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PubMed1978

A defect in catecholamine neurons in patients with prolactin-secreting pituitary adenoma.

Although basal plasma concentrations of dopamine, noradrenaline, and adrenaline in patients with prolactin-secreting pituitary adenoma are normal, responses to oral bromocriptine are not. 1 and 2 h after bromocriptine, plasma concentrations of these three catecholamines are decreased in normal men but not in patients with hyperprolactinaemia secondary to prolactin-secreting pituitary adenoma or in normoprolactinaemic patients in whom a pituitary adenoma has been removed. Patients with prolactin-secreting pituitary adenoma probably have a defect in the regulation of brain catecholamine metabolism.

Adenoma↗
PubMed2005

Cell-to-cell movement of the CAPRICE protein in Arabidopsis root epidermal cell differentiation.

CAPRICE (CPC), a small, R3-type Myb-like protein, is a positive regulator of root hair development in Arabidopsis. Cell-to-cell movement of CPC is important for the differentiation of epidermal cells into trichoblasts (root hair cells). CPC is transported from atrichoblasts (hairless cells), where it is expressed, to trichoblasts, and generally accumulates in their nuclei. Using truncated versions of CPC fused to GFP, we identified a signal domain that is necessary and sufficient for CPC cell-to-cell movement. This domain includes the N-terminal region and a part of the Myb domain. Amino acid substitution experiments indicated that W76 and M78 in the Myb domain are critical for targeted transport, and that W76 is crucial for the nuclear accumulation of CPC:GFP. To evaluate the tissue-specificity of CPC movement, CPC:GFP was expressed in the stele using the SHR promoter and in trichoblasts using the EGL3 promoter. CPC:GFP was able to move from trichoblasts to atrichoblasts but could not exit from the stele, suggesting the involvement of tissue-specific regulatory factors in the intercellular movement of CPC. Analyses with a secretion inhibitor, Brefeldin A, and with an rhd3 mutant defective in the secretion process in root epidermis suggested that intercellular CPC movement is mediated through plasmodesmata. Furthermore, the fusion of CPC to tandem-GFPs defined the capability of CPC to increase the size exclusion limit of plasmodesmata.

Amino Acid Substitution↗
PubMed1987

Fluid transport by airway epithelia.

Airway epithelia possess transepithelial ion transport processes which may help to regulate the fluid content of airway secretions. Chloride secretion promotes fluid movement from blood to airway lumen. Active absorption of Na favours fluid movement in the opposite direction. The balance between these two processes can be altered by a number of agents which stimulate Cl secretion. The importance of ion transport for normal mucociliary clearance is suggested by the finding that airway epithelia in patients with cystic fibrosis are unable to secrete chloride. This defect may cause the characteristically sticky and tenacious mucous secretions which are the major cause of death in this disease.

Animals↗
PubMed1995

Insulin secretory defects in polycystic ovary syndrome. Relationship to insulin sensitivity and family history of non-insulin-dependent diabetes mellitus.

The increased prevalence of non-insulin-dependent diabetes mellitus (NIDDM) among women with polycystic ovary syndrome (PCOS) has been ascribed to the insulin resistance characteristic of PCOS. This study was undertaken to determine the role of defects in insulin secretion as well as familial factors to the predisposition to NIDDM seen in PCOS. We studied three groups of women: PCOS with a family history of NIDDM (PCOS FHx POS; n = 11), PCOS without a family history of NIDDM (PCOS FHx NEG; n = 13), and women without PCOS who have a family history of NIDDM (NON-PCOS FHx POS; n = 8). Beta cell function was evaluated during a frequently sampled intravenous glucose tolerance test, by a low dose graded glucose infusion, and by the ability of the beta cell to be entrained by an oscillatory glucose infusion. PCOS FHx POS women were significantly less likely to demonstrate appropriate beta cell compensation for the degree of insulin resistance. The ability of the beta cell to entrain, as judged by the spectral power for insulin secretion rate, was significantly reduced in PCOS FHx POS subjects. In conclusion, a history of NIDDM in a first-degree relative appears to define a subset of PCOS subjects with a greater prevalence of insulin secretory defects. The risk of developing NIDDM imparted by insulin resistance in PCOS may be enhanced by these defects in insulin secretion.

Adult↗
PubMed2004

Nutrient-stimulated insulin secretion in mouse islets is critically dependent on intracellular pH.

