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)

Isolated human pancreatic islets converted [3H8]arachidonate to compounds with the high-performance liquid-chromatographic mobility of cyclooxygenase products, including prostaglandin E2 (PGE2), PGF2 alpha, and the lipoxygenase product 12-HETE. Human islet synthesis of PGE2, PGF2 alpha, and 12-HETE from endogenous arachidonate was demonstrated with stable isotope dilution-gas chromatographic-negative ion-chemical ionization-mass spectrometric analysis. Pharmacologic inhibition of arachidonate metabolism by both lipoxygenase and cyclooxygenase pathways with BW 755C strongly suppressed glucose-induced insulin secretion from perifused human islets, and the selective cyclooxygenase inhibitor indomethacin enhanced insulin secretion. These findings are similar to those reported for islets isolated from rats and suggest that arachidonate metabolites may modulate glucose-induced insulin secretion in humans.
Diabetes 1988 Jul
PMID:Arachidonic acid metabolism and insulin secretion by isolated human pancreatic islets. 313 62

The temporal in vivo expression of the eicosanoids (products of the cyclooxygenase pathway and one product of the 12-lipoxygenase pathway, hepoxilin A3) was investigated after bolus intravenous injection of arachidonic acid in the normal rat and in the genetic rat model of type I insulin-dependent diabetes, the diabetic BB rat. The temporal relationship between the expression of these products and plasma insulin concentrations was also investigated to determine whether any correlation existed between the rise in plasma insulin levels and any of the newly formed eicosanoids. Measurements of the eicosanoids present in whole blood were carried out using the deuterium isotope dilution technique involving separation of pentafluorobenzyl esters, O-methyl oximes, and trimethylsilyl ether derivatives by high-resolution gas chromatography and specific detection by negative ion chemical ionisation mass spectrometry in the selected ion mode. Injection of arachidonic acid resulted in large and statistically significant increases in the blood concentrations of all products within 1 min, with thromboxane B2 (the stable product of thromboxane A2) and trioxilin A3 (the stable product of hepoxilin A3) being the highest (4.5-12 ng/mL). The mean concentrations of thromboxane B2 and trioxilin A3 in blood appeared greater in the diabetic BB rat than in the normal rat, while the opposite was found for 6-keto PGF1 alpha (the stable product of prostacyclin). The apparent greater ratio of thromboxane B2 to 6-keto PGF1 alpha in the diabetic BB rat than in the normal rat supports a prothrombotic nature of platelets associated with diabetes.
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PMID:Appearance of prostaglandins, thromboxane B2, and hepoxilin A3 in the circulation of the normal and diabetic (BB) rat after arachidonic acid administration--correlation with plasma insulin. 314 76

