Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

357 IDMs and 20 healthy newborns of non-diabetic mothers were examined at term for body measurements, red blood cell count, serum bilirubin, cord blood insulin and blood glucose during the first postnatal week. The stage of maternal diabetes did not influence the course of neonatal bilirubin levels, but the IDMs had prolonged and higher bilirubinaemia compared with the controls. Hyperbilirubinaemia was found to be most prominent in newborns with an increased birthweight/length ratio and was not simply related to macrosomia (LGA). These infants had significantly lower blood glucose concentrations immediately after birth, whereas cord blood insulin was found to be identical between the IDM sub-groups. Bilirubinaemia in heavy for length infants was slightly correlated to haematocrit. For the pathogenesis of hyperbilirubinaemia in IDMs induction of heme oxygenase (due to a lack of energy provision following a phosphorylation disorder) is discussed. Nutritional support (early feeding, glucose infusions) does not affect the course of bilirubinaemia.
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PMID:Neonatal jaundice in infants of diabetic mothers. 270 15

Diabetes-induced alterations in heme and hemoproteins, as well as its relationship to drug-mediated induction of ALA Synthase (ALA-S), were examined in female Sprague-Dawley rats. Animals were rendered diabetic by a single i.v. injection of streptozotocin (STZ, 65 mg/kg) and measurements were made at various times after treatment. The basal levels of the key enzymes involved in heme synthesis, ALA-S and ALA-dehydratase (ALA-D), were decreased about 36% and 54%, respectively, 44-46 days after diabetes induction. Furthermore, the catabolism of heme that occurs via microsomal heme oxygenase progressively decreases in activity during the course of diabetes, and reaches 69% of control in 90-day diabetic animals. The basal levels of heme, cytochromes P-450 and b5 were elevated about twofold in diabetic rats as compared with their corresponding control values. The activity of benzo(a)pyrene hydroxylase in diabetic rats was also increased in proportion to the microsomal content of cytochrome P-450. In contrast, delta 4-hydrogenase, the rate-limiting enzyme in corticosterone metabolism, exhibited a 35-65% decrease in activity throughout the experimental period. Tryptophan pyrrolase activity (total, holo-, and apoenzyme) was elevated about 2.5-fold in STZ diabetic rats. In vivo insulin therapy of diabetic animals antagonized the effect of the diabetic state on the above measured parameters. Treatment with aminoglutethimide resulted in about a twofold elevation in ALA-S activity in control as well as chronically diabetic rats. However, a similar stimulatory response in ALA-S activity to CoCl2 administration was observed only in control or insulin-treated diabetic rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1984 Jan
PMID:Diabetes-induced metabolic alterations in heme synthesis and degradation and various heme-containing enzymes in female rats. 660 90

Alterations in heme biosynthetic and degradative capabilities and in the activities of several heme-containing enzymes were examined in hepatic tissues of streptozotocin (STZ)-diabetic female Sprague-Dawley rats. Activities were measured 10, 30 and 90 days following the administration of STZ (65 mg/kg, i.v.). The activities of the key enzymes involved in heme synthesis, delta-aminolevulinic acid (ALA) synthase, ALA dehydratase, and uroporphyrinogen synthase, were decreased markedly in STZ-diabetic rats as compared to sham-operated animals. Furthermore, the catabolism of heme which occurs via microsomal heme oxygenase (MHO) remained unaltered in these animals. Microsomal content of heme and cytochrome P-450, and the activities of tryptophan pyrrolase and the drug-metabolizing enzymes benzo[a]pyrene (BP) hydroxylase and aniline hydroxylase, were increased in the livers of diabetic rats. By contrast, the activity of the heme-containing enzyme catalase was decreased in these animals. Cobalt chloride produced a marked increase in MHO with a concomitant decrease in microsomal content of cytochrome P-450 and its associated BP hydroxylase activity in normal as well as chronically diabetic rats. It was of interest, however, that the increase in ALA synthase that is normally produced by this metal was not seen in chronic diabetic animals. Thus, chronic diabetes produced subtle and important disruptions in cellular metabolism, which may have been the result of long-term alterations in key enzymes involved in heme synthesis.
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PMID:Heme and hemoproteins in streptozotocin-diabetic female rats. 668 50

Exposure of proteins to reducing sugars results in nonenzymatic glycation with the ultimate formation of advanced glycation end products (AGEs). One means through which AGEs modulate cellular functions is through binding to specific cell surface acceptor molecules. The receptor for AGEs (RAGE) is such a receptor and is a newly identified member of the immunoglobulin superfamily expressed on endothelial cells (ECs), mononuclear phagocytes (MPs), and vascular smooth muscle cells (SMCs) in both vivo and in vitro. Binding of AGEs to RAGE results in induction of cellular oxidant stress, as exemplified by the generation of thiobarbituric acid-reactive substances, expression of heme oxygenase type I, and activation of the transcription factor NF-kB, with consequences for a range of cellular functions. AGEs on the surface of diabetic red cells enhance binding to endothelial RAGE and result in enhanced oxidant stress in the vessel wall. By using reagents to selectively block access to RAGE, the role of this receptor in AGE-mediated perturbation of cellular properties can be dissected in detail.
Diabetes 1996 Jul
PMID:RAGE: a novel cellular receptor for advanced glycation end products. 867 99

