration.
Pregnancy may unmask subclinical forms of both nephrogenic and neurogenic diabetes insipidus. This exacerbation may result from both increased vasopressinase activity and diminished renal responsiveness to vasopressin.
A radioimmunoassay has been developed that permits reliable measurements of plasma arginine vasopressin (AVP) at concentrations as low as 0.5 pg/ml in sample volumes of 1 ml or less. Nonhormonal immunoreactivity associated with the plasma proteins is eliminated by acetone precipitation before assay, leaving unaltered a component that is immunologically and chromatographically indistinguishable from standard AVP. Storage of plasma results in a decline in AVP concentration and, thus, must be carefully regulated. The plasma AVP values obtained by our method approximate the anticipated levels and vary in accordance with physiologic expections. In recumbent normal subjects, plasma AVP ranged from (mean +/-SD) 5.4+/-3.4 pg/ml after fluid deprivation to 1.4+/-0.8 pg/ml after water loading, and correlated significantly with both plasma osmolality (r=0.52; P<0.001) and urine osmolality (r=0.77; P<0.001). After fluid restriction, plasma AVP was uniformly normal relative to plasma osmolality in patients with nephrogenic diabetes insipidus and primary polydipsia but was distinctly subnormal in all patients with pituitary diabetes insipidus. The infusion of physiologic amounts of posterior pituitary extract caused a dose-related rise in plasma vasopressin that afterwards declined at the expected rate (t(1/2)=22.5+/-4 min). We conclude that, when used appropriately, our radioimmunoassay method provides a useful way of assessing AVP function in man.
Introduction:
Central diabetes insipidus (CDI) is a frequent complication of pituitary surgery but its diagnosis lacks standardized criteria. Copeptin, a surrogate marker of arginine vasopressin (AVP) release, is triggered by psycho-physical stresses such as pituitary surgery. Low post-operative copeptin could predict CDI onset. The aims of this study were the validation of copeptin as a predictor of post-neurosurgical CDI and the identification of the optimal timing for its determination.
Methods:
Sixty-six consecutive patients operated for a hypothalamic-pituitary lesion were evaluated. Copeptin was determined pre-operatively and at 1, 6, 12, 24 and 48 hours post-extubation. Fifty-eight patients were reassessed after 3-6 months post-surgery to confirm transient (3 cases) or permanent CDI (5 cases) diagnosis.
Results:
A marked copeptin peak was identified at 1 hour after extubation, when a value below or equal to 12.8 pmol/L had a good accuracy in identifying CDI cases (AUC 0.866, 95% CI 0.751 - 0.941). Moreover, a copeptin peak above 4.2 pmol/L excluded permanent forms (AUC 1, 95% CI 0.629 - 1). Regression analysis identified copeptin as the only significant predictor of CDI (OR 0.86, CI 95 % 0.75 - 0.98, p = 0.02). A copeptin T1/T0 ratio below or equal to 1.47 identified patients at risk of isolated biochemical alterations even in absence of an overt CDI.
Conclusions:
A prompt increase of copeptin is expected at 1 hour after extubation. The absence of this peak is a reliable predictor of post-neurosurgical CDI.
Background
Differential diagnosis of diabetes insipidus is challenging. The most reliable approach is hypertonic saline-stimulated copeptin measurements. However, this test is based on the induction of hypernatraemia and requires close monitoring of plasma sodium concentrations. Arginine-stimulated copeptin measurements might provide an alternative, simple, and safe test.
Methods
In this prospective diagnostic study, we recruited a development cohort from University Hospital Basel, Basel, Switzerland, and a validation cohort from five centres in Basel, Aarau, Luzern, Bern, and St Gallen, Switzerland, and the University Hospital Würzburg, Würzburg, Germany. For both cohorts, patients were eligible for inclusion if they were aged 18 years or older, were newly referred with polyuria (>50 mL/kg bodyweight per day) or had a known diagnosis of central diabetes insipidus or primary polydipsia. We also recruited a comparator cohort of healthy controls in parallel to each cohort, comprising adults (aged 18 years and older, with normal drinking habits, and no history of polyuria) and children who underwent arginine stimulation to diagnose growth hormone deficiency (children were only included in the comparator cohort to the development cohort as proof of concept). Patients and healthy controls underwent arginine stimulation with measurement of plasma copeptin at baseline and 30, 45, 60, 90, and 120 min. The primary objective in the development cohort was to determine the diagnostic accuracy of plasma copeptin concentrations to discriminate between diabetes insipidus and primary polydipsia, and in the validation cohort was to confirm those results. Adverse effects of the test were monitored in all participants, with tolerability of the test rated using a visual analogue scale (VAS) that ranged from no (0) to maximum (10) discomfort. This trial is registered with ClinicalTrials.gov, number NCT00757276.
Findings
Between May 24, 2013, and Jan 11, 2017, 52 patients were enrolled in the development cohort (12 [23%] with complete diabetes insipidus, nine [17%] with partial diabetes insipidus, and 31 [60%] with primary polydipsia) alongside 20 healthy adults and 42 child controls. Between Oct 24, 2017, and June 27, 2018, 46 patients were enrolled in the validation cohort (12 [26%] with complete diabetes insipidus, seven [15%] with partial diabetes insipidus, and 27 [59%] with primary polydipsia) alongside 30 healthy adult controls (two patients in this cohort were excluded from the main analysis because of early vomiting during the test). In the pooled patient and control datasets, median arginine-stimulated copeptin concentrations increased in healthy adult controls (from 5·2 pM [IQR 3·3–10·9] to a maximum of 9·8 pM [6·4–19·6]) and in participants with primary polydipsia (from 3·6 pM [IQR 2·4–5·7] to a maximum of 7·9 pM [5·1–11·8]), but only minimally in those with diabetes insipidus (2·1 pM [IQR 1·9–2·7] to a maximum of 2·5 pM [1·9–3·1]). In the development cohort, a cutoff of 3·5 pM at 60 min provided the highest diagnostic accuracy of 94% (95% CI 84–98). The accuracy of this cutoff in the validation cohort was 86% (95% CI 73–94). By pooling the data from both cohorts, an optimal accuracy of 93% (95% CI 86–97) was reached at a cutoff of 3·8 pM copeptin at 60 min (sensitivity 93%, 95% CI 86–98; specificity 92%, 95% CI 84–100). The test was safe and well tolerated, with median VAS scores of 3·5 (IQR 2–4) in patients with diabetes insipidus, 3 (2–4) in those with primary polydipsia, 1 (1–3) in healthy adults, and 1 (0–5) in healthy children in the pooled participant dataset.
