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)

To determine whether platelet prostaglandin production in patients with liver cirrhosis was as impaired as platelet aggregation, serum thromboxane production was studied in 52 patients with liver cirrhosis; 12 patients had consumed more than 80 gr of alcohol/day, for more than ten years; 13 patients had also had diabetes mellitus for more than two years. A reduced thromboxane synthesis by platelets of liver disease patients was observed; the parallel decrease of both platelet thromboxane and serum PGE2 formation may also suggest a decrease in arachidonic acid availability for prostaglandin and thromboxane production. A smaller reduction of thromboxane and PGE2 formation in cirrhotics with diabetes mellitus or chronic alcohol intake was also observed.
 ...
PMID:Platelet thromboxane production in liver cirrhosis. 386 39

To assess whether the beneficial effects of salicylates compounds and sulfonylureas on insulin secretion in patients with noninsulin-dependent diabetes mellitus could be ascribed to inhibition of prostaglandin E (PGE) synthesis, insulin responses to iv glucose pulses were determined in diabetic patients during infusion of lysine acetylsalicylate (LAS) or tolbutamide, with or without a concurrent infusion of PGE2. In these diabetic patients, the augmenting effects of LAS on glucose-induced insulin secretion were abolished by PGE2 infusion. Partial restoration by tolbutamide infusion of the first and second phases of glucose-induced insulin secretion was not affected by the administration of PGE2. The stimulatory effects of LAS and tolbutamide on insulin secretion were additive, suggesting separate mechanisms of action. Since salicylates and sulfonylureas lower plasma glucose concentrations, we also evaluated whether prevention of the fall in the prestimulus glucose level could result in a further amplification of insulin release. Resetting the prestimulus glucose level to control values by infusing glucose caused a further increase in the second, but not the first, phase of glucose-induced insulin secretion, indicating that the prestimulus glucose level had a role in regulating subsequent insulin release. These results indicate that salicylates, but not sulfonylureas, exert their acute insulinotropic effect in noninsulin-dependent diabetic patients by inhibiting endogenous PGE synthesis and support the idea that endogenous PGE may play a role in the impaired insulin response to glucose in this form of human diabetes.
 ...
PMID:Effects of salicylate, tolbutamide, and prostaglandin E2 on insulin responses to glucose in noninsulin-dependent diabetes mellitus. 392 28

Insulin therapy was withdrawn from 15 well-controlled type I diabetic subjects for no longer than 18 h to examine the sequence with which 13,14-dihydro-15-keto-PGE2 (PGE-m), glucagon, norepinephrine, and epinephrine increased in circulating blood in diabetic subjects becoming ketoacidotic. Fourteen of 15 patients had increments in PGE-m; 12/12, 12/15, and 13/15 had increments in glucagon, norepinephrine, and epinephrine, respectively. Six of the 15 patients developed mild diabetic ketoacidosis (DKA) by 12-18 h; all had nonmeasurable C-peptide levels. This DKA group had significantly greater increments of PGE-m (835 +/- 130 versus 276 +/- 111 pg/ml, mean +/- SEM, P less than 0.01) but not glucagon, norepinephrine, or epinephrine compared with the 9 non-DKA patients. In the DKA group, there were significant PGE-m and glucagon increments in the circulation by 3 h, significant norepinephrine increments by 9 h, and epinephrine increments in 5/6 patients by 12 h (not statistically significant) of insulin withdrawal. These studies document that (1) PGE-m accumulates in the circulation during DKA, (2) PGE-m and glucagon increase before catecholamines, and (3) PGE-m, glucagon, and catecholamine levels promptly return to normal levels when insulin therapy is reinstituted. It is suggested that elevated PGE-m levels early in the onset of DKA may represent a host-defense mechanism.
Diabetes 1985 Aug
PMID:Prostaglandin E2 metabolite levels during diabetic ketoacidosis. 392 65

