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PubMed2001

Exercise induced hypoglycaemic hyperinsulinism.

BACKGROUND: Hyperinsulinism in childhood is often caused by genetic defects involving the regulation of insulin secretion leading to recurrent episodes of hypoglycaemia. We report two patients with exercise induced hypoglycaemia. METHODS: Standardised short exercise tests with frequent blood glucose and plasma insulin measurements were performed in the patients and young healthy controls. RESULTS: Short term exercise resulted in insulin induced hypoglycaemia 15 to 50 minutes after the end of exercise. A massive burst of insulin secretion was observed within a few minutes of the start of exercise in both patients. By contrast glucose and insulin concentrations remained unchanged in healthy controls. CONCLUSIONS: Hyperinsulinaemic hypoglycaemia after moderate physical exercise represents a rarely described phenotype of hyperinsulinism with an as yet unknown defect in the regulation of insulin secretion. It should be suspected in individuals with recurrent exercise related syncope or disturbance of consciousness.

Adolescent↗
PubMed1992

Effect of 12,13-phorbol dibutyrate and ionomycin on defective B cells in common variable immunodeficiency.

Secretion of IgM and IgG in vitro by B cells from patients with common variable immunodeficiency (CVI) has been used to classify the disease into three groups. On stimulation with anti-IgM and IL-2, group A patients' cells fail to secrete IgM or IgG, group B patients' cells secrete no IgG and significantly lower levels of IgM than normal cells, and group C patients' cells produce normal levels of both isotypes. Direct activation of protein kinase C using 12,13-phorbol dibutyrate and ionomycin followed by IL-2 or IL-4 has been reported to induce immunoglobulin secretion by normal human B cells. We therefore attempted to induce B cells from group A and group B CVI patients to secrete IgM and IgG after direct activation of protein kinase C together with IL-2 or IL-4. The data show that the failure of secretion of immunoglobulin by B cells from CVI patients could not be reversed using this approach. This finding suggests that the activation channel involving protein kinase C in B cells from CVI patients is not involved in the defect in cell differentiation.

B-Lymphocytes↗
PubMed1989

A central nervous system defect in biosynthesis of corticotropin-releasing hormone is associated with susceptibility to streptococcal cell wall-induced arthritis in Lewis rats.

We have recently found that susceptibility to streptococcal cell wall (SCW)-induced arthritis in Lewis (LEW/N) rats is due, in part, to defective inflammatory and stress mediator-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis. Conversely, the relative arthritis resistance of histocompatible Fischer (F344/N) rats is related to their intact responses to the same stimuli. Specifically, LEW/N rats, in contrast to F344/N rats, have markedly impaired plasma corticotropin and corticosterone responses to SCW, recombinant human interleukin 1 alpha, the serotonin agonist quipazine, or synthetic rat/human corticotropin-releasing hormone (CRH). To explore the mechanism of this defect, we examined the functional integrity of the hypothalamic CRH neuron in LEW/N rats compared to F344/N rats. LEW/N rats, in contrast to F344/N rats, showed profoundly deficient paraventricular nucleus CRH mRNA levels and hypothalamic CRH content in response to SCW. Compared to F344/N rats, there was no increase in LEW/N hypothalamic CRH content or CRH release from explanted LEW/N hypothalami in organ culture in response to recombinant interleukin 1 alpha. These data provide strong evidence that the defective LEW/N corticotropin and corticosterone responses to inflammatory and other stress mediators, and the LEW/N susceptibility to experimental arthritis, are due in part to a hypothalamic defect in the synthesis and secretion of CRH. The additional finding of deficient expression in LEW/N rats of the hypothalamic enkephalin gene, which is coordinately regulated with the CRH gene in response to stress, suggests that the primary defect is not in the CRH gene but is instead related to its inappropriate regulation.

Animals↗
PubMed2006

Interaction of lipoprotein lipase and receptor-associated protein.

Receptor-associated protein (RAP) is a recognized chaperone/escort protein for members of the low density lipoprotein receptor family. In this report, we show that RAP binds to lipoprotein lipase (LPL) and may play a role in the maturation of LPL. Binding of highly purified RAP to LPL was demonstrated in vitro by solid phase assays, surface plasmon resonance, and rate zonal centrifugation. The dissociation constant for this interaction measured by the first two techniques ranged between 2.4 and 13 nM, values similar to those reported for the binding of RAP to LRP or gp330. The specificity of the interaction was demonstrated by competition with a panel of LPL monoclonal antibodies. Rate zonal centrifugation demonstrated the presence of a stable complex with an apparent Mr consistent with the formation of a complex between monomeric LPL and RAP. RAP x LPL complexes were co-immunoprecipitated in adipocyte lysates or from solutions of purified LPL and RAP. The interaction was also demonstrated in whole cells by cross-linking experiments. RAP-deficient adipocytes secreted LPL with a specific activity 2.5-fold lower than the lipase secreted by control cells. Heparin addition to cultured RAP-deficient adipocytes failed to stimulate LPL secretion in the medium, suggesting defective binding of the lipase to the plasma membrane. These studies demonstrate that RAP binds to LPL with high affinity both in purified systems and cell extracts and that RAP-deficient adipocytes secrete poorly assembled LPL. A function of RAP may be to prevent premature interaction of LPL with binding partners in the secretory pathway, namely LRP and heparan sulfate proteoglycan.

Adipocytes↗
PubMed1994

Physiological increase in plasma insulin concentration suppresses proinsulin secretion in normal controls but not in subjects with glucose intolerance.

Since insulin negatively controls its own secretion, we examined if insulin also inhibits the secretion of its precursor, proinsulin, in subjects with varying degrees of glucose tolerance. Under comparable hyperinsulinemia (50-70 microU/ml) achieved by the euglycemic insulin clamp technique, plasma C-peptide concentrations were equally suppressed to approximately 40-50% in nonobese subjects with normal glucose tolerance (NGT) (n = 13, 35.5 +/- 3.7%, M +/- SEM), borderline glucose intolerance (BGI) (n = 12, 46.7 +/- 5.6%), and non-insulin-dependent diabetes mellitus (NIDDM) (n = 12, 48.9 +/- 5.4%). In contrast, plasma proinsulin concentrations were slightly but significantly suppressed in NGT (4.1 +/- 0.2 to 3.7 +/- 0.2 pmol/L, P < 0.05), but not in patients with BGI (4.6 +/- 0.3 to 4.8 +/- 0.5 pmol/L, NS) and NIDDM (5.5 +/- 0.5 to 4.9 +/- 0.4 pmol/L, NS). The basal concentrations of proinsulin increased as glucose tolerance declined (P < 0.05 between NGT and NIDDM). These results suggest that the basal secretion of proinsulin by beta-cells seems relatively insensitive to insulin compared with C-peptide, and that the insulin-proinsulin feedback loop is disturbed in glucose-intolerant subjects. Therefore, a defective feedback inhibition of proinsulin secretion by insulin may be partly involved in the disproportionate increase of plasma proinsulin concentrations in patients with NIDDM.

Adult↗
PubMed1997

Non-invasive Salmonella typhimurium mutants are avirulent because of an inability to enter and destroy M cells of ileal Peyer's patches.

Salmonella typhimurium initiates infection of a host by invading M cells of Peyer's patches within the small intestine. The ability of the bacteria to invade mammalian cells has been shown to be regulated by environmental conditions, including oxygen concentrations, osmolarity, and growth phase. We have previously created oxygen-regulated Tn5lacZY S. typhimurium mutants that are defective in invasion. We have now identified the invasion genes disrupted by eight of the transposon insertions. These genes encode transcriptional regulators (hilA and invF), type III secretory components (orgA, invG and spaR) and secreted proteins (invC and invD). Examination of the protein-secretion profiles of the non-invasive mutants indicated that each of the mutants was defective in secretion of between one and six proteins. We have also demonstrated that the loss of tissue culture cell invasiveness corresponds to an inability to invade and destroy M cells of Peyer's patches in a murine ligated loop model. Virulence studies, performed in mice, demonstrated that these defects significantly reduced the ability of the mutants to cause murine typhoid fever by an oral route of infection. Virulence by an intraperitoneal route of infection was unaffected. The data indicate that in vitro invasiveness, invasion-protein secretion, and M-cell invasion are critical indicators of S. typhimurium virulence.

Amino Acid Sequence↗
PubMed1998

A complex composed of SycN and YscB functions as a specific chaperone for YopN in Yersinia pestis.

Human pathogenic Yersinia resist host defences, in part through the expression and delivery of a set of plasmid-encoded virulence proteins termed Yops. A number of these Yops are exported from the bacteria directly into the cytoplasm of their eukaryotic host's cells upon contact with these cells. The secreted YopN protein (also known as LcrE) is required to block Yop secretion in the presence of calcium in vitro or before contact with a eukaryotic cell in vivo. In this study, we characterize the role of the tyeA, sycN and yscB gene products in the regulation of Yop secretion in Yersinia pestis. Mutants specifically defective in the expression of TyeA, SycN or YscB were no longer able to block Yop secretion in the presence of calcium. In addition, the secretion of YopN was specifically reduced in both the sycN and the yscB deletion mutants. Protein cross-linking and immunoprecipitation studies in conjunction with yeast two-hybrid analyses showed that SycN and YscB interact with one another to form a SycN/YscB complex. Yeast three-hybrid analyses demonstrated that the SycN/YscB complex, but not SycN or YscB alone, specifically associates with YopN. SycN and YscB share amino acid sequence similarity and structural similarities with the specific Yop chaperones SycE and SycH. Together, these results indicate that a complex composed of SycN and YscB functions as a specific chaperone for YopN in Y. pestis.

Antigens, Bacterial↗
PubMed2000

Diverse roles of K(ATP) channels learned from Kir6.2 genetically engineered mice.

The regulation of insulin secretion from pancreatic beta-cells depends critically on the activities of their plasma membrane ion channels. ATP-sensitive K+ channels (K(ATP) channels) are present in many cells and regulate a variety of cellular functions by coupling cell metabolism with membrane potential. The activity of the K(ATP) channels in pancreatic beta-cells is regulated by changes in the ATP and ADP concentrations (ATP/ADP ratio) caused by glucose metabolism. Thus, the K(ATP) channels are the ATP and ADP sensors in the regulation of glucose-induced insulin secretion. K(ATP) channels are also the target of sulfonylureas, which are widely used in the treatment of type 2 diabetes. Molecular cloning of the two subunits of the pancreatic beta-cell K(ATP) channel, Kir6.2 (an inward rectifier K+ channel member) and SUR1 (a receptor for sulfonylureas), has provided great insight into its structure and function. Kir6.2 subunits form the K+ ion-permeable pore and primarily confer inhibition of the channels by ATP, while SUR1 subunits confer activation of the channels by MgADP and K+ channel openers, such as diazoxide, as well as inhibition by sulfonylureas. The SUR1 subunits also enhance the sensitivity of the channels to ATP. To determine the physiological roles of K(ATP) channels directly, we have generated two kinds of genetically engineered mice: mice expressing a dominant-negative form of Kir6.2 specifically in the pancreatic beta-cells (Kir6.2G132S Tg mice) and mice lacking Kir6.2 (Kir6.2 knockout mice). Studies of these mice elucidated various roles of the K(ATP) channels in endocrine pancreatic function: 1) the K(ATP) channels are the major determinant of the resting membrane potential of pancreatic beta-cells, 2) both glucose- and sulfonylurea-induced membrane depolarization of beta-cells require closure of the K(ATP) channels, 3) both glucose- and sulfonylurea-induced rises in intracellular calcium concentration in beta-cells require closure of the K(ATP) channels, 4) both glucose- and sulfonylurea-induced insulin secretions are mediated principally by the K(ATP) channel-dependent pathway, 5) the K(ATP) channels are important for beta-cell survival and architecture of the islets, 6) the K(ATP) channels are important in the differentiation of islet cells, and 7) the K(ATP) channels in glucose-responsive cells generally participate in coupling glucose sensing with cell excitability. Interestingly, despite the severe defect in glucose-induced insulin secretion, Kir6.2 knockout mice show only a very mild impairment in glucose tolerance. However, when the knockout mice become obese with age, they develop fasting hyperglycemia and glucose intolerance, while neither fasting hyperglycemia nor glucose intolerance is evident in the aged knockout mice without obesity, suggesting that both the genetic defect in glucose-induced insulin secretion and the acquired insulin resistance due to environmental factors are necessary to develop diabetes in Kir6.2 knockout mice. Thus, Kir6.2G132S Tg mice and Kir6.2 knockout mice provide a model of type 2 diabetes and clarify the various roles of K(ATP) channels in endocrine pancreatic function.

Adenosine Triphosphate↗
PubMed1993

[Prolactin secretion in patients with endometriosis and its relationship to luteal phase defect and infertility].

UNLABELLED: Serum prolactin (PRL) levels and PRL response to TRH stimulation were studied in 49 patients with endometriosis (EM) during mid-luteal phase. Eight cases with other gyn-diseases and 14 normal fertile women served as controls. Their luteal function were also estimated by three serum progesterone(P) measurements during the luteal phase and endometrial dating in the late luteal phase. RESULTS: The incidence of hyperprolactinemia in EM group (32.7%), and in EM with primary infertility group (61.5%) was significantly higher than that in normal controls (7.1%) (P < 0.05). However, the PRL secretory capacity was not positively correlated to the severity of EM. There was no difference in serum P levels between EM and two control groups. But delayed endometrial maturation was shown in 6 EM infertile cases suggesting luteal phase defect, an incidence of 27.3% (6/22) in EM group or 42.9% (6/14) in EM infertile group. Five out of the six were hyperprolactinemic and had no other identified causes of infertility. These data implied that hyperprolactinemia may impair the luteal function causing infertility in EM patients.

Adult↗
PubMedDate not supplied

A review of new developments in type 2 diabetes in human beings and cats.

Cats appear to be one of the few non-human species that develop a type of diabetes mellitus analogous to human Type 2, or non-insulin-dependent diabetes mellitus (NIDDM). In this review, some current theories on diabetogenesis are discussed. In both cats and human beings, Type 2 diabetes is characterized by impaired insulin secretion due to a functional defect in pancreatic beta-cells, and insulin resistance. In both species, amyloid deposition occurs in pancreatic islets and is derived from the newly discovered pancreatic hormone islet amyloid polypeptide (IAPP), or amylin. Amylin also reduces insulin secretion and induces insulin resistance. Thus, the hypothesis of amylin being intimately involved in the pathogenesis of human and feline Type 2 diabetes appears justified. Obesity is a frequent concomitant problem in feline and human Type 2 diabetes and contributes to the insulin resistance characteristic of the disease.

Animals↗
PubMed2003

Identification of a novel pre-S2 mutation in a subgroup of chronic carriers with spontaneous clearance of hepatitis B virus surface antigen.

BACKGROUND AND AIM: The aim of the present study was to investigate whether spontaneous seroclearance of hepatitis B surface antigen (HBsAg) in patients with chronic hepatitis B could be attributed to the presence of pre-S/S gene mutations. METHODS: Of 34 hepatitis B virus (HBV) carriers who experienced spontaneous seroclearance of HBsAg, 30 were still seropositive for HBV DNA. The serum samples of these carriers were subjected to sequence analysis. RESULTS: A novel pre-S2 mutation, G149R, was found in nine (group I) but not in 17 (group II) patients carrying HBV DNA with intact pre-S/S reading frames. In the remaining four patients (group III), only aberrant pre-S/S transcripts were found in their sera. Distinct patterns of amino acid substitutions specific to group I and II patients were identified. Superinfection by hepatitis C or D virus occurred predominantly in group II patients (P = 0.019). Superinfection by HBV of a different genotype occurred predominantly in patients without hepatitis C or D virus superinfection (P = 0.013). Site-directed mutagenesis experiments showed that secretion of HBsAg was not defective in the pre-S2 G149R mutant. CONCLUSIONS: In a particular subgroup (group I) of patients, seroclearance of HBsAg was not caused by superinfection of other hepatitis viruses, nor was it caused by failure of HBsAg secretion or detection. Instead, a yet unrecognized mechanism associated with emergence of a novel pre-S2 mutation is responsible.

Adult↗
PubMed1999

[Physiopathological fundamentals of type 2 diabetes].