Interpretation
Arginine-stimulated copeptin measurements are an innovative test for diabetes insipidus with high diagnostic accuracy, and could be a simplified, novel, and safe diagnostic approach to diabetes insipidus in clinical practice.
Funding
Swiss National Science Foundation and University Hospital Basel.
Background
The indirect water-deprivation test is the current reference standard for the diagnosis of diabetes insipidus. However, it is technically cumbersome to administer, and the results are often inaccurate. The current study compared the indirect water-deprivation test with direct detection of plasma copeptin, a precursor-derived surrogate of arginine vasopressin.
Methods
From 2013 to 2017, we recruited 156 patients with hypotonic polyuria at 11 medical centers to undergo both water-deprivation and hypertonic saline infusion tests. In the latter test, plasma copeptin was measured when the plasma sodium level had increased to at least 150 mmol per liter after infusion of hypertonic saline. The primary outcome was the overall diagnostic accuracy of each test as compared with the final reference diagnosis, which was determined on the basis of medical history, test results, and treatment response, with copeptin levels masked.
Results
A total of 144 patients underwent both tests. The final diagnosis was primary polydipsia in 82 patients (57%), central diabetes insipidus in 59 (41%), and nephrogenic diabetes insipidus in 3 (2%). Overall, among the 141 patients included in the analysis, the indirect water-deprivation test determined the correct diagnosis in 108 patients (diagnostic accuracy, 76.6%; 95% confidence interval [CI], 68.9 to 83.2), and the hypertonic saline infusion test (with a copeptin cutoff level of >4.9 pmol per liter) determined the correct diagnosis in 136 patients (96.5%; 95% CI, 92.1 to 98.6; P<0.001). The indirect water-deprivation test correctly distinguished primary polydipsia from partial central diabetes insipidus in 77 of 105 patients (73.3%; 95% CI, 63.9 to 81.2), and the hypertonic saline infusion test distinguished between the two conditions in 99 of 104 patients (95.2%; 95% CI, 89.4 to 98.1; adjusted P<0.001). One serious adverse event (desmopressin-induced hyponatremia that resulted in hospitalization) occurred during the water-deprivation test.
Conclusions
The direct measurement of hypertonic saline–stimulated plasma copeptin had greater diagnostic accuracy than the water-deprivation test in patients with hypotonic polyuria. (Funded by the Swiss National Foundation and others; ClinicalTrials.gov number, NCT01940614.)
Background:
Copeptin is the C-terminal fragment of the arginine vasopressin (AVP) prohormone whose measurement is more robust than that of AVP. Similar release and clearance characteristics have been suggested promoting copeptin as a surrogate marker.
Aim:
To characterize the physiology of osmotically-regulated copeptin release and its half-life in direct comparison to plasma AVP.
Methods:
Ninety-one healthy volunteers underwent a standardized three-phase test protocol including (i) osmotic stimulation into the hypertonic range by hypertonic-saline infusion followed by osmotic suppression via (ii) oral water load and (iii) subsequent glucose infusion. Plasma copeptin, AVP, serum sodium and osmolality levels were measured in regular intervals.
Results:
In phase 1 an increase in median osmotic pressure (289 [286; 291] to 311 [309; 314] mOsm/kgH2O) caused similar release kinetics of plasma copeptin (4 [3.1; 6] to 29.3 [18.6; 48.2] pmol/L) and AVP (1 [0.7; 1.6] to 10.3 [6.8; 18.8] pg/mL). Subsequent osmotic suppression to 298 [295; 301] mOsm/kg at the end of phase 3, revealed markedly different decay kinetics between both peptides - an estimated initial half-life of copeptin being approximately 2-times longer than that of AVP (26 min vs 12 min).
Conclusion:
Copeptin is released in equimolar amounts with AVP in response to osmotic stimulation, suggesting its high potential as an AVP surrogate for differentiation of osmotic disorders. Furthermore, we here describe first time the decay kinetics of copeptin in response to osmotic depression enabling to identify a half-life for copeptin in direct comparison to AVP.
Importance
If not promptly recognized, endocrine dysfunction can be life threatening. The incidence and risk of developing such adverse events (AEs) following the use of immune checkpoint inhibitor (ICI) regimens are unknown.
Objective
To compare the incidence and risk of endocrine AEs following treatment with US Food and Drug Administration–approved ICI regimens.
Data Sources
A PubMed search through July 18, 2016, using the following keywords was performed: “ipilimumab,” “MDX-010,” “nivolumab,” “BMS-963558,” “pembrolizumab,” “MK-3475,” “atezolizumab,” “MPDL3280A,” and “phase.”
Study Selection
Thirty-eight randomized clinical trials evaluating the usage of these ICIs for treatment of advanced solid tumors were identified, resulting in a total of 7551 patients who were eligible for a meta-analysis. Regimens were categorized by class into monotherapy with a PD-1 (programmed cell death protien 1) inhibitor, a CTLA-4 (cytotoxic T-lymphocyte-associated protein-4) inhibitor, or a PD-L1 (programmed cell death 1 ligand 1) inhibitor, and combination therapy with PD-1 plus CTLA-4 inhibitors.
Data Extraction and Synthesis
The data were extracted by 1 primary reviewer (R.B.-S.) and then independently reviewed by 2 secondary reviewers (W.T.B. and A.C.G.-C.) following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Inferences on the incidence of AEs were made using log-odds random effects models.
Main Outcomes and Measures
Incidence of all-grade hypothyroidism, hyperthyroidism, hypophysitis, primary adrenal insufficiency, and insulin-deficient diabetes.
Results
Overall, 38 randomized clinical trials comprising 7551 patients were included in this systematic review and meta-analysis. The incidence of both hypothyroidism and hyperthyroidism was highest in patients receiving combination therapy. Patients on the combination regimen were significantly more likely to experience hypothyroidism (odds ratio [OR], 3.81; 95% CI, 2.10-6.91, P < .001) and hyperthyroidism (OR, 4.27; 95% CI, 2.05-8.90; P = .001) than patients on ipilimumab. Compared with patients on ipilimumab, those on PD-1 inhibitors had a higher risk of developing hypothyroidism (OR 1.89; 95% CI, 1.17-3.05; P = .03). The risk of hyperthyroidism, but not hypothyroidism, was significantly greater with PD-1 than with PD-L1 inhibitors (OR, 5.36; 95% CI, 2.04-14.08; P = .002). While patients who received PD-1 inhibitors were significantly less likely to experience hypophysitis than those receiving ipilimumab (OR, 0.29; 95% CI, 0.18-0.49; P < .001), those who received combination therapy were significantly more likely to develop it (OR, 2.2; 95% CI, 1.39-3.60; P = .001). For primary adrenal insufficiency and insulin-deficient diabetes no statistical inferences were made due to the smaller number of events.
