Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The vascular reactivity of forearm arterioles was measured in 16 control subjects (C) and 30 insulin-dependent diabetic (IDDM) subjects, 16 of whom were shown to have microvascular and/or neuropathic complications (DC) including 8 with autonomic neuropathy (DCa) and 14 were shown to be free of complications (DNC). Forearm blood flow was measured by strain gauge plethysmography basally, following a cold pressor stress and following a period of arterial occlusion (reactive hyperaemia). The tests were repeated 24 h later following aspirin treatment. Both C and DNC showed a significant reduction in blood flow in the cold pressor test (C 0.64 +/- 0.12, DNC 0.89 +/- 0.22 ml/100 ml forearm tissue/min reduction in flow P < 0.005), while DC showed no significant response. Reactive hyperaemia was significantly greater in C than in DNC or DC (8.37 +/- 1.14, 5.51 +/- 1.27 and 4.95 +/- 0.75 ml/100 ml tissue/min, respectively, P < 0.02). In the DC group, DCa had significantly less response than those without autonomic neuropathy. Aspirin treatment restored the response of DNC but not DC to normal, suggesting that the abnormality in the former group may have been due to overproduction of a vasoconstrictive cyclooxygenase product (such as thromboxane A2). It is concluded that the abnormalities of vasomotor responses in diabetic subjects are complex and are apparently dependent on autonomic neuropathy, humoral and perhaps structural changes.
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PMID:Forearm arterial vascular responsiveness in insulin-dependent diabetic subjects. 826 13

A 26-year-old female with severe complications from type I diabetes mellitus of 17 years' duration (proliferative retinopathy, nephropathy with renal failure and nephrotic syndrome) developed rapid deterioration of vision in the right eye to 6/60 over a period of several weeks. There were no other neurological signs. Ophthalmological examination showed no worsening of the diabetic retinopathy, but the presence of bilateral optic atrophy, confirmed by visual evoked potentials. CT scan did not reveal any retrobulbar process, and MR scans of both the optic nerves and the visual pathways were unremarkable. The clinical features and the investigations pointed towards ischaemic optic atrophy. Detailed platelet studies showed intravascular platelet activation and an ADP-inducible increase in aggregation, although thromboxane formation was almost absent because of cyclooxygenase inhibition by acetylsalicylic acid. These findings suggest that the ischaemia was due to microcirculatory disturbances secondary to diabetic microangiopathy and platelet hyperreactivity.
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PMID:[Optic neuropathy in type-1 diabetes and acetylsalicylic acid-refractory thrombocyte activation]. 844 10

Endothelial dysfunction is known to occur in chemically-induced animal models of diabetes. The BB diabetic rat is a genetic diabetes-prone model which more closely resembles Type I diabetes mellitus. In this study, we examined the role of superoxide anion radical and cyclooxygenase activity on endothelial dysfunction in aorta of the spontaneous diabetic BB rat. Vascular endothelial function was studied in vitro in aortic rings from 8-wk diabetic rats and age-matched nondiabetic littermates. There was no alteration in reactivity to norepinephrine as a result of diabetes. Relaxation to acetylcholine (but not nitroglycerin) was impaired in diabetic rings. Relaxation to acetylcholine was abolished by 100 microM L-nitroarginine but unaltered by an equimolar concentration of aminoguanidine (an inducible nitric oxide synthase inhibitor) in both control and diabetic rings. Incubation with 10 microM indomethacin did not alter relaxation to acetylcholine in either control or diabetic rings. In contrast, addition of 20 U/ml superoxide dismutase enhanced relaxation to acetylcholine in diabetic rings but had no effect on relaxation to acetylcholine in control rings. Thus, nitric oxide-mediated, endothelium-dependent relaxation is diminished in aortic rings of the genetic diabetic BB rat. Furthermore, superoxide anion radicals but not cyclooxygenase products play an important role in endothelial dysfunction in this genetic diabetic model.
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PMID:Evaluation of the mechanism of endothelial dysfunction in the genetically-diabetic BB rat. 863 17

Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease that is characterized by selective destruction of insulin-secreting beta-cells. Cytokines have been implicated as effector molecules that participate in both islet inflammation and beta-cell destruction during the development of IDDM. In this study, the effects of cytokines on the expression of inducible nitric oxide synthase (iNOS) and inducible cyclooxygenase (COX-2) by human islets were examined. In combination, the cytokines, human recombinant interleukin-1 beta (IL-1 beta), human recombinant tumor necrosis factor-alpha (TNF-alpha), and human recombinant interferon-gamma (IFN-gamma), induce the time-dependent formation of nitrite and prostaglandin E2 (PGE2) by human islets. The nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) completely inhibits cytokine-induced nitrite formation and attenuates PGE2 production by human islets. L-NMMA does not inhibit cytokine-induced expression of COX-2 by human islets, suggesting that nitric oxide may directly activate cyclooxygenase, an effect that has been previously demonstrated for isolated rat islets. This combination of cytokines (IL-1 beta, TNF-alpha, and IFN-gamma) also induces the expression of iNOS mRNA by human islets as demonstrated by both reverse transcriptase-polymerase chain reaction and Northern blot analysis. We further show that the tyrosine kinase inhibitors genistein and herbimycin A prevent IL-1 beta plus IFN-gamma-induced expression of COX-2 and iNOS and the production of PGE2 and nitric oxide by human islets. These results demonstrate that cytokines induce the expression of iNOS and COX-2 by human islets and that cytokine-induced expression of both COX-2 and iNOS by human islets appears to require the activation of a tyrosine kinase(s).
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PMID:Tyrosine kinase inhibitors prevent cytokine-induced expression of iNOS and COX-2 by human islets. 876 39

The effect of type 1 diabetes mellitus on hypoxia-induced coronary vasodilation was studied in isolated perfused rabbit hearts. Four groups of hearts were compared: control hearts from normal rabbits perfused with physiological buffer (5 mM glucose and 2 mM pyruvate added), hearts from alloxan-induced diabetic rabbits (same perfusion as control), hyperglycemic hearts from normal rabbits perfused with 22 mM glucose and 2 mM pyruvate, and hyperosmotic hearts from normal rabbits perfused with 5 mM glucose, 2 mM pyruvate, and 8.5 mM choline chloride. Hypoxia was produced by perfusion with a mixture of N2- and O2- saturated solutions. Endothelium-dependent and -independent dilators were also tested. Papaverine-induced coronary vasodilatation was unaltered, whereas that of serotonin and adenosine was significantly reduced in hyperglycemic and hyperosmotic hearts but not in diabetic hearts perfused with normoglycemic buffer. Hypoxia (PO2 from 515 +/- 86 to 131 +/- 24 mmHg; 1 mmHg = 133.3 Pa) caused a significant coronary vasodilatation in normal hearts (-66 +/- 3%). This vasodilatation was reduced slightly in diabetic (-45 +/- 7%, p < 0.05) and severely in hyperglycemic (-21 +/- 5%, p < 0.05) and hyperosmotic (-24 +/- 5%, p < 0.05) hearts. The adenosine-receptor antagonist 8-phenyltheophylline (10 microM) reduced hypoxia-induced vasodilatation in normal and diabetic hearts. However, inhibition of prostaglandin synthesis with diclofenac (1 microM), which reduces hypoxia-induced vasodilatation in normal hearts, had no effect in diabetic hearts. In conclusion, alloxan-induced type 1 diabetes mellitus in rabbits is accompanied by a reduced coronary vasodilator response to hypoxia. The contribution of adenosine in this response is unaffected. However, the abated contribution of cyclooxygenase products may account for the reduced vasodilatation during hypoxia in this particular model.
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PMID:Altered hypoxia-induced coronary vasodilatation in diabetic rabbit heart. 953 35

Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease believed to be caused by an inflammatory process in the pancreas leading to selective destruction of the beta cells. Inducible cyclooxygenase (COX-2) is expressed under inflammatory conditions and its product prostaglandin E(2) (PGE(2)) is an important inflammation mediator. We report here that administration of the selective COX-2 inhibitor NS-398 prevents the onset of diabetes in mice brought on by multiple low-doses of streptozotocin (STZ). Histological observations indicated that STZ-mediated destruction of beta cells was prevented by NS-398 treatment. Delayed (day 3) administration of NS-398 was also protective in this model. No protective effect was observed when NS-398 was administered prior to a high, toxic dose of STZ. These results demonstrate the critical importance of COX-2 activity in autoimmune destruction of beta cells, and point to the fact that COX-2 inhibition can potentially develop into a preventive therapy against IDDM.
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PMID:COX-2 inhibition prevents insulin-dependent diabetes in low-dose streptozotocin-treated mice. 1087 67

Heat shock protein 60 (hsp60) is a target antigen in autoimmune diabetes and injections of human hsp60 for tolerance induction were found to protect non-obese diabetic (NOD) mice, an animal model of human type 1 diabetes, from disease development. We tested whether innate immune cells of NOD mice exhibit an abnormal response to extracellular hsp60. Bone marrow derived macrophages (BMM) were grown from NOD, C57BL/6J, non-obese non-diabetic (NON) mice, and NOD-related congenic variants differing in the Idd-3, Idd-10/18, or major histocompatibility complex (MHC) region. Hsp60-stimulated BMM of NOD mice were found to produce high levels of interleukin (IL)-12(p70). The addition of IL-10 downregulated, whereas cyclooxygenase inhibitors elevated, IL-12(p70) production of activated BMM. BMM of NON, NON-NOD-H-2(g7) as well as of NOD-NON-H-2(nbl) mice produced significantly less IL-12(p70) than BMM of NOD mice, indicating that an interaction between the MHC haplotype and non-MHC genes of the NOD mouse is required for hyperresponsiveness to hsp60.
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PMID:Heat shock protein 60 elicits abnormal response in macrophages of diabetes-prone non-obese diabetic mice. 1205 8