The cytokine IL-1 beta has previously been demonstrated to induce the expression of the stress genes iNOS, hsp70, heme oxygenase and Mn-SOD in rat pancreatic islets in vitro. The aim of this study was to determine whether the IL-1 beta-induced effects are specific for the insulin producing beta-cell, or whether other islet cells, such as the glucagon-producing alpha-cell, respond to IL-1 beta addition. Purified rat alpha- and beta-cell suspensions were obtained by fluorescence-activated cell sorting and incubated with or without IL-1 beta (25 U/ml) for 24 h. The alpha- and beta-cell contents of hsp70, heme oxygenase and Mn-SOD and medium nitrite levels were determined. It was found that IL-1 beta exposure induced the production of nitric oxide in beta-cells, but not in alpha-cells. Moreover, the expression of hsp70, heme oxygenase and Mn-SOD was also induced in beta-cells, but not in alpha-cells. There were no detectable levels of hsp70 in alpha-cells. It is concluded that the stress gene response following IL-1 beta exposure is markedly different in alpha- and beta-cells. This finding may be of importance for the understanding of the autoimmune destruction of beta-cells in insulin-dependent diabetes mellitus.
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PMID:Interleukin-1 beta induces the expression of hsp70, heme oxygenase and Mn-SOD in FACS-purified rat islet beta-cells, but not in alpha-cells. 871 14

We hypothesized that one mechanism underlying advanced periodontal disease in diabetes may involve oxidant stress in the gingiva, induced by the effects of Advanced Glycation Endproducts (AGEs), the irreversible products of non-enzymatic glycation and oxidation of proteins and lipids which accumulate in diabetic plasma and tissue. Infusion of AGE albumin, a prototypic ligand, into mice resulted in increased generation of thiobarbituric acid reactive substances (TBARS) compared with infusion of non-glycated albumin in the gingiva, as well as in the lung, kidney and brain. Pretreatment of the animals with the antioxidants probucol or N-acetylcysteine (NAC) prevented the generation of TBARS in the gingiva. Affinity-purified antibody to AGEs demonstrated increased immunoreactivity for AGEs in the vasculature and connective tissues of the gingiva in streptozotocin-induced diabetic mice compared to non-diabetic controls. Increased immunoreactivity for AGEs was also demonstrated in the gingiva of diabetic humans compared with non-diabetic individuals via immunohistochemistry and ELISA. Consistent with these data, immunohistochemistry for heme oxygenase-1, a marker of enhanced oxidant stress, was increased in the gingival vasculature of diabetic mice and humans compared with non-diabetic controls. These data suggest that AGEs present in diabetic gingiva may be associated with a state of enhanced oxidant stress, a potential mechanism for accelerated tissue injury.
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PMID:Advanced glycation endproducts (AGEs) induce oxidant stress in the gingiva: a potential mechanism underlying accelerated periodontal disease associated with diabetes. 891 55

In order to study the contribution of oxidant stress to the pathogenesis of experimental diabetic retinopathy, male streptozotocin diabetic Lewis rats were treated with the antioxidant and lipid-lowering compound nicanartine (80 mg/kg; n = 8, blood glucose level 16.7 +/- 3.9 mmol/l; HbA1 11.8 +/- 1.6%) by oral supplementation for 6 months and compared with untreated diabetic (n = 6; blood glucose 18.1 +/- 1.4 mmol/l; HbA1 11.5 +/- 1.5%) and untreated, non-diabetic rats (n = 8; blood glucose 4.0 +/- 0.6 mmol/l; HbA1 4.8 +/- 0.9%). Diabetic retinopathy was evaluated by computer-assisted quantitative morphometry including measurement of autofluorescent advanced glycated end-products and immunohistochemistry for heme oxygenase I. Antioxidant treatment did not inhibit the 3.1-fold increase of retinal advanced glycation end products, while the expression of heme oxygenase I in both vascular and glial structures was markedly reduced. Chronic hyperglycaemia led to a 37.3% increase in endothelial cells (p < 0.001 vs normal controls) and a 26.6% reduction in pericyte numbers (p < 0.001 vs controls). Both abnormalities were significantly ameliorated by nicanartine (p < 0.001 vs diabetic controls). No effect was observed on the formation of acellular capillaries or microaneurysms. These data indicate that antioxidant therapy with nicanartine is of limited benefit in diabetic retinopathy, at least in the rodent model of streptozotocin-induced diabetes.
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PMID:Antioxidant treatment of experimental diabetic retinopathy in rats with nicanartine. 922 40