Conclusions and Relevance
Our study provides more precise data on the incidence of endocrine dysfunctions among patients receiving ICI regimens. Patients on combination therapy are at increased risk of thyroid dysfunction and hypophysitis.
Introduction: The normal pituitary bright spot seen on unenhanced T1-weighted magnetic resonance imaging is thought to result from the T1-shortening effect of the vasopressin stored in the posterior pituitary. Individual variations in its size may be difficult to differentiate from pathological conditions resulting in either absence of the pituitary bright spot or in T1-hyperintense lesions of the sella. The objective of this paper was to define a range of normal dimensions of the pituitary bright spot and to illustrate some of the most commonly encountered pathologies that result in absence or enlargement of the pituitary bright spot.
Material and Methods: We selected normal pituitary MRIs from 106 patients. The size of each pituitary bright spot was measured in the longest axis and in the dimension perpendicular to this axis to describe the typical dimensions. We also present cases of patients with pituitary abnormalities to highlight the differences and potential overlap between normal and pathological pituitary imaging.
Results: All of the subjects were found to have pituitary bright spots, and the mean dimensions were 4.8 mm in the long axis and 2.4 mm in the short axis. The dimension of the pituitary bright spot in the long axis decreased with age. The distribution of dimensions of the pituitary bright spot was normal, indicating that 99.7% of patients should have a pituitary bright spot measuring between 1.2 and 8.5 mm in its long axis and between 0.4 and 4.4 mm in its short axis, an interval corresponding to three standard deviations below and above the mean. In cases where the dimension of the pituitary bright spot is outside of this range, pathological conditions should be considered.
Conclusions: The pituitary bright spot should always be demonstrated on T1-weighted MRI, and its dimensions should be within the identified normal range in most subjects. Outside of this range, pathological conditions affecting the pituitary bright spot should be considered.
Advances in the management of traumatic brain injury, subarachnoid haemorrhage and intracranial tumours have led to improved survival rates and an increased focus on quality of life of survivors. Endocrine sequelae of the acute brain insult and subsequent neurosurgery, peri-operative fluid administration and/or cranial irradiation are now well described. Unrecognized acute hypopituitarism, particularly ACTH/cortisol deficiency and diabetes insipidus, can be life-threatening. While hypopituitarism may be transient, up to 30% of survivors of TBI have chronic hypopituitarism, which can diminish quality of life and hamper rehabilitation. Patients who survive SAH may also develop hypopituitarism, though it is less common than following TBI. The growth hormone axis is most frequently affected. There is also accumulating evidence that survivors of intracranial malignancy, who have required cranial irradiation, may develop hypopituitarism. The time course of the development of hormone deficits is varied and predictors of pituitary dysfunction are unreliable. Furthermore diagnosis of GH and ACTH deficiency require dynamic testing which can be resource intensive. Thus the surveillance and management of neuroendocrine dysfunction in neurosurgical patients poses significant logistic challenges to endocrine services. Diagnosis and management of pituitary dysfunction can be rewarding however. Appropriate hormone replacement can improve quality of life, prevent complications such as muscle atrophy, infection and osteoporosis, and improve engagement with physiotherapy and rehabilitation.
The reliability of provocative stimuli of GH secretion in the diagnosis of GH deficiency is still controversial. Until now, normative values of GH response to various stimuli have not been established properly. In 472 children and adolescents with normal stature (n = 295, height SDS range -1.5 to 1.2) or normal short stature (n = 177, height SDS range -3.7 to -1.8), we studied the GH response to physical exercise, insulin-induced hypoglycemia, arginine (ARG), clonidine, levodopa, glucagon, pyridostigmine (PD), GHRH, PD + GHRH, and ARG + GHRH. The peak GH responses (range) to various stimuli were: 1) physical exercise: 3.0-28.3 micrograms/L; 2) insulin-induced hypoglycemia: 2.7-46.4 micrograms/L; 3) ARG: 0.5-48.4 micrograms/L; 4) clonidine: 3.8-86.0 micrograms/L; 5) levodopa: 1.9-40.0 micrograms/L; 6) glucagon: 1.9-49.5 micrograms/L; 7) PD: 2.5-35.0 micrograms/L; 8) GHRH: 2.7-102.7 micrograms/L; 9)PD + GHRH: 19.6-106.0 micrograms/L; and 10) ARG + GHRH: 19.4-120.0 micrograms/L. Our results show that all conventional stimuli of GH secretion frequently failed to increase GH levels, showing values lower than that arbitrarily assumed, so far, as minimum normal GH peak, i.e. 7 or 10 micrograms/L. When combined with PD or ARG (substances inhibiting hypothalamic somatostatin release), GHRH becomes the most powerful test to explore the secretory capacity of somatotrope cells (the GH response being always higher than 19 micrograms/L). Therefore, only GHRH combined with PD or ARG may be able to clearly differentiate normal children from patients with GH deficiency, though a normal GH response to these tests cannot rule out the existence of GH hyposecretory state because of hypothalamic dysfunction.
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 occuring 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.
A dehydration procedure has been used to identify patients with partial antidiuretic hormone (ADH) deficiency. The test consists of water deprivation until the osmolality of hourly voided urines reaches a plateau and then relating the urine osmolality at which this occurs to the osmolality recorded after subsequent injection of ADH. In patients with normal neurohypophysial function and patients with primary polydipsia, urine osmolality at the end of such a period of deprivation was much greater than plasma osmolality and did not increase more than 5% after the injection of 5 units of aqueous vasopressin. In patients with severe ADH deficiency urine osmolality before ADH was much less than plasma osmolality; after ADH injection, however, it was increased by more than 50%. Thirteen patients in whom urine osmolality was greater than plasma osmolality after water deprivation and was further increased by 9% to 67% after ADH injection were considered to have partial ADH deficiency. Some patients with ADH deficiency apparently exhausted their limited neurohypophysial ADH stores during prolonged dehydration, with resultant change from partial to severe hormone deficiency.