Glomeruli isolated from streptozotocin-diabetic rats produced significantly greater amounts of immunoreactive prostaglandin (PG)E2, PGF2 alpha, and prostacyclin (PGI2) measured as the stable metabolite 6-keto-PGF1 alpha than control glomeruli. These data led to studies to determine whether the vasoactive glomerular mesangial cell exhibited alterations in arachidonic acid metabolism in diabetes. Therefore, we isolated and cultured under identical conditions, mesangial cells from normal and streptozotocin-diabetic rats. Normal mesangial cells produced predominantly PGE2 (57-72%) with PGE2 greater than PGF2 alpha greater than PGI2 after stimulation of acylhydrolase with melittin. Mesangial cells from diabetic rats produced predominantly PGI2 (55-73%) with PGI2 greater than PGE2 greater than PGF2 alpha. A similar prostaglandin profile was obtained when arginine vasopressin (AVP) was used to stimulate acylhydrolase activity. In addition, diabetic mesangial cells synthesized greater amounts of prostaglandins than normal mesangial cells cultured for the same number of passages. When cultured under high-glucose conditions (in tissue culture medium with a final glucose concentration of 550 mg/dl) to mimic the diabetic state in vitro, normal mesangial cells produced proportionately greater amounts of PGE2, PGF2 alpha and PGI2; no alteration to predominantly PGI2 production was observed. Insulin addition to the high-glucose condition tended to attenuate prostaglandin production. Diabetic mesangial cells likewise produced more prostaglandins when cultured under high-glucose conditions; however, the increases were not proportional among the 3 prostaglandins examined. PGE2 production increased to a greater degree than PGI2. With insulin present in the high-glucose condition, there was a disproportional attenuation of all prostaglandins produced, with PGI2 decreasing more than PGE2. Thus, the streptozotocin-induced diabetic state resulted in an alteration in mesangial cell arachidonic acid metabolism.
 ...
PMID:The effects of insulin, glucose and diabetes on prostaglandin production by rat kidney glomeruli and cultured glomerular mesangial cells. 635 25

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

Spleen cells of diabetes-prone BB Wistar rats were found to generate excessively low proliferative responses, and interleukin 2 (IL-2) levels in response to T-dependent mitogens. This abnormality was not due solely to abnormal T cell numbers since: (a) addition of BB spleen cells of BB splenic macrophages to normal major histocompatibility complex (MHC)-matched Wistar Furth (WF) spleen cells resulted in severe suppression of concanavalin A (Con A)-, phytohemagglutinin (PHA)-, and pokeweed mitogen (PWM)-mediated proliferation, and IL-2 production; (b) macrophage depletion from BB spleen cells, but not B cell or T cell depletion, removed completely the suppressive effects of BB cells on WF cells; (c) macrophage depletion greatly enhanced the response of BB lymphocytes to T-dependent mitogens. Although suppressor macrophages could also be found in the spleen of WF control rats they were present in much smaller numbers than in the spleen of BB rats. The suppressive effect of BB macrophages was partially reduced by addition of the prostaglandin synthetase inhibitor indomethacin to cultures. Furthermore, indomethacin (but not catalase or PMA) considerably augmented IL-2 secretion of Con A-stimulated BB spleen cells, but had little effect on WF spleen cells. In contrast, prostaglandins E1 and E2 (PGE1 and PGE2) suppressed IL-2 production. While IL-2 secretion was severely depressed in BB rats unstimulated and lipopolysaccharide (LPS)-stimulated IL-1 secretion by splenic macrophages was normal. BB macrophages did not inactivate IL-2. Low IL-2 production and macrophage-mediated suppression were features of all BB rats tested.
 ...
PMID:Immune dysfunction in diabetes-prone BB rats. Interleukin 2 production and other mitogen-induced responses are suppressed by activated macrophages. 660 15

Metabolism of exogenous and endogenous arachidonic acid (AA) to several cyclo-oxygenase products has been studied by bioassay, radioimmunoassay and radiochemical assay in isolated lungs from rats made diabetic with streptozotocin and compared with that occurring in lungs from untreated rats. From exogenous AA, more PGE2, PGF2 alpha and PGD2 were formed in diabetic lungs than in control lungs, although amounts of PGI2 and TxA2 formed did not differ between the two sets of lungs. From endogenous AA, the synthesis of PGI2 in diabetic lungs was nearly half that in controls lungs. Such a deficiency in the unstimulated synthesis of a potent anti-aggregatory substance would contribute to the hyperaggregable state observed in diabetes.
 ...
PMID:Altered prostaglandin synthesis in isolated lungs of rats with streptozotocin-induced diabetes. 675 87