BACKGROUND: Many mechanistic steps underlying nutrient-stimulated insulin secretion (NSIS) are poorly understood. The influence of intracellular pH (pHi) on insulin secretion is widely documented, and can be used as an investigative tool. This study demonstrates previously unknown effects of pHi-alteration on insulin secretion in mouse islets, which may be utilized to correct defects in insulin secretion. METHODS: Different components of insulin secretion in mouse islets were monitored in the presence and absence of forced changes in pHi. The parameters measured included time-dependent potentiation of insulin secretion by glucose, and direct insulin secretion by different mitochondrial and non-mitochondrial secretagogues. Islet pHi was altered using amiloride, removal of medium Cl-, and changing medium pH. Resulting changes in islet pHi were monitored by confocal microscopy using a pH-sensitive fluorescent indicator. To investigate the underlying mechanisms of the effects of pHi-alteration, cellular NAD(P)H levels were measured using two-photon excitation microscopy (TPEM). Data were analyzed using Student's t test. RESULTS: Time-dependent potentiation, a function normally absent in mouse islets, can be unmasked by a forced decrease in pHi. The optimal range of pHi for NSIS is 6.4-6.8. Bringing islet pHi to this range enhances insulin secretion by all mitochondrial fuels tested, reverses the inhibition of glucose-stimulated insulin secretion (GSIS) by mitochondrial inhibitors, and is associated with increased levels of cellular NAD(P)H. CONCLUSIONS: Pharmacological alteration of pHi is a potential means to correct the secretory defect in non-insulin dependent diabetes mellitus (NIDDM), since forcing islet pHi to the optimal range enhances NSIS and induces secretory functions that are normally absent.

Journal Article↗
PubMed2004

Epidemiology of diabetes and obesity in the United States.

The increased prevalence of type 2 diabetes parallels the increased prevalence of obesity. Abdominal obesity contributes to insulin resistance. To overcome the insulin resistance, the pancreas makes more insulin, keeping the glucose in the normal range. Eventually, the pancreas will fail, resulting in elevated levels of blood glucose. Thus, to develop type 2 diabetes, an individual must have a defect in insulin sensitivity with an accompanying defect in insulin secretion. In the early stages of the disease, glucose can be controlled with appropriate therapeutic lifestyle changes aimed at lowering insulin resistance. As the disease progresses, one has to use medications. Insulin secretagogues increase insulin levels, whereas insulin sensitizers, such as metformin and thiazolidinediones, decrease insulin resistance. The defect in insulin secretion is progressive, and eventually, almost every patient needs exogenous insulin, which may be delayed with appropriate lifestyle changes. Insulin resistance is associated with a clustering of metabolic abnormalities called the insulin-resistance syndrome, which is a component of the metabolic syndrome. Insulin-resistance syndrome includes obesity, hypertension, dyslipidemia, and elevated levels of plasminogen activator inhibitor type 1. These abnormalities increase the risk of cardiovascular disease. Of people with type 2 diabetes, 70% die from premature cardiovascular disease. Prevention of the complications of diabetes requires good control of not only blood glucose but also other manifestations of the insulin-resistance syndrome, including hypertension and lipid abnormalities.

Blood Glucose↗
PubMed2000

Inactivation of lmpA, encoding a LIMPII-related endosomal protein, suppresses the internalization and endosomal trafficking defects in profilin-null mutants.

Profilin is a key phosphoinositide and actin-binding protein connecting and coordinating changes in signal transduction pathways with alterations in the actin cytoskeleton. Using biochemical assays and microscopic approaches, we demonstrate that profilin-null cells are defective in macropinocytosis, fluid phase efflux, and secretion of lysosomal enzymes but are unexpectedly more efficient in phagocytosis than wild-type cells. Disruption of the lmpA gene encoding a protein (DdLIMP) belonging to the CD36/LIMPII family suppressed, to different degrees, most of the profilin-minus defects, including the increase in F-actin, but did not rescue the secretion defect. Immunofluorescence microscopy indicated that DdLIMP, which is also capable of binding phosphoinositides, was associated with macropinosomes but was not detected in the plasma membrane. Also, inactivation of the lmpA gene in wild-type strains resulted in defects in macropinocytosis and fluid phase efflux but not in phagocytosis. These results suggest an important role for profilin in regulating the internalization of fluid and particles and the movement of material along the endosomal pathway; they also demonstrate a functional interaction between profilin and DdLIMP that may connect phosphoinositide-based signaling through the actin cytoskeleton with endolysosomal membrane trafficking events.