Abstract The stress hormone copeptin, which is co-secreted with arginine vasopressin, increases in seriously ill patients and can predict outcome in several organic diseases. Information about the influence of psychological stress on copeptin levels is lacking, but is important for interpretation of copeptin levels in the clinical setting. The aim of this study was to evaluate the influence of psychological stress on copeptin levels. We measured copeptin levels in 25 healthy medical students before and after a written examination. The primary endpoint was change in copeptin levels from immediately prior to examination compared to after the examination. Median copeptin levels prior to the examination were significantly higher than those after its conclusion. Similar results were found for serum cortisol and salivary cortisol. Serum cortisol prior to examination was significantly higher in students with a superior examination result, compared to those with a lower score. In conclusion, psychological stress leads to a subtle increase in copeptin level and might therefore be taken into account as a confounding factor in disorders with small diagnostic copeptin range. Higher Cortisol levels, but not copeptin, correlated with a better academic performance in this cohort of students.
Objective:
The prognostic/diagnostic biomarker copeptin, an arginine vasopressin surrogate, reflects physical stress. Whether copeptin concentration increases upon psychological stress is unknown. We investigated psychological stress effects on copeptin secretion in healthy volunteers and patients with central diabetes insipidus (DI).
Design:
A prospective observational study was conducted to study the relation between copeptin concentration and psychological stress.
Methods:
A total of 20 healthy adults (ten female) and eight patients with central DI (four female) underwent the Trier Social Stress Test including, in order, 30-min waiting period, 10-min anticipation period, 10-min test period and 40-min recovery. Serum copeptin and cortisol concentrations and self-rated stress component feelings were determined in the pre-/post-anticipation period, post-test period and twice post-recovery.
Results:
In healthy volunteers, the median (25th-75th percentile) copeptin concentration peaked immediately during the post-test period at 5.1 (3.2-7.0) pmol/l, vs 3.7 (2.6-5.4) pmol/l at baseline. Over the measurement course, copeptin concentration significantly elevated (coefficient; 95% CI) (0.14; 0.06-0.23, P=0.002). The important predictors of increase in copeptin concentration were feelings of tension (0.06; 0.04-0.08, P<0.001) and avoidance (0.07; 0.04-0.10; P<0.001). Copeptin and cortisol levels were associated (0.43; 0.13-0.72, P<0.005). Patients with DI had lower baseline concentrations (1.55 (1.2-3.1) pmol/l) when compared with healthy volunteers, P=0.006. Patients with DI showed no increase upon psychological stress (peak 2.15 pmol/l (1.5-2.28), P=0.79). By contrast, cortisol values were similar in patients and volunteers.
Conclusions:
In healthy volunteers, copeptin levels significantly increased after psychological stress testing; this response was blunted in patients with DI.
Context/objective:
To clarify ambiguous published data, we determined whether standardized nutrient intake influences serum copeptin concentrations.
Materials/methods:
Thirty healthy volunteers underwent oral glucose tolerance testing (OGTT) and mixed-meal tolerance testing (MMTT), respectively drinking 300 ml/237 ml of glucose-containing or fat/protein/carbohydrate-containing fluid. Copeptin was measured 30 min pre-("baseline")-180 min post-fluid intake.
Results:
Median [25th-75th percentile] copeptin fell from 4.9 [3.6-8.3]/4.9 [3.6-7.1] pmol/l at OGTT/MMTT baselines to 3.2 (2.8-5.9)/4.1 (2.7-6.1) pmol/l at post-OGTT/post-MMTT nadirs (150 min/120 min; p < 0.001, linear mixed-effect modeling).
Discussion/conclusions:
Regardless of nutrient type ingested, copeptin did not increase, suggesting values can be interpreted independently of prandial status.
Context:
Vasopressin plays a central role in water homeostasis but it has also been recognized to be associated with adverse effects in several chronic diseases. Recently, copeptin has been increasingly used as a surrogate for vasopressin, as they are co-secreted, and copeptin is easier to measure. However, the relationship between plasma concentrations of copeptin (P(cop)) and vasopressin (P(vp)) has only been studied in relatively small numbers of selected people.
Objective:
This study sought to evaluate the relationship between P(vp) and P(cop) in a community-based population and in people with chronic kidney disease (CKD).
Design, setting, and participants:
P(vp), P(cop), and urinary osmolarity (Uosm) were compared in 500 participants of the DESIR study, and in 83 ambulatory people with CKD.
Results:
Median [interquartile range] of P(cop) and P(vp) in the DESIR study were 4.13 [3.58] pmol/L and 0.92 [1.93] pmol/L, respectively. Log-transformed P(cop) and P(vp) concentrations correlated significantly and positively (r = 0.686, P < .001) and they correlated inversely with estimated U(osm) (P < .001). Copeptin explained only approximately half of the vasopressin variation. In CKD, P(cop) and P(vp) both increased with decreasing estimated glomerular filtration rate (eGFR), but P(cop) increased much faster than P(vp). The P(cop)/P(vp) ratios in the lower and upper quintile groups of eGFR were 14.3 [18.3] and 5.3 [4.5], P < .001, respectively.
Conclusions:
This study in a normal population, the largest ever with measurements of both peptides, shows that copeptin and vasopressin concentrations correlated well. But their relationship is distorted in CKD, suggesting that the peptide clearances differ when the renal function is impaired.
Context:
The differential diagnosis of diabetes insipidus (DI) is often challenging but essential, because treatment may vary substantially. This article analyzes the database and performance of currently used differential diagnostic tests for DI and discusses future perspectives for diagnostic improvement.
Evidence acquisition:
A review of electronic and print data comprising original and review articles retrieved from the PubMed or Cochrane Library database up to January 2012 was conducted. The search term "polyuria polydipsia syndrome" was cross-referenced with underlying forms of disease and associated clinical, diagnostic, and therapeutic MeSH terms. In addition, references from review articles and textbook chapters were screened for papers containing original data. Search results were narrowed to articles containing primary data with a description of criteria for the differential diagnosis of DI.
Evidence synthesis:
Fifteen articles on differential diagnosis of DI were identified, mainly consisting of small series of patients, and mostly covering only part of the differential diagnostic spectrum of DI. Test protocols differed, and prospective validation of diagnostic criteria was consistently missing. Inconsistent data were reported on the diagnostic superiority of direct plasma arginine vasopressin determination over the indirect water deprivation test. Both test methods revealed limitations, especially in the differentiation of disorders with a milder phenotype.
Conclusion:
The available data demonstrate limitations of current biochemical tests for the differential diagnosis of DI, potentially leading to incorrect diagnosis and treatment. The newly available assay for copeptin, the C terminus of the vasopressin precursor, holds promise for a higher diagnostic specificity and simplification of the differential diagnostic protocol in DI.
