UMLS:C0011849 - FACTA Search

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

It is unclear whether the abnormal relaxation seen in diabetes is due to decreased levels of nitric oxide (NO) and how eicosapentaenoic acid (EPA, C20:5 omega 3) affects the endothelial production of NO. We investigated the effects of EPA ethyl ester (EPA-E) and elevated glucose on NO production by human endothelial cells (HUE). EPA-E (0.3 mM) significantly enhanced [NO2] production and the intracellular concentration of free Ca2+ within 3 min after EPA-E was added to the cultures. High levels of glucose (27.5 mM) significantly increased endothelial glucose, sorbitol and fructose, and inhibited [NO2-] production. However, EPA-E (0.3 mM) prevented the inhibition of [NO2-] production due to the activation of the Ca(2+)-calmodulin system of NO synthase. EPA-E decreased the glucose-mediated inhibition of NO production by HUE. These results suggest this agent might ameliorate endothelial dysfunction associated with diabetes.
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PMID:Eicosapentaenoic acid enhances nitric oxide production by cultured human endothelial cells. 912 7

The insulin-induced platelet anti-aggregating effect is attributed to a nitric oxide (NO)-mediated increase of cyclic guanosine monophosphate (cGMP). The aim of this work, carried out in human platelets, is to show whether insulin increases NO synthesis in platelets and whether it enhances not only cGMP but also cyclic adenosine monophosphate (cAMP) in these cells. We observed that 1) insulin dose-dependently increases NO production, evaluated as citrulline synthesis from L-arginine (n = 4, P = 0.015); 2) insulin dose-dependently increases not only cGMP but also cAMP: for instance, after 8 min of insulin incubation at 1,920 pmol/l, cAMP increased from 39.8 +/- 1.4 to 121.3 +/- 12.6 pmol/10(9) platelets (n = 16, P = 0.0001); 3) when insulin is incubated for 120 min, the increase of cGMP and cAMP shows a plateau between 2 and 20 min, and while the effect on cGMP is significant until 120 min, the effect on cAMP is no more significant at 60 and 120 min; 4) insulin increases the effects on cAMP of the adenylate cyclase agonists Iloprost and forskolin (n = 5, P = 0.0001) and enhances their platelet anti-aggregating effects (n = 6 and 8, respectively; P = 0.0001); and 5) the inhibition of NO synthase by N(G)-monomethyl-L-arginine blunts both the insulin effects on basal cGMP and cAMP (n = 4) and those on the Iloprost- and forskolin-induced cAMP increase (n = 5). Thus, insulin increases NO synthesis in human platelets, and, through NO, enhances both cGMP and cAMP. The platelet anti-aggregating effect exerted by insulin is, therefore, a NO-mediated phenomenon involving both cGMP and cAMP.
Diabetes 1997 May
PMID:Insulin stimulates nitric oxide synthesis in human platelets and, through nitric oxide, increases platelet concentrations of both guanosine-3', 5'-cyclic monophosphate and adenosine-3', 5'-cyclic monophosphate. 913 39

