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)

Defective leukocyte-endothelial interactions have been observed in experimental type 1 diabetes. One of the mechanisms involved in the late complications of diabetes mellitus is the formation of free radicals species. Antioxidant treatment has been demonstrated to have beneficial effects on the complications observed in this pathology. Using intravital microscopy to visualize venules of the internal spermatic fascia, we demonstrated that the defective leukocyte-endothelial interactions in alloxan-induced diabetic rats could be corrected by probucol treatment. The defects were quantitated by the number of leukocytes rolling along the venular endothelium, sticking to the venular wall after topical application of zymosan-activated plasma (10%-0.1 ml) or leukotriene B4 (1 microM/0.1 ml) and migrated after the application of a local irritant stimulus (carrageenan, 100 microg/0.1 ml). Leukocyte counts, erythrocyte velocity and venular shear rate, unaltered in diabetic rats, were not modified by this treatment. Reactive oxygen species formation by endothelial cells increased in diabetic preparations, and the reduced expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and P-selectin in cross-sections of the whole testis of the animals, were both restored by the antioxidant agent. Therefore, antioxidant treatment improves leukocyte-endothelial interaction in diabetic rats at least in part by restoring the expression of adhesion molecules in venules of diabetic rats.
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PMID:Probucol restores the defective leukocyte-endothelial interaction in experimental diabetes. 1457 7

The diabetic effects of alloxan (type I diabetes mellitus) were investigated in 40 Wistar albino rats (18 controls and 22 diabetics). Alloxan in sterile physiological saline was injected into animals intravenously. After the induction of diabetes with alloxan, the ultrastructure of the capillaries in the gingiva was examined by transmission electron microscopy. The thickness of the basement membranes was observed closely adherent to the endothelial cells of the capillary alloxan-diabetic rats. It was greatly thickened owing to the increase in its amorphous, granular and filamentous material with occasional scattered collagen fibres. In some sections, the capillary lumens of the diabetics were closed by epithelial cells. Loss of cytoplasmic material and hyalinization were seen in some smooth muscle cells. In addition, the mitochondrial cristae of smooth muscle cell and epithelial cells disappeared. There was endothelial integrity throughout the smooth muscle cells.
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PMID:The ultrastructure of the capillaries in the gingiva of alloxan-induced diabetic rats. 1462 68

Impaired endothelial nitric oxide synthase (eNOS) function is associated with erectile dysfunction in diabetes mellitus, but the exact molecular basis for the eNOS defect in the diabetic penis remains unclear. We investigated whether hyperglycemia increases O-GlcNAc modification of eNOS in the penis, preventing phosphorylation at the primary positive regulatory site on the enzyme and hampering mechanisms of the erectile response. Type I diabetes mellitus was induced in male rats by alloxan (140 mg/kg, i.p.). After 5 wk, the diabetic rat penis exhibited increased O-GlcNAc modification of eNOS and decreased eNOS phosphorylation at Ser-1177 at baseline compared with the control rat penis; eNOS phosphorylation at Thr-495, Ser-615, and Ser-633 was not affected. In addition, eNOS phosphorylation at Ser-1177 was impaired in the diabetic rat penis in response to penile blood flow (shear stress) elicited by electrical stimulation of the cavernous nerve (ES) and to recombinant human VEGF165. Phosphorylation of Akt, a mediator of shear stress-induced eNOS phosphorylation at Ser-1177, was decreased in the diabetic penis at baseline, but it was restored by ES. Erectile response to shear stress elicited by ES and to VEGF was decreased in diabetic compared with control rats. This work demonstrates that eNOS inactivation occurs in the diabetic penis by a glycosylation mechanism specifically at Ser-1177, by which the enzyme is rendered incapable of activation by fluid shear stress stimuli and VEGF signaling. In vivo penile erection paradigm supports the physiologic relevance of O-GlcNAc modification in vascular disorders associated with diabetes.
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PMID:Inactivation of phosphorylated endothelial nitric oxide synthase (Ser-1177) by O-GlcNAc in diabetes-associated erectile dysfunction. 1608 13

Alloxan is a classical diabetogen which is used to achieve beta-cell destruction and type 1 diabetes due to its selective cytotoxic effect on pancreatic beta-cells. Although alloxan-induced diabetes is widely used in the laboratory to mimic diabetic pathology and for screening antidiabetic drugs, there has not been any comprehensive research in vivo on its diabetogenicity. In our study, alloxan-induced diabetic mice were generated by a single intravenous injection of alloxan (100 mg/kg). Our data show that these mice possess hyperglycemia, hypoinsulinism and morphological characteristics of impaired pancreas that are consistent with the accepted diabetogenic effects of alloxan. Alloxan is believed to confer its diabetogenic effect by inhibiting pancreatic glucokinase activity, leading to pancreatic beta-cell death. We examined the effects of alloxon on the other major site of glucokinase expression, the liver. Our results show that alloxan treatment led to an 81% reduction in glucokinase immunoreactivity and a greater than 90% reduction in glucokinase enzymatic activity in the liver, suggesting that alloxan's toxicity is not specific to the pancreas. Given the important role of glucokinase as a glucose sensor, and our findings on the effects of alloxon on liver glucokinase activity we propose that the effects on the liver are the primary contributor to pathogenesis in alloxan-induced diabetes. Alloxan-induced diabetes is thus a multifactor-promoted diabetes model which still could be used to examine the antidiabetic effects of compounds prompting insulin secretion and increasing liver-specific glucokinase activity. Despite alloxan-induced diabetes being inconsistent with the natural pathogenesis of human diabetes, further research on the causes of decreased glucokinase activity will help us to unravel the pathogenesis of diabetes and its complications.
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PMID:Hepatic glucokinase activity is the primary defect in alloxan-induced diabetes of mice. 1776 29