Type 2 diabetes is characterized by 2 major defects: 1. a dysregulation of pancreatic hormone secretion (quantitative and qualitative (early phase, pulsatility) decrease of insulin secretion, increase in glucagon secretion); 2. a decrease in insulin action on target tissues (insulin resistance). The defects in insulin action on target tissues are characterized by a decreased in muscle glucose uptake and by an increased hepatic glucose production. These abnormalities are linked to several defects in insulin signaling mechanisms and in several steps regulating glucose metabolism (transport, key enzymes of glycogen synthesis or of mitochondrial oxidation). These postreceptors defects are amplified by the presence of high circulating concentrations of free fatty acids in obese diabetic subjects (Randle cycle). The increased hepatic glucose production is due to a stimulation of gluconeogenesis secondarily to the enhanced glucagon secretion and to the presence of high circulating concentrations of free fatty acids in obese diabetic subjects (provision of obligatory cofactors such as acetyl-CoA).

Diabetes Mellitus, Type 2↗
PubMed2003

Functions and effectors of the Salmonella pathogenicity island 2 type III secretion system.

Salmonella enterica uses two functionally distinct type III secretion systems encoded on the pathogenicity islands SPI-1 and SPI-2 to transfer effector proteins into host cells. A major function of the SPI-1 secretion system is to enable bacterial invasion of epithelial cells and the principal role of SPI-2 is to facilitate the replication of intracellular bacteria within membrane-bound Salmonella-containing vacuoles (SCVs). Studies of mutant bacteria defective for SPI-2-dependent secretion have revealed a variety of functions that can be attributed to this secretion system. These include an inhibition of various aspects of endocytic trafficking, an avoidance of NADPH oxidase-dependent killing, the induction of a delayed apoptosis-like host cell death, the control of SCV membrane dynamics, the assembly of a meshwork of F-actin around the SCV, an accumulation of cholesterol around the SCV and interference with the localization of inducible nitric oxide synthase to the SCV. Several effector proteins that are translocated across the vacuolar membrane in a SPI-2-dependent manner have now been identified. These are encoded both within and outside SPI-2. The characteristics of these effectors, and their relationship to the physiological functions listed above, are the subject of this review. The emerging picture is of a multifunctional system, whose activities are explained in part by effectors that control interactions between the SCV and intracellular membrane compartments.

Actins↗
PubMed2005

Pancreatic beta-cell lipoprotein lipase independently regulates islet glucose metabolism and normal insulin secretion.

Lipid and glucose metabolism are adversely affected by diabetes, a disease characterized by pancreatic beta-cell dysfunction. To clarify the role of lipids in insulin secretion, we generated mice with beta-cell-specific overexpression (betaLPL-TG) or inactivation (betaLPL-KO) of lipoprotein lipase (LPL), a physiologic provider of fatty acids. LPL enzyme activity and triglyceride content were increased in betaLPL-TG islets; decreased LPL enzyme activity in betaLPL-KO islets did not affect islet triglyceride content. Surprisingly, both betaLPL-TG and betaLPL-KO mice were strikingly hyperglycemic during glucose tolerance testing. Impaired glucose tolerance in betaLPL-KO mice was present at one month of age, whereas betaLPL-TG mice did not develop defective glucose homeostasis until approximately five months of age. Glucose-simulated insulin secretion was impaired in islets isolated from both mouse models. Glucose oxidation, critical for ATP production and triggering of insulin secretion mediated by the ATP-sensitive potassium (KATP) channel, was decreased in betaLPL-TG islets but increased in betaLPL-KO islets. Islet ATP content was not decreased in either model. Insulin secretion was defective in both betaLPL-TG and betaLPL-KO islets under conditions causing calcium-dependent insulin secretion independent of the KATP channel. These results show that beta-cell-derived LPL has two physiologically relevant effects in islets, the inverse regulation of glucose metabolism and the independent mediation of insulin secretion through effects distal to membrane depolarization.

Animals↗
PubMed1995

Prothymosin alpha 1 modulates lymphokine-activated killer cell activity and IL-2 production by peripheral blood lymphocytes from melanoma patients in vitro.