The purpose of this study was to evaluate the effects of interferon-gamma (IFN-gamma) alone and in combination with interleukin 1beta (IL-1beta) on inducible nitric-oxide synthase (iNOS) mRNA and protein expression, nitrite production, and insulin secretion by islets of Langerhans. Treatment of rat islets with IL-1beta results in a concentration-dependent increase in the production of nitrite that is maximal at 5 units/ml. Individually, 0. 1 unit/ml IL-1beta or 150 units/ml rat IFN-gamma do not stimulate iNOS expression or nitrite production by rat islets; however, in combination, these cytokines induce the expression of iNOS and the production of nitrite to levels similar in magnitude to the individual effects of 5 units/ml IL-1beta. The islet beta-cell, selectively destroyed during insulin-dependent diabetes mellitus, appears to be one islet cellular source of iNOS as 150 units/ml rat IFN-gamma and 0.1 unit/ml IL-1beta induced similar effects in primary beta-cells purified by fluorescence-activated cell sorting and in the rat insulinoma cell line, RINm5F. iNOS expression and nitrite production by rat islets in response to 150 units/ml rat IFN-gamma and 0.1 unit/ml IL-1beta are correlated with an inhibition of insulin secretion and islet degeneration that are prevented by the iNOS inhibitor aminoguanidine. The mechanism by which IFN-gamma increases the sensitivity of beta-cells for IL-1-induced iNOS expression appears to be associated with an increase in the stability of iNOS mRNA. Last, cellular damage during physical dispersion of islets results in the release of sufficient amounts of IL-1beta to induce iNOS expression and nitrite production in the presence of exogenously added rat IFN-gamma. The cellular source of IL-1beta under these conditions is believed to be resident islet macrophages as depletion of macrophages prior to dispersion prevents IFN-gamma-induced iNOS expression and nitrite formation by dispersed islet cells. These studies show that the T-lymphocyte cytokine, IFN-gamma, increases the sensitivity of rat islets to the effects of IL-1beta on iNOS expression and nitrite production by 10-fold, in part, through the stabilization of iNOS mRNA. Our studies also support an effector role for IFN-gamma, in concert with resident islet macrophage release of IL-1beta, in mediating beta-cell destruction during the development of autoimmune diabetes.
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PMID:Interferon-gamma increases the sensitivity of islets of Langerhans for inducible nitric-oxide synthase expression induced by interleukin 1. 915 21

The rate of renal filtration is in large part responsible for volume and electrolyte balance in an organism. Integral components of the renal glomerulus are the mesangial cells (MCs), excitable renal pericytes that regulate the glomerular filtration rate by modulating the surface area of the capillaries. Similar to vascular smooth muscle, the signal transduction pathways and ion selective channels regulating isotonic and isometric contraction of MCs are dependent on the voltage-gated Ca influx. During the response to contractile agonists, both Cl and nonselective cation channels play critical roles to depolarize the membrane potential and activate Ca channels. The relaxation pathways involve a negative-feedback mechanism that counteracts mesangial contraction by regulating voltage-dependent Ca signaling. Part of the feedback response involves the activation of plasmalemmal K channels, which hyperpolarize the membrane potential and inhibit voltage-gated Ca entry. This calcium- and voltage-activated feedback K (BKCa) channel shares biophysical, pharmacologic, and molecular properties with the BKCa channels identified in brain and muscle, and with the sio gene product as expressed in Xenopus laevis oocytes. Systemic hormones, such as atrial natriuretic peptide, and paracrine factors, such as nitric oxide (NO), use guanosine 3',5'-cyclic monophosphate (GMP) as a second messenger and enhance the gain in this feedback system by decreasing the voltage and Ca activation thresholds for BKCa. Diabetes mellitus is often associated with high rates of glomerular filtration, mesangial expansion, and secretory abnormalities of the basement membrane. NO-mediated increases in negative-feedback regulation of mesangial tone may attribute, in part, to the pathology of hyperfiltration. Stimulation of inducible nitric oxide synthetase in glomerular MCs by inflammatory cytokines is a possible positive-feedback pathway that contributes to further glomerular destruction. In addition, high ambient glucose, through modulation of BKCa activity, facilitates MC relaxation and thus propagates hyperfiltration. Since cellular arachidonic acid is metabolically linked to extracellular glucose, this fatty acid is a possible mediator of the pathologic actions of hyperglycemia. Clarification of the signal transduction pathways and ionic mechanisms regulating the normal and dysfunctional tones of MCs is essential for rational clinical management of glomerular disease and critical to understanding fluid and electrolyte homeostasis.
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PMID:Regulation of filtration rate by glomerular mesangial cells in health and diabetic renal disease. 918 87

