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

The type 3 form of maturity-onset diabetes of the young (MODY3) results from mutations in the gene encoding the transcription factor, hepatocyte nuclear factor-1alpha (HNF-1alpha). The mechanism by which mutations in only one allele of the HNF-1alpha gene impair pancreatic beta-cell function is unclear. The functional form of HNF-1alpha is a dimer--either a homodimer or a heterodimer with the structurally related protein HNF-1beta--that binds to and activates transcription of the genes whose expression it regulates. HNF-1alpha is composed of three functional domains: an amino-terminal dimerization domain (amino acids 1-32), a DNA-binding domain with POU-like and homeodomain-like motifs (amino acids 150-280), and a COOH-terminal transactivation domain (amino acids 281-631). Because the dimerization domain is intact in many of the mutant forms of HNF-1alpha found in MODY subjects, these mutant proteins may impair pancreatic beta-cell function by forming nonproductive dimers with wild-type protein, thereby inhibiting its activity; that is, they are dominant-negative mutations. This hypothesis was tested by comparing the functional properties of the frameshift mutation P291fsinsC, the most common mutation identified to date in MODY3 patients, and wild-type HNF-1alpha. P291fsinsC-HNF-1alpha showed no transcriptional transactivation activity in HeLa cells, which lack endogenous HNF-1alpha. Overexpression of P291fsinsC-HNF-1alpha in MIN6 cells, a mouse beta-cell line, resulted in an approximately 40% inhibition of the endogenous HNF-1alpha activity in a dosage-dependent manner. Furthermore, heterodimer formation between wild-type and P291fsinsC mutant proteins were observed by electrophoretic mobility shift assay. These data suggest that the P291fsinsC mutation in HNF-1alpha functions as a dominant-negative mutation. However, other mutations, such as those in the promoter region and dimerization domain, may represent loss of function mutations. Thus mutations in the HNF-1alpha gene may lead to beta-cell dysfunction by two different mechanisms.
Diabetes 1998 Aug
PMID:Mutation P291fsinsC in the transcription factor hepatocyte nuclear factor-1alpha is dominant negative. 970 22

The aim of this study was to examine lipid peroxidation and activities of key antioxidant enzymes in kidneys of rats with streptozotocin (STZ)-induced diabetes and the effect of aminoguanidine on diabetes-induced alterations. Three groups, 6 rats each, were studied: control animals, not treated diabetic rats and rats treated with aminoguanidine (AG; 1 g/liter of drinking water). After 6 and 12 weeks the animals were sacrificed and lipid peroxidation products and activities of antioxidant enzymes were determined in their kidney homogenates. Malondialdehyde (MDA) content was significantly elevated and activities of SOD and catalase decreased in the kidneys of STZ-diabetic rats. AG treatment attenuated the increase in MDA content and diminutions of activities of SOD and catalase in the kidneys of diabetic rats. These results confirm oxidative stress in the kidney of rats with STZ diabetes and point to an antioxidant effect of AG in experimental diabetes.
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PMID:Effect of aminoguanidine on lipid peroxidation and activities of antioxidant enzymes in the diabetic kidney. 981 97

1. Nonenzymatic protein glycosylation is a possible mechanism contributing to oxidative stress and vascular disease in diabetes. In this work, the influence of 14%-glycosylated human oxyhaemoglobin (GHHb), compared to the non-glycosylated protein (HHb), was studied on several growth parameters of rat cultured vascular smooth muscle cells (VSMC). A role for reactive oxygen species was also analysed. 2. Treatment of VSMC for 48 h with GHHb, but not with HHb, increased planar cell surface area in a concentration dependent manner. The threshold concentration was 10 nM, which increased cell size from 7965+/-176 to 9411+/-392 microm2. Similarly, only GHHb enhanced protein content per well in VSMC cultures. 3. The planar surface area increase induced by 10 nM GHHb was abolished by superoxide dismutase (SOD; 50 200 u ml(-1)), deferoxamine (100 nM-100 microM), or dimethylthiourea (1 mM), while catalase (50 200 u ml(-1)) or mannitol (1 mM) resulted in a partial inhibition of cell size enhancement. 4. When a known source of oxygen free radicals was administered to VSMC, the xanthine/xanthine oxidase system, the results were analogous to those produced by GHHb. Indeed, enhancements of cell size were observed, which were inhibited by SOD, deferoxamine, or catalase. 5. These results indicate that, at low concentrations, GHHb induces hypertrophy in VSMC, this effect being mediated by superoxide anions, hydrogen peroxide, and/or hydroxyl radicals. Therefore, glycosylated proteins can have a role in the development of the structural vascular alterations associated to diabetes by enhancing oxidative stress.
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PMID:Vascular smooth muscle cell hypertrophy induced by glycosylated human oxyhaemoglobin. 983 96