Gene regulation in the cardiovascular tissues of diabetic subjects has been reported to be altered. To examine abnormal activities in transcription factors as a possible cause of this altered gene regulation, we studied the activity of two redox-sensitive transcription factors--nuclear factor-kappaB (NF-kappaB) and activating protein-1 (AP-1)--and the change in the mRNA content of heme oxygenase-1, which is regulated by these transcription factors in the cardiac tissues of rats with streptozotocin-induced diabetes. Increased activity of NF-kappaB and AP-1 but not nuclear transcription-activating factor, as determined by an electrophoretic mobility shift assay, was found in the hearts of 4-week diabetic rats. Glycemic control by a subcutaneous injection of insulin prevented these diabetes-induced changes in transcription factor activity. In accordance with these changes, the mRNA content of heme oxygenase-1 was increased fourfold in 4-week diabetic rats and threefold in 24-week diabetic rats as compared with control rats (P < 0.01 and P < 0.05, respectively). Insulin treatment also consistently prevented changes in the mRNA content of heme oxygenase-1. The oral administration of an antioxidant, probucol, to these diabetic rats partially prevented the elevation of the activity of both NF-kappaB and AP-1, and normalized the mRNA content of heme oxygenase-1 without producing any change in the plasma glucose concentration. These results suggest that elevated oxidative stress is involved in the activation of the transcription factors NF-kappaB and AP-1 in the cardiac tissues of diabetic rats, and that these abnormal activities of transcription factors could be associated with the altered gene regulation observed in the cardiovascular tissues of diabetic rats.
Diabetes 1998 Aug
PMID:Altered activities of transcription factors and their related gene expression in cardiac tissues of diabetic rats. 970 34

Carbon monoxide (CO) has been suggested as a novel messenger molecule in the brain. We now report on the cellular localization and hormone secretory function of a CO-producing constitutive heme oxygenase (HO-2) in mouse islets. Islet homogenates produced large amounts of CO which were suppressed dose-dependently by the HO inhibitor zincprotoporphyrin-IX (ZnPP-IX). We also show, for the first time, that glucose markedly stimulates the HO activity (CO production) in intact islets. A further potentiation was induced by the HO substrate hemin. Western blot showed that islet tissue expressed HO-2, and confocal microscopy revealed that HO-2 resided in insulin, glucagon, somatostatin, and pancreatic polypeptide cells. ZnPP-IX dose-dependently inhibited, whereas hemin enhanced, both insulin and glucagon secretion from glucose-stimulated islets. Stimulation or inhibition of CO production was accompanied by corresponding changes in islet cGMP levels. Exogenously applied CO stimulated insulin and glucagon release from isolated islets, whereas exogenous nitric oxide (NO) inhibited insulin and stimulated glucagon release. Islets stimulated by glucose or L-arginine displayed a marked increase in their NO-synthase (NOS) activity. Such an increase was suppressed by hemin, conceivably because NOS activity was inhibited by hemin-derived CO. Consequently, hemin enhanced L-arginine-induced insulin secretion. Insulin release stimulated by either hemin-derived CO or exogenous CO was strongly inhibited by the guanylate cyclase inhibitor ODQ, but it was unaffected by ZnPP-IX. Glucagon release induced by CO (but not by hemin) was inhibited by ODQ and partly inhibited by ZnPP-IX. We propose that the islets of Langerhans are equipped with a heme oxygenase-carbon monoxide pathway, which constitutes a novel regulatory system of physiological importance for the stimulation of insulin and glucagon release. This pathway is stimulated by glucose, is at least partly dependent on the cGMP system, and displays interaction with islet NOS activity.
Diabetes 1999 Jan
PMID:Heme oxygenase and carbon monoxide: regulatory roles in islet hormone release: a biochemical, immunohistochemical, and confocal microscopic study. 989 24

Previous work has shown that interleukin-1beta (IL-1beta) alters protein expression in beta-cells. This alteration is associated with cell death in isolated rat islets but not in isolated rat beta-cells. We examined whether IL-1beta pretreatment of isolated beta-cells influences their sensitivity to toxic agents. After a 24-h culture with IL-1beta (30 U/ml), beta-cells exhibited a lower expression of the beta-cell-specific protein transcription factor pancreatic and duodenal homeobox gene (PDX)-1, glucose transporter GLUT2, and proinsulin convertase PC2, with a marked reduction (60-70%) in glucose-induced insulin production and selective sensitivity to the toxins alloxan (ALX) and streptozotocin (STZ). On the other hand, the cells presented an increased expression of Mn-superoxide dismutase, heat shock protein 70, inducible heme oxygenase, and inducible nitrite oxide synthase. This IL-1beta-induced alteration in beta-cell phenotype resulted in a reduced cellular sensitivity to the beta-cell-specific toxins ALX and STZ; the production of nontoxic conditions of nitric oxide (NO) also rendered the cells less susceptible to radical-induced damage. Exposure to IL-1beta can thus protect beta-cells against conditions that cause necrosis; however, it did not protect against apoptosis induced by the additional presence of interferon-gamma or tumor necrosis factor-alpha. Release of IL-1beta in the endocrine pancreas is thus not necessarily the cause of massive NO-dependent beta-cell destruction. On the contrary, IL-1beta may protect these cells against necrosis, though with a loss of their characteristic phenotype and homeostatic functions.
Diabetes 2000 Mar
PMID:Interleukin-1beta-induced alteration in a beta-cell phenotype can reduce cellular sensitivity to conditions that cause necrosis but not to cytokine-induced apoptosis. 1086 54


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