Abnormalities in glomerular function have been observed frequently in the early stages of both clinical and experimental diabetes mellitus. Because prostaglandins (PGs) are present in the glomerulus and have profound effects on glomerular hemodynamics, and because abnormalities of PG metabolism have been noted in other tissues from diabetics, we studied PG biosynthesis in glomeruli obtained from rats in the early stages of experimental diabetes mellitus. Streptozotocin, 60 mg/kg, was administered intravenously to male Sprague-Dawley rats. Control rats received an equal volume of the vehicle. Glomeruli were isolated 9-23 d later. Production of eicosanoids was determined by two methods: by direct radioimmunoassay after incubation of glomeruli under basal conditions and in the presence of arachidonic acid (C20:4), 30 microM, and by radiometric high-performance liquid chromatography (HPLC) after incubation of glomeruli with [14C]C20:4. When assessed by radioimmunoassay, mean basal production of both prostaglandin E2 (PGE2) and prostaglandin F2 alpha (PGF2 alpha) was twofold greater in the diabetic animals whereas production of thromboxane B2 (TXB2) was not significantly greater than control. In response to C20:4, both PGE2 and PGF2 alpha were also greater in the diabetic animals, but these differences were not statistically significant. The increased rate of basal PG production did not appear to be related directly to the severity of the diabetic state as reflected by the degree of hyperglycemia at the time of sacrifice. In fact, the rates of glomerular PG production in the individual diabetic animals correlated inversely with the plasma glucose concentration. The increased rate of PG synthesis did not appear to be due to a nonspecific effect of streptozotocin inasmuch as glomerular PG production was not increased significantly in streptozotocin-treated rats which were made euglycemic by insulin therapy. Furthermore, addition of streptozotocin, 1-10 mM, to the incubation media had no effect on PGE2 production by normal glomeruli. PGE2 production by normal glomeruli was also not influenced by varying the glucose concentration in the incubation media over a range of 1-40 mM. When metabolism of [14C]C20:4 was evaluated by high-performance liquid chromatography conversion to labeled PGE2, PGF2 alpha, TXB2, and hydroxyheptadecatrienoic acid by diabetic glomeruli was two- to threefold greater compared with that in control glomeruli, whereas no significant difference in conversion to 12- and 15-hydroxyeicosatetraenoic acid occurred. These findings indicate that glomerular cyclooxygenase but not lipoxygenase activity was increased in the diabetic animals. A concomitant increase in glomerular phospholipase activity may also have been present to account for the more pronounced differences in PG production noted in the absence of exogenous unlabeled C20:4. These abnormalities in PG biosynthesis by diabetic glomeruli may contribute to the altered glomerular hemodynamics in this pathophysiologic setting.
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PMID:Increased prostaglandin production by glomeruli isolated from rats with streptozotocin-induced diabetes mellitus. 315 47

We have studied the functional importance of renal eicosanoids in renal hemodynamics of seven newly diagnosed insulin-dependent diabetes mellitus (IDDM) patients by treatment with two structurally unrelated inhibitors of cyclooxygenase (i.e., piroxicam and sulindac). Glomerular filtration rate (GFR), renal plasma flow (RPF), daily urinary excretion of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha, the stable hydrolysis product of prostacyclin), and thromboxane B2 (TXB2, the stable hydrolysis product of thromboxane A2) were measured before, during, and after piroxicam (all patients) or sulindac (3 patients) treatment. Urinary excretion of 6-keto-PGF1 alpha was significantly increased (P less than .01) in diabetic patients compared with seven healthy subjects, whereas urinary excretion of TXB2 was unchanged. The baseline value of GFR was significantly (P less than .01) higher in diabetic compared with normal volunteers, whereas baseline RPF was comparable in both groups. Piroxicam (20 mg/day) reduced urinary excretion of 6-keto-PGF1 alpha and TXB2 by 65.7 +/- 26 and 64.6 +/- 33%, respectively. These biochemical changes were temporally associated with the approximately 19% decrease in GFR (P less than .01). A week after discontinuation of the drug, GFR and urinary excretion of 6-keto-PGF1 alpha were still significantly (P less than .05) reduced, whereas urinary excretion of TXB2 returned to control values. In contrast, urinary excretion of eicosanoids and renal function were not affected by sulindac (0.4 g/day) treatment. No functional changes were detected in healthy subjects despite a similar suppression of renal cyclooxygenase activity when they were treated with piroxicam.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1988 Aug
PMID:Renal hemodynamics and urinary excretion of 6-keto-prostaglandin F1 alpha and thromboxane B2 in newly diagnosed type I diabetic patients. 339 43

Glomerular hyperfiltration is an early functional renal lesion seen both in experimental and human diabetes mellitus. This increase in the glomerular filtration rate has been thought to be mediated, in part, by changes in vasoregulatory hormones such as the prostanoids. The present study was designed to measure glomerular prostanoid production in rats with experimental diabetes to determine whether the biochemical changes in prostanoid production could be consistent with the hemodynamic alterations noted. Sprague-Dawley rats were studied either 7 or 28 days after intravenous streptozotocin administration (60 mg/kg). Measurements of the glomerular filtration rate were performed in two groups of diabetic animals 28 days after streptozotocin administration: one group with intact prostanoid production, the other having received a cyclooxygenase inhibitor for the 4-week period. Similar studies were performed in nondiabetic control rats. Measurements of glomerular prostanoid production were performed in control and diabetic animals 7 days after streptozotocin administration. The results of these studies indicate that experimental diabetes mellitus is associated with an increase in the glomerular filtration rate and that this increase can be blocked by the administration of a cyclooxygenase inhibitor. In addition, the determination of levels of various glomerular prostanoids indicated an increased production of prostacyclin and a decreased production of thromboxane during this period of hyperfiltration. Thus, these data support the premise that altered prostanoid biosynthesis may be one of the biochemical mediators of the hyperfiltration seen in early experimental diabetes mellitus.
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PMID:Effect of experimental diabetes on glomerular filtration rate and glomerular prostanoid production in the rat. 380 32

The importance of cyclooxygenase and lipoxygenase pathways in the determination of collagen abnormalities in diabetes was investigated. Pharmacological agents with antiprostaglandin activity, such as indomethacin, naproxen, and aspirin, were able to prevent the rise in thermal rupture time of tail collagen in diabetic rats. Paracetamol was without effect. The action of indomethacin on diabetic collagen was abolished by concurrent administration of sodium benoxaprofen, an inhibitor of lipoxygenase, to the diabetic rats. Collagen abnormalities in diabetes may be regulated by a balance of the cyclooxygenase and lipoxygenase pathways. Antiprostaglandin agents may have a role in the prevention of some diabetic complications.
Diabetes 1985 Jan
PMID:The effects of cyclooxygenase and lipoxygenase inhibitors on the collagen abnormalities of diabetic rats. 391 59

Treatment of isolated, perifused rat islets with exogenous PLA2 in amounts ranging from 1 to 1000 mU/ml caused a dose-dependent increase in the rate of insulin secretion. This effect of PLA2 was rapid and seen in the absence of added exogenous fuel. It differed from glucose-induced insulin release in temporal pattern: high concentrations of PLA2 caused a single phase of secretion, and high levels of glucose caused a biphasic pattern of secretion. Like glucose-induced release, PLA2-induced release was partially dependent on extracellular calcium because D600 caused a significant inhibition of release induced by PLA2 at 5 mU/ml. Concentrations of BW755c and NDGA, inhibitors of both the cyclooxygenase and lipoxygenase or only the lipoxygenase pathways of arachidonic acid metabolism, which completely blocked the insulin secretory response to 10 mM glucose, had no effect on the secretory response to 5 mU/ml of PLA2. These inhibitors also inhibited glucose usage by the islets. Finally, although repeated brief exposure of islets to stimulatory concentrations of glucose lead to a progressive increase in the magnitude of both the first and second phases of insulin secretion, repeated brief exposures to PLA2 lead to a progressive decrease in response to each new exposure. Nonetheless, those islets that had been exposed several times to exogenous PLA2, and no longer displayed a response to a further PLA2 exposure, responded normally to the addition of 10 mM glucose. These results indicate that PLA2 is a potent insulin secretagogue, that it shares some of the characteristics of glucose as a secretagogue, but that in many significant ways differs markedly from glucose in its effects on insulin release from isolated islets.
Diabetes 1985 May
PMID:Effect of exogenous phospholipase A2 on insulin secretion from perifused rat islets. 392 20