We have previously reported that endothelium-dependent, nitric oxide (NO)-mediated vasorelaxation is impaired in diabetic mesenteric arteries. We hypothesized that vasoconstrictor responses should therefore be enhanced. The purpose of this study was to determine whether diabetic mesenteric arteries exhibit increased vasoconstrictor responses, and to investigate if these changes are receptor and/or NO mediated. Thirty age-matched male Sprague-Dawley rats were divided into control (C) and diabetic (D, streptozotocin: 60 mg/kg) groups and studied after 4 weeks. Terminal branches of ileal mesenteric arteries (300 +/- 9 microns) were isolated, pressurized, and superfused with modified Krebs solution. Changes in vessel internal diameter were measured and dose-response curves (DRC) for each vasoactive agent were determined. Each vessel was initially constricted with 40 mM of KC1 to determine maximal vasoconstriction. Phenylephrine (Phe, 10(-8)-10(-4) M) and UK14304 (10(-9)-10(-5) M) were used to determine alpha 1- and alpha 2-receptor responses, respectively. Similar studies were performed in the presence of N omega-nitro-L-arginine methyl ester (L-NAME, 10(-4) M), a competitive inhibitor of NO synthase. Maximal response (Max), area under the curve (AUC), and vessel sensitivity (ED50) for each DRC were calculated. Comparisons among groups were made using analysis of variance and Student's t test with Bonferroni correction. There were no differences in vasoconstrictor responses induced by KCl (C: 82 +/- 2% vs D: 80 +/- 1%). alpha 1-vasoconstrictor responses to Phe were enhanced in diabetes with significantly higher Max (96 +/- 2% vs 83 +/- 3%), and AUC (1.92 +/- 0.09 vs 1.56 +/- 0.08), but no difference in ED50. The addition of L-NAME enhanced only Phe-induced vasoconstrictor response significantly in control rats. Thus, differences in Phe-induced vasoconstrictor responses between C and D were abolished in the presence of L-NAME. alpha 2-vasodilator responses induced by UK14304 were similar between C and D and unaffected by L-NAME. alpha 1-, but not alpha 2-, vasoconstrictor responses are enhanced in streptozotocin-induced diabetic rats. These enhanced responses can be duplicated by treatment of control vessels with L-NAME.
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PMID:Nitric oxide inhibition simulates the enhancement of alpha 1 agonist-induced vasoconstriction in diabetes. 924 59

Diabetes mellitus leads to micro- and macroangiopathy with endothelial dysfunction. To investigate the direct influence of high glucose on endothelial cell structure and possible pharmacologic effects, seven different experimental protocols were carried out on endothelial cells in culture. There were four control groups with either 5 mM D-glucose alone, 5 mM D-glucose plus 15 mM L-glucose (for osmotic control), 5 mM D-glucose plus 500 nM celiprolol, or 5 mM D-glucose plus 57 nM nitrendipine. Three experimental groups had either 20 mM D-glucose alone, 20 mM D-glucose plus 500 nM celiprolol or 20 mM D-glucose plus 57 nM nitrendipine. Treatment of all groups started at the third passage of the cells and lasted until confluence was reached (5-8 days). The endothelial cells were fixed in paraformaldehyde and stained either with hematoxylin-eosin solution, with nitro blue tetrazolium for nicotinamide adenine dinucleotide phosphate (NADPH)- diaphorase staining, or actin staining with phalloidin was carried out. For quantitative analysis of the histologic specimens, the slides were viewed via a microscope and a videocamera. The pictures were converted digitally and could be analyzed with the videopicture-analyzing system, JAVA. In the four control groups, neither treatment with 15 mM L-glucose nor administration of celiprolol or nitrendipine had an effect on cell, cytoplasm, and nuclear area. The number of giant or polynuclear cells and the histochemical NADPH-diaphorase activity were not altered. Incubation of endothelial cells with 20 mM D-glucose for 5-8 days resulted in a significant increase in total and cytoplasmic area, as well as in the number of giant and polynuclear cells, whereas the nuclear area and the NADPH-diaphorase activity were significantly reduced. Concomitant treatment with celiprolol was able to reverse these alterations in endothelial structure significantly but had only a weak effect on the NADPH-diaphorase. Nitrendipine had no beneficial effect on the high D-glucose-induced cell alterations. The actin staining of the control cells showed the typical actin pattern with most of the actin filaments arranged at the periphery of the cells. Administration of 20 mM D-glucose resulted in a disturbance of the actin pattern, with most of the actin filaments now arranged in the middle of the cells. However, neither celiprolol nor nitrendipine exhibited a significant influence on this altered actin structure. High D-glucose treatment over several days thus leads to severe changes in endothelial cell structure, and celiprolol may have a beneficial effect on these hyperglycemia-induced cell alterations.
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PMID:High D-glucose induces alterations of endothelial cell structure in a cell-culture model. 926 45

