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)

It is unknown whether and to what extent changes in various endothelial functions and adrenergic responsiveness are related to the development of microvascular complications in type 1 diabetes. Therefore, endothelium-dependent and endothelium-independent vasodilatation, endothelium-dependent hemostatic factors, and one and two adrenergic vasoconstrictor responses were determined in type 1 patients with and without microvascular complications. A total of 34 patients with type 1 diabetes were studied under euglycemic conditions on two occasions (11 without microangiopathy, 10 with proliferative and preproliferative retinopathy previously treated by laser coagulation, 13 with microalbuminuria, and 12 healthy volunteers also were studied). Forearm vascular responses to brachial artery infusions of N(G)-monomethyl-L-arginine (L-NMMA), sodium nitroprusside, acetylcholine (ACh), clonidine, and phenylephrine were determined. The ACh infusions were repeated during coinfusion of L-arginine. Furthermore, plasminogen activator inhibitor type 1 (PAI-1) activity, tissue plasminogen activator antigen levels, von Willebrand factor antigen levels, tissue factor pathway inhibitor (TFPI) activity, and endothelin-1 levels were measured. No differences in endothelium-dependent or endothelium-independent vasodilatation or adrenergic constriction were observed between the diabetic patients and the healthy volunteers. In comparison to the first ACh infusion, the maximal response to repeated ACh during L-arginine administration was reduced in the diabetic patients, except in the patients with proliferative and preproliferative retinopathy previously treated by laser coagulation. In these patients, the combined infusion of L-arginine and ACh resulted in an enhanced response. TFPI activity was elevated, and PAI-1 activity was reduced in the type 1 diabetic patients. Furthermore, PAI-1 activity was positively correlated with urinary albumin excretion (r = 0.48, P < 0.01) and inversely correlated with the vasodilatory response to the highest ACh dose (r = -0.37, P < 0.05). The response to the highest ACh and L-NMMA dose were positively correlated with mean arterial blood pressure (r = 0.32, P < 0.01; r = 0.41, P < 0.01, respectively). Forearm endothelium-dependent and endothelium-independent vasodilatation and adrenergic responsiveness were unaltered in type 1 diabetic patients with and without microvascular complications. Relative to healthy control subjects, endothelium-dependent vasodilatation was depressed during a repeated ACh challenge (with L-arginine coinfusion) in the diabetic patients without complications or with microalbuminuria. In contrast, this vasodilatation was enhanced in the patients with retinopathy. Elevation of TFPI was the most consistent marker of endothelial damage of all the endothelial markers measured.
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PMID:Endothelium-dependent vasodilatation, plasma markers of endothelial function, and adrenergic vasoconstrictor responses in type 1 diabetes under near-normoglycemic conditions. 1034 20

Nitric oxide (NO) may contribute to pancreatic beta cell damage during the development of type 1 diabetes. Its formation can be triggered by cytokines which induce the expression of the inducible form of nitric oxide synthase (iNOS) in pancreatic islets. In the iNOS-catalyzed reaction, arginine is converted into citrulline and NO. Cellular NO formation may be regulated by the availability of arginine. Arginine can be provided extracellularly, entering the cell mainly through the cationic amino acid transporter system y+CAT, and intracellularly, by protein degradation or synthesis from citrulline (the citrulline-NO cycle). This study demonstrates for the first time that the citrulline-NO cycle is induced in FACS-purified rat beta cells exposed to interleukin-1beta(IL-1beta) and that extracellular arginine or citrulline is required for NO production by beta cells. Moreover, the accumulation of arginine was higher in IL-1beta-treated beta cells than in control cells.beta cells expressed mRNAs for the two y+CAT transporters CAT-2A and CAT-2B with no change in transporter expression after exposure to IL-1beta. It is concluded that the activation of the citrulline-NO cycle and an increase in arginine accumulation may be adaptive responses in cytokine-exposed beta-cells to assure an adequate arginine supply for continuous NO production in the presence of low extracellular arginine levels which may prevail during insulitis.
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PMID:Interleukin 1beta increases arginine accumulation and activates the citrulline-NO cycle in rat pancreatic beta cells. 1034 79