Non insulin-dependent diabetes mellitus (Type II) is characterized by the loss of the acute insulin response to glucose. Met-enkephalin, catecholamines and prostaglandin E (PGE) have all been reported to inhibit the acute insulin response to glucose in normal humans. To evaluate the hypothesis that an increased sensitivity to these endogenous substances may play a role in defective insulin secretion in diabetes, we evaluated the effects of three blocking drugs upon the impaired insulin response to glucose in Type II diabetic subjects, as well as glucose-induced insulin secretion in normal humans. In diabetics, acute insulin responses to glucose were significantly increased by all the agents tested (naloxone, phentolamine and lysine acetylsalicylate), but only the cyclooxygenase inhibitor significantly augmented second phase insulin secretion and glucose disappearance rates. The combined infusion of the three agents caused a striking increase of the acute insulin response to glucose (response before: 3 +/- 2 uU/ml; after: 22 +/- 6 uU/ml, p less than 0.01). This was accompanied by a ninefold augmentation of the second phase of insulin secretion which was the result of a synergistic interaction between the three drugs (response significantly higher than the sum of single effects). In normals, insulin responses to glucose were also significantly increased by the combined infusions of the drugs, but to a significantly lesser extent than that of diabetics. This different degree of insulin potentiation between normals and diabetics under the infusion of the three agents persisted even when the prestimulus glucose level of normals was matched to that of diabetics by a glucose infusion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Impaired insulin secretion in human diabetes mellitus. Interactions between naloxone, phentolamine and lysine acetylsalicylate upon glucose induced insulin release. 393 37

In perfused hearts of streptozotocin-diabetic rats the kinetics of a fluoresce indicator transit was measured after pulse injection of FITC-dextran 3. The fluorescence changes on the left ventricle could be described by two pseudo first-order processes with half times in the range of seconds (t/2) corresponding to the intravascular washout and a slow process (T/2) corresponding to the exchange between the extra- and the intravascular space. In diabetes both half times became prolonged, and the amount of FITC-dextran 3 exchanged between the two compartments was reduced, indicating an impaired transcoronary transport in diabetic hearts. There was a time-dependent reduction in the basal release of prostacyclin in hearts of control and diabetic rats. However, studied hearts of diabetic rats released less 6-keto-prostaglandin F1 alpha (PGF1 alpha) than controls. This impaired release of 6-oxo-PGF1 alpha could be prevented partly by adrenalectomy. Because diabetic hearts release more 6-oxo-PGF1 alpha than controls after application of arachidonic acid, these data suggest that the supply of arachidonic acid for the synthesis of prostaglandins is impaired in diabetes, but not the cyclooxygenase pathway itself. The reduced transcoronary transport and the impaired synthesis of prostacyclin might be early steps in the development of microangiopathic myocardial alterations in diabetes.
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PMID:Reduced transcoronary exchange and prostaglandin synthesis in diabetic rat heart. 620 88

Altered responsiveness to and metabolism of various eicosanoids in diabetic animals and patients has been reported by several investigators. The purpose of this investigation was to examine the coronary vascular responsiveness of alloxan-diabetic rats to the leukotrienes. Hearts from 12- to 16-week-old alloxan-diabetic rats and weight-matched controls were perfused at constant flow by the Langendorff method. Coronary vasoactivity to leukotrienes B4, C4, D4 and E4 was assessed by measuring the change in coronary perfusion pressure upon infusion of these eicosanoids. Hearts from diabetic rats showed increased responsiveness to leukotrienes C4 (4-40 nM) and D4 (10-100 nM). Both control and diabetic rat hearts were only slightly responsive to leukotriene E4, and no difference between the two groups existed in the reactivity to this leukotriene. Neither group was responsive to the chemotactic leukotriene, B4. Perfusion of the hearts with the cyclooxygenase inhibitor, ibuprofen, failed to alter the coronary vascular responses to the leukotrienes. The coronary constrictor effects of the leukotrienes are the primary effect of these agents on the rat heart, since heart rate does not change significantly, and changes in contractile force are secondary to the coronary vascular constriction. These alterations in responsiveness to leukotrienes may play a role in the cardiovascular complications associated with diabetes.
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PMID:Altered coronary vascular responsiveness to leukotrienes in alloxan-diabetic rats. 632 35


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