Isolated rat adipocytes produce prostacyclin (PGI2) in relatively large quantities during norepinephrine (NE)-induced lipolysis. The endogenous NE-induced production rate of PGI2, calculated from the NE-induced production rate of PGI2 observed in our studies (2.2 ng/10(6) cells/2 h) and from the number of fat cells in the normal organism, is 1.46 ng/kg/min for rats, 4.46 ng/kg/min for men, and 11.86 ng/kg/min for women. These rates are comparable to the exogenous PGI2 infusion rate that alters platelet aggregation and blood pressure in rats and humans. Exogenous PGI2 failed to modify the rate of NE-induced lipolysis. Inhibition of endogenous PGI2 production by indomethacin had no effect on the rate of NE-induced lipolysis when either a maximal or submaximal lipolytic concentration of NE was used. PGI2 [rather than prostaglandin (PG) E2] may be the substance that accounts for the functional vasodilatation that accompanies hormone-induced lipolysis. PGI2 is produced in large quantities than PGE2 during NE-induced lipolysis and is a more potent vasodilator than PGE2. Its instability can account for the inability of previous investigators to detect a vasodilator substance in the venous effluent of adipose tissue. The production of PGI2 by adipocytes may be an important modulator of the regulation of vascular tone and platelet aggregation by catecholamines in the vascular bed of adipose tissue and perhaps other tissues. PGI2 produced by adipocytes, by virtue of its ability to cause vasodilatation and inhibit platelet aggregation, may contribute to the maintenance of luminal patency in the vascular bed of adipose tissue and possibly other tissue as well.
Diabetes 1981 Feb
PMID:Prostacyclin production by isolated adipocytes. 700 68

The effects of Prostacyclin (PGI2) infusion on insulin secretion and glucose tolerance were investigated in 7 healthy subjects. PGI2 infusion caused no statistically significant changes of either glucose or insulin concentration, over the range 2.5-20 ng/Kg/min. A constant PGI2 infusion (10 ng/Kg/min) did not inhibit acute insulin responses to a glucose (20 g i.v.) pulse (response before PGI2 = 612 +/- 307%; during PGI2 = 515 +/- 468%, mean +/- SD, mean change 3-5 min insulin, % basal; P=NS). Glucose disappearance rates were similar after the first and second glucose pulse. Thus, in contrast to PGE2, PGI2 does not affect insulin secretion nor glucose disposal at doses producing platelet and vascular changes. It is hypothesized that an altered PGI2/PGE2 balance in diabetes may represent a link between vascular, platelet and metabolic changes.
 ...
PMID:Prostacyclin does not affect insulin secretion in humans. 701 16

Inhibition of Na+,K(+)-ATPase activity by hyperglycemia could be an important etiological factor of chronic complications in diabetic patients. The biochemical mechanism underlying hyperglycemia's inhibitory effects has been thought to involve the alteration of the protein kinase C (PKC) pathway since agonists of PKC can normalize hyperglycemia-induced inhibition of Na+,K(+)-ATPase activity. Paradoxically, elevated glucose levels and diabetes have been shown to increase PKC activities in vascular cells. The present study tested the hypothesis that the inhibition of Na+,K(+)-ATPase activity is mediated by the sequential activation of PKC and cytosolic phospholipase A2 (cPLA2). In cultured rat vascular smooth muscle cells (VSMC), increasing glucose levels in the medium from 5.5 to 22 mM elevated cPLA2 activity and increased [3H]arachidonic acid release and PGE2 production by 2.3-, 1.7- and 2-fold, respectively. Similar increases in cPLA2 activity were also induced by elevated glucose levels in human VSMC and rat capillary endothelial cells. The activation of cPLA2 was mediated by PKC since the increases in cPLA2 phosphorylation and enzymatic activity were inhibited by the PKC inhibitor GFX. In contrast, elevation of glucose levels decreased Na+,K(+)-ATPase activity as measured by ouabain-sensitive 86Rb uptake by twofold in rat VSMC. Surprisingly, both PMA, a PKC agonist, and GFX, a PKC inhibitor, were able to prevent glucose-induced decreases in 86Rb uptake. Further, the PLA2 inhibitor AACOCF3 abolished both glucose-induced activation of cPLA2 and the decrease in 86Rb uptake. These data indicated that hyperglycemia is inhibiting Na+,K(+)-ATPase activity by the sequential activation of PKC and cPLA2, resulting in the liberation of arachidonic acid and increased the production of PGE2, which are known inhibitors of Na+,K(+)-ATPase.
 ...
PMID:Identification of the mechanism for the inhibition of Na+,K(+)-adenosine triphosphatase by hyperglycemia involving activation of protein kinase C and cytosolic phospholipase A2. 763 66


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