Biological Transport↗
PubMed1997

Immunoglobulin binding protein (BiP) function is required to protect cells from endoplasmic reticulum stress but is not required for the secretion of selective proteins.

BiP/GRP78 is a lumenal stress protein of the endoplasmic reticulum (ER) that interacts with polypeptide folding intermediates transiting the secretory compartment. We have studied the secretion and the stress response in Chinese hamster ovary (CHO) cells that overexpress either wild-type immunoglobulin binding protein (BiP) or a BiP deletion molecule (residues 175-201) that can bind peptides and ATP but is defective in ATP hydrolysis and concomitant peptide release. Overexpressed wild-type BiP was localized to the ER and unique vesicles within the nucleus, whereas overexpressed ATPase-defective BiP was localized to the ER and cytoplasmic vesicles but was absent from the nucleus. Compared with wild-type CHO cells, overexpression of ATPase-defective BiP prevented secretion of factor VIII, a coagulation factor that extensively binds BiP in the lumen of the ER. Under these conditions factor VIII was stably associated with the ATPase-defective BiP. In contrast, the secretion of monocyte/macrophage colony stimulating factor, a protein that is not detected in association with BiP, was not affected by overexpression of ATPase-defective BiP. These results show that BiP function is not required for secretion of some proteins and suggest that some proteins do not interact with BiP upon transport through the ER. The presence of unfolded protein in the ER induces transcription of BiP and also elicits a general inhibition of protein synthesis. Overexpression of wild-type BiP prevented the stress-mediated transcriptional induction of BiP in response to either calcium ionophore A23187 treatment or tunicamycin treatment. In contrast, overexpression of ATPase-defective BiP did not prevent the stress induction of BiP, showing that the ATPase activity is required to inhibit transcriptional induction. Overexpression of wild-type BiP, but not ATPase-defective BiP, increased survival of cells treated with A23187. The increased survival mediated by overexpressed wild-type BiP correlated with reduced translation inhibition in response to the stress condition. These results indicate that overexpressed BiP alleviated the stress in the ER to prevent BiP transcriptional induction and permit continued translation of cellular mRNAs.

Adenosine Triphosphatases↗
PubMed1994

Reduced interferon-gamma secretion in neonates and subsequent atopy.

Low interferon-gamma (IFN-gamma) secretion has been found in individuals with active atopic disease. Whether this is a cause or result of the disease process is uncertain. Cord blood IFN-gamma secretion was examined in 35 neonates who were then prospectively followed up for 1 year for the development of atopic disease. Infants who developed either symptoms of atopic disease or a positive IgE-mediated skin prick test at 12 months of age produced significantly less IFN-gamma at birth compared with those who did not (p = 0.005). This reduced secretion of IFN-gamma at birth indicates that the defect in interferon secretion is a primary component of the atopic state rather than an effect of the disease process.

Breast Feeding↗
PubMed1996

Differential secretion of interleukin-8 by human epithelial cell lines upon entry of virulent or nonvirulent Yersinia enterocolitica.

Epithelial cells of the intestinal mucosa are among the first cells encountered by invasive pathogens. Bacterial invasion of the mucosa gives rise to an inflammatory response, characterized by the influx of polymorphonuclear leukocytes. The chemotactic stimulus responsible for this accumulation is unknown, but several in vitro studies have demonstrated that epithelial cells secrete the chemokine interleukin-8 (IL-8), a potent chemoattractant of polymorphonuclear leukocytes, upon bacterial entry. In this study we analyzed the secretion of IL-8 by human intestinal (T84) and cervical (HeLa) epithelial cell lines in response to infection with the enteric pathogen Yersinia enterocolitica. IL-8 was secreted by T84 and HeLa cells in response to invasion by Y. enterocolitica. Virulent Y. enterocolitica induced a significantly lower level of IL-8 secretion than nonvirulent Y. enterocolitica. Subsequent analysis employing a mutant defective in Yop secretion and various yop mutants showed that the reduced secretion of IL-8 is due to the presence of Yop proteins. Our data suggest that YopB and YopD are required for the suppressive effect.

Bacterial Outer Membrane Proteins↗
PubMed1975

Determinants of human adipose tissue lipoprotein lipase. Effect of diabetes and obesity on basal- and diet-induced activity.