Central diabetes insipidus is a rare clinical condition with a heterogenous aetiology. Up to 40% of cases are classified as idiopathic, although many of these are thought to have an autoimmune basis. Published data have suggested that anterior hypopituitarism is common in childhood-onset idiopathic diabetes insipidus. We aimed to assess the incidence of anterior hypopituitarism in a cohort of adult patients with idiopathic diabetes insipidus.
We performed a retrospective review of the databases of two pituitary investigation units. This identified 39 patients with idiopathic diabetes insipidus. All had undergone magnetic resonance imaging scanning and dynamic pituitary testing (either insulin tolerance testing or GHRH/arginine and short synacthen testing) to assess anterior pituitary function.
One patient had partial growth hormone deficiency; no other anterior pituitary hormonal deficits were found. Thirty-three percent had at least one autoimmune disease in addition to central diabetes insipidus.
Our data suggest that anterior hypopituitarism is rare in adult idiopathic diabetes insipidus. Routine screening of these patients for anterior hypopituitarism may not, therefore, be indicated. The significant prevalence of autoimmune disease in this cohort supports the hypothesis that idiopathic diabetes insipidus may have an autoimmune aetiology.
The present study sought to identify confounding factors for the interpretation of copeptin levels in healthy individuals. The natriuretic peptides are recognized as diagnostic and prognostic tools in HF (heart failure). Interpretation of BNP (brain natriuretic peptide) and NTproBNP (N-terminal pro-BNP) levels is multifaceted as their secretion is influenced by many variables. A newly identified glycopeptide called copeptin is comparable with the natriuretic peptides in the diagnosis and prognosis of HF and as a prognostic biomarker after AMI (acute myocardial infarction). Copeptin, derived from the C-terminal portion of the precursor to AVP (arginine vasopressin), is secreted stoichiometrically with vasopressin, hence it can be used as a surrogate marker of the AVP system. In the present study, 706 healthy volunteers were recruited from a local HF screening study. Participants with a history of cardiovascular disease and those with echocardiographic abnormalities were excluded from the study. Copeptin and NTproBNP levels were assayed using in-house immunoluminometric assays. Median copeptin levels were significantly higher in the male volunteers compared with the females [median (range): 4.3 (0.4-44.3) compared with 3.2 (1.0-14.8) pmol/l; P<0.001]. In males, copeptin was correlated with eGFR (estimated glomerular filtration rate; r(s)=-0.186, P<0.001). In females, the correlation of copeptin with eGFR was weak (r(s)=-0.097, P=0.095). DT (deceleration time) and left atrial size correlated with higher copeptin levels (r(s)=0.085, P=0.029 and r(s)=0.206, P<0.001 respectively). Only gender (P<0.001), eGFR (P<0.001), left atrial size (P=0.04) and DT (P=0.02) remained independently predictive of plasma copeptin. The present study suggests that gender and renal function specific partition values should be used to interpret copeptin values in future studies of this biomarker in HF or ischaemic heart disease.
To evaluate changes in both the N-terminal (arginine vasopressin; AVP) and C-terminal (copeptin) fragments of the vasopressin prohormone before, during, and after an ultramarathon race and to assess vasopressin and copeptin concentrations in runners with and without hyponatremia.
Observational study.
Three trials (2 sodium balance and 1 hyponatremia treatment) in 2 separate approximately 160-km footraces [Western States Endurance Run (WSER) and Javelina Jundred (JJ100)].
Six hyponatremic and 20 normonatremic runners; 19 finishers with 7 completing 100 km.
Plasma AVP ([AVP]p), copeptin ([copeptin]p), sodium ([Na]p), and protein (%plasma volume change; %PV) concentrations.
In the WSER Sodium Trial, a 3-fold prerace to postrace increase in both [AVP]p (0.7 ± 0.4 to 2.7 ± 1.9 pg/mL; P < 0.05) and [copeptin]p (10.3 ± 12.5 to 28.2 ± 16.3 pmol/L; nonsignificant) occurred, despite a 2 mEq/L decrease in [Na]p (138.7 ± 2.3 to 136.7 ± 1.6 mEq/L; NS). A significant correlation was noted between [AVP]p and [copeptin]p postrace (r = 0.82; P < 0.05). In the WSER Treatment Trial, despite the presence of hyponatremia pretreatment versus posttreatment ([Na]p = 130.3 vs 133.5 mEq/L, respectively), both [AVP]p (3.2 vs 2.1 pg/mL) and [copeptin]p (22.5 vs 24.9 pmol/L) were well above the detectable levels. A significant correlation was noted between [AVP]p and [copeptin]p 60 minutes after treatment (r = 0.94; P < 0.05). In the JJ100 Sodium Trial, significant correlations were found between [copeptin]p change and %PV change (r = -0.34; P < 0.05) and between [AVP]p change and [Na]p change (r = 0.39; P < 0.05) but not vice-versa.
[Copeptin]p seems to be a reliable surrogate of stimulated [AVP]p during exercise. Nonosmotic vasopressin stimulation occurs during ultradistance running. [Copeptin]p may better reflect chronic (%PV) vasopressin secretion under conditions of endurance exercise.
The water deprivation test (WDT) with direct or indirect measurement of plasma arginine vasopressin (AVP) is the method of choice for the differential diagnosis of the polydipsia-polyuria syndrome. In theory, direct measurement of AVP is highly attractive but is hampered by technical difficulties.
The aim of the study was to evaluate the utility of copeptin, a surrogate of AVP secretion, in the diagnostic work-up of the polyuria-polydipsia syndrome and to compare its performance with the current diagnostic standard.
In two tertiary referral centers, 20 healthy subjects and 50 patients with polydipsia-polyuria syndrome underwent WDT with measurements of both plasma AVP and copeptin levels. The reference diagnosis was based on clinical information and treatment response.
Twenty-two patients (44%) were diagnosed with primary polydipsia, 17 (34%) with partial central diabetes insipidus (DI), nine (18%) with complete central DI, and two (4%) with nephrogenic DI. The indirect WDT led to a correct diagnosis in 35 of 50 patients (70%). The direct WDT with AVP or copeptin measurement correctly diagnosed 23 patients (46%) or 36 patients (72%), respectively. Baseline copeptin values greater than 20 pmol/liter identified patients with nephrogenic DI, and concentrations below 2.6 pmol/liter indicated complete central DI. The ratio between Δ copeptin (0800 to 1600 h) and serum sodium concentration at 1600 h yielded optimal diagnostic accuracy, allowing us to also discern partial central DI from primary polydipsia (sensitivity 86%, and specificity 100%).