The effects of prothymosin alpha 1 (Pro alpha 1) on the natural killer (NK), lymphokine (IL-2)-activated killer (LAK) cell activity and the phytohaemagglutinin (PHA)-induced IL-2 secretion of peripheral blood T-lymphocytes (PBL) from 34 malignant melanoma patients of all clinical stages were studied in vitro. On average, melanoma patients showed lower NK and LAK cell activities than healthy donors. In particular, patients with metastases revealed an impaired NK cell activity. However, individuals showed a broad range of LAK cell sensitivity to Pro alpha 1 depending, among other factors, on the disease stage. LAK cell activities were not correlated to tumour stage. Patients' impaired LAK cell activity could be restored by Pro alpha 1. Only patients at stage II (regional metastases) responded to Pro alpha 1. The IL-2 secretion from PBL melanoma and healthy donors did not differ, Pro alpha 1 administration was without any significant effect. However, stage III (distant metastases) PBL expressed significantly lower IL-2 levels, compared to stage I (primary tumours). The highest IL-2 levels was found to be associated with tumour stage II. Pro alpha 1 enhanced the IL-2 secretion from stage I PBL. Therefore Pro alpha 1 administration abrogated the defective LAK cell activity and IL-2 secretion of PBL, mainly from patients at early melanoma stages.

Adult↗
PubMed2001

Cystic fibrosis and the use of pharmacogenomics to determine surrogate endpoints for drug discovery.

Cystic fibrosis (CF) is caused by a mutation in the CFTR gene, encoding a chloride channel. For the most common mutation, Delta F508, the basis of the deficit is the failure of the mutant CFTR channel protein to traffic properly to the apical plasma membrane of the affected epithelial cell. The trafficking failure results in loss of the cyclic adenosine monophosphate (cAMP)-activated chloride channel function of the CFTR protein in the plasma membrane. The lung is the principal site affecting patient morbidity and mortality in CF. The main reason is that the CF airway epithelial cells also secrete high levels of the proinflammatory cytokine interleukin (IL)-8, resulting in massive cellular inflammation, infection, tissue damage and lung destruction. The relationship between the trafficking defect, the loss of chloride channel activity, and inflammation is not known. However, gene therapy of CF lung epithelial cells with the wild-type CFTR gene can repair the chloride channel defect, as well as suppress the intrinsic hypersecretion of IL-8. Repair of both defective channels and high IL-8 secretion can also be effected by treatment with the candidate CF drug CPX, which is in clinical trials in CF patients. CPX acts by binding to the mutant CFTR protein, and helps the protein to mature and gain access to the plasma membrane. CPX also suppresses the synthesis and secretion of IL-8 from CF epithelial cells, presumably by virtue of its repair of the trafficking defect of mutant CFTR. To guide pharmacogenomic experiments we have therefore hypothesized that the genomic signature of CF epithelial cells treated with CPX should resemble the signature of the same cells repaired by gene therapy. We have developed two algorithms for identifying genes modified by repair of CFTR defects. The GRASP algorithm uses a statistical test to identify the most profoundly changing genes. The GENESAVER algorithm allows us to identify those genes whose pattern of expression changes in-phase or out-of-phase with IL-8 secretion by CF cells. For the latter algorithm we modified IL-8 secretion from CF cells by treatment with wild-type CFTR, with CPX, or by exposure to bacteria. The results have supported the hypothesis, and have provided a basis for considering the common pharmacogenomic expression signature as a surrogate endpoint for CF drug discovery. Significantly, the nature of the hypothesis, as well as the algorithm developed for this study, can be easily applied to pharmacogenomic studies with other goals.

Animals↗
PubMed1993

Cloning and gene defects in microsomal triglyceride transfer protein associated with abetalipoproteinaemia.

The microsomal triglyceride transfer protein (MTP), which catalyses the transport of triglyceride, cholesteryl ester and phospholipid between phospholipid surfaces, is a heterodimer composed of the multifunctional protein, protein disulphide isomerase, and a unique large subunit with an apparent M(r) of 88K (refs 1-3). It is isolated as a soluble protein from the lumen of the microsomal fraction of liver and intestine. The large subunit of MTP was not detectable in four unrelated subjects with abetalipoproteinaemia, a rare autosomal recessive disease characterized by a defect in the assembly or secretion of plasma lipoproteins that contain apolipoprotein B (ref. 6). We report here the isolation and sequencing of complementary DNA encoding the large subunit of MTP. A comparison of this sequence to corresponding genomic sequences from two abetalipoproteinaemic subjects revealed a homozygous frameshift mutation in one subject and a homozygous nonsense mutation in the other. The results indicate that a defect in the gene for the large subunit of MTP is the proximal cause of abetalipoproteinaemia in these two subjects, and that MTP is required for the secretion of plasma lipoproteins that contain apolipoprotein B.

Abetalipoproteinemia↗