Reactive oxygen species (ROS) play a critical role in the pathogenesis of human diseases. A cytosine to adenine transversion in the mitochondrially encoded NADH dehydrogenase subunit 2 (mt-ND2, human; mt-Nd2, mouse) gene results in resistance against type 1 diabetes and several additional ROS-associated conditions. Our previous studies have demonstrated that the adenine-containing allele (mt-Nd2(a)) is also strongly associated with resistance against type 1 diabetes in mice. In this report we have confirmed that the cytosine-containing allele (mt-Nd2(c)) results in elevated mitochondrial ROS production. Using inhibitors of the electron transport chain, we show that when in combination with nuclear genes from the alloxan-resistant (ALR) strain, mt-Nd2(c) increases ROS from complex III. Furthermore, by using alamethicin-permeabilized mitochondria, we measured a significant increase in electron transport chain-dependent ROS production from all mt-Nd2(c)-encoding strains including ALR.mt(NOD), non-obese diabetic (NOD), and C57BL/6 (B6). Studies employing alamethicin and inhibitors were able to again localize the heightened ROS production in ALR.mt(NOD) to complex III and identified complex I as the site of elevated ROS production from NOD and B6 mitochondria. Using submitochondrial particles, we confirmed that in the context of the NOD or B6 nuclear genomes, mt-Nd2(c) elevates complex I-specific ROS production. In all assays mitochondria from mt-Nd2(a)-encoding strains exhibited low ROS production. Our data suggest that lowering overall mitochondrial ROS production is a key mechanism of disease protection provided by mt-Nd2(a).
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PMID:mt-Nd2a suppresses reactive oxygen species production by mitochondrial complexes I and III. 1828 Dec 88

ALR/Lt, a NOD-related mouse strain, was selected for resistance to alloxan free radical-mediated diabetes (ALD). Despite extensive genomic identity with NOD (>70%), ALR mice display strong resistance to autoimmune type 1 diabetes (T1D) due to both an unusual elevation in systemic antioxidant defenses and a reduction in cellular ROS production that extends to the beta cell level. Reciprocal backcross to NOD previously linked the ALR-derived T1D resistance to Chr. 3, 8, and 17 as well as to the ALR mt-Nd2(a) allele encoded by the mitochondrial genome (mtDNA). To determine whether any of the ALR-derived loci protecting against T1D also protected against ALD, 296 six-week-old F2 mice from reciprocal outcrosses were alloxan-treated and assessed for diabetes onset, and a genome-wide scan (GWS) was conducted. GWS linked mt-Nd2 as well as three nuclear loci with alloxan-induced diabetes. A dominant ALR-derived ALD resistance locus on Chr. 8 colocalized with the ALR-derived T1D resistance locus identified in the previous backcross analysis. In contrast, whereas ALR contributed a novel T1D resistance locus on Chr. 3 marked by Susp, a more proximal ALR-derived region marked by Il-2 contributed ALD susceptibility, not resistance. In addition, a locus was mapped on Chr. 2, where heterozygosity provided heightened susceptibility. Tests for alloxan sensitivity in ALR conplastic mice encoding the NOD mt-Nd2(c) allele and NOD mice congenic for the protective Chr. 8 locus supported our mapping results. Alloxan sensitivity was increased in ALR.mt(NOD) mice, whereas it was decreased by congenic introduction of ALR genome on Chr. 8 into NOD. These data demonstrate both similarities and differences in the genetic control of T1D versus ROS-induced diabetes.
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PMID:Commonalities of genetic resistance to spontaneous autoimmune and free radical--mediated diabetes. 1871 26

