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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Our previous data suggested that lipoxygenation of endogenously released arachidonic acid (AA) is a critical step in stimulus-secretion coupling in the pancreatic beta cell. In the current study using monolayer cultures of neonatal rat islet cells, exogenous arachidonic acid (AA) (5 micrograms/ml) potently stimulated insulin release in the presence of a substimulatory glucose concentration, and potentiated release induced by glucose. Since the latter stimulatory effect of AA is prevented by inhibitors of the lipoxygenase pathway, we examined the effects of various lipoxygenase pathway products on glucose-induced insulin secretion. The mediator was not one of the stable end-products of either limb of the lipoxygenase pathway: 12- or 5-hydroxyeicosatetraenoic acid (HETE) (0.5-2000 ng/ml) did not alter insulin release, whereas 11-HETE, 15-HETE, leukotriene (LT)B4 and the delta 6 trans isomers of LTB4, LTC4 and 11-trans LTC4 all inhibited insulin release. Furthermore, diethylcarbamazine, a selective leukotriene synthesis inhibitor, did not prevent AA- or glucose-induced insulin release, arguing against a role for LTs as the mediator of AA's stimulatory effect. However, the unstable intermediate 12-hydroperoxyeicosatetraenoic acid (12-HPETE), and positional isomers of 12-HPETE, potentiated glucose-induced insulin secretion.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1984 Feb
PMID:Effects on glucose-induced insulin secretion of lipoxygenase-derived metabolites of arachidonic acid. 631 13

Hyperglycemic diabetics are prone to unusual or especially severe infections; at the cellular level, diabetic polymorphonuclear leukocytes (PMNs) show defects in several antimicrobial functions. However, the basis for these defects is unknown, and they may not be fully ascribable to hyperglycemia, hypoinsulinemia or acidosis alone. Recently, it has been shown that several important PMN functions may be mediated (at least in part) by metabolites of arachidonic acid synthesized via the lipoxygenase pathway, especially arachidonate hydroperoxides and leukotriene (LT) B4. We speculate that synthesis of these mediators may be deficient in severely hyperglycemic diabetics (fasting plasma glucose greater than 250-300 mg/dl) due to deficiencies of substrate (arachidonic acid) synthesis and release. Such defects might be expected since, in animal studies, severe insulin lack and glucagon excess inhibit the desaturation of precursor fatty acids to arachidonic acid. On the other hand, whereas low levels of lipid peroxides or their derivatives may be required in certain cells for normal function, excessive levels of such compounds also are detrimental to cellular function and could play a role as well in the complications of milder or partially treated diabetics who manifest high basal insulin levels. For example, cells which may be particularly sensitive to an excess of peroxides include islet beta cells, PMNs and possibly vascular endothelial cells (all of which appear to be deficient in glutathione peroxidase). These observations suggest a role for accumulation of lipid peroxides in the impaired insulin secretion, defective PMN function and possibly endothelial death and increased vascular (retinal, endothelial, and renal) permeability of some milder diabetics. The available data are compatible with the speculation that in partially treated or lesser degrees of hyperglycemia, increased arachidonate synthesis and excessive lipid peroxidation may be present. Although it remains to be established that all of the results from experimentally-induced diabetics can be extrapolated to humans, these findings suggest that the cell damage attendant upon peroxide generation might be susceptible to prophylactic treatment with anti-oxidants such as alpha-tocopherol or ascorbic acid. In the more severe or later stages of hyperglycemia, a deficiency of lipoxygenase-derived products may supervene; dietary modifications designed to increase essential fatty acid availability might present a unique ancillary therapeutic approach at this stage of diabetes.
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PMID:Altered arachidonic acid synthesis and lipid peroxidation in diabetes mellitus: possible roles in leukocyte dysfunction and other cellular defects. 642 13

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

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.
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PMID:Hypersensitivity to norepinephrine in vasa deferentia from diabetic rats. Possible participation of metabolic products of arachidonic acid. 643 31

We examined the ability of heart, aorta and lung obtained from alloxan diabetic rats as well as control rats to produce peptide leukotrienes (LT). The isolated perfused heart preparation as well as incubated minced tissue preparations were studied. Upon infusion of the Ca++ ionophore A23187, hearts from diabetic rats produced significantly less peptide LT when compared to control hearts. Lung tissue from diabetic animals incubated with A23187 also produced less immunoreactive peptide leukotrienes (iLT) when compared to the control group. In both preparations, incubation with the lipoxygenase inhibitor propyl gallate significantly inhibited the production of iLT in both the diabetic and control group. The observed differences in production of leukotrienes may alter vascular reactivity and thus play a role in the cardiovascular complications observed in diabetes.
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PMID:Leukotriene production in isolated tissues of diabetic rats. 644 Jan 51