Immune-mediated beta-cell damage induces diverse intracellular signals, leading to transcription of different genes which may either contribute to beta-cell repair and/or defence or lead to cell death. The cytokine interleukin-1beta (IL-1) is a potential mediator of beta-cell dysfunction and damage in type 1 diabetes mellitus. To understand the molecular actions of this cytokine upon beta-cells, this study aimed at the cloning of genes induced in FACS-purified rat pancreatic beta-cells by a 6- or 24-h exposure to IL-1 by using differential display of mRNA with reverse transcription-polymerase chain reaction (DDRT-PCR). Among these cytokine-induced genes, a gene encoding for rat serine protease inhibitor (SPI-3) was isolated. SPI-3 may be involved in cellular defence responses against inflammatory stress. RT-PCR analysis confirmed that SPI-3 mRNA expression in rat beta-cells is increased by IL-1 at an early stage (2 h), with maximal accumulation during 6-12 h and decline after 24 h. Similar observations were made in mouse pancreatic islets and in the rat insulinoma cell line RINm5F. IFN-gamma neither increased SPI-3 gene expression nor potentiated its induction by IL-1 in rat beta-cells. The stimulatory effects of IL-1 on SPI-3 mRNA expression were decreased by co-incubation with an inhibitor of gene transcription (actinomycin D), an inhibitor of protein synthesis (cycloheximide) or an inhibitor of NF-kappaB activation (PDTC). On the other hand, a blocker of inducible nitric oxide synthase (iNOS) activity (N(G)-methyl-L-arginine) did not prevent IL-1-induced SPI-3 expression. Thus, SPI-3 mRNA expression following IL-1 exposure depends on gene transcription, protein synthesis and activation of the nuclear transcription factor NF-kappaB, but it is independent of NO formation.
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PMID:IL-1beta induces serine protease inhibitor 3 (SPI-3) gene expression in rat pancreatic beta-cells. Detection by differential display of messenger RNA. 1054 73

Capillary hyperperfusion precedes and contributes to the occurrence of diabetic microangiopathy. Vascular tone is regulated by the balance of vasodilating and vasoconstricting factors, of which nitric oxide (NO; an endothelium dependent vasodilator) and norepinephrine (NE; a potent vasoconstrictor), respectively, are of primary importance. To investigate the role of these factors in hyperperfusion, we measured forearm blood flow (FBF) in 50 patients with noncomplicated type 1 diabetes (DP) and 50 healthy control subjects (CS) under baseline conditions and during intrabrachial infusion of N(G)-monomethyl-L-arginine (L-NMMA), an endothelium-dependent vasoconstrictor, and acetylcholine (ACh), an endothelium-dependent vasodilator. Furthermore, we determined arterial plasma NE concentration at baseline and then determined alpha-adrenergic receptor sensitivity by measuring FBF response to intra-arterially infused NE. We found that basal FBF was increased in DP (2.9+/-0.1 versus 2.0+/-0.1 mL. min(-1). dL(-1) in CS; P<0.01). L-NMMA caused a similar vasoconstriction in both groups (28.5+/-1. 7% in DP versus 31.2+/-2.2% in CS; P=NS). Maximum blood flow during infusion of ACh was not different (23.3+/-1.9 mL. min(-1). dL(-1) in DP versus 20.1+/-1.6 in CS). Arterial plasma NE concentrations were significantly decreased in DP (0.57+/-0.03 versus 0.81+/-0.05 nmol/L in CS; P<0.01). The vasoconstrictive effect of NE was increased in DP (slope log dose-response curve, 31.3+/-1.5 versus 24.3+/-1.8 in CS; P<0.01). We conclude that basal FBF is increased in noncomplicated type 1 diabetes. We found no evidence of a disturbance of basal or stimulated NO production. Arterial plasma NE concentrations are decreased in noncomplicated type 1 diabetes. This may explain the vasodilatation at baseline and the increased vascular response to intra-arterially NE.
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PMID:Elevated skeletal muscle blood flow in noncomplicated type 1 diabetes mellitus: role of nitric oxide and sympathetic tone. 1056 85

