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

Published information derived from studies of prostaglandins on carbohydrate homeostasis and insulin secretion has been considered somewhat controversial by many investigators. An analysis of the literature published since 1876 suggests that this controversy has its roots in imprecise terminology and overgeneralization of data rather than irreconcilable scientific experiments. The two major sources of confusion have been failure to distinguish glucose-induced acute insulin responses from insulin secretion in general and failure to appreciate that the behavior of indomethacin is not consistent with the effects of other nonsteroidal antiinflammatory drugs (cyclooxygenase inhibitors) on glucose homeostasis and insulin secretion. When acute insulin responses to glucose specifically are examined and data from indomethacin studies are excluded, the available information consistently indicates that prostaglandin E has adverse effects on glucose homeostasis and insulin secretion.
Diabetes 1983 Mar
PMID:Hypothesis. PGE, carbohydrate homeostasis, and insulin secretion. A suggested resolution of the controversy. 633 2

As an initial step to investigate the possibility that abnormal polymorphonuclear leukocyte (PMNL) function in diabetes might be related to abnormalities of arachidonic acid metabolism, product of the cyclooxygenase pathway were assayed in PMNL from 27 insulin-treated diabetic subjects and 27 age- and sex-matched nondiabetic subjects. It was found that the major prostanoid products formed were thromboxane B2 (TxB2) and prostaglandin E (PGE). Production of both these substances was greatly enhanced in PMNL from control and diabetic subjects by exposure to a killed preparation of Staphylococcus aureus (S. aureus) or to zymosan. There was a marked reduction in the production of TXB2 by PMNL from diabetic subjects in response to stimulation by both S. aureus [670 +/- 98 (SE) versus 1010 +/- 76 pg/10(6) PMNL/90 min, P less than 0.01] and zymosan (583 +/- 53 versus 1034 +/- 46 pg/10(6) PMNL/90 min, P less than 0.001). Similarly, production of PGE was significantly reduced in diabetics in response to both S. aureus (145 +/- 29 versus 232 +/- 16 pg/10(6) PMNL/90 min, P less than 0.05) and zymosan (181 +/- 21 versus 271 +/- 27 pg/10(6) PMNL/90 min, P less than 0.01). There was no relation between the plasma glucose at the time of the test and the production of either prostanoid. Diminished production of cyclooxygenase products of arachidonic acid metabolism should be added to the known abnormalities of PMNL in diabetes. In view of the demonstrated or inferred effects of cyclooxygenase products on aspects of PMNL function, this observation may be important in understanding the pathogenesis of PMNL dysfunction in diabetes.
Diabetes 1983 Jul
PMID:Diminished production of thromboxane B2 and prostaglandin E by stimulated polymorphonuclear leukocytes from insulin-treated diabetic subjects. 634 41

Although exogenous prostaglandins are recognized modulators of insulin secretion, the relationship between their endogenous synthesis and insulin secretion has not been rigorously studied in isolated adult rat islets. Using 3H-arachidonic acid as a tracer, we evaluated the effect of glucose stimulation upon the incorporation of this fatty acid into islet phospholipids and prostaglandins (separated by extraction and sequential silicic acid, thin-layer and paper chromatography). We observed that 3H-arachidonic acid was incorporated into islet phospholipids and prostaglandins under basal conditions (0.3 mg/ml glucose). Furthermore, exposure of islets to a stimulatory glucose concentration led to significant increases in the recovery of 3H-arachidonic acid-derived radioactivity in islet phosphatidylethanolamine, phosphatidylserine, sphingomyelin, and phosphatidylinositol as well as into all of the measured prostaglandins (A2, B2, D2, E2, and F2 alpha). The most marked increases in recovered radioactivity resulting from a stimulatory glucose concentration were in islet phosphatidylethanolamine and prostaglandin A2 (which we believe to be derived, in large part, from endogenously synthesized prostaglandin E2). These glucose-induced increases in 3H-arachidonic acid-derived radioactivity in both the phospholipid and the prostaglandin fractions were eliminated by the inhibition of phospholipase A2 activity with mepacrine or by the inhibition of cyclooxygenase activity with sodium salicylate. When islets prelabeled with 3H-arachidonic acid were exposed to a high glucose concentration in a perifusion system, there was a brisk extracellular release of radioactivity (presumably representing unidentified prostaglandins) that began within 1 min and that peaked slightly before the peak of the first phase of insulin secretion.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1983 Jun
PMID:Endogenous prostaglandin synthesis and glucose-induced insulin secretion from the adult rat pancreatic islet. 635 79

