Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “secretion defect”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,513 records · Page 84Linked to original sources
PubMed2006

Androgen receptor in sertoli cell is essential for germ cell nursery and junctional complex formation in mouse testes.

To examine the role of androgen receptor (AR) in Sertoli cells (SC), we used a SC-specific AR knockout (S-AR-/y) mouse to further evaluate the chronological changes of seminiferous tubules and the molecular mechanisms of SC androgen/AR signals on spermatogenesis. Testes morphology began changing as early as postnatal day (PD) 10.5 in wild-type (WT), but not in S-AR-/y mice. After puberty (PD 50), the SC nuclei of WT testes migrated to the basal area of the seminiferous epithelium; however, in S-AR-/y testes, SC nuclei were disarranged and dislocated. Results from electron microscopy further showed an obvious duplication of basal lamina of the seminiferous epithelium in S-AR-/y testes at PD 50 compared with WT testes. Using quantitative RT-PCR analyses, the expression of SC gene profiles were compared in PD 10.5 testes. In S-AR-/y testes, the expression levels of 1) vimentin were significantly increased and laminin alpha5 was significantly decreased in PD 10.5, which contributed to functional defects in cytoskeletons and production of the basement membrane component of SC leading to cell morphology deterioration and thus affecting the integrity of seminiferous epithelium; 2) claudin-11, occludin, and gelsolin were significantly decreased in PD 10.5, which contributed to defects in intact junctional complex formation of SC leading to impairment of the integrity of the blood-testis barrier; 3) calcium channel, voltage-dependent, P/Q-type, alpha1A subunit; tissue-type plasminogen activator; transferrin; and epidermal fatty-acid-binding protein were significantly decreased in PD 10.5, which contributed to functional defects in production and/or secretion of specific proteases, transport proteins, and paracrine factors of SC, leading to impairment of its germ cells' nursery functions.

Animals↗
PubMed1980

17 beta-hydroxysteroid dehydrogenase deficiency in malignant interstitial cell carcinoma of the testis.

A partial defect in testosterone (T) secretion due to a 17 beta-hydroxysteroid dehydrogenase deficiency has been documented in a patient with advanced metastatic interstitial cell carcinoma of the testis. Basal serum T was decreased (83 ng/ml), whereas androstenedione was markedly elevated (847 ng/ml). Dehydroepiandrosterone sulfate and estrone were moderately increased, while LH, FSH, and estradiol were minimally increased. After hCG administration, androstenedione rose to much greater degree than T. Fluoxymesterone failed to suppress circulating androgens and estrogens to below basal values, although LH and FSH were suppressed to immeasurable levels. These data support a partial enzyme deficiency within the tumor. They also suggest that although the tumor was autonomous, it still was capable of being stimulated by exogenous gonadotropins.

17-Hydroxysteroid Dehydrogenases↗
PubMed1984

Virilization without adrenal hyperplasia in 21-hydroxylase deficiency during fetal life.

The characteristic excess production of androgens in the cortisol 21-hydroxylase defect is generally considered to be secondary to ACTH stimulation of alternate pathways. Whenever a morphological examination of the adrenals has been possible in this disorder, adrenocortical hyperplasia was a constant finding. The availability of methods for the prenatal diagnosis of the 21-hydroxylase defect has made it possible to examine some of the manifestations of this disorder during fetal life. We studied a severely virilized 20-week-old aborted female fetus with the 21-hydroxylase defect whose adrenals were neither grossly enlarged nor microscopically hyperplastic. In a pregnancy at risk for congenital adrenal hyperplasia due to a 21-hydroxylase deficiency, amniocentesis was performed in the 18th week of gestation. The 21-hydroxylase defect was established by HLA typing and highly elevated levels of 17-hydroxyprogesterone, testosterone, and androstendione in amniotic fluid. After counselling, the parents, who already had a girl with the salt-wasting form of 21-hydroxylase deficiency, wished termination of the pregnancy. The aborted 20-week-old fetus was within the normal range for gestational age in weight and height. The external genitalia were ambiguous and extremely virilized, with an enlarged clitoris and fused labioscrotal folds. A urogenital sinus opened at the base of the clitoris. The internal organs were female, with a normal uterus and ovaries. Both adrenals were normal in size and weight for their gestational age. Histological examination of the adrenals revealed no abnormalities, and no hyperplasia was detectable. Thus, the adrenals in the 21-hydroxylase defect during fetal life secrete excessive amounts of androgens and cause virilization in the absence of adrenocortical hyperplasia.

Adrenal Hyperplasia, Congenital↗
PubMed1989

Comparison of serum placental protein hormone levels in diabetic and normal pregnancy.