Unlike most other mammalian cells, beta-cells of Langerhans constitutively express cyclooxygenase (COX)-2 rather than COX-1. COX-2 is also constitutively expressed in type 1 diabetes (T1D) patients' periphery blood monocytes and macrophage. To understand the role of COX-2 in the beta-cell, we investigated COX-2 expression in beta-cells and islet infiltrates of NOD and BALB/c mice using fluorescence immunohistochemistry and cytochemical confocal microscopy and Western blotting. Immunostaining showed that COX-2 is expressed in islet-infiltrating macrophages, and that the expression of insulin and COX-2 disappeared concomitantly from the beta-cells when NOD mice progressed toward overt diabetes. Also cultured INS-1E cells coexpressed insulin and COX-2 but clearly in different subcellular compartments. Treatment with celecoxib increased insulin release from these cells in a dose-dependent manner in glucose concentrations ranging from 5 to 17 mM. Excessive COX-2 expression by the islet-infiltrating macrophages may contribute to the beta-cell death during insulitis. The effects of celecoxib on INS-1E cells suggest that PGE(2) and other downstream products of COX-2 may contribute to the regulation of insulin release from the beta-cells.
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PMID:Cellular distribution and contribution of cyclooxygenase COX-2 to diabetogenesis in NOD mouse. 1239 72

Free radical formation evoked by proinflammatory cytokines has been suggested to be involved in the destruction of beta-cells in the course of type 1 diabetes development. However, there is no direct evidence to support this hypothesis. In this study, we used electron paramagnetic resonance spectroscopy in conjunction with spin-trapping methodology to directly determine whether cytokines give rise to free radical formation in the islets. Our results demonstrate that direct, in vivo administration of tumor necrosis factor-alpha (1,000 units), interleukin-1beta (1,000 units), and interferon-gamma (2,000 units) into the rat pancreas through a bile duct cannula leads to the formation of lipid-derived free radicals in this tissue. These free radicals most likely are generated by the beta-cells because previous depletion of these cells by streptozotocin abolished the cytokine-induced free radical formation. Furthermore, macrophage depletion was found to decrease the production of free radicals. Inhibition of the enzyme inducible cyclooxygenase (COX-2) and the transcription factor nuclear factor-kappaB (NF-kappaB) significantly diminished the free radicals' signal intensity, implicating these factors in the formation of free radicals. We have also demonstrated that cytokine treatment leads to the activation of NF-kappaB in the pancreatic islets of the rats.
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PMID:Free radicals and the pathogenesis of type 1 diabetes: beta-cell cytokine-mediated free radical generation via cyclooxygenase-2. 1288 15

Type I diabetes mellitus is an autoimmune disease characterized by the selective destruction of the insulin-secreting beta-cell found in pancreatic islets of Langerhans. Cytokines such as interleukin-1 (IL-1), interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha) mediate beta-cell dysfunction and islet degeneration, in part, through the induction of the inducible isoform of nitric-oxide synthase and the production of nitric oxide by beta-cells. Cytokines also stimulate the expression of the inducible isoform of cyclooxygenase, COX-2, and the production of prostaglandin E(2) (PGE(2)) by rat and human islets; however, the role of increased COX-2 expression and PGE(2) production in mediating cytokine-induced inhibition of islet metabolic function and viability has been incompletely characterized. In this study, we have shown that treatment of rat islets with IL-1beta or human islets with a cytokine mixture containing IL-1beta + IFN-gamma +/- TNF-alpha stimulates COX-2 expression and PGE(2) formation in a time-dependent manner. Co-incubation of rat and human islets with selective COX-2 inhibitors SC-58236 and Celecoxib, respectively, attenuated cytokine-induced PGE(2) formation. However, these inhibitors failed to prevent cytokine-mediated inhibition of insulin secretion or islet degeneration. These findings indicate that selective inhibition of COX-2 activity does not protect rat and human islets from cytokine-induced beta-cell dysfunction and islet degeneration and, furthermore, that islet production of PGE(2) does not mediate these inhibitory and destructive effects.
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PMID:Role of cyclooxygenase-2 in cytokine-induced beta-cell dysfunction and damage by isolated rat and human islets. 1547 50


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