Enhancement of arachidonic acid metabolism results in increased insulin secretion. To determine which pathways of arachidonic acid metabolism were involved in this stimulation, we studied the effects of various inhibitors of arachidonate metabolism on arginine-induced insulin and glucagon secretion in the isolated, perfused rat pancreas. The release of PGE2 from the pancreas was monitored to document the efficacy of the inhibitory drugs. p-Bromophenacyl bromide, a phospholipase A2 inhibitor, diminished PGE2 release and significantly inhibited both the early and late phases of insulin and glucagon release in response to arginine. Flurbiprofen, a specific cyclooxygenase inhibitor, decreased the early phase of insulin release and inhibited both phases of arginine-stimulated glucagon secretion; these decreases were concurrent with a large inhibition of PGE2 release. Nordihydroguaiaretic acid, a lipoxygenase inhibitor, at a dose of 10(-5) M did not affect PGE2 release, inhibited the early phase of insulin release, and did not modify glucagon secretion. The combination of flurbiprofen and nordihydroguaiaretic acid, although the most potent in inhibiting PGE2, lowered only the early phase of insulin and had no effect on glucagon secretion. We conclude that: (1) endogenous cyclooxygenase-derived metabolites of arachidonic acid promote insulin and glucagon release, (2) endogenous lipoxygenase products preferentially stimulate insulin release, and (3) phospholipase A2 activity has an intrinsic modulatory effect on insulin and glucagon secretion.
Diabetes 1984 Oct
PMID:Possible role of endogenous arachidonic acid metabolites in stimulated release of insulin and glucagon from the isolated, perfused rat pancreas. 643 60

Arachidonic acid metabolism via the cyclooxygenase pathway and the effects of aspirin and indomethacin were studied in whole retinas of rats with streptozotocin-induced diabetes. Diabetes was induced by intravenous injection of streptozotocin (60 mg/kg) and the animals were examined 5-6 weeks later. Whole retinas of nondiabetic and diabetic animals were incubated for 1 1/2 hours, and the amounts of prostacyclin and prostaglandin E2 (PGE2) accumulated in the media were measured. The amounts of PGE2 in the media of diabetic retinas was significantly lower than levels in media of nondiabetic group. However, the amounts of prostacyclin accumulated in the media of nondiabetic and diabetic retinas did not differ significantly. Addition of arachidonic acid (A.A.) to the incubation media caused an enhancement in the amounts of PGE2 and prostacyclin in the incubation media of both diabetic and nondiabetic retinas. Addition of indomethacin or aspirin to the incubation media caused a reduction of prostacyclin and PGE2 levels in the media of both groups.
 ...
PMID:Arachidonic acid metabolism by retinas of rats with streptozotocin-induced diabetes. 643 60

Contractile responses to norepinephrine of the vas deferens isolated from normal and diabetic rats as well as tissue radio-conversion of exogenous arachidonic acid, were studied. Vasa deferentia from rats with acute streptozotocin-induced diabetes showed hypersensitivity to exogenous norepinephrine (NE). This increased contractile response was associated with the interaction of the agonist with alpha adrenoceptors. Inhibitors of cyclooxygenase increased and inhibitors of lipoxygenase(s) abolished the enhanced response to NE of diabetic vas deferens. Vasa deferentia from both normal and diabetic rats, converted (1-14C)-arachidonic acid (AA) into PGF, PGE, PGD and thromboxane (TX) B2, but the % of AA metabolites formed was significantly higher in the diabetic than in the normal condition. Moreover, the predominant prostanoid generated by tissue preparations from diabetic animals was PGD2. Taken together the present experimental findings indicate that preparations from rats with acute streptozotocin-induced diabetes have an augmented reactivity towards NE, which appeared associated with changes in metabolites of AA generated via cyclooxygenase and lipoxygenase catalized pathways.
 ...
PMID:Hypersensitivity to norepinephrine in vasa deferentia from diabetic rats. Possible participation of metabolic products of arachidonic acid. 643 31

Autoimmune diabetes is characterized by an early infiltration of lymphocytes into and around islets, which is followed by selective destruction of the insulin-secreting beta-cell. Cytokines released during this inflammatory reaction have been implicated as effector molecules which mediate beta-cell destruction. In vitro treatment of rat islets with the cytokine IL-1 beta results in an inhibition of glucose-stimulated insulin secretion that is mediated by the overproduction of nitric oxide. IL-1 beta also stimulates the production of the cyclooxygenase (COX) product prostaglandin E2 (PGE2). In this study we have examined the effects of IL-1 beta on both inducible nitric oxide synthase (iNOS) and inducible cyclooxygenase (iCOX) expression, and the direct effects of nitric oxide on the activity of COX. Treatment of rat islets with 5 units/mL IL-1 beta induces a similar time-dependent production of both nitrite and PGE2. IL-1 beta-induced nitrite and PGE2 production is attenuated by the NOS inhibitor NG-monomethyl-L-arginine (NMMA), but NMMA has no inhibitory effect on the expression of either iCOX or iNOS as determined by immunoprecipitation. Actinomycin D prevents IL-1 beta-induced iCOX and iNOS expression and the production of both nitrite and PGE2 by islets, suggesting that mRNA transcription is required for IL-1 beta-induced expression of both iNOS and iCOX. The effects of exogenous arachidonic acid on both constitutive COX (cCOX) and iCOX activity were also investigated.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:IL-1 beta induces the coexpression of both nitric oxide synthase and cyclooxygenase by islets of Langerhans: activation of cyclooxygenase by nitric oxide. 750 13