Pancreatic beta-cells are more sensitive to several toxins (e.g., streptozotocin, alloxan, cytokines) than the other three endocrine cell types in the islets of Langerhans. Cytokine-induced free radicals in beta-cells may be involved in beta-cell-specific destruction in type 1 diabetes. To investigate if this sensitivity represents an acquired trait during beta-cell maturation, we used two in vitro cultured cell systems: 1) a pluripotent glucagon-positive pre-beta-cell phenotype (NHI-glu) that, after in vivo passage, matures into an insulin-producing beta-cell phenotype (NHI-ins) and 2) a glucagonoma cell-type (AN-glu) that, after stable transfection with pancreatic duodenal homeobox factor-1 (PDX-1), acquires the ability to produce insulin (AN-ins). After exposure to interleukin (IL)-1beta, both of the insulin-producing phenotypes were significantly more susceptible to toxic effects than their glucagon-producing counterparts. Nitric oxide (NO) production was induced in both NHI phenotypes, and inhibition with 0.5 mmol/l N(G)-monomethyl-L-arginine (NMMA) fully protected the cells. In addition, maturation into the NHI-ins phenotype was associated with an acquired dose-dependent sensitivity to the toxic effect of streptozotocin. Our results support the hypothesis that the exquisite sensitivity of beta-cells to IL-1beta and streptozotocin is an acquired trait during beta-cell maturation. These two cell systems will be useful tools for identification of molecular mechanisms involved in beta-cell maturation and sensitivity to toxins in relation to type 1 diabetes.
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PMID:Beta-cell maturation leads to in vitro sensitivity to cytotoxins. 1058 Apr 20

The murine MHC class II variant I-Ad confers susceptibility to herpes simplex virus (HSV)-induced keratitis and relative protection against type 1 diabetes mellitus. The association to these autoimmune diseases appears to be largely determined by the peptide sidechain specificity of the P9 pocket, which we therefore have analyzed in detail. Assessment of T-cell responses and I-Ad binding capacity of position 446-substituted analogs of an IgG2a allotype b (IgG2a(b)) heavy chain peptide demonstrates that engagement of the P9 pocket is crucial for effective peptide presentation. Sidechain size rather than charge decides the capacity to engage the P9 pocket. Thus, small, uncharged sidechains are accepted, whereas acidic and aromatic amino acids as well as lysine and arginine are disfavored. The specificity of the P9 pocket of I-Ad (serine beta57) is distinct from that of the diabetes-associated I-Ag7 (aspartic acid beta57), supporting the contention that the polymorphism at residue beta57 influences diabetes susceptibility via P9-specific effects on the repertoires of self peptides presented to T cells. Furthermore, the data rationalize the susceptibility to HSV-induced keratitis conferred by the a and the protection conferred by the b allotypes of the IgG2a heavy chain. Keratitogenic T cells, which cross-react with the viral UL6 protein and a corneal antigen, are silenced in IgG2a(b) mice because of antigenic mimicry with gamma2a(b) 435-451. Our finding that the lysine P9 residue of the corresponding gamma2a(a) allopeptide precludes high-affinity binding to I-Ad indicates that the susceptibility of IgG2a(a) mice reflects inefficient thymic presentation of autologous IgG2a and thus failure to purge the T-cell repertoire of the pathogenic clones.
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PMID:The P9 peptide sidechain specificity of I-Ad. 1065 74