1. Oxygen free radicals have been suggested to be a contributory factor in complications of diabetes mellitus. There are many reports indicating the changes in parameters of oxidative stress in diabetes mellitus. In this study we aimed to identify whether oxidative stress occurs in the liver and pancreas in the initial stages of development of diabetes. 2. We therefore investigated the lipid peroxide level (thiobarbituric acid-reactive substances, TBARS) and activities of antioxidant enzymes [superoxide dismutase (SOD), catalase and glutathione peroxidase] in liver and pancreas of control and streptozotocin-induced diabetic rats at various stages of development of diabetes. 3. Male Sprague-Dawley rats were divided into two groups: group I, control (n = 42) and group II, diabetic (n = 42). Each group was further subdivided into seven groups consisting of six rats each. Rats in these subgroups were studied at weekly intervals (0 to 6 weeks). Plasma glucose levels, TBARS levels and activities of antioxidant enzymes were measured in liver and pancreas at various time intervals. 4. There was a significant (P < 0.05) and progressive increase in TBARS levels of liver and pancreas in the diabetic group. Total SOD and Cu-Zn-SOD activity increased (P < 0.05) with progression of diabetes while Mn-SOD activity showed no significant change in either tissue. Catalase and glutathione peroxidase activities increased significantly (P < 0.05) in liver and pancreas. 5. Immunohistochemical study of pancreatic islet revealed a decrease in the expression of insulin with progression of diabetes. However, glucagon and somatostatin showed an increase in immunoreactivity and a difference in their distribution pattern. 6. The findings of the present study suggest that oxidative stress starts at early onset of diabetes mellitus and increases progressively. In conclusion, the structural damage to these tissues or complications of diabetes mellitus may be due to oxidative stress.
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PMID:Increased oxidative stress in rat liver and pancreas during progression of streptozotocin-induced diabetes. 985 60

Recent studies have shown that mutations in four transcription factors, hepatocyte nuclear factor-4 alpha (HNF-4 alpha), hepatocyte nuclear factor-1 alpha (HNF-1 alpha), hepatocyte nuclear factor-1 beta (HNF-1 beta), and insulin promoter factor-1 (IPF-1), are responsible for maturity onset diabetes of the young (MODY) which is characterised by an early age of onset and autosomal dominant inheritance. MODY is not an uncommon disorder and in fact could account for about 2 to 5% of all cases of type 2 diabetes. Moreover, mutations in HNF-1 beta, which functions as a homodimer or a heterodimer with HNF-1 alpha, have been identified in a few families with MODY and severe kidney disease. Mutations in the coding regions or in the promotors of these nuclear factors are responsible for severe insulin secretory defects and for major hyperglycaemia associated with microvascular complications. The role of transcription factors in the development of the more common late-onset type 2 diabetes is still under investigation. Some mutations in HNF-1 alpha were identified in subjects with atypical forms of insulin-dependent diabetes, and a mutation in HNF-4 alpha and several mutations in IPF-1 were found in type 2 diabetic families with typical late-onset NIDDM. Altogether, these data suggest that non-MODY monofactorial forms of late-onset NIDDM, due to islet transcription factor defects, exist.
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PMID:Nuclear factors and type 2 diabetes. 988 71