There is evidence that the vasodilator action of insulin is mediated by the release of nitric oxide (NO). We hypothesized that euglycemic hyperinsulinemia might increase renal and ocular blood flow, and that the vasodilator capacity of insulin might be NO-dependent. Euglycemic insulin clamps were performed in 10 healthy subjects. Sixty minutes after the start of insulin administration, an intravenous coinfusion of N-monomethyl-L-arginine (L-NMMA), an inhibitor of NO synthase, or of norepinephrine (NE), an endothelium-independent vasoconstrictor, was started. Renal plasma flow was measured by para-aminohippurate (PAH) clearance method. Ocular hemodynamics were assessed by laser interferometric measurement of fundus pulsations and Doppler sonographic measurement of blood flow velocity in the ophthalmic artery. Renal plasma flow and ocular fundus pulsations were increased by insulin. L-NMMA almost completely abolished the vasodilative effects of insulin, whereas the effects of combined infusion of insulin and NE were approximately the sum of the hemodynamic changes induced by each agent alone. The results show that during euglycemic hyperinsulinemia, renal and ocular blood flow are increased, which may be mediated either by a local vasodilator effect or a systemic increase in flow. The hemodynamic effects of insulin in the kidney and the eye are at least partially dependent on NO synthesis. Because the insulin plasma levels we obtained are in the high physiological range, it may be assumed that insulin plays a role in renal and ocular blood flow regulation.
Diabetes 1997 Nov
PMID:Renal and ocular hemodynamic effects of insulin. 935 38

Recently published data have provided evidence that nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) are signaling intermediates in the pathway through which muscle contraction stimulates glucose transport. As exercise promotes both NO production and calcium flux, we examined the relationships between NO-stimulated glucose uptake and calcium-, contraction-, and phosphatidylinositol-3-kinase (PI-3-K)-mediated glucose transport in the isolated incubated rat epitrochlearis muscle preparation. The NO donor sodium nitroprusside (SNP; 10 mmol/l) and dibutyryl cGMP (100 micromol/l) accelerated epitrochlearis glucose transport four- to fivefold above basal levels (P < 0.001) in a manner similar to in vitro contractile activity and the calcium releasing agent N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W7; 100 micromol/l). In the case of SNP, this effect could be completely attributed to an increase in cell surface GLUT4. The effect of SNP on glucose transport was not inhibitable by either wortmannin (1.5 micromol/l) or dantrolene (12.5 micromol/l). Similarly, neither calcium nor contraction stimulation of glucose transport was affected by the NO synthase inhibitors NG-monomethyl-L-arginine (L-NMMA; 100 micromol/l) or 7-nitroindazole (1 mmol/l). Furthermore, whereas SNP raised epitrochlearis cGMP levels tenfold (P < 0.001), neither in vitro contractile activity nor W7 significantly elevated cGMP. These results indicate that NO/cGMP can markedly stimulate skeletal muscle glucose transport by increasing GLUT4 levels at the cell surface by a mechanism that does not depend on activation of PI-3-K. In addition, since calcium/contraction-stimulated glucose transport is not blocked by NO synthase inhibition and did not elevate cGMP, NO/cGMP may be part of a novel pathway that is distinct from both the insulin- and contraction-activated mechanisms.
Diabetes 1997 Nov
PMID:Nitric oxide stimulates skeletal muscle glucose transport through a calcium/contraction- and phosphatidylinositol-3-kinase-independent pathway. 935 48