Conflicting data exist concerning maternal serum concentrations of placental hormones during pregnancy in women with diabetes mellitus. To resolve some of these discrepancies, women participating in the NICHD-Diabetes in Early Pregnancy Study were studied. In this collaborative study, pregnancy was identified within 21 days of conception by serum hCG measurements. We prospectively collected 185 blood samples from 35 insulin-dependent diabetic women and 166 blood samples from 31 control women, all between 5 and 37 weeks gestation. Serum concentrations of hCG, pregnancy-specific beta-1-glycoprotein, placental lactogen, and hCG alpha were measured serially. The relationship between serum hormone, fasting blood glucose, 1-h postprandial blood glucose, and glycosylated hemoglobin concentrations was compared. Serum hCG alpha levels were significantly lower in the diabetic women than in control women at multiple time points during the first and second trimesters, while no consistent differences in the serum concentrations of hCG or pregnancy-specific beta-1-glycoprotein were found between pregnant diabetic and control women. Serum placental lactogen levels were significantly lower in diabetic women at 9-10 weeks and 20 weeks gestation. There were no correlations between fasting blood glucose, 1-h postprandial blood glucose, or glycosylated hemoglobin and any of the placental protein levels in the diabetic women. These data are consistent with a defect in synthesis and/or secretion of hCG alpha by the cytotrophoblast during the first two trimesters of pregnancy in insulin-requiring diabetic women.

Adult↗
PubMed2003

Candidate gene association study in type 2 diabetes indicates a role for genes involved in beta-cell function as well as insulin action.

Type 2 diabetes is an increasingly common, serious metabolic disorder with a substantial inherited component. It is characterised by defects in both insulin secretion and action. Progress in identification of specific genetic variants predisposing to the disease has been limited. To complement ongoing positional cloning efforts, we have undertaken a large-scale candidate gene association study. We examined 152 SNPs in 71 candidate genes for association with diabetes status and related phenotypes in 2,134 Caucasians in a case-control study and an independent quantitative trait (QT) cohort in the United Kingdom. Polymorphisms in five of 15 genes (33%) encoding molecules known to primarily influence pancreatic beta-cell function-ABCC8 (sulphonylurea receptor), KCNJ11 (KIR6.2), SLC2A2 (GLUT2), HNF4A (HNF4alpha), and INS (insulin)-significantly altered disease risk, and in three genes, the risk allele, haplotype, or both had a biologically consistent effect on a relevant physiological trait in the QT study. We examined 35 genes predicted to have their major influence on insulin action, and three (9%)-INSR, PIK3R1, and SOS1-showed significant associations with diabetes. These results confirm the genetic complexity of Type 2 diabetes and provide evidence that common variants in genes influencing pancreatic beta-cell function may make a significant contribution to the inherited component of this disease. This study additionally demonstrates that the systematic examination of panels of biological candidate genes in large, well-characterised populations can be an effective complement to positional cloning approaches. The absence of large single-gene effects and the detection of multiple small effects accentuate the need for the study of larger populations in order to reliably identify the size of effect we now expect for complex diseases.

ATP-Binding Cassette Transporters↗
PubMed2005

Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic beta cells.

Sir2 and insulin/IGF-1 are the major pathways that impinge upon aging in lower organisms. In Caenorhabditis elegans a possible genetic link between Sir2 and the insulin/IGF-1 pathway has been reported. Here we investigate such a link in mammals. We show that Sirt1 positively regulates insulin secretion in pancreatic beta cells. Sirt1 represses the uncoupling protein (UCP) gene UCP2 by binding directly to the UCP2 promoter. In beta cell lines in which Sirt1 is reduced by SiRNA, UCP2 levels are elevated and insulin secretion is blunted. The up-regulation of UCP2 is associated with a failure of cells to increase ATP levels after glucose stimulation. Knockdown of UCP2 restores the ability to secrete insulin in cells with reduced Sirt1, showing that UCP2 causes the defect in glucose-stimulated insulin secretion. Food deprivation induces UCP2 in mouse pancreas, which may occur via a reduction in NAD (a derivative of niacin) levels in the pancreas and down-regulation of Sirt1. Sirt1 knockout mice display constitutively high UCP2 expression. Our findings show that Sirt1 regulates UCP2 in beta cells to affect insulin secretion.

Adenosine Diphosphate↗
PubMedDate not supplied

Growth hormone response to GHRH during lifespan.

