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

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

1. The aims of this study were first, to examine whether deficits in nerve conduction in streptozotocin-diabetic rats could be reversed by a 10% dietary supplement of evening primrose oil. Second, to determine the time-course of reversal, and third, to assess whether the effects could be blocked by the cyclo-oxygenase inhibitor flurbiprofen (5 mg kg-1 day-1). 2. One-month diabetes produced 20% and 15% deficits in sciatic motor and saphenous sensory conduction velocity respectively, which were maintained over 2 months diabetes. 3. The effect of 1-month evening primrose oil treatment on abnormalities caused by an initial month of untreated diabetes was examined. Motor and sensory nerve conduction velocity were restored to the non-diabetic level. 4. Resistance to hypoxic conduction failure was investigated for sciatic nerve trunk in vitro. The 80% conduction failure times were 29% and 55% prolonged by 1- and 2-month diabetes respectively. Evening primrose oil did not reverse the increased hypoxic resistance following 1-month untreated diabetes. 5. Sciatic nerve endoneurial capillary density was not significantly affected by diabetes, but was 16% increased in diabetic rats with reversal by evening primrose oil treatment for 1 month compared to 2-month untreated diabetes. 6. Serial motor conduction velocity measurement after 3-month untreated diabetes revealed complete normalization by evening primrose oil within 4 days. Cessation of treatment resulted in a rapid decline in conduction velocity over 24 h. 7. In a preventive study of 2-month duration, 6 groups of rats were used. These comprised non-diabetic controls, diabetic rats, and evening primrose oil-treated diabetic rats, both with and without flurbiprofen treatment. Flurbiprofen had no significant effect in non-diabetic rats, but produced an 11% worsening of motor conduction velocity and a 21% reduction of sciatic capillary density in diabetic rats. Evening primrose oil prevented the decreases in conduction velocity and increased hypoxic resistance with diabetes, and caused a 23% increase in capillary density. Flurbiprofen completely blocked the effect of evening primrose oil on conduction velocity, resistance to hypoxia, and capillarization.8. Six main conclusions were reached. First, evening primrose oil rapidly reverses conduction deficits in diabetic rats. Second, the effects of treatment may be very short-lived, suggesting a primary metabolic action. Third, evening primrose oil cannot reverse established changes in hypoxic resistance over 1-month treatment. Fourth, long-term treatment causes angiogenesis, suggesting a vascular action. Fifth,products of cyclo-oxygenase-mediated metabolism are necessary for maintaining vasa nervorum integrity in diabetic rats. Sixth, evening primrose oil probably acts by providing substrate for vasodilator prostanoid synthesis by vasa nervorum.
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PMID:The effects of evening primrose oil on nerve function and capillarization in streptozotocin-diabetic rats: modulation by the cyclo-oxygenase inhibitor flurbiprofen. 840 50

Pentoxifylline has several actions that improve blood rheology and tissue perfusion and may therefore potentially be applicable to diabetic neuropathy. The aims of this study were to ascertain whether 2 weeks of treatment with pentoxifylline could correct nerve conduction velocity and blood flow deficits in 6-week streptozotocin-diabetic rats and to examine whether the effects were blocked by co-treatment with the cyclooxygenase inhibitor, flurbiprofen, or the nitric oxide synthase inhibitor, NG-nitro-L-arginine. Diabetic deficits in sciatic motor and saphenous sensory nerve conduction velocity were 56.5% and 69.8% corrected, respectively, with pentoxifylline treatment. Sciatic endoneurial blood flow was approximately halved by diabetes and this deficit was 50.4% corrected by pentoxifylline. Flurbiprofen co-treatment markedly attenuated these actions of pentoxifylline on nerve conduction and blood flow whereas NG-nitro-L-arginine was without effect. Thus, pentoxifylline treatment confers neurovascular benefits in experimental diabetic neuropathy, which are linked at least in part to cyclooxygenase-mediated metabolism.
Int J Exp Diabetes Res 2000
PMID:Pentoxifylline effects on nerve conduction velocity and blood flow in diabetic rats. 1146 90

