Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The time-course of the reaction of H1 and total histone with glucose, acetaldehyde or both has been studied using the NBT reduction test and fluorescence. With both methods, purified H1 histone gave higher absorbance with acetaldehyde than with a 1:1 combination of glucose and acetaldehyde. For total histone, the opposite was found; a 1:1 combination of the above two aldehydes had the higher absorbance. As an explanation, the possibility of different reactivity of the amino groups with glucose and acetaldehyde is proposed. A possible simultaneous interaction between glucose, acetaldehyde and serum protein, mainly albumin, may alter the results of the diagnostic protein glycation methods, e.g. of the fructosamine test, and, therefore, also the monitoring of diabetes.
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PMID:The kinetics of the addition of glucose and acetaldehyde to histone proteins. 808 May 96

To assess the role of insulin receptor (IR) tyrosine kinase in human insulin resistance, we examined the kinase activity of IR of skeletal muscle biopsies from eight lean and five obese nondiabetics and six obese subjects with noninsulin-dependent diabetes mellitus (NIDDM). Biopsies were taken during euglycemic clamps at insulin infusion rates of 0, 40, 120, and 1200 mU/m2.min. IRs were immobilized on insulin agarose beads, and autophosphorylation and histone 2B phosphorylation were measured. Phosphatase and protease inhibitors preserved the in vivo phosphorylation state of the IRs. Glucose disposal rates (GDR) were reduced according to insulin dose by 23-30% in the obese (P < 0.05) and 43-64% in the NIDDM subjects (P < 0.0005). IR autophosphorylation was increased up to 9-fold in controls and was reduced (P = 0.04) in NIDDM compared to obese subjects. Histone-2B kinase was increased up to 6-fold in controls and was reduced by 50% in NIDDM. Kinase values by both methods were similar in lean and obese controls. In vivo stimulation of kinase was well correlated to the increase in GDR, as was the decrement in kinase in NIDDM to the decrement in GDR. These results suggest that defects in muscle IR kinase are significant in the in vivo insulin resistance of NIDDM, but not that of obesity.
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PMID:Role of human skeletal muscle insulin receptor kinase in the in vivo insulin resistance of noninsulin-dependent diabetes mellitus and obesity. 810 37

ADP-ribosylation of proteins has been observed in numerous animal tissues including chicken heterophils, rat brain, human platelets, and mouse skeletal muscle. ADP-ribosylation in these tissues is thought to modulate critical cellular functions such as muscle cell development, actin polymerization, and cytotoxic T lymphocyte proliferation. Specific substrates of the ADP-ribosyltransferases have been identified; the skeletal muscle transferase ADP-ribosylates integrin alpha 7 whereas the chicken heterophil enzyme modifies the heterophil granule protein p33 and the CTL enzyme ADP-ribosylates the membrane-associated protein p40. Transferase sequence has been determined which should assist in elucidating the role of ADP-ribosylation in cells. There is sequence similarity among the vertebrate transferases and the rodent RT6 alloantigens. The RT6 family of proteins are NAD glycohydrolases that have been shown to possess auto-ADP-ribosyltransferase activity whereas the mouse Rt6-1 is also capable of ADP-ribosylating histone. Absence of RT6+ T cells has been associated with the development of an autoimmune-mediated diabetes in rodents. Humans have an RT6 pseudogene and do not express RT6 proteins. The reversal of ADP-ribosylation is catalyzed by ADP-ribosylarginine hydrolases, which have been purified and cloned from rodent and human tissues. In principle, the transferases and hydrolases could form an intracellular ADP-ribosylation regulatory cycle. In skeletal muscle and lymphocytes, however, the transferases and their substrates are extracellular membrane proteins whereas the hydrolases described thus far are cytoplasmic. In cultured mouse skeletal muscle cells, processing of the ADP-ribosylated integrin alpha 7 was carried out by phosphodiesterases and possibly phosphatases, leaving a residual ribose attached to the (arginine)protein. Several bacterial toxin and eukaryotic mono-ADP-ribosyltransferases, and perhaps other NAD-utilizing enzymes such as the RT6 alloantigens share regions of amino acid sequence similarity, which form, in part, the catalytic site. The catalytic cleft, found in the bacterial toxins that have been studied thus far, contains a critical glutamate and other amino acids that function to position NAD for nucleophilic attack at the N-glycosidic linkage, for either ADP-ribose transfer or NAD hydrolysis. Amino acid differences among the transferases at the active site may be required for accommodating the different ADP-ribose acceptor molecules.
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PMID:Structure and function of eukaryotic mono-ADP-ribosyltransferases. 889 63

The signal transduction of the formyl-Met-Leu-Phe (FMLP) receptor in polymorphonuclear leukocytes (PMNLs) from patients with non-insulin-dependent diabetes mellitus (NIDDM) was compared to that of PMNLs obtained from healthy volunteers. According to our previous studies in this group of patients neither the decrease in insulin binding capacity nor the enhanced insulin-degrading enzyme activity was involved. In control PMNLs, 10 nM FMLP induced a pertussis toxin-sensitive increase in phosphatidyl inositol (PI) cleavage and a subsequent Ca2+ signaling from the intracellular pools. On the other hand, the FMLP-induced protein kinase C (PKC) activation and translocation into the membrane could not be detected in these cells via the measurement of 32P incorporation into histone. In contrast, in PMNLs of this special group of patients suffering from NIDDM the FMLP stimulus produced a significantly low increase in PI cleavage and Ca2+ signaling from the intracellular pools. Moreover, in resting PMNLs of these patients with NIDDