Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-1 (IL-1) impairs insulin secretion from pancreatic islets and may contribute to the pathogenesis of insulin-dependent diabetes mellitus. IL-1 increases islet expression of nitric oxide (NO) synthase, and the resultant overproduction of NO participates in inhibition of insulin secretion because NO synthase inhibitors, e.g. NG-monomethyl-arginine (NMMA), prevent this inhibition. While exploring effects of IL-1 on islet arachidonic acid metabolism, we found that IL-1 increases islet production of the 12-lipoxygenase product 12-hydroxyeicosatetraenoic acid 12-(HETE). This effect requires NO production and is prevented by NMMA. Exploration of the mechanism of this effect indicates that it involves increased availability of the substrate arachidonic acid rather than enhanced expression of 12-lipoxygenase. Evidence supporting this conclusion includes the facts that IL-1 does not increase islet 12-lipoxygenase protein or mRNA levels and does not enhance islet conversion of exogenous arachidonate to 12-HETE. Mass spectrometric stereochemical analyses nonetheless indicate that 12-HETE produced by IL-1-treated islets consists only of the S-enantiomer and thus arises from enzyme action. IL-1 does enhance release of nonesterified arachidonate from islets, as measured by isotope dilution mass spectrometry, and this effect is suppressed by NMMA and mimicked by the NO-releasing compound 3-morpholinosydnonimine. Although IL-1 increases neither islet phospholipase A2 (PLA2) activities nor mRNA levels for cytosolic or secretory PLA2, a suicide substrate which inhibits an islet Ca(2+)-independent PLA2 prevents enhancement of islet arachidonate release by IL-1. IL-1 also impairs esterification of [3H8]arachidonate into islet phospholipids, and this effect is prevented by NMMA and mimicked by the mitochondrial ATP-synthase inhibitor oligomycin. Experiments with exogenous substrates indicate that NMMA does not inhibit and that the NO-releasing compound does not activate islet 12-lipoxygenase or PLA2 activities. These results indicate that a novel action of NO is to increase levels of nonesterified arachidonic acid in islets.
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PMID:Interleukin-1 enhances pancreatic islet arachidonic acid 12-lipoxygenase product generation by increasing substrate availability through a nitric oxide-dependent mechanism. 855 27

The oxidative processes (oxygen consumption, superoxoid anion generation, arachidonic acid cascade) of human polymorphonuclear granulocytes (PMNs) obtained from patients suffering from thyroid disorders of autoimmune origin (Graves' disease and Hashimoto's thyroiditis), and non autoimmune origin (toxic adenoma) were investigated. All Graves' and toxic adenoma patients were hyperthyroid. Hashimoto's thyroiditis patients were euthyroid. Healthy age and sex matched volunteers served as controls. The results are as follows: 1) In PMNs from both hyperthyroid groups (Graves' disease and toxic adenoma), independently from the autoimmune origin of the disease, a significantly increased Antimycin A sensitive mitochondrial oxygen consumption and a slightly increased superoxide anion generation were detected. 2) In both autoimmune thyroid disease groups (Graves' disease and Hashimoto's thyroiditis)--depending on the functional state of the thyroid gland--a significantly altered intracellular killing activity was measured. 3) An increased arachidonic acid cascade--triggered by opsonized zymozan (OZ)--was detected in both autoimmune thyroid diseases. The increased arachidonic acid cascade was sensitive to phospholipase A2 inhibiting Mepacrin treatment. 4) The PMNs from both autoimmune thyroid diseases produced large amount of leukotriens (LTs)--LTC4 and LTB4--after stimulation through their Fc receptors but the synthesis of prostagalandins (PGs) has not changed. There are no data indicating local, specific effects of circulating leukotriens in the thyroid gland itself, but based on authors' data, their general, regulating role on both the endocrine-- as well as on the immune system--seems to be plausible.
Exp Clin Endocrinol Diabetes 1996
PMID:Parameters of respiratory burst and arachidonic acid metabolism in polymorphonuclear granulocytes from patients with various thyroid diseases. 874 Sep 42

Activation of the polyol pathway under hyperglycemic conditions is proposed to contribute to the development of diabetic nephropathy. The mechanisms by which this activation may lead to functional and structural changes within the kidney are yet to be definitively established. We have examined in vitro the steps linking increased polyol pathway activity resulting from hyperglycemia to prostaglandin production. Following the demonstration of increased prostaglandin E (PGE) levels in glomeruli from diabetic rats (14.9 +/- 2.5 v 59.1 +/- 19.4 ng PGE/mg protein), a specific inhibitor of aldose reductase, HOE-843, was used in vitro to analyze the response to hyperglycemia of the steps preceding prostaglandin production. In explants of glomeruli from control animals, increasing the glucose concentration in vitro from 5.6 mmol/L to 25 mmol/L resulted in a significant increase in the flux of glucose through the pentose phosphate pathway ([PPP] 1.29 +/- 0.08 v 2.00 +/- 0.11 nmol/h), de novo diacylglycerol synthesis (2.2 +/- 0.1 v 3.1 +/- 0.2 micromol/mg protein), membrane protein kinase C (PKC) activity (18.7 +/- 0.5 v 24.3 +/- 0.75 pmol/microg protein), and in vitro phospholipase A2 (PLA2) activity (2.18 +/- 0.46 v 3.83 +/- 1.07 nmol arachidonic acid hydrolyzed/min/mg cytosolic protein). For all parameters measured, the increase resulting from the increased glucose concentration could be prevented by in vitro addition of HOE-843 for 24 hours before measurement. These findings provide evidence to suggest a mechanism linking increased polyol pathway activity and an increase in PLA2 activity to increased prostaglandin production, which is observed in diabetes of recent onset and may ultimately lead to changes associated with the development of diabetic nephropathy.
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PMID:Effect of inhibition of aldose reductase on glucose flux, diacylglycerol formation, protein kinase C, and phospholipase A2 activation. 900 67

An early increased formation of renal prostaglandins in diabetes which follows the hydrolysis of cellular phospholipids by cytosolic phospholipase A2 is of considerable importance in determining subsequent cellular function. As the disposition of concomitantly formed lysophosphatidylcholine may also affect cellular function, we investigated the cellular fate of exogenous lysophosphatidylcholine in mesangial cell-enriched glomerular cores and showed that in cells taken from diabetic rats there is an increased net reformation of phosphatidylcholine. Positional distribution of labelled palmitate from sn-1 position palmitate-labelled lysophosphatidylcholine showed distribution to both sn-1 and sn-2 position of the phosphatidylcholine formed with a significantly increased sn-2 position labelling in diabetes. Although both a coenzyme A-dependent acyltransferase activity and a coenzyme A-independent transacylase activity could be shown in these cells, the increased phosphatidylcholine formation in cells taken from diabetic animals was due to an increase in coenzyme A-independent transacylase activity. By contrast, an increase in coenzyme-A independent transacylase activity could not be demonstrated in cultured mesangial cells maintained with prolonged raised glucose concentrations. Cell homogenates possess the ability to transfer fatty acid from lysophosphatidylcholine to lysophosphatidylcholine and lysophosphatidylethanolamine with subsequent formation of phosphatidylcholine and phosphatidylethanolamine, respectively. In preparations from diabetic animals phosphatidylethanolamine formed in this manner was increased in the presence of an inhibitor of cytosolic phospholipase A2, indicating that it may provide a substrate for phospholipase A2 activity; an effect not seen in cultured cells maintained at raised glucose concentrations. It is concluded that one effect of an altered disposition of lysophosphatidylcholine in cells from diabetic animals would be to spare fatty acids released following phospholipase A2 hydrolysis of phospholipid, possibly providing the substrate for prostaglandin production, an effect not seen with raised glucose alone.
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PMID:Differential disposition of lysophosphatidylcholine in diabetes compared with raised glucose: implications for prostaglandin production in the diabetic kidney glomerulus in vivo. 915 Feb 50

The mechanisms by which diabetes impairs cognitive function are not well-established. In the present study, we determined the electrophysiological and biochemical nature of disturbances in the mechanism of long-term potentiation (LTP) in diabetic rats. As previously reported, the administration of streptozotocin (STZ) was found to reduce the magnitude of LTP in the CA1 region of the hippocampus, while the same treatment did not interact with the capacity of the hippocampus to generate long-term depression induced by low-frequency stimulation. In addition, STZ treatment did not modify the component of excitatory postsynaptic potentials mediated by activation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors, suggesting that NMDA receptor function remained intact in STZ-treated slices. At the biochemical level, the capacity of calcium to increase [3H](RS)-alpha-amino-3-hydroxy-5-methylisoxazole propionic acid (3H-AMPA) binding to glutamate/AMPA receptors in rat brain tissue sections was markedly affected in most regions of the hippocampus of STZ-treated rats. Moreover, changes in 3H-AMPA binding properties elicited by both exogenous phospholipase A2 and melittin, a potent activator of endogenous phospholipases, were also altered in synaptoneurosomes from diabetic rats. Taken together, the present data suggest that the loss of LTP maintenance in STZ-treated rats is more likely the result of disruption of calcium-dependent processes that are suspected to modulate postsynaptic AMPA receptors during synaptic potentiation. Understanding the biochemical factors participating in the impairment of AMPA receptor modulation might provide important clues revealing the very basis of memory deficits in diabetes.
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PMID:Impaired modulation of AMPA receptors by calcium-dependent processes in streptozotocin-induced diabetic rats. 936 22

Insulin secretion induced by cholecystokinin-8 (CCK-8) was recently suggested to involve phospholipase A2 (PLA2) activation. In this study, we examined whether CCK-8 stimulates the Ca2+-independent form of PLA2 in isolated rat islets, in comparison with stimulation by the PLA2-activating cholinergic agonist carbachol. We found that CCK-8 (100 nmol/l; 5.6 mmol/l glucose) induces lysophosphatidylcholine accumulation from [3H]palmitate-prelabeled islets (170 +/- 39%; P = 0.003) as well as arachidonic acid (AA) efflux from [3H]AA-prelabeled islets (190 +/- 13%; P < 0.001), and that p-amylcinnamoylantranilic acid (ACA) (50 micromol/l)-mediated PLA2 inhibition reduces CCK-8-induced AA efflux (52 +/- 11%; P = 0.001) and insulin secretion (67 +/- 16%; P < 0.001). Neither the Ca2+ channel antagonist verapamil (100 micromol/l) nor the Ca2+ATPase inhibitor thapsigargin (1 micromol/l) affected CCK-8-induced AA efflux and insulin secretion. Furthermore, despite removal of extracellular Ca2+, CCK-8 still increased AA efflux (48 +/- 14%; P = 0.006) and insulin secretion (105 +/- 46%; P = 0.025). In contrast, carbachol (100 micromol/l)-stimulated AA efflux was reduced by verapamil by 36 +/- 6% (P < 0.001) and abolished by removal of extracellular Ca2+. Overnight protein kinase C (PKC) downregulation by 12-O-tetradecanoyl phorbol-13-acetate (TPA) (500 nmol/l) reduced CCK-8-induced AA efflux (45 +/- 12%; P = 0.003) and insulin secretion (40 +/- 16%; P = 0.020). No additive action regarding either AA formation or insulin secretion was seen by combining TPA overnight and ACA, which implies the involvement of an additional PLA2- and PKC-independent signaling mechanism. The results show that CCK-8, in contrast to carbachol, activates Ca2+-independent PLA2 in islets and that the PLA2-activating capacity of CCK-8 is partly PKC dependent. Hence, Ca2+-independent PLA2 seems important for the insulinotropic effect of CCK-8, but not for that of carbachol.
Diabetes 1998 Sep
PMID:Ca2+-independent phospholipase A2 contributes to the insulinotropic action of cholecystokinin-8 in rat islets: dissociation from the mechanism of carbachol. 972 32

In this study, male Sprague-Dawley rats weighing 70 +/- 5 g were divided into a control (normal) group and three different diabetes mellitus (DM) groups that were supplemented with catechin-free (DM-0C), 0.5% catechin dietary (DM-0.5C), and 1% catechin (DM-1.0C). The animals were maintained on an experimental diet for four weeks. At this point, they were injected with streptozotocin (STZ) to induce diabetes, and they were sacrificed on the 6th day to determine the activities of phospholipase A2 (PLA2) and the changes of phospholipid species by catechin supplementation. In liver tissues, no significant differences were found between the PC hydrolysis of a normal group and a diabetic group; however, PE hydrolysis of the DM-0C, DM-0.5C, and DM-1.0C groups increased by 68.9%, 34.01%, and 26.9%, respectively, compared with the normal group. Although the PLA2 activity of the DM-0C group in the liver tissues increased 91% compared with the normal group, the PLA2 activity of DM-0.5C and DM-1.0C, which were fed catechin, increased 50% and 56%, respectively, compared with the normal group. In the liver tissues, peroxide values of the DM-0C, the DM-0.5C, and the DM-1.0C groups were increased 109%, 32.8%, and 46.7%, respectively, compared with the normal group. Based on these results for STZ-induced diabetic rats, lipid peroxidation seems to be accelerated specifically with the increased PLA2 activities. Thus if antioxidants like catechin were supplementation, the activity of PLA2 and PE hydrolysis can be altered and the accumulation of lipid peroxide would be decreased. Therefore we concluded that the antioxidant catechin for diabetic animals can significantly reduce PLA2 activities and lipid peroxide formation.
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PMID:Effects of green tea catechin on hepatic microsomal phospholipase A2 activities and changes of hepatic phospholipid species in streptozotocin-induced diabetic rats. 991 87

