Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute pancreatitis was experimentally produced in dogs to study the effect of the disease on glucose tolerance. The k value (glucose disappearance coefficient measured in percentage decrease of glucose/min) calculated from the high-dose intravenous glucose-tolerance test was used to evaluate the glucose tolerance of each dog. Thirty dogs were allotted to 3 groups of 10 dogs each as follows: group I--nonsurgical control dogs; group II--surgical control dogs; and group III--pancreatitis-affected dogs. To increase their susceptibility to diabetes, 50% partial pancreatectomies and ductal catheterizations were performed on group II and III dogs. Saline solution was infused into the ductal systems of group II dogs, and staphylococcal alphatoxin was infused into the ductal systems of group III dogs to produce pancreatitis. The results indicated that (1) high-dose intravenous glucose-tolerance test was an effective tool for determining decreased glucose tolerance in dogs; (2) glucose tolerance of group III dogs was markedly decreased compared with that of group I and II dogs; (3) staphylococcal alpha-toxin produced signs of moderately severe pancreatitis; and (4) 50% partial pancreatectomy and saline solution infusion produced clinical and clinicopathologic signs of mild pancreatitis. To determine if a simplified k value (calculated using 2 or 3 blood samples) could closely approximate the standard k value (calculated using 6 blood samples), simplified k values were derived from the 5- and 60-minute blood sample values. These values closely approximated the standard k values, indicating the simplified value may be used in the clinical situation. The standard k value, however, is preferred for investigative work.
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PMID:Effect of staphylococcal alpha-toxin pancreatitis on glucose tolerance in the dog. 94 22

The addition to different types of cells of an inositol-phosphate glycan, generated by the phospholipase C-catalyzed hydrolysis of a insulin-sensitive glycosyl-phosphatidylinositol (glycosyl-PI), mimics some of the biological effects of this hormone. Recently, a specific, time-, dose-, and energy-dependent transport system for this inositol-phosphate glycan has been identified in isolated rat hepatocytes. Here, we show that streptozotocin-induced diabetes mellitus reduced (by about 60%) the basal content of the insulin-sensitive glycosyl-PI in isolated rat hepatocytes. Moreover, streptozotocin-induced diabetes blocked the hydrolysis of the glycosyl-PI in response to insulin, diminished inositol phosphate-glycan uptake by the hepatocytes, and abolished the stimulatory effect of this compound on glycogen synthesis. All these metabolic changes caused by streptozotocin administration were reversed by treatment of the animals with insulin. Our results support the hypothesis that insulin resistance in streptozotocin-induced diabetic rats is related to the impairment of glycosyl-PI metabolism.
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PMID:Impairment of glycosyl-phosphatidylinositol-dependent insulin signaling system in isolated rat hepatocytes by streptozotocin-induced diabetes. 139 18

Growth hormone (GH) and insulin-like growth factor I (IGF-I) exert a variety of actions in renal tissue. To shed light upon the renal GH-IGF I axis we have characterized the cell biology of GH and IGF I in two parts of the nephron that are targets for these peptides, proximal tubule and collecting duct. Receptors for both GH and IGF I are present in the basolateral membrane of the renal proximal tubular cell. GH activates phospholipase C and IGF I stimulates phosphorylation of its receptor at this site. Both peptides directly enhance gluconeogenesis in proximal tubule. GH stimulates IGF I gene expression in collecting duct. IGF I of collecting duct origin could act as a paracrine growth factor in other portions of the nephron. IGF I may be causative of renal hypertrophy that occurs in the settings of hypersomatotropism, unilateral nephrectomy (compensatory hypertrophy) and diabetes mellitus.
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PMID:Renal cellular biology of growth hormone and insulin-like growth factor I. 165 79

The RT6 alloantigen of the rat is expressed on most peripheral T cells but not on thymocytes and thus represents a marker for postthymic T lymphocyte maturation in this species. Diabetes-prone (DP) BB rats exhibit a genetically determined T cell lymphopenia associated with a deficiency of RT6+ T cells. In this study we have analyzed the expression of RT6 on lymph node (LN) cells and intestinal intraepithelial lymphocytes (IEL) in two DP BB strains (BB/OK and BB/Mol) and two control strains (non-lymphopenic BB/PhiK and LEW) by flow cytometry. In the DP BB rats the number of LN T cells was substantially reduced (less than 25% TcR2+ cells) and completely lacked RT6 expression. The IEL population was also reduced in number and in marked contrast to normal rats consisted predominantly of CD4+ cells. The majority of IEL, however clearly expressed RT6. Treatment with a phosphatidylinositol (PI)-specific phospholipase C markedly reduced the RT6 density showing that PI-mediated anchoring of RT6 in the cell membrane also applies to IEL of DP BB rats. The results demonstrate that the DP BB strains possess a functional RT6 gene and are also able to generate the PI anchor. The defect in RT6 expression is thus unlikely to be the primary cause of the T cell lymphopenia.
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PMID:Diabetes-prone BB rats express the RT6 alloantigen on intestinal intraepithelial lymphocytes. 171 8

In nonobese diabetic (NOD) mice, T cells play a major role in mediating autoimmunity against pancreatic islet beta-cells. We and others previously reported that age-related alterations in the thymic and peripheral T cell repertoire and function occur in prediabetic NOD mice. To study the mechanism responsible for these T cell alterations, we examined whether a defect exists in the thymus of NOD mice at the level of TCR-mediated signaling after activation by Con A and anti-CD3. We found that thymocytes from NOD mice respond weakly to Con A- and anti-CD3-induced proliferation, compared with thymocytes from control BALB/c, BALB.B, (BALB.B x BALB.K)F1, C57BL/6, and nonobese non-diabetic mice. This defect correlates with the onset of insulitis, because it can be detected at 7 to 8 weeks of age, whereas younger mice displayed a normal T cell responsiveness. Thymic T cells from (NOD x BALB/c)F1 mice, which are insulitis- and diabetes-free, exhibit an intermediate stage of unresponsiveness. This T cell defect is not due to a difference in the level of CD3 and IL-2R expression by NOD and BALB/c thymocytes, and both NOD CD4+ CD8- and CD4- CD8+ mature thymic T cells respond poorly to Con A. BALB/c but not NOD thymic T cells respond to Con A in the presence of either BALB/c or NOD thymic APC, suggesting that the thymic T cell defect in NOD mice is intrinsic to NOD thymic T cells and is not due to an inability of NOD APC to provide a costimulatory signal. The defect can be partially reversed by the addition of rIL-2 to NOD thymocytes. To determine whether a defect in signal transduction mediates this NOD thymic T cell unresponsiveness, we tested whether these cells elevate their intracellular free Ca2+ ion concentration in response to Con A. An equivalent Con A-induced increase in Ca2+ ion concentration in both NOD and BALB/c thymocytes was observed, suggesting a normal coupling between the CD3 complex and phospholipase C in NOD thymocytes. In contrast to their low proliferative response to Con A or anti-CD3, NOD thymocytes respond normally (i.e., as do BALB/c thymocytes) to the combinations of PMA plus the Ca2+ ionophore ionomycin and PMA plus Con A but weakly to Con A plus ionomycin. Our data suggest that the age-related NOD thymocyte unresponsiveness to Con A and anti-CD3 results from a defect in the signaling pathway of T cell activation that occurs upstream of protein kinase C activation.
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PMID:Defective thymic T cell activation by concanavalin A and anti-CD3 in autoimmune nonobese diabetic mice. Evidence for thymic T cell anergy that correlates with the onset of insulitis. 182 15

Incubation of isolated cardiac myocytes from rat hearts with heparin or phosphatidylinositol-specific phospholipase C (PLC) resulted in the release of lipoprotein lipase (LPL) into the medium. The release of LPL by the combination of heparin and PLC was not additive, and preincubation of cardiac myocytes with heparin eliminated the release of LPL in a subsequent incubation with PLC. This evidence suggests that LPL may be bound ionically to heparan sulfate proteoglycans that are covalently linked to the cell surface of cardiac myocytes by a phosphatidylinositol-glycan membrane anchor; a second pool of LPL may also be bound to proteoglycans attached directly to the myocardial cell surface. The induction of diabetes by the administration of streptozotocin (100 mg/kg for 3-4 days) to rats resulted in a decrease in the initial cellular activity of LPL and a marked reduction in the heparin-induced secretion of LPL into the medium of cardiac myocytes. The intravenous administration of insulin (5 U for 1 h) in diabetic rats reversed the effects of diabetes on cellular and heparin-releasable LPL activities. Diabetes also reduced the PLC-induced release of LPL. The reduction in the release of LPL from diabetic cardiac myocytes could result in a decrease in functional LPL activity at the capillary endothelium of whole hearts.
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PMID:Diabetes reduces heparin- and phospholipase C-releasable lipoprotein lipase from cardiomyocytes. 184 7

Glycosylated phosphatidylinositol (gly-Pl) molecules have been implicated as precursors for insulin-sensitive second messengers (1-4) and lipid-anchored membrane proteins (5-9). The relationship between the diverse functions of these lipids and their predicted structural heterogeneity within gly-Pl subtypes was examined in human T lymphocytes. Four subtypes of gly-Pl molecules were identified in T lymphocytes after separation over high-performance thin-layer chromatography by sensitivity to Pl-specific phospholipase C and nitrous acid. Antibody probes of the glycan domain of gly-Pl were developed and used to assess the partial sensitivity of gly-Pl to insulin action. This analysis showed that the effects of insulin are linked to differential utilization of only two of the four gly-Pl subtypes in T lymphocytes. Polar fragments of this reaction were identified in extracellular supernatants from insulin-treated cells. The biological significance of insulin-dependent gly-Pl hydrolysis was demonstrated by insulin and inositol phosphoglycan regulation of glucose metabolism in intact lymphocytes. These results support the hypothesis that multifunctional roles of gly-Pl are served by discrete gly-Pl populations and that metabolites of gly-Pl subsets participate as signaling elements in insulin action.
Diabetes 1991 Oct
PMID:Differential regulation of glycosylated phosphatidylinositol subtypes by insulin. 193 92