Eicosanoids (prostaglandins) can alter renin secretion and angiotensin (ANG) II action. We have studied the effects of both prostacyclin and a lipoxygenase (LO) product, 12-hydroxyeicosatetraenoic acid (12-HETE), on renin in normal and streptozotocin-induced diabetic rats. 12-HETE is not only a potent inhibitor of basal renin secretion but also a key mediator of ANG II-induced renin inhibition. We have also examined the effects of ANG II on 12-HETE formation in normal and diabetic animals. Both plasma (3.9 +/- 0.9 vs. 0.8 +/- 0.1 ng ANG I.ml-1.h-1, P < 0.01) and tissue (38 +/- 6 vs. 21 +/- 2 ng ANG I.mg tissue-1.h-1, P < 0.05) renin activity levels were markedly reduced in diabetic animals. Iloprost (10(-6) mol/l), a stable analog of prostacyclin, had similar stimulatory effects on renin secretion in both normal and diabetic tissues, but the response was enhanced by LO inhibition in diabetic tissue. 12-HETE (10(-7) mol/l) had an exaggerated effect on renin inhibition in diabetic tissue (78 +/- 2% normal vs. 65 +/- 4% diabetic, P < 0.05). Similarly, ANG II (10(-8) mol/l) inhibition of renin was significantly enhanced in diabetic rats (P < 0.001). However, ANG II did not produce an exaggerated increase in 12-HETE in diabetic renal tissue. Insulin reversed the inhibitory effects of ANG II on renin in normal rats, but it blunted the effect of ANG II in diabetic rats. These studies suggest that, while the capacity of renal cortical tissue to synthesize 12-HETE in response to ANG II is not altered, 12-HETE and ANG II actions are exaggerated in diabetes, and this may contribute to reduced renin production.
Diabetes 1995 Mar
PMID:Renin response to 12-hydroxyeicosatetraenoic acid is increased in diabetic rats. 753 33

We have studied the liver 15-hydroxyeicosatetraenoic acid (15-HETE) and leukotriene B4 (LTB4) levels in streptozotocin- (ST)-induced diabetes in rats using liquid chromatography and radioimmunological techniques. Diabetic rats showed significant alterations of liver lipoxygenase metabolites when compared to controls. These 15-HETE and LTB4 increases were concomitant with raised levels of plasma and tissue thromboxane B2 (TXB2) and also urinary 2,3-dinor-TXB2 in plasma and urine, respectively. These changes confirm an activation of 5- and 15-lipoxygenase in the liver 3 days after i.p. ST administration.
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PMID:Liver lipoxygenase arachidonic acid metabolites in streptozotocin-induced diabetes in rats. 770 6

The specific activities of superoxide dismutase, catalase, and glutathione S-transferase (mu subtype) were significantly lower in the brains of mice with type II diabetes than in the brains of control mice. On the other hand, the specific activity of glutathione peroxidase was unaltered. The concentration of vitamin E, but not that of total glutathione and ascorbate, was increased in the brains of the type II diabetic mice. The relative amount of polyunsaturated fatty acids (as determined with soybean lipoxygenase) was increased in whole brains and crude synaptosomal membranes of the type II diabetic mice. Endogenous levels of thiobarbituric acid-positive material were decreased in both whole brain homogenates and crude synaptosomal membranes of the db/db mice. Susceptibility of lipids within whole brain homogenates and crude synaptosomal membranes of mice with type II diabetes to peroxidation with iron/ascorbate was also markedly decreased compared with that of controls. Vitamin E is known to quench lipid peroxidation. Therefore, decreased lipid peroxidation in the type II mouse brain may be due to increased vitamin E content.
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PMID:Antioxidant defense systems in the brains of type II diabetic mice. 779 Aug 73

Basic and clinical investigations into the roles of arachidonate-derived compounds in regulating renal function under normal and pathophysiological conditions continued to expand over the past year. Exciting new insights regarding the pathobiology of thromboxane A2 revealed new roles for this potent cyclooxygenase-derived vasoconstrictor in the glomerular dysfunction that accompanies inflammatory disorders and insulin-dependent diabetes. Major advances have extended our understanding of the proinflammatory actions of leukotriene B4 and other 5-lipoxygenase compounds in mediating glomerular injury during experimental glomerulonephritis. Intriguingly, emerging evidence suggests the presence of an anti-inflammatory arm in the lipoxygenase pathway, ie, 15-lipoxygenase, products of which may act as endogenous leukotriene antagonists. New information has also become available about the renal biology of cytochrome P-450 metabolites of arachidonic acid as well as about nonenzymatically generated biologically potent eicosanoids, the F2-isoprostanes.
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PMID:Arachidonate and renal function. 792 69

The mechanisms responsible for diabetes mellitus-induced enhancement of prostaglandin (PG) F2 alpha response were investigated in vascular smooth muscles isolated from diabetic mice and rats. Streptozocin (150 mg/kg, i.v. bolus, 6 week-elapsed)-ddY mice and (60 mg/kg, i.v. bolus)-Wistar rats and genetically diabetic GK-rats were used. The responses to PGF2 alpha were enhanced in small blood vessels such as mesenteric arteries (diabetic rats) and veins (diabetic mice) and they were reduced in large blood vessels such as the aorta and vena cava (diabetic rats). The enhanced response to PGF2 alpha in diabetic blood vessels was significantly inhibited by nordihydroguaiaretic acid (NDGA) (0.03 mM) and phenidone (0.05 mM), lipoxygenase inhibitors, cycloheximide (1 mg/kg, i.v.), a protein synthesis inhibitor and actinomycin D (2.8 mg/kg, i.v.), a RNA polymerase inhibitor, but neither inhibited by cyclooxygenase inhibitors, a thromboxane antagonist, nor Ca2+ antagonists. The PGF2 alpha response was also enhanced with aging alone, whereas the extent of enhancement was less than that with diabetes mellitus, and not significantly blocked by NDGA. These results demonstrate that diabetes mellitus-induced imbalance in the regulation of the eicosanoid metabolic pathways (suppressed cyclooxygenase and accelerated lipoxygenase) may cause the enhancement of PGF2 alpha-induced responses in small blood vessels.
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PMID:Diabetes mellitus-induced enhancement of prostaglandin F2 alpha-responses is inhibited by lipoxygenase- but not cyclooxygenase-inhibitors in mesenteric veins and arteries of mouse and rat. 802 31


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