1. The aim of this study was to examine the mechanism of impaired platelet-mediated endothelium-dependent vasodilation in diabetes. Exposure of human platelets to high glucose in vivo or in vitro impairs their ability to cause endothelium-dependent vasodilation. While previous data suggest that the mechanism for this involves increased activity of the cyclo-oxygenase pathway, the signal transduction pathway mediating this effect is unknown. 2. Platelets from diabetic patients as well as normal platelets and normal platelets exposed to high glucose concentrations were used to determine the role of the polyol pathway, diacylglycerol (DAG) production, protein kinase C (PKC) activity and phospholipase A2 (PLA2) activity on vasodilation in rabbit carotid arteries. 3. We found that two aldose-reductase inhibitors, tolrestat and sorbinil, caused only a modest improvement in the impairment of vasodilation by glucose exposed platelets. However, sorbitol and fructose could not be detected in the platelets, at either normal or hyperglycaemic conditions. We found that incubation in 17 mM glucose caused a significant increase in DAG levels in platelets. Furthermore, the DAG analog 1-oleoyl-2-acetyl-sn-glycerol (OAG) caused significant impairment of platelet-mediated vasodilation. The PKC inhibitors calphostin C and H7 as well as inhibitors of PLA2 activity normalized the ability of platelets from diabetic patients to cause vasodilation and prevented glucose-induced impairment of platelet-mediated vasodilation in vitro. 4. These results suggest that the impairment of platelet-mediated vasodilation caused by high glucose concentrations is mediated by increased DAG levels and stimulation of PKC and PLA2 activity.
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PMID:Effect of protein kinase C and phospholipase A2 inhibitors on the impaired ability of human diabetic platelets to cause vasodilation. 1043 97

Diabetic neuropathy is the most common secondary complication of diabetes mellitus. Several pathogenetic factors have been proposed for diabetic neuropathy. The present investigation was undertaken to study different components of signal transduction from discrete brain regions from streptozotocin-induced diabetic rats. Rats were sacrificed after 1 and 3 months of induction of diabetes, and a control group was also studied in parallel to ascertain the specificity of diabetes-associated changes. Blood glucose level and protein content of discrete brain regions were also estimated. Signal transduction cascade components like protein kinase A, protein kinase C, cAMP, phospholipase C, phospholipase A2, diacylglycerol and inositol phosphate levels were assayed in control and diabetic groups of rats. Significant attenuation in phosphoinositide metabolism along with activation of protein kinase activities were observed. These findings provide evidence to suggest a mechanism linking changes in signal transduction cascade, which is observed in 1- and 3-month diabetic rats, which ultimately leads to development of diabetic neuropathy.
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PMID:Impact of diabetes on CNS: role of signal transduction cascade. 1043 78

We investigated the effect of antibiotics for the prevention of infectious complications subsequent to endscopic treatment of the colon and rectum. Thirty-three patients who underwent endoscopic polypectomies and/or hot-biopsies were divided into two groups: (A, n = 17) with and (B, n = 16) without prophylactic administration of antibiotics. The oral lavage solution method with isotonic magnesium citrate was used for bowel preparation. For group A, 250 mg of kanamycin was administered orally four times, at 30-min intervals, after the oral lavage solution of isotonic magnesium citrate was administered, and 3.2 g of clavulanic acid-ticarcillin was administered by drip infusion after the endoscopic treatment. Latent inflammatory reactions were assessed based on blood cell analysis, erythrocyte sedimentation rate, serum C-reactive protein, and serum phospholipase A2 activity before and the day after the endoscopic treatment. Postoperative platelet, white blood cell, and neutrophil counts were significantly increased in group B, while increases in these parameters were all suppressed in group A. These results suggested that bacterial infections developed subsequent to endoscopic surgery on the colon and rectum. Although we do not need to administer antibiotics to all patients, in patients at high risk of infection, such as those with leukemia or diabetes mellitus, endoscopic polypectomy or hot-biopsy of the colon and rectum should be performed with the administration of antibiotics.
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PMID:Prevention of infectious complications subsequent to endoscopic treatment of the colon and rectum. 1181 Apr 96


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