Alterations in cyclooxygenase (COX) pathway activity have been implicated in the pathogenesis of experimental diabetic neuropathy (EDN). These studies explore the relationships between COX-mediated and acetyl-L-carnitine (ALC)-sensitive defects that contribute to functional, metabolic, and vascular abnormalities of EDN. The effects of nonselective COX inhibition with flurbiprofen were contrasted with selective COX-2 inhibition with meloxicam, administered alone and in combination with ALC in nondiabetic (ND) and streptozotocin-induced diabetic (STZ-D) rats. Flurbiprofen treatment of ND rats replicated many of the biochemical and physiological abnormalities of EDN, i.e., reduced motor nerve conduction velocity (MNCV), total and endoneurial nerve blood flow (NBF), Na,K-ATPase activity, and myo-inositol (MI) and taurine content. In STZ-D rats, however, flurbiprofen paradoxically prevented endoneurial NBF deficits but not MNCV slowing. Coadministration of 50 mg x kg(-1) x day(-1) ALC prevented reductions in MNCV, Na,K-ATPase activity, and endoneurial NBF in flurbiprofen-treated ND and STZ-D rats. In contrast, selective COX-2 inhibition with meloxicam was without effect on MNCV, NBF, or MI content in ND rats and prevented MNCV slowing and NBF deficits in STZ-D rats. Western blot analysis showed unchanged sciatic nerve COX-1 protein but increased COX-2 protein abundance in STZ-D versus ND rats. These results imply 1) a tonic role of the COX-1 pathway in the regulation of nerve osmolytes and Na,K-ATPase activity and the maintenance of NBF in ND animals and 2) activation of the COX-2 pathway as an important mediator of NBF and MNCV deficits in EDN.
Diabetes 2002 Aug
PMID:Dissection of metabolic, vascular, and nerve conduction interrelationships in experimental diabetic neuropathy by cyclooxygenase inhibition and acetyl-L-carnitine administration. 1214 79

Body weight regulation is mediated through several major signaling pathways, some of which have been delineated by positional cloning of spontaneous genetic mutations in mice. Lepr(db/db) mice are obese due to a defect in the signaling portion of the leptin receptor, which has led to extensive study of this highly conserved system over the past several years. We have created an allelic series at Lepr for the further examination of LEPR signaling phenotypes using both the FLP /frt and CRE /loxP systems. By inserting a frt-PGK-neo-frt sequence in Lepr intron 16, we have generated a conditional gene repair Lepr allele ( Lepr-neo) that elicits morbid obesity, diabetes, and infertility in homozygous mice, recapitulating the obesity syndrome of Lepr(db/db) mice. Thus, in vivo excision of the PGK-neo cassette with a FLP recombinase transgene restores the lean and fertile phenotype to Lepr(flox/flox) mice. In the same construct, we have also inserted loxP sites that flank Lepr coding exon 17, a region that encodes a JAK docking site required for STAT3 signaling. CRE-mediated excision of Lepr coding exon 17 from Lepr with a frameshift in subsequent exons results in a syndrome of obesity, diabetes, and infertility in LeprDelta17/Delta17 mice, which is indistinguishable from Lepr(neo/neo) and Lepr(db/db) mice. We conclude that suppression of Lepr gene expression by PGK-neo is phenotypically equivalent to deletion of the Lepr signaling motifs, and therefore the Lepr(neo/neo) mouse may be used to investigate conditional gene repair of Lepr signaling deficiency.
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PMID:An allelic series for the leptin receptor gene generated by CRE and FLP recombinase. 1538 15

Obesity is associated with several diseases including diabetes, nonalcoholic steatohepatitis (NASH), hypertension, cardiovascular disease, and cancer. Therefore, anti-obesity drugs have the potential to prevent these diseases. In the present study, we demonstrated that flurbiprofen, a nonsteroidal anti-inflammatory drug (NSAID), exhibited therapeutic potency against obesity. Mice were fed a high-fat diet (HFD) for 6 months, followed by a normal-chow diet (NCD). The flurbiprofen treatment simultaneously administered. Although body weight was significantly decreased in flurbiprofen-treated mice, growth was not affected. Flurbiprofen also reduced the HFD-induced accumulation of visceral fat. Leptin resistance, which is characterized by insensitivity to the anti-obesity hormone leptin, is known to be involved in the development of obesity. We found that one of the possible mechanisms underlying the anti-obesity effects of flurbiprofen may have been mediated through the attenuation of leptin resistance, because the high circulating levels of leptin in HFD-fed mice were decreased in flurbiprofen-treated mice. Therefore, flurbiprofen may exhibit therapeutic potential against obesity by reducing leptin resistance.
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PMID:Therapeutic potential of flurbiprofen against obesity in mice. 2481 92