The aim of this study is to investigate how the semisynthetic bile acid; 3alpha,7alpha-dihydroxy-12-keto-5beta-cholanate, also known as 12-monoketocholic acid (MKC) influences the ileal permeation of the antidiabetic drug gliclazide in healthy and diabetic rats. Male Wistar rats were divided into 10 groups (n = 32), of which 5 comprised healthy rats (1 to 5) and 5 diabetic rats (6 to 10). Group 1 was used to measure the permeation of gliclazide (200 microg/ml) alone (control) while in groups 2 to 5 gliclazide permeation was measured in the presence of MKC (50 microg/ml), glibenclamide (100 mug/ml), rifampicin (100 mug/ml) and verapamil (30 microg/ml), respectively, using Ussing chambers. Groups 6 to 10 were treated in the same way, after the induction of type 1 diabetes with alloxan (iv 30 mg/kg). In tissues from healthy rats, there was a 9-fold reduction in the mucosal to serosal permeation of gliclazide in the presence of MKC (p < 0.001) while glibenclamide and rifampicin reduced the permeation of gliclazide in both directions; mucosal to serosal and serosal to mucosal and verapamil had no effect. In contrast, in diabetic rats, there was no net transport of gliclazide alone or after the addition of MKC, glibenclamide, rifampicin or verapamil. The lack of any net flux of gliclazide in diabetic rats suggests the lack of action of drug transporters involved or the suppression of their expression. Furthermore, MKC-induced inhibition of mucosal to serosal unidirectional flux of gliclazide, in healthy rats, can be the result of the selective inhibition of Mrp3.
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PMID:Influence of the semisynthetic bile acid (MKC) on the ileal permeation of gliclazide in healthy and diabetic rats. 1879 22

Reactive oxygen species (ROS) cause irreversible damage to biological macromolecules, resulting in many diseases. Reduced water (RW) such as hydrogen-rich electrolyzed reduced water and natural reduced waters like Hita Tenryosui water in Japan and Nordenau water in Germany that are known to improve various diseases, could protect a hamster pancreatic beta cell line, HIT-T15 from alloxan-induced cell damage. Alloxan, a diabetogenic compound, is used to induce type 1 diabetes mellitus in animals. Its diabetogenic effect is exerted via the production of ROS. Alloxan-treated HIT-T15 cells exhibited lowered viability, increased intracellular ROS levels, elevated cytosolic free Ca(2+) concentration, DNA fragmentation, decreased intracellular ATP levels and lowering of glucose-stimulated release of insulin. RW completely prevented the generation of alloxan-induced ROS, increase of cytosolic Ca(2+) concentration, decrease of intracellular ATP level, and lowering of glucose-stimulated insulin release, and strongly blocked DNA fragmentation, partially suppressing the lowering of viability of alloxan-treated cells. Intracellular ATP levels and glucose-stimulated insulin secretion were increased by RW to 2-3.5 times and 2-4 times, respectively, suggesting that RW enhances the glucose-sensitivity and glucose response of beta-cells. The protective activity of RW was stable at 4 degrees C for over a month, but was lost by autoclaving. These results suggest that RW protects pancreatic beta-cells from alloxan-induced cell damage by preventing alloxan-derived ROS generation. RW may be useful in preventing alloxan-induced type 1-diabetes mellitus.
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PMID:Protective mechanism of reduced water against alloxan-induced pancreatic beta-cell damage: Scavenging effect against reactive oxygen species. 1900 14

Responses of platelets from diabetic and diabetic-hyperlipidemic pigs were studied. Pigs were made diabetic with single dose of alloxan, which acts by selectively destroying insulin-producing pancreatic beta cells thus inducing type 1 diabetes. Pigs were kept for 1 or 12 wk, during which thrombin-induced aggregation was monitored in washed platelets. The platelets showed increased sensitivity to aggregation within 1 wk of induction of diabetes. Hyperlipidemia alone for 12 wk did not increase platelet hypersensitivity, but hyperlipidemia together with diabetes significantly increased thrombin-induced platelet aggregation. Because this hypersensitivity occurred in washed platelets, this characteristic appears to be independent of any contribution by plasma factors or other blood cells. The hypersensitivity of platelets from diabetic pigs correlated with decreased activity of mitogen-activated protein kinase. These studies offer the first evidence that platelet hyperactivity occurs during the early stages (within a week) of induction of diabetes in pigs and before manifestation of other cardiovascular problems.
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PMID:Platelets from diabetic pigs exhibit hypersensitivity to thrombin. 1900 74

Protection of pancreatic beta cells is an approach to prevent autoimmune type 1 diabetes (T1D) and to protect transplanted islets. Reactive oxygen species (ROS) are important mediators of beta cell death during the development of T1D. We have examined the role of elevated ROS dissipation in the prevention of T1D using the ALR mouse strain. The selection of ALR, for resistance against alloxan-induced free radical-mediated diabetes, led to a strain of mice with an elevated systemic as well as pancreatic ROS dissipation. Independent genetic mapping studies have identified ALR-derived diabetes protective loci. Conplastic and congenic mouse as well as cell line studies have confirmed the genetic mapping and demonstrated that the elevated ROS dissipation protects ALR beta cells from autoimmune destruction. Our data support the hypothesis that elevated ROS dissipation protects beta cells against autoimmune destruction and prevents T1D development.
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PMID:Role of increased ROS dissipation in prevention of T1D. 1912 Feb 87


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