To evaluate oxidative stress in type I diabetes mellitus, two antioxidant enzymes in erythrocytes, copper-zinc superoxide dismutase (SOD EC 1.15.1.1.) and seleno-dependent glutathione peroxidase (GSH-Px; EC 1.11.19), and two indexes of peroxidation in plasma, thiobarbituric acid reactive substances (TBARS) and organic hydroperoxides (OHP), were measured in 118 patients with insulin-dependent diabetes mellitus (IDDM), classified in accordance with the presence or absence of vascular complications and the degree of metabolic control established by the HbA1c level. Ninety healthy subjects made up the control group. According to our results, plasmatic TBARS and OHP concentrations are significantly higher in diabetics than in controls, and these differences are accentuated in diabetic people with vascular disorders. The GSH-Px activity was significantly reduced in diabetic patients with poor and medium metabolic control in relation to the control group, regardless of the existence or absence of vascular disorders. No differences in SOD activity between diabetic and control groups were found. A significant positive correlation between TBARS and HPO (r=0.683, p<0.001) was found in both the control and diabetic groups. Among the lipid parameters studied, there were only significantly positive correlations between TBARS and total cholesterol; TBARS and triglycerides; OHP and total cholesterol and OHP and triglycerides. Positive correlations between TBARS and HbA1c and between OHP and and HbA1c, and negative correlations between GSH-Px and HbA1c and between SOD and HbA1c were also found. The multiple regression analysis shows that TBARS and HPO correlate negatively with GSH-Px. There was no significant correlation with SOD.
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PMID:Lipid peroxidation and antioxidant enzyme activities in patients with type 1 diabetes mellitus. 1035 23

The effects of hydrogen peroxide (H2O2, 1 nM-5 mM) on the tone of the rings of aorta precontracted with phenylephrine (PE) were studied in 4-5 months streptozotocin (STZ)-diabetic rats and their age-matched controls. H2O2 induced brief contraction before relaxation in endothelium-containing rings that was more pronounced in diabetic rats. Removal of the endothelium or pretreatment of rings with N(G)-nitro-L-arginine methyl ester (L-NAME, 100 microM) abolished H2O2-induced immediate and transient increase in tone, but preincubation with indomethacin (10 microM) had no effect on contractions induced by H2O2 in both group of animals. Pretreatment with L-NAME or indomethacin as well as absence of endothelium produced an inhibition of H2O2-induced relaxation that was more pronounced in diabetic rings. Chronically STZ-diabetes resulted in a significant increase in H2O2-induced maximum relaxation that was largely endothelium-dependent. Decreased sensitivity (pD2) of diabetic vessels to vasorelaxant action of H2O2 was normalized by superoxide dismutase (SOD, 80 U/ml). Pretreatment with SOD had no effect on H2O2-induced maximum relaxations in both group of animals but led to an increase in H2O2-induced contractions in control rats. When the rings pretreated with diethyldithiocarbamate (DETCA, 5 mM), H2O2 produced only contraction in control rats, and H2O2-induced relaxations were markedly depressed in diabetic rats. H2O2 did not affect the tone of intact or endothelium-denuded rings in the presence of catalase (2000 U/ml). Aminotriazole (AT, 10 mM) failed to affect H2O2-induced contractions or relaxations in all rings. Our observations suggest that increased production of oxygen-derived free radicals (OFRs) in diabetic state leads to a decrease in SOD activity resulting an increase in endogenous superoxide anions (O2*-), that is limited cytotoxic actions, and an increase in catalase activity resulting a decrease in both H2O2 concentrations and the production of harmful hydroxyl radical (*OH) in diabetic aorta in long-term. Present results indicate that increased vascular activity of H2O2 may be an important factor in the development of vascular disorders associated with chronically diabetes mellitus. Enhanced formation of *OH, that is a product of exogenous H2O2 and excess O2*, seems to be contribute to increased relaxations to exogenously added H2O2 in chronically diabetic vessels.
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PMID:Increased activity of H2O2 in aorta isolated from chronically streptozotocin-diabetic rats: effects of antioxidant enzymes and enzymes inhibitors. 1044 15

We report on long-term delivery of an interferon-gamma (IFN gamma) inhibitory protein by intramuscular (i.m.) gene therapy. IFN gamma is a cytokine that plays an important role in many inflammatory disorders, including autoimmune insulin-dependent diabetes mellitus (IDDM) in NOD mice and (in various strains) multiple low-dose streptozotocin (STZ)-induced diabetes (MDSD). By cDNA insertion into plasmid VICAL VR-1255 we constructed an expression vector encoding a soluble IFN gamma receptor/IgG1 heavy chain (all murine) fusion protein (IFN gamma R/IgG1). This protein is secreted as a homodimer and neutralizes IFN gamma in vitro. We show that i.m. injections of this vector as naked DNA in mice results in secretion of IFN gamma R/IgG1, with serum levels exceeding 100 ng/ml for months after treatment. These levels are sufficient to neutralize IFN gamma in vivo, and to prevent either MDSD or cyclophosphamide (CYP)-accelerated diabetes in NOD mice, which are both characterized by systemic release of IFN gamma. In these diseases gene therapy considerably reduces inflammation in the islets of Langerhans (insulitis). Also, circulating IFN gamma R/IgG1 blocked IFN gamma-enhanced nitric oxide production by peritoneal macrophages. The fusion protein is constructed from non-immunogenic self elements, avoiding a neutralizing immune response and making it suitable for prolonged therapy of numerous inflammatory disorders.
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PMID:Prevention of autoimmune diabetes by intramuscular gene therapy with a nonviral vector encoding an interferon-gamma receptor/IgG1 fusion protein. 1050

Alloxan is a diabetogenic agent which apparently acts through formation of superoxide radicals formed by redox cycling. Superoxide radicals are also formed by a variety of mechanisms in hyperglycemia. We exposed extracellular-superoxide dismutase (EC-SOD) null mutant and wild-type mice to alloxan, and followed up both the initial diabetes induction and the long-term course of the hyperglycemia. The null mutant mice responded with a modestly enhanced hyperglycemia compared to the wild type controls. In the long-term follow-up all mice eventually regained glycemic control, although it took longer for individuals with higher initial hyperglycemia. This delaying effect of the hyperglycemia was much more pronounced in the null mutant mice. These data suggest that the difference in initial diabetes induction between the groups is due to interception by EC-SOD of extracellular superoxide radicals produced by alloxan. The delayed recovery in the null mutant mice suggests that superoxide radicals released as a result of hyperglycemia impair beta-cell regeneration and that EC-SOD provides some protection. Mouse islets were found to contain little EC-SOD, whereas the content of the cytosolic Cu- and Zn-containing SOD was very high. This low EC-SOD activity may contribute to the high alloxan susceptibility of beta-cells, and may also cause a high susceptibility to superoxide radicals produced by activated inflammatory leukocytes and in hyperglycemia.
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PMID:Enhanced alloxan-induced beta-cell damage and delayed recovery from hyperglycemia in mice lacking extracellular-superoxide dismutase. 1051 83

Previous studies have suggested that reactive oxygen species (ROS) are mediators in the teratogenic process of diabetic pregnancy. In an animal model for diabetic pregnancy, offspring of the H rat strain show minor dysmorphogenesis when the mother is diabetic, whereas the offspring of diabetic rats of a sister strain, U, display major morphologic malformations. Earlier studies have shown that embryonic catalase activity is higher in the H than in the U strain, and maternal diabetes increases this difference in activity. The aim of this study was to characterize the influence of genetic predisposition on diabetic embryopathy by comparing the mRNA levels of ROS-metabolizing enzymes in the two strains. We determined the mRNA levels of catalase, glutathione peroxidase, gamma-glutamylcystein-synthetase, glutathione reductase, and superoxide dismutase (CuZn-SOD and Mn-SOD) in day 11 embryos of normal and diabetic H and U rats using semiquantitative reverse transcription-polymerase chain reaction. The mRNA levels of catalase and Mn-SOD were increased in H embryos as a response to maternal diabetes, and no differences were found for the other genes. Sequence analysis of the catalase promoter indicated that the difference in mRNA levels may result from different regulation of transcription. Sequence analysis of the catalase cDNA revealed no differences between the two strains in the translated region, suggesting that the previously observed difference in the electrophoretic mobility in zymograms is due to posttranslational modifications. An impaired expression of scavenging enzymes in response to ROS excess can thus be an integral part of a genetic predisposition to embryonic dysmorphogenesis.
Diabetes 2000 Jan
PMID:Increased mRNA levels of Mn-SOD and catalase in embryos of diabetic rats from a malformation-resistant strain. 1061 56


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