The hormonal control of glycogen synthase and phosphorylase interconversion was investigated in hepatocytes isolated from lean and genetically obese (fa/fa) rats. In cells from obese animals, the inactivation of synthase by 4 beta-phorbol 12 beta-myristate 13 alpha-acetate (PMA), phospholipase C, vasopressin and the alpha 1-adrenergic agonist phenylephrine was markedly impaired, and the property of PMA to counteract phosphorylase activation by phenylephrine was attenuated. The maximal response of phosphorylase activation to phenylephrine and vasopressin was increased in obese-rat hepatocytes, but the sensitivity to these hormones was similar to that in lean-rat hepatocytes. These observations indicate that the defect in protein kinase C that we reported previously in heart of insulin-resistant fa/fa rats [van de Werve, Zaninetti, Lang, Vallotton & Jeanrenaud (1987) Diabetes 36, 310-319] is probably also expressed in liver.
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PMID:Altered regulation of glycogen metabolism by vasopressin and phenylephrine in hepatocytes from insulin-resistant obese (fa/fa) rats. Role of protein kinase C. 211 21

Despite significant advances in past years on the chemistry and biology of insulin and its receptor, the molecular events that couple the insulin-receptor interaction to the regulation of cellular metabolism remain uncertain. Progress in this area has been complicated by the pleiotropic nature of the actions of insulin. These most likely involve a complex network of pathways resulting in the coordination of mechanistically distinct cellular effects. Because the well-recognized mechanisms of signal transduction (i.e., cyclic nucleotides, ion channels) appear not to be central to insulin action, investigators have searched for a novel second-messenger system. A low-molecular-weight substance has been identified that mimics certain actions of insulin on metabolic enzymes. This substance has an inositol glycan structure, and is produced by the insulin-sensitive hydrolysis of a glycosylphosphatidylinositol in the plasma membrane. This hydrolysis reaction, which is catalyzed by a specific phospholipase C, also results in the production of a structurally distinct diacylglycerol that may selectively regulate one or more of the protein kinases C. The glycosyl-phosphatidylinositol precursor for the inositol glycan enzyme modulator is structurally analogous to the recently described glycosyl-phosphatidylinositol membrane protein anchor. Preliminary studies suggest that a subset of proteins anchored in this fashion may be released from cells by a similar insulin-sensitive phospholipase-catalyzed reaction. Future efforts will focus on the precise role of the metabolism of glycosyl phosphatidylinositols in insulin action.
Diabetes Care 1990 Mar
PMID:Second messengers of insulin action. 213 71

Lymphocytes bearing the T-lymphocyte differentiation antigen RT6 play an important immunoregulatory role in the development of autoimmune diabetes in BB rats. Immunofluorescence studies suggest that diabetes-prone (DP)- but not diabetes-resistant (DR)-BB rat lymphocytes fail to express RT6 antigen during ontogeny. Two alloantigenic forms of the molecule exist, i.e., RT6.1 and RT6.2; both are linked to cell membranes by a phosphatidylinositol (PI) linkage. In these studies, PI-phospholipase C (PLC) treatment of lymphocytes from BB and normal rats followed by immunoabsorption and sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of released proteins with anti-RT6 allotype-specific monoclonal antibodies was performed. RT6.1 in several nondiabetic rat strains was found to consist of a family of nonglycosylated and variably glycosylated molecules: an N-Glycanase-resistant 24,000- to 26,000-Mr peptide and four N-Glycanase-sensitive peptides of 29,000, 31,000, 33,000, and 34,000 Mr. In contrast, RT6.2 was found to be a 24,000- to 26,000-Mr nonglycosylated polypeptide. The electrophoretic pattern of RT6.1 was observed to be the same when the antigen was extracted from W3/25+ (CD4+) versus W3/25- T lymphocytes or from resting versus mitogen-activated cells. A pattern of bands characteristic of the RT6.1 antigen found in normal rat strains was detected after PLC treatment or detergent solubilization of lymphocytes obtained from DR rats. In contrast, no evidence of either RT6 species was found after PLC or detergent treatment of comparable numbers of T lymphocytes from DP-BB rats. Interestingly, T lymphocytes from Wistar-Furth (RT6.2+) x DP (RT6-) F1 crosses were observed to coexpress both RT6.2 and RT6.1 molecules, with the electrophoretic pattern of RT6.1 being similar to that obtained in DR and other rat strains. This study provides biochemical evidence that DP rats may have an intact RT6a structural gene.
Diabetes 1990 Oct
PMID:Biochemical studies of RT6 alloantigens in BB/Wor and normal rats. Evidence for intact unexpressed RT6a structural gene in diabetes-prone BB rats. 221 79


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