Copeptin holds promise as a diagnostic tool in the polyuria-polydipsia syndrome, improving significantly the diagnostic accuracy of the direct WDT.
Copeptin, the C-terminal moiety of provasopressin, is cosecreted with vasopressin. Copeptin may be a useful parameter to characterize disorders of water homeostasis and can be readily measured in plasma or serum. However, it is unknown to date how circulating copeptin and vasopressin levels correlate at different plasma osmolalites.
To correlate plasma copeptin with plasma osmolality and vasopressin concentrations in healthy subjects during iso-, hypo-, and hyperosmolar states.
Plasma osmolalities, copeptin, and vasopressin levels were measured in 20 volunteers at baseline, after an oral water load, and during and after iv infusion of 3% saline. Correlation coefficients were determined between plasma osmolalites and copeptin and vasopressin concentrations, as well as between vasopressin and copeptin concentrations.
Median plasma osmolalities decreased from 290 mOsm/kg (range, 284-302) at baseline to 281 (273-288) mOsm/kg after water load and rose to 301 (298-307) mOsm/kg after hypertonic saline. Median plasma copeptin concentrations decreased from 3.3 (1.1-36.4) pm at baseline to 2.0 (0.9-10.4) pm after water load and increased to 13.6 (3.7-43.3) pm after hypertonic saline. Vasopressin and copeptin concentrations correlated with plasma osmolality (Spearman's rank correlation coefficient 0.49 and 0.77, respectively). There was a close correlation of vasopressin and copeptin concentrations (Spearman's rank correlation coefficient 0.8).
Plasma vasopressin and copeptin correlate strongly over a wide range of osmolalities in healthy individuals. Therefore, the measurement of copeptin, which remains stable for several days, is a useful alternative to vasopressin measurements and will likely facilitate the differential diagnosis of disorders of water metabolism.
Copeptin (the glycosylated 39–amino acid C-terminal fragment of the arginine vasopressin (AVP)1 precursor peptide), when measured with a novel assay (1), has emerged as a promising marker for the early diagnosis of acute myocardial infarction (MI)(2) and a powerful prognostic marker in a variety of settings. The underlying mechanism is thought to be the role of copeptin as a measure of a high individual stress level(3). Interestingly, exercise seems to elicit a significant increase in circulating copeptin concentrations within minutes(4). The aim of our study was to assess the copeptin response to exercise and its determinants.
We studied 414 consecutive patients undergoing myocardial perfusion scintigraphy (n = 253) or cardiopulmonary exercise testing (CPET) (n = 161) with upright symptom-limited cycle ergometer tests (increments of 10–25 W/min). In the CPET cohort, arterial samples for blood gas analysis were obtained at rest and peak exercise and were analyzed immediately. In all patients, venous blood was drawn immediately from a catheter in an antecubital vein with the patient in the seated position (rest) before the test and immediately after test termination (peak exercise). These samples were collected in EDTA-containing tubes, placed on ice, and centrifuged at 3000 g . Plasma samples were stored at …
Early prediction of outcome in patients with ischemic stroke is important. Vasopressin is a stress hormone. Its production rate is mirrored in circulating levels of copeptin, a fragment of provasopressin. We evaluated the prognostic value of copeptin in acute stroke patients.
In a prospective observational study, copeptin was measured using a new sandwich immunoassay on admission in plasma of 362 consecutive patients with an acute ischemic stroke. The prognostic value of copeptin to predict the functional outcome (defined as a modified Rankin Scale score of <or=2 or >or=3), mortality within 90 days, was compared with the National Institutes of Health Stroke Scale score and with other known outcome predictors.
Patients with an unfavorable outcomes and nonsurvivors had significantly increased copeptin levels on admission (p <0.0001 and p <0.0001). Receiver operating characteristics to predict functional outcome and mortality demonstrated areas under the curve of copeptin of 0.73 (95% confidence interval [CI], 0.67-0.78) and 0.82 (95% CI, 0.76-0.89), which was comparable with the National Institutes of Health Stroke Scale score but superior to C-reactive protein and glucose (p <0.01). In multivariate logistic regression analysis, copeptin was an independent predictor of functional outcome and mortality, and improved the prognostic accuracy of the National Institutes of Health Stroke Scale to predict functional outcome (combined areas under the curve, 0.79; 95% CI, 0.74-0.84; p <0.01) and mortality (combined areas under the curve, 0.89; 95% CI, 0.84-0.94; p <0.01).
Copeptin is a novel, independent prognostic marker improving currently used risk stratification of stroke patients. Ann Neurol 2009;66:799-808.
The purpose of this study was to examine the incremental value of copeptin for rapid rule out of acute myocardial infarction (AMI).
The rapid and reliable exclusion of AMI is a major unmet clinical need. Copeptin, the C-terminal part of the vasopressin prohormone, as a marker of acute endogenous stress may be useful in this setting.
In 487 consecutive patients presenting to the emergency department with symptoms suggestive of AMI, we measured levels of copeptin at presentation, using a novel sandwich immunoluminometric assay in a blinded fashion. The final diagnosis was adjudicated by 2 independent cardiologists using all available data.
The adjudicated final diagnosis was AMI in 81 patients (17%). Copeptin levels were significantly higher in AMI patients compared with those in patients having other diagnoses (median 20.8 pmol/l vs. 6.0 pmol/l, p < 0.001). The combination of troponin T and copeptin at initial presentation resulted in an area under the receiver-operating characteristic curve of 0.97 (95% confidence interval: 0.95 to 0.98), which was significantly higher than the 0.86 (95% confidence interval: 0.80 to 0.92) for troponin T alone (p < 0.001). A copeptin level <14 pmol/l in combination with a troponin T < or =0.01 microg/l correctly ruled out AMI with a sensitivity of 98.8% and a negative predictive value of 99.7%.
The additional use of copeptin seems to allow a rapid and reliable rule out of AMI already at presentation and may thereby obviate the need for prolonged monitoring and serial blood sampling in the majority of patients. (Advantageous Predictors of Acute Coronary Syndromes Evaluation [APACE]; NCT00470587).
The concept that secretion of the antidiuretic hormone, arginine vasopressin, is regulated by the osmolality of body water originated with the pioneering studies of Verney over 25 years ago [1]. In a classical series of experiments, this investigator showed that the injection of hypertonic saline into the carotid artery of conscious, hydrated dogs resulted in a prompt and reversible fall in urine output that was indistinguishable from that produced by the i.v. injection of small amounts of pituitary extract. On the basis of this and other indirect evidence, Verney concluded that the release of vasopressin from the neurohypophysis was controlled by an intracranial osmoreceptor that was extremely sensitive to changes in the blood concentration of sodium and certain other solutes.