The role of nitric oxide (NO) and free radicals in the development of microvascular disease in type 1 diabetes remains unclear. We have measured NO and isoprostane (a stable marker of in vivo lipid peroxidation) production in 13 type 1 diabetic subjects with normal urinary albumin excretion and 13 healthy volunteers. Whole-body NO synthesis was quantified by measuring the urinary excretion of 15N-nitrate after the intravenous administration of L-[15N]2-arginine. The urinary excretion of the major urinary metabolite of 15-F2t-isoprostane (8-iso-prostaglandin-F2alpha), 2,3-dinor-5,6-dihydro-F2t-IsoP, was quantified as a marker of in vivo lipid peroxidation. Whole-body NO synthesis was significantly higher in diabetic subjects compared with control subjects (342 vs. 216 nmol 15N-nitrate/mmol creatinine [95% CI of the difference 45-207], P = 0.005). This increase was not explained by a difference in renal function between the 2 groups. There was no difference in 2,3-dinor-5,6-dihydro-F2t-IsoP excretion between diabetic subjects and control subjects (44.8+/-7.8 vs. 41.4+/-10.0 ng/mmol creatinine, mean +/- 95% CI). However, there was an inverse correlation between NO synthesis and free radical activity in subjects with diabetes (r = -0.62, P = 0.012) that was not observed in control subjects (r = 0.37, P = 0.107). We conclude that whole-body NO synthesis is higher in type 1 diabetic subjects with normal urinary albumin excretion than in control subjects. The inverse correlation between isoprostane production and NO synthesis in diabetic subjects is consistent with the hypothesis that NO is being inactivated by reactive oxygen species.
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PMID:Nitric oxide synthesis and isoprostane production in subjects with type 1 diabetes and normal urinary albumin excretion. 1090 97

Preceding the onset of type 1 diabetes mellitus, pancreatic islets are infiltrated by macrophages secreting interleukin-1beta (IL-1beta) which induces beta-cell apoptosis and exerts inhibitory actions on islet beta-cell insulin secretion. IL-1beta seems to act chiefly through induction of nitric oxide (NO) synthesis. Hence, IL-1beta and NO have been implicated as key effector molecules in type 1 diabetes mellitus. In this paper, the influence of endogenously produced and exogenously delivered NO on the regulation of cell proliferation, cell viability and discrete parts of the stimulus-secretion coupling in insulin-secreting RINm5F cells was investigated. Because vitamin E may delay diabetes onset in animal models, we also investigated whether tocopherols may protect beta-cells from the suppressive actions of IL-1 and NO in vitro. To this end, the impact of NO on insulin secretory responses to activation of phospholipase C (by carbamylcholine), protein kinase C (by phorbol ester), adenylyl cyclase (by forskolin), and Ca(2+) influx through voltage-activated Ca(2+) channels (by K(+)-induced depolarization) was monitored in culture after treatment with IL-1beta or by co-incubation with the NO donor spermine-NONOate. It was found that cell proliferation, viability, insulin production and the stimulation of insulin release evoked by carbamylcholine and phorbol ester were impeded by IL-1beta or spermine-NONOate, whereas the hormone output by the other secretagogues was not altered by NO. Pretreatment with gamma-tocopherol (but not alpha-tocopherol) afforded a partial protection against the inhibitory effects of NO, whereas specifically inhibiting inducible NO synthase with N-nitro-L-arginine completely reversed the IL-1beta effects. In contrast, inhibiting guanylyl cyclase with ODQ (1H-[1,2, 4]oxadiazolo[4,3-alpha]-quinoxaline-1-one) or blocking low voltage-activated Ca(2+) channels with NiCl(2) failed to influence the actions of NO. In conclusion, our data show that NO inhibits growth and insulin secretion in RINm5F cells, and that gamma-tocopherol may partially prevent this. The results suggest that phospholipase C or protein kinase C may be targeted by NO. In contrast, cGMP or low voltage-activated Ca(2+) channels appear not to mediate the toxicity of NO in these cells. These adverse effects of NO on the beta-cell, and the protection by gamma-tocopherol, may be of importance for the development of the impaired insulin secretion characterizing type 1 diabetes mellitus, and offer possibilities for intervention in this process.
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PMID:gamma-tocopherol partially protects insulin-secreting cells against functional inhibition by nitric oxide. 1103 27