The role of insulin in the regulation of human adipose tissue lipoprotein lipase was evaluated. Adipose tissue heparin-releasable lipoprotein lipase (thought to be related to peripheral clearance of plasma triglycerides) was low in insulin-deficient, untreated hyperglycemic diabetic subjects (P less than 0.001) and treatment of hyperglycemia returned the activity to normal. In chronic hyperinsulinism, represented by obesity, heparin-releasable activity among control subjects was correlated to percent of ideal body weight (r=0.53, P less than 0.05) and to fat cell size (r=0.61, P less than 0.02). Acetone-ether powder lipoprotein lipase activity (presumed to reflect total tissue enzyme) was also related to percent of ideal body weight (r=0.76, P less than 0.001 for controls; r=0.67, P less than 0.05 for diabetics) and to fat cell size (r=0.71, P less than 0.01 for controls; r=0.85, P less than 0.01 for diabetics. Postprandial-stimulated insulin secretion was related to diet-induced changes in lipoprotein lipase in control subjects; both were dependent upon the amount of dietary carbohydrate. In contrast, the diabetic patients with low insulin responses, failed to increase lipoprotein lipase activity with feeding. The changes in heparin-releasable (r=0.66, P less than 0.01) and acetone-ether powder (r=0.69, P less than 0.01) activity during feeding were related to the percent increase in plasma insulin. Thus, insulin appears to be important in the regulation of human adipose tissue lipoprotein lipase activity. Elevated insulin levels in obesity and increased insulin secretion after eating were associated with increased lipoprotein lipase activity. Defects in insulin secretion, both in postabsorptive and postprandial states, are associated with low adipose tissue lipoprotein lipase and may lead to hypertriglyceridemia in diabetic man.

Adipose Tissue↗
PubMed1999

Stratum corneum lipid abnormalities in UVB-irradiated skin.

Stratum corneum (SC) lipids are of particular importance in maintaining the permeability barrier function. Although many studies have demonstrated that UVB irradiation of mammalian skin reduces barrier function, the responsible alterations in SC lipid profiles are not known. In this study, we investigated both compositional and morphological alterations in SC lipids with the development of barrier abnormalities caused by daily UVB irradiation in hairless rat skin. The UVB irradiation of suberythemal doses (0.5 minimal erythema dose) significantly increased transepidermal water loss (TEWL) relative to nonirradiated control, indicating a diminished barrier function. Under these conditions, the total amounts of major SC lipid species (ceramides, cholesterol, free fatty acids) in UVB-irradiated SC did not differ from those in nonirradiated SC. However, electron microscopic observations revealed marked abnormalities in the intercellular domains of UVB-irradiated SC, where naturally occurring intercellular multilamellar structures were often absent and leaving the area with the appearance of an empty space. Moreover, in UVB-irradiated SC, individual corneocytes often showed small amounts of intercellular deposition product with abnormal lamellar structure, where lamellar body sphingomyelinase activity was present. These observations demonstrated a partial failure of lamellar body secretion in UVB-irradiated SC and suggested that a defect in the secretion of lamellar body-derived lipids and enzymes to SC intercellular space is, at least in part, responsible for the observed abnormal intercellular structure and barrier disruption.

Animals↗
PubMed1989

Insulin secretion and cAMP metabolism in HIT cells. Reciprocal and serial passage-dependent relationships.

The HIT cell is a variably glucose-responsive clonal line of pancreatic islet beta-cells. To ascertain whether insulin responsiveness to glucose, arginine, isoproterenol, forskolin, and K+ varied in a predictable fashion, full concentration-response curves with these agonists were examined with cells from a span of 25 passages. Basal and stimulated cAMP metabolism were also examined. The findings indicate that insulin responses to glucose diminish progressively with increasing passage number and that studies of glucose-induced insulin secretion should be limited to passages 81 and earlier. This defect in insulin secretion is a general rather than a glucose-specific phenomenon in that insulin responses to the other nonglucose secretagogues also diminished with increasing passage number. All changes in glucose-stimulated responses were limited to diminutions in maximal responses; no alterations in apparent half-maximal effective concentrations (EC50s) were observed. In contrast to the continually diminishing insulin responsiveness observed, hormone inhibition by somatostatin of insulin secretion and basal cAMP metabolism remained intact throughout the passages examined. Interestingly, a reciprocal relationship between insulin responsiveness and cAMP responsiveness was observed. Dramatic cAMP responses to isoproterenol and forskolin were observed with the later passages. We conclude that loss of insulin responsivity in HIT cells is a passage-dependent process that is serial rather than sporadic and global rather than glucose specific. Dramatic reciprocal changes in cAMP metabolism occur in the later passages.