Efforts to confirm and extend these observations were limited for many years by the lack of a suitable method for measuring vasopressin directly at the low concentrations normally present in body fluids. Recently, however, several laboratories have succeeded in developing sensitive and specific radioimmunoassay methods that permit the hormone to be measured at physiologic concentrations with greater ease and precision [2,3]. As reviewed in the following pages, these new assay methods now have made it possible to begin to characterize osmoregulatory function in a more concrete and comprehensive way and also to use such information to analyze systematically certain clinical disorders of salt and water balance.
This chapter describes anti-diuretic hormone arginine vasopressin (AVP), lysine vasopressin (EVP), urinary AVP, plasma AVP-osmolality, and the chromatographic behavior of purified bovine AVP on Sephadex G-15 with different eluting solvents or sample composition. As immunoassay methods can be used successfully to develop simple and accurate assays, plasma AVP has re-stimulated much investigative interest and, as a consequence, many other laboratories are beginning to develop their own assay procedures. It has been known for almost 30 years that the secretion of AVP can be influenced by a number of factors, including changes in blood osmolality, volume, and pressure. However, the relative potency of these variables and the way in which they interact in regulating secretion of the hormone under different conditions of salt and water balance has been a subject of some dispute. The advent of the immunoassay technique has now made it possible to begin to define these aspects of AVP physiology in more precise and comprehensive terms. The osmoregulation of AVP can be readily understood by analyzing the relationship between plasma AVP and plasma osmolality under different conditions of water balance.
To investigate the value of MR in differentiating patients with primary polydipsia, who have an intact neurohypophyseal system, from those with central diabetes insipidus, who have impaired synthesis and/or release of vasopressin.
Eighteen patients with clinically significant hypotonic polyuria were diagnosed endocrinologically as having primary polydipsia or diabetes insipidus (central or nephrogenic). These patients, and 92 patients without sellar disease, were then imaged with 1.5-T, T1-weighted, thin sagittal sections without gadolinium contrast.
Normal hyperintense signal of the neurohypophysis was present in 90 of 92 patients without sellar disease. The signal was also present in all six patients with primary polydipsia. In contrast, the hyperintense signal was absent in all eight patients with central diabetes insipidus. Three of the four patients with nephrogenic diabetes insipidus also had an absent hyperintense signal.
T1-weighted MR may prove important in differentiating patients with central diabetes insipidus from those with primary polydipsia.
We have recently reported that the posterior pituitary contains PRL-releasing factor (PRF), a small (less than 5000 mol wt) peptide which induces a rapid, hormone-specific, and concentration-dependent stimulation of PRL secretion. Although the identity of posterior pituitary PRF is yet unknown, it is distinct from known PRL secretagogues. Recently, the vasopressin-associated glycopeptide (VAG), which is concentrated in the posterior pituitary, was suggested as a PRF. To investigate whether VAG functions as a PRF, we used Brattleboro rats, which are deficient in arginine vasopressin (AVP), AVP-associated neurophysin, and VAG. Homozygous (DI) and heterozygous (HZ) lactating Brattleboro rats were used. The water consumption of pregnant DI rats (greater than 300 ml/day) was 6-fold higher than that of HZ rats. To correct their water imbalance, DI rats were implanted with osmotic minipumps containing the vasopressin analog 1-desamino-8-D-arginine vasopressin. On days 7-8 of lactation, pups were separated for 6 h, and blood was collected from the dams via a jugular cannula. Upon introduction of the pups, plasma PRL levels increased 100-fold in both DI and HZ rats and remained elevated for the duration of suckling. The suckling-induced rises in plasma oxytocin in DI and HZ rats were also superimposable. The weight gains of the pups of DI and HZ mothers were similar. PRF activity was determined using perifused anterior pituitary cells. Posterior pituitaries from DI and HZ rats contained equivalent amounts of PRF activity. Moreover, purified rat VAG (1.5 and 6.0 micrograms) failed to stimulate PRL release from pituitary cells. The posterior pituitary content of immunoreactive AVP was 2500-fold higher in HZ rats, but the contents of dopamine and oxytocin were similar. It is concluded that VAG neither mediates the suckling-induced rise of plasma PRL, nor stimulates PRL secretion from perifused anterior pituitary cells. Furthermore, posterior pituitaries from DI and HZ rats contain equivalent amounts of PRF activity. Collectively, these data indicate that VAG is not the posterior pituitary PRF.
To determine how arginine (Arg) stimulates GH secretion, we investigated its interaction with GHRH in vivo and in vitro. Six normal men were studied on four occasions: 1) Arg-TRH, 30 g arginine were administered in 500 mL saline in 30 min, followed by an injection of 200 μg TRH; 2) GHRH-Arg-TRH, 100 μg GHRH-(1-44) were give iv as a bolus immediately before the Arg infusion, followed by 200 μg TRH, iv; 3) GHRH test, 100 μg GHRH were given as an iv bolus; and 4) TRH test, 200 μg TRH were given iv as a bolus dose. Blood samples were collected at 15-min intervals for 30 min before and 120 min after the start of each infusion. Anterior pituitary cells from rats were coincubated with Arg (3, 6, 15, 30, and 60 mg/mL) and GHRH (0.05, 1, 5, and 10 nmol/L) for a period of 3 h. Rat GH was measured in the medium. After Arg-TRH the mean serum GH concentration increased significantly from 0.6 to 23.3 ± 7.3 (±SE) μg/L at 60 min. TRH increased serum TSH and PRL significantly (maximum TSH, 11.1 ± 1.8 mU/L; maximum PRL, 74.6 ± 8,4 μg/L). After GHRH-Arg-TRH, the maximal serum GH level was significantly higher (72.7 ± 13.4 μg/L) than that after Arg-TRH alone, whereas serum TSH and PRL increased to comparable levels (TSH, 10.2 ± 3.0 mU/L; PRL, 64.4 ± 13.6 μg/L). GHRH alone increased serum GH to 44.9 ± 9.8 μg/L, significantly less than when GHRH, Arg, and TRH were given. TRH alone increased serum TSH to 6.6 ± 0.6 mU/L, significantly less than the TSH response to Arg-TRH. The PRL increase after TSH only also was lower (47.2 ± 6.8 μg/L) than the PRL response after Arg-TRH. In vitro Arg had no effect on basal and GHRH-stimulated GH secretion. Our results indicate that Arg administered with GHRH led to higher serum GH levels than did a maximally stimulatory dose of GHRH or Arg alone. The serum TSH response to Arg-TRH also was greater than that to TRH alone. We conclude that the stimulatory effects of Arg are mediated by suppression of endogenous somatostatin secretion.