Diabetes mellitus has profound adverse effects on vascular and, in particular, endothelial function. Although pressure-induced constriction ("myogenic tone") is a major contributor to the regulation of blood flow, little is known about the effects of diabetes on this response. Diabetes has been shown to diminish the dilation of cerebral arteries to synthetic ATP-sensitive K+ (KATP) channel openers. In this study, we explored the effects of diabetes induced in rats by streptozotocin on cerebral artery (250 to 300 microns) myogenic tone and on vasodilations to the synthetic KATP channel openers pinacidil and levcromakalim. Elevation of intravascular pressure caused a graded membrane potential depolarization and constriction, which was greater in arteries from diabetic rats compared with normal rats (at 60 mm Hg, 5 mV more depolarized and 22 microns more constricted). Pressurized arteries (at 60 mm Hg) from diabetic rats were 5- to 15-fold less sensitive to pinacidil and levcromakalim than were control arteries (EC50 values for pinacidil and levcromakalim were 1.4 and 0.6 mumol/L, respectively, in diabetic animals and 0.3 and 0.04, respectively, in control animals; P < .05). Removal of the endothelium or addition of a NO synthase inhibitor, NG-nitro-L-arginine (LNNA), in control arteries decreased the sensitivity to KATP channel openers and depolarized and constricted control arteries to levels similar to those observed in arteries from diabetic animals. Sodium nitroprusside caused a membrane potential hyperpolarization and enhanced the response to pinacidil in arteries from diabetic animals. Removal of the endothelium or LNNA had little effect on the apparent KATP channel opener sensitivity, the membrane potential, and pressure-induced constrictions of arteries from diabetic animals. The results are consistent with the hypothesis that this type of diabetes leads to a decrease in tonic NO release from the endothelium, which in turn causes membrane potential depolarization and vasoconstriction, resulting in a diminished response to KATP channel openers.
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PMID:Increased myogenic tone and diminished responsiveness to ATP-sensitive K+ channel openers in cerebral arteries from diabetic rats. 940 Mar 80

We previously reported the impaired HCO3- secretion and the increased mucosal susceptibility to acid in the duodenum of streptozotocin (STZ)-induced diabetic rats. In this study, we investigated the salutary effect of the NO synthase inhibitor L-NAME (NG-nitro-L-arginine methyl ester) on these changes and compared it with those of insulin. Animals were injected streptozotocin (STZ: 70 mg/kg, ip) and used after 1, 3-4, and 5-6 weeks of diabetes with blood glucose levels of > 300 mg/dL. Under urethane anesthesia the HCO3- secretion was measured in the proximal duodenal loop using a pH-stat method and by adding 10 mM HCl. L-NAME (20 mg/kg x 2) or insulin (4 units/rat) was administered sc for 4-5 weeks, starting 1 week after STZ treatment. The duodenal HCO3- secretory responses to various stimuli such as mucosal acidification (10 mM HCl for 10 min), 16,16-dimethyl prostaglandin E2 (dmPGE2: 10 micrograms/kg, i.v.), and vagal stimulation (0.5 mA, 2 ms, 3 Hz) were significantly decreased in STZ-treated rats, depending on the duration of diabetes. Repeated administration of L-NAME, starting from 1 week after STZ treatment, significantly reduced blood glucose levels toward normal values and restored the HCO3- responses to various stimuli in STZ rats, the effects being similar to those observed after supplementation of insulin. Diabetic rats developed duodenal lesions after perfusion of the duodenum with 150 mM HCl for 4 h, but this ulcerogenic response was significantly inhibited by the repeated treatment with L-NAME as well as insulin. We conclude that L-NAME is effective in ameliorating hyperglycemic conditions in STZ-diabetic rats, similar to insulin, and restores the impaired HCO3- secretion and the increased mucosal susceptibility to acid in diabetic rat duodenums.
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PMID:Impaired duodenal bicarbonate secretion in diabetic rats. Salutary effect of nitric oxide synthase inhibitor. 940 1

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