Recent evidence has shown that growth hormone-releasing hormone (GHRH) enables investigation of the pathophysiology of GH secretion in a variety of different states, but it cannot be used as a test for probing pituitary somatotrophic function, due to the extreme inter- and intra-subject variability in normal subjects. This task is better accomplished when compounds which deprive the pituitary of inhibitory (somatostatinergic) influences, e.g. pyridostigmine, arginine, etc., are given in combination with GHRH. Administration of GHRH in both animals and humans reveals a state of GH hyperresponsiveness in the immediate postnatal period, which is likely to be due to a reduced pituitary sensitivity to somatostatin. GH responses to GHRH are relatively constant throughout the different stages of pubertal development, though further studies are needed to confirm these findings, and decline after the third-fourth decade in men, after menopause in women. It is apparent that during aging the releasable pool of GH is preserved and that impaired GH secretion is due to defective hypothalamic GHRH function and a relative predominance of somatostatinergic function.

Aging↗
PubMed2000

Bone regeneration using Bioglass: an experimental study in rabbit tibia.

Bioglass (BG) has been shown recently to be osteoconductive and osteopromotive in different experimental and clinical conditions. The aim of the present study was to evaluate BG particles in bone defects in rabbit tibia. In control sites, bone was observed only in the peripheral areas of the defects, while in test sites, newly formed bone was found around all BG particles, even those located in the central portion of the defect. Osteoblasts were actively secreting osteoid matrix directly on the granules' surface. BG seems to be a highly osteoconductive material.

Animals↗
PubMed1982

Integrated regulation of very low density lipoprotein triglyceride and apolipoprotein-B kinetics in non-insulin-dependent diabetes mellitus.

Turnover rates of plasma very low density lipoprotein (VLDL) triglyceride (TG) and apolipoprotein-B (apo-B) were significantly increased in age- and weight-matched groups of normolipemic and hyperlipemic mild diabetics, and hyperlipemic moderately severe diabetics when compared with normolipemic controls. As in the normolipemic subjects, a significant correlation between VLDL TG and apo-B turnover rates was found in all diabetic groups, suggesting that integration of TG and apo-B production at synthetic and/or secretory sites is retained in diabetes, thus resulting in increased secretion of VLDL particles of normal composition. In normolipemic mild diabetic subjects, the fractional turnover rates of VLDL TG and apo-B were also significantly increased so that increased removal accompanied increased VLDL production. In the hyperlipemic diabetics, however, the fractional turnover rates were significantly reduced, hence the increased in VLDL removal was not sufficient to compensate for enhanced production. In normolipemic mild diabetic patients, low density lipoprotein (LDL) formation was increased, only a small fraction of VLDL apo-B being removed via a non-LDL pathway, presumably as remnant VLDL. In hyperlipemic mild diabetics, removal of VLDL apo-B via both the LDL and non-LDL pathways was increased. In hyperlipemic moderately severe diabetes, LDL formation was not increased; catabolism of VLDL apo-B through the non-LDL route was however, fivefold greater than normal. We conclude that increased VLDL secretion is a fundamental defect in non-insulin-dependent diabetes. In hyperlipemic individuals, VLDL removal is also impaired. The increase in LDL and/or VLDL remnant formation, regardless of prevailing plasma lipid levels or the severity of diabetes, provides a source of cholesterol which may account for the atherogeneity of this disorder.

Adult↗
PubMed1996

The human glucokinase gene beta-cell-type promoter: an essential role of insulin promoter factor 1/PDX-1 in its activation in HIT-T15 cells.

The glycolytic enzyme glucokinase plays a primary role in the glucose-responsive secretion of insulin, and defects of this enzyme can cause NIDDM. As a step toward understanding the molecular basis of glucokinase (GK) gene regulation, we assessed the structure and regulation of the human GK gene beta-cell-type promoter. The results of reporter gene analyses using HIT-T15 cells revealed that the gene promoter was comprised of multiple cis-acting elements, including two primarily important cis-motifs: a palindrome structure, hPal-1, and the insulin gene cis-motif A element-like hUPE3. While both elements were bound specifically by nuclear proteins, it was the homeodomain-containing transcription factor insulin promoter factor 1 (IPF1)/STF-1/PDX-1 that bound to the hUPE3 site: IPF1, when expressed in CHO-K1 cells, became bound to the hUPE3 site and activated transcription. An anti-IPF1 antiserum used in gel-mobility shift analysis supershifted the DNA protein complex formed with the hUPE3 probe and nuclear extracts from HIT-T15 cells, thus supporting the involvement of IPF1 in GK gene activation in HIT-T15 cells. In contrast to the insulin gene, however, neither the synergistic effect of the Pan1 expression on the IPF1-induced promoter activation nor the glucose responsiveness of the activity was observed for the GK gene promoter. These results revealed some conservative but unique features for the transcriptional regulation of the beta-cell-specific genes in humans. Being implicated in insulin and GK gene regulations as a common transcription factor, IPF1/STF-1/PDX-1 is likely to play an essential role in maintaining normal beta-cell functions.

Amino Acid Sequence↗
PubMed2000

A model to explore the interaction between muscle insulin resistance and beta-cell dysfunction in the development of type 2 diabetes.

Type 2 diabetes is a polygenic disease characterized by defects in both insulin secretion and insulin action. We have previously reported that isolated insulin resistance in muscle by a tissue-specific insulin receptor knockout (MIRKO mouse) is not sufficient to alter glucose homeostasis, whereas beta-cell-specific insulin receptor knockout (betaIRKO) mice manifest severe progressive glucose intolerance due to loss of glucose-stimulated acute-phase insulin release. To explore the interaction between insulin resistance in muscle and altered insulin secretion, we created a double tissue-specific insulin receptor knockout in these tissues. Surprisingly, betaIRKO-MIRKO mice show an improvement rather than a deterioration of glucose tolerance when compared to betaIRKO mice. This is due to improved glucose-stimulated acute insulin release and redistribution of substrates with increased glucose uptake in adipose tissue and liver in vivo, without a significant decrease in muscle glucose uptake. Thus, insulin resistance in muscle leads to improved glucose-stimulated first-phase insulin secretion from beta-cells and shunting of substrates to nonmuscle tissues, collectively leading to improved glucose tolerance. These data suggest that muscle, either via changes in substrate availability or by acting as an endocrine tissue, communicates with and regulates insulin sensitivity in other tissues.

Acute-Phase Reaction↗
PubMed2006

Diabetes insipidus: diagnosis and treatment of a complex disease.

Diabetes insipidus, characterized by excretion of copious volumes of dilute urine, can be life-threatening if not properly diagnosed and managed. It can be caused by two fundamentally different defects: inadequate or impaired secretion of antidiuretic hormone (ADH) from the posterior pituitary gland (neurogenic or central diabetes insipidus) or impaired or insufficient renal response to ADH (nephrogenic diabetes insipidus). The distinction is essential for effective treatment.

Diabetes Insipidus↗
PubMed1999

Pharmacologic therapy for type 2 diabetes mellitus.

Type 2 diabetes mellitus is a chronic metabolic disorder that results from defects in both insulin secretion and insulin action. An elevated rate of basal hepatic glucose production in the presence of hyperinsulinemia is the primary cause of fasting hyperglycemia; after a meal, impaired suppression of hepatic glucose production by insulin and decreased insulin-mediated glucose uptake by muscle contribute almost equally to postprandial hyperglycemia. In the United States, five classes of oral agents, each of which works through a different mechanism of action, are currently available to improve glycemic control in patients with type 2 diabetes. The recently completed United Kingdom Prospective Diabetes Study (UKPDS) has shown that type 2 diabetes mellitus is a progressive disorder that can be treated initially with oral agent monotherapy but will eventually require the addition of other oral agents, and that in many patients, insulin therapy will be needed to achieve targeted glycemic levels. In the UKPDS, improved glycemic control, irrespective of the agent used (sulfonylureas, metformin, or insulin), decreased the incidence of microvascular complications (retinopathy, neuropathy, and nephropathy). This review examines the goals of antihyperglycemic therapy and reviews the mechanism of action, efficacy, nonglycemic benefits, cost, and safety profile of each of the five approved classes of oral agents. A rationale for the use of these oral agents as monotherapy, in combination with each other, and in combination with insulin is provided.

Acarbose↗
PubMed1999

[Hypo-osmolar hyponatremic syndromes: physiopathology and clinical aspects].

Hyponatremia in virtually all patients results from water retention due to an inability to excrete ingested water. In most cases, this defect represents the persistent secretion of ADH (such as in effective circulating volume depletion, and in the syndrome of inappropriate ADH secretion), although free water excretion can also be limited in disorders in which ADH levels may be appropriately suppressed (such as in advanced renal failure, and in primary polydipsia). The symptoms of hyponatremia primarily reflect neurologic dysfunction induced by cerebral edema and are related both to the severity and to the rapidity of reductions in the plasma sodium concentration. The degree of cerebral edema which occurs in acute hyponatremia is much less with chronic hyponatremia, because the brain cells lose solutes, leading to the osmotic movement of water out the cells and less brain swelling. In general, hyponatremia is corrected acutely by giving Na+ to patients who are volume-depleted and by restricting water intake in patients who are normovolemic or edematous. The optimal rate of correction should be defined to prevent the risk of central demyelinating lesions.

Adrenal Insufficiency↗
PubMed1999

[Common variable immunodeficiency: a rare humoral immunodeficiency with frequent later change of diagnosis].

Common variable immunodeficiency (CVIS) is a condition associated with a deficiency of humoral immunity. The typical patient is an adolescent or adult with a history of recurrent upper respiratory tract infections over many years. Despite the long history the illness is not readily recognised and diagnosis is usually delayed until the patient is admitted to hospital for a severe respiratory tract infection and is being worked up for causes of immunodeficiency. The diagnosis of CVIS is based on the finding of an immunoglobulin deficiency in immunoelectrophoresis or documentation of reduced IgG subclasses. Typically this leads to upper respiratory tract infections and malabsorption, as illustrated by the case reports. Pathophysiologically this disease is characterised by malfunction of B cells with defective gammaglobulin production or secretion. 7 patients were substituted with IgG, leading to decreased susceptibility to infection and a reduction in hospital admissions due to severe infections.

Adult↗
PubMed2002

[B-cell anomalies in systemic lupus erythematosus].

Systemic lupus erythematosus is a non-organ-specific autoimmune disease characterized biologically by B lymphocyte hyperactivity and the production of autoantibodies directed against various cellular components, in particular nuclear antigens. Different strains of mice spontaneously develop a lupus-like disease and constitute a guidelight for human SLE. Both polyclonal B cell stimulation and clonal expansion induced by self-antigens participate in B cell hyperactivity observed in human and mouse SLE. B cells are hyperactive to various stimuli, in particular those delivered by T cells through surface molecules or cytokines. The consequences are an increased production of immunoglobulins and the development of autoantibodies thought to induce the major part of tissue lesions. B cells also participate in the pathological process as antigen-presenting and cytokine-secreting cells. An intrinsic defect of B cells is suspected to be responsible for B cell anomalies as illustrated by certain spontaneous murine models of SLE (motheaten mice) and by lupus-like syndromes observed in mice rendered deficient for genes controlling the B-cell receptor (BCR) signaling pathway. Genome wide scan analysis of various lupus strains allowed to identify several loci predisposing to lupus among which certain are associated with B cell hyperactivity suggesting that the intrinsic defect is inherited.

Animals↗
PubMed1992

[Hypophyseal dysfunction and tumors].

Some pituitary hormones secrete hormones while others do not. Nonsecreting tumors can interfere with normal pituitary hormone secretion and produce tumor symptoms and signs like headaches and visual field defects. The most frequent hormone-secreting tumors are prolactinomas. Growth hormone or ACTH or gonadotropin or gonadotropin-alpha and beta chain-producing tumors are less frequent, TSH producing tumors are extremely rare. The most important elements of the diagnostic work-up are clinical signs and symptoms, assessment of pituitary function (measurement of TSH, free T4, LH, FSH, oestradiol/free testosteron, growth hormone, IGF-1, prolactin, ACTH, Cortisol, serum and urine osmolality), CT and/or MRI and, in patients with large tumors, a visual field exam. The treatment of choice of pituitary tumors is often surgery. Alternative therapies are radiation treatment (in nonoperable patients or when hormone levels are persistently elevated after pituitary surgery) and drug treatment (dopamine agonists in hyperprolactinemia, somatostatin analogues in acromegaly). Pituitary hormone deficiencies are treated depending on the specific deficiency with thyroxine, cortisone, oestrogen/gestagen/testosterone gonadotropines or ADH analogues.

Adenoma↗
PubMedDate not supplied

Pseudohypoaldosteronism: case report and discussion of the syndrome.

A 41-year-old man, complaining of leg cramps, was found to have persistent hyperkalemia. Except for mild hypertension, his physical examination and laboratory values to exclude connective tissue diseases and diabetes mellitus were normal. Renal function testing revealed a normal glomerular filtration rate and tubular capacity to acidify and dilute, as well as near-normal ability to concentrate his urine. Hormonal evaluation revealed a normal cortisol, as well as normal resting and stimulated renin and aldosterone levels. A selective defect in tubular potassium secretion was demonstrated. In the absence of aldosterone deficiency or renal dysfunction, it was assumed that the patient had primary renal resistance to aldosterone, known as pseudohypoaldosteronism. Treatment with hydrochlorothiazide controlled his hyperkalemia and hypertension. His case emphasizes the diagnostic and therapeutic factors that should be considered in evaluating and treating a non-hospitalized patient with sustained hyperkalemia.

Adult↗