We and others have previously documented increased resting and exercise-induced skeletal muscle blood flow in young subjects with Type I (insulin-dependent) diabetes mellitus compared with healthy controls. Both NO and prostanoids are important regulators of vascular tone and may therefore contribute to this hyperaemia. The aim of the present study was to determine the contribution of NO and vasodilator prostanoids to this skeletal muscle hyperaemia in diabetes. We assessed the effects of infusion into the intrabrachial artery of the cyclo-oxygenase inhibitor acetylsalicylic acid (ASA; aspirin) and of the L-arginine analogue N(G)-monomethyl-L-arginine (L-NMMA) on skeLetal muscle blood flow in subjects with Type I diabetes mellitus (DM subjects) and control subjects. Blood flow was measured by venous occlusion plethysmography. Isotonic forearm exercise involved 2 min of wrist flexion and extension. Resting flow (forearm blood flow; FBF) was augmented in DM subjects, as was peak exercise-related blood flow (PFBF) and the volume repaid to the forearm 5 min after exercise (AUC 5, where AUC is area under the flow-time curve) (P<0.05), even when accounting for differences in basal flow. Infusion of L-NMMA reduced resting flow by 48% in controls (P<0.005) and by 12% in DM subjects (not significant). L-NMMA reduced PFBF and AUC 5 by 29% (P<0.05) and 39% (P<0.0005) respectively in controls, but had no significant effect on these parameters in DM subjects. Infusion of ASA reduced FBF, PFBF and AUC 5 in both DM (P<0.05) and control (P<0.05) subjects, but the magnitude of this reduction was greater in DM than in control subjects (ANOVA, P<0.05), even when differences in resting FBF were accounted for. Indeed, ASA eliminated the differences in FBF, PFBF and AUC 5 between DM and control subjects. Thus increased release of vasodilator prostanoids, rather than of NO, appears to account for skeletal muscle hyperaemia in Type I diabetes.
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PMID:Vasodilator prostanoids, but not nitric oxide, may account for skeletal muscle hyperaemia in Type I diabetes mellitus. 1105 18

Cytokines have been implicated in the process of pancreatic beta-cell destruction that leads to type 1 diabetes. This study investigates the beta-cell expression of pro- and antiapoptotic proteins from the Bcl-2 family and their variation during cytokine-mediated apoptosis. Exposure of rat beta-cells to the combination of IL-1beta plus interferon-gamma causes a time-dependent increase in apoptotic cells starting after 3 d (<10% on d 3 and 28 +/- 2% on d 7). This effect was preceded by a marked down-regulation of two antiapoptotic proteins, Bcl-2 and Bax-omega (respectively reduced by 60% and 80% after 3 d), whereas no changes occurred in the expression of Bcl-x(L) and the proapoptotic protein Bax-alpha. No apoptosis or down-regulation of Bcl-2 and Bax-omega proteins was observed with individual cytokines or in the presence of N-methyl-L-arginine, an inhibitor of nitric oxide synthase. The lowered Bcl-2 protein content was associated with a decrease in Bcl-2 mRNA, which was initiated after 24 h of exposure. In MIN6 cells, the cytokine-induced suppression of Bcl-2- and Bax-omega, and apoptosis, occurred within 24 h. Primary rat beta-cells exhibited a higher expression of Bax-omega than MIN6 cells or than other rat cell types. These data suggest that suppression of the antiapoptotic proteins Bcl-2 and Bax-omega mediates cytokine-induced apoptosis of beta-cells. The beta-cell-specific expression of Bax-omega makes this protein a possible effector in the protection of this cell type against apoptosis.
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PMID:Specific expression of Bax-omega in pancreatic beta-cells is down-regulated by cytokines before the onset of apoptosis. 1175 24


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