This review discusses recent experimental findings in prostacyclin, nitric oxide and endothelin research. Prostacyclin formation by endothelial cells in atherosclerosis and diabetes is reviewed and the synthesis of prostacyclin by cyclooxygenase 1 and 2 (COX-1 and COX-2) is discussed. Further work on nitric oxide describes its involvement in septic and haemorrhagic shock and its interactions with the cyclooxygenase pathway. Recent studies in endothelin research include the development of both selective and orally active receptor antagonists, characterization of endothelin converting enzymes and the involvement of endothelin-1 in inflammation and wound repair.
 ...
PMID:Regulatory mechanisms of the vascular endothelium: an update. 762 May 13

We examined the effects of diabetes on eicosanoid metabolism and endothelium-dependent relaxation in isolated aorta from alloxan-induced diabetic rabbits and that from normal rabbits incubated in increased concentrations (44 mM) of glucose in vitro for 6 h. Immunoreactive 15-hydroxyeicosatetraenoic acid (HETE) was assayed in the incubation media of isolated aortic segments. Basal and acetylcholine (ACh)-stimulated release of 15-HETE was significantly greater in aorta of diabetic animals as compared with those of normal rabbits. Incubation of aortic segments from normal rabbits in increased concentrations of glucose caused a significant increase in basal and ACh-stimulated release of 15-HETE; and the release was significantly greater in aortic segments with endothelium than in segments without endothelium. Basal and ACh-stimulated release of 15-HETE was inhibited by indomethacin, a cyclooxygenase inhibitor. 15-HETE caused contractions of aortic rings that were inhibited by the prostaglandin H2 (PGH2) thromboxane A2 (TXA2) receptor blocker SQ-29548, but not by the TXA2 synthase inhibitor carbethoxyhexyl imidazole or indomethacin. Treatment of aortic rings with subthreshold concentrations of 15-HETE impaired ACh-induced relaxation; this was prevented by treatment with SQ-29548. Thus, abnormal release of endothelium-derived 15-HETE may play a role in endothelial cell dysfunction and increased vasoconstriction in diabetes by a mechanism that involves interaction with PGH2/TXA2 receptors.
 ...
PMID:15-Hydroxyeicosatetraenoic acid and diabetic endothelial dysfunction in rabbit aorta. 763 Jan 53

Coronary atherosclerosis is the process underlying virtually all the clinical manifestations of ischemic heart disease. When ulcer or fissure in the fibrous cap of the atheroma occur, platelet adhesion to subendothelium, aggregation and further platelet recruitment culminate in thrombus formation. These mechanisms are known to be responsible for most cases of acute events in patients with ischemic heart disease. Inside platelets, aspirin blocks the synthesis of thromboxane A2 by irreversibly inhibiting cyclooxygenase. Aspirin is recommended not only for treatment of patients with acute coronary syndromes (unstable angina, acute myocardial infarction), but also for secondary prevention of vascular events in chronic coronary syndromes. Aspirin prevents myocardial infarction in patients with chronic stable angina and reduces mortality, reinfarction and stroke in survivors of an acute myocardial infarction. Aspirin, alone or in combination with dipyridamole, prevents early and late occlusion of aortocoronary vein grafts. It is useful also in patients undergoing coronary angioplasty. Such benefits extend to all patients regardless of age, sex, history of hypertension or diabetes. Higher daily doses (900-1500 mg) are not more effective than lower doses (75-325 mg). Other antiplatelet drugs are not more effective than aspirin, which has the best risk-to-benefit and cost-to-benefit ratios. Ticlopidine is a reasonable alternative for use in preventing vascular events among patients intolerant to aspirin. Warfarin is an effective antithrombotic alternative to aspirin for secondary prevention after a myocardial infarction. However aspirin is easier to administer and follow-up when compared with warfarin. Warfarin should be preferred in high risk patients with left ventricular dysfunction with or without a mural thrombus, and those with associated atrial fibrillation.
 ...
PMID:[Low-dose aspirin in the long-term treatment of the patient with ischemic heart disease]. 763 59


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>