All of the classically-described hypothalamic, hypophysiotropic factors that regulate anterior pituitary hormone secretion have now been isolated and identified except for prolactin releasing factor. We report here that the 39-amino acid glycopeptide comprising the carboxyterminus of the neurohypophysial vasopressin-neurophysin precursor stimulates prolactin release from cultured pituitary cells as potently as does thyrotropin releasing hormone but has no effect on the secretion of other pituitary hormones. Furthermore, antisera to the glycopeptide administered to lactating rats attenuated suckling-induced prolactin secretion. Thus, this glycopeptide appears to be the neurohypophysial prolactin releasing factor.
Diabetes insipidus (DI) is a syndrome characterized by chronic polyuria and polydipsia. It can result from any of three basic defects: (a) inadequate urinary concentration caused by a deficiency in the secretion or action of the antidiuretic hormone vasopressin (neurogenic or nephrogenic DI), or excessive intake of water caused by a defect in (b) thirst or (c) psychological function (dipsogenic or psychogenic DI). These four types of DI can be differentiated clinically only if they present in a complete and classical form. However, more sophisticated diagnostic approaches involving assays of plasma vasopressin or closely monitored trials of antidiuretic therapy usually are necessary when the patient has mild or incomplete defects in thirst or vasopressin function. Accurate diagnostic differentiation among the four basic types of DI is essential not only for safe and effective management but also for a proper understanding of the basic physiology and pathophysiology of water homeostasis.
Patients with cranial diabetes insipidus are unable to concentrate urine, and depend on thirst and water intake to prevent hypertonic dehydration. Using a visual analogue scale (0-10 cm) we studied osmotically stimulated thirst induced by hypertonic saline infusion in 15 patients with diabetes insipidus and 15 healthy controls. Plasma osmolality in the patients rose from 292 ±1 to 316±1 mOsm/kg (p<0.001), and 13 patients showed a progressive rise in thirst ratings (1.4 ±0.4 to 8.1 ±0.3 cm, p<0.001) with abolition of thirst by drinking, in a similar fashion to controls. Water intake following infusion was greater in patients than controls (p<0. 001). Linear regression analysis of thirst and plasma osmolality showed no difference in the osmotic threshold for thirst onset, or the sensitivity of thirst osmoreceptors, between 13 of the patients and the control group. One patient was shown to be hypodipsic and compulsive water drinking was demonstrated in another: abnormal thirst perception caused abnormalities of salt and water balance in these two patients.
Most patients with cranial diabetes insipidus have normal thirst mechanisms, though clinically significant hypodipsia or hyperdipsia may co-exist with vasopressin deficiency.
We describe three patients who have polydipsia and polyuria due to an abnormality in the osmoregulation of thirst. The clinical manifestations of the syndrome are similar to those of neurogenic diabetes insipidus. Thus, under basal conditions the patients have thirst, normal to high normal levels of plasma osmolality, and low levels of plasma vasopressin. Moreover, antidiuretic therapy greatly reduces thirst and polydipsia as well as polyuria. The only clinically distinguishing feature of the response is that thirst and water intake decrease less rapidly than water excretion. As a consequence, the patients with this syndrome develop variable degrees of dilutional hyponatremia and hypoosmolemia during treatment. The plasma vasopressin response to osmotic stimulation is relatively normal. In most of the patients, the osmotic threshold for vasopressin release is at the upper limit of normal, but this finding only explains their modest elevation in basal plasma osmolality. Thirst and water intake also change as a function of plasma osmolality. However, the threshold or "set" of the thirst osmostat appears to be abnormally low. The degree of downward resetting varies from patient to patient, but is always sufficient to stimulate thirst and water intake at levels of plasma osmolality below the normal range. This abnormality can account not only for the thirst and polyuria under basal conditions but also for the overhydration that occurs during antidiuretic therapy. The pathogenesis of the osmoregulatory abnormality is unknown but may be due to disruption of one or more of the afferent pathways that regulate the "set" of the thirst and vasopressin osmostats.
Several authors have described syndromes of diabetes insipidus that begin during gestation and remit after delivery. Baron et al. recently described three pregnant women with diabetes insipidus resistant to arginine vasopressin (AVP). Since excessive plasma levels of vasopressinase activity were not excluded as a cause of the disorder, the authors labeled the disease as vasopressin-resistant, but not nephrogenic, diabetes insipidus. They suggested, as had others, that some instances of pregnancy-associated diabetes insipidus may be due to an enhanced activity of vasopressinase. This report describes the occurrence in a woman in the third trimester of pregnancy of diabetes insipidus characterized by massive polyuria, markedly elevated plasma vasopressinase activity, and a lack of response to large intravenous doses of AVP but a prompt response to desmopressin acetate, a vasopressinase-resistant analogue of AVP. The polyuria resolved with the disappearance of vasopressinase, and at 40 days post partum, the osmolality of an early-morning urine sample from the patient was 750 mOsm per kilogram of water.
The prolactin (PRL) response to placebo, sulpiride (2.5, 5, 10 and 20 mg im) and arginine HC1 infusion (0.33G/kg) was examined in young (18-25 yrs) and old (65-75 yrs) normal men. Analysis of variance for the sulpiride data showed no significant dose x age group interaction or dose X age group X period interaction. There was, however, a significant age group X period interaction (p less than 0.05). PRL concentrations were significantly lower in the old subjects (N = 9) compared with the young (N = 9) 15 min after 2.5, 5, or 10 mg but not significantly after 20 mg sulpiride or at any other time interval. The areas under the concentration-time curves and the mean individual peak PRL concentrations were not significantly different between the two groups. The pattern of findings suggests a delayed absorption of sulpiride in the elderly rather than a change in pituitary dopamine (DA) receptor sensitivity to account for the lower PRL concentrations at 15 min. Differences in magnitude of the PRL response between the four doses of sulpiride were small and results suggest that the 2.5 mg dose is close to that required to saturate DA receptors on the lactotrophe and that the 10 and 20 mg doses are sufficient to completely block pituitary DA receptors. There was no significant age effect on arginine-induced PRL secretion (N = 11 in each group).(ABSTRACT TRUNCATED AT 250 WORDS)