Animals↗
PubMed1998

Intact proinsulin, des 31,32 proinsulin, and specific insulin concentrations among nondiabetic and diabetic subjects in populations at varying risk of type 2 diabetes.

OBJECTIVE: To examine hyperinsulinemia, insulin secretion, and beta-cell function in Pima Indians, South Asians, and whites, populations at varying risk of diabetes. RESEARCH DESIGN AND METHODS: We investigated 136 Pima Indian, 98 Asian, and 80 white nondiabetic and 172 Pima Indian, 40 Asian, and 49 white diabetic subjects. Highly specific assays for insulin, intact proinsulin, and des 31,32 proinsulin were used. Insulin secretion was assessed using ratio of increment (0 to 30 min) in insulin to glucose concentrations during an oral glucose tolerance test (OGTT). RESULTS: Nondiabetic Pima Indians were significantly more obese than Asians and whites. Pima Indian subjects had significantly higher (P < 0.01) fasting insulin concentrations (median 109 pmol/l, range 40-250) than Asian (37 pmol/l, range 17-91) and white (30 pmol/l, range 10-82) subjects. These differences remained significant when controlled for obesity. Nondiabetic Pima Indians also had higher fasting C-peptide concentrations and higher early insulin secretion during an OGTT. Fasting concentrations of intact proinsulin and des 31,32 proinsulin were also significantly higher in Pima Indians (P < 0.01). However, the proportion of proinsulin-like molecules was significantly lower (P < 0.01) in Pima Indians (median 7.9% vs. 12.7% for South Asians and 12.2% for whites). Subjects with diabetes from the three ethnic groups showed significantly higher fasting insulin concentrations but lower 30-min insulin and lower ratios of increment (0-30 min) in insulin to glucose concentrations than did nondiabetic subjects. The proportion of proinsulin-like molecules was not significantly different in diabetic subjects from the three ethnic groups. CONCLUSIONS: These specific assays for insulin indicate that after adjusting for obesity nondiabetic Pima Indians are truly hyperinsulinemic, which is consistent with their insulin resistance as measured by other methods. Hyperinsulinemia in this population with a high risk of diabetes is likely to be due to enhanced insulin secretion. Furthermore, in Pima Indians, the predominant beta-cell secretory product is insulin and not its precursors. We conclude that the differences in the risk of diabetes among these three groups are not due to differences in insulin secretion or insulin processing. Subjects with type 2 diabetes have defective early insulin secretion during OGTTs but show fasting hyperinsulinemia even when specific assays for insulin are used.

Adult↗
PubMed1988

[Pathogenesis and therapy of type I and type II diabetes mellitus].

Diabetes mellitus is a heterogenous syndrome. Insulin dependent type I diabetes is characterised by progressive beta-cell-loss, resulting in a deterioration of insulin secretion. Cause of the beta-cell-destruction is a chronic autoimmune process, which starts already months to years before manifestation of the disease. New advances in the diagnosis of the autoimmune mechanisms, which are responsible for type I diabetes might help to prevent type I diabetes by immunization or immunosuppressive therapy in the near future. At the moment multiple daily insulin injections are the substitution therapy of the choice in type I diabetes mellitus. This kind of therapy is designed to imitate the physiologic dynamics of insulin secretion in healthy subjects. In non insulin dependent diabetes a defect in insulin action seems to be the primary cause of the disease although there are also defects in insulin secretion in type II diabetes mellitus. Most type II diabetics are overweight at the beginning of the disease and the primary goal of therapy in these patients is normalization of bodyweight and improvement of peripheral and hepatic insulin sensitivity. Regular exercise is seen as a cornerstone in the treatment of type I and type II diabetes. Besides the acute blood glucose lowering effect of exercise, regular exercise has beneficial effects on the circulatory system and muscle system, leads to an increase in insulin sensitivity, to a decrease of the daily insulin dosage and to a stabilization of metabolic control. Furthermore beneficial effects of exercise on plasma lipids and lipoproteins are reported. In overweight diabetics regular exercise facilitates normalization of body weight.

Diabetes Mellitus, Type 1↗
PubMed1975

[The role of glucagon in hyperglycemia. A review (author's transl)].

Glucagon is secreted not only by A2-cells of the pancreatic islets but also by A cells in the gastric fundus and duodenum. Several reports have demonstrated that the glucagon plasma concentration is increased in genetic diabetes as well as in many conditions associated with a decreased glucose tolerance such as hepatic cirrhosis, myocardial infarction, infectious diseases, burns, taumatic shock, glucagonomas, acute pancreatitis, acromegaly, pheochromacytoma and Cushing's syndrome. Hyperglucagonemia is particularly important in diabetic ketoacidosis and in non-ketotic hyperosmolar coma. The mechanisms responsible for the diabetic's hyperglucagonemia remain controversial. According to several authors, the increased glucagon secretion is, for its main part, secondary to a prolonged defect in insulin secretion and thus relatively insensitive to an acute insulin administration. According to others, the A cell abnormality is of primary origin, independant from insulin deficiency and its effects are cumulative with those of the insulin lack. Several reports dealing with induced or spontaneous experimental diabetes are in favor of the first or the second hypothesis. It appears likely that glucagon plays a role in the metabolic derangments of diabetes. Indeed, hepatic glucose production is closely related to the ratio of molar concentrations of insulin and glucagon. Finally, in insulin-dependant diabetics, somatostatin infusion reduces plasma glucagon concentration and blood glucose and prevents the development of ketosis after withdrawal of insulin therapy. These results illustrate the contribution of glucagon in the pathogenesis of hyperglycemia and ketosis. Several arguments have been accumulated in favor of the following concept: diabetes hyperglycemia results both from glucose under-utilization secondary to insulin lack and from hepatic glucose over-production due to glucagon excess. Although controversial, the role of glucagon in ketogenesis appears likely.

Acromegaly↗
PubMed2001

pasilla, the Drosophila homologue of the human Nova-1 and Nova-2 proteins, is required for normal secretion in the salivary gland.

From a screen for genes expressed and required in the Drosophila salivary gland, we identified pasilla (ps), which encodes a set of proteins most similar to human Nova-1 and Nova-2. Nova-1 and Nova-2 are nuclear RNA-binding proteins normally expressed in the CNS where they directly regulate splicing. In patients suffering from paraneoplastic opsoclonus myoclonus ataxia (POMA), Nova-1 and Nova-2 proteins are present as auto-antigens. Consistent with a role in splicing, PS is localized to nuclear puncta. The salivary glands of ps mutants internalize normally and maintain epithelial polarity. However, the mutant salivary glands develop irregularities in overall morphology and have defects in apical secretion. The secretory defects in ps mutants provide a potential mechanism for the loss of motor function observed in POMA patients.

Alleles↗
PubMed1997

Platelet activation with combination of ionophore A23187 and a direct protein kinase C activator induces normal secretion in patients with impaired receptor mediated secretion and abnormal signal transduction.

Defects in signal transduction mechanisms may underlie the impaired aggregation and secretion in patients with congenital platelet function defects (CPD). Both protein kinase C (PKC) induced pleckstrin phosphorylation and cytoplasmic Ca2+ mobilization play a major role in secretion. We postulated that combined platelet activation with a cell permeable direct PKC activator 1,2-dioctanoyl-sn-glycerol (DiC8) and ionophore A23187, which possibly bypass the steps involved in the intracellular synthesis of two major mediators (inositol trisphosphate, diacylglycerol), may induce normal dense granule secretion in patients with impaired receptor mediated secretion. We studied eight CPD patients with abnormal aggregation and secretion in response to several different surface receptor-mediated agonists despite the presence of normal dense granule contents. Receptor mediated Ca2+ mobilization and/or pleckstrin phosphorylation were abnormal in seven patients. Platelet activation with a combination of ADP (8 microM) with DiC8 (200 microM) or A23187 (10 microM) improved secretion in four patients. However, platelet activation with a combination of 200 microM DiC8 with 10 microM A23187, or 100 microM DiC8 with 5 microM A23187 induced normal secretion in platelet-rich plasma in all patients. These studies suggest that in such patients with CPD the ultimate process of exocytosis or secretion per se is intact and impaired secretion results from abnormalities in early signal transduction events, possibly upstream of diacylglycerol formation and calcium mobilization. Detailed studies are needed to delineate the specific abnormalities in these heterogenous patients with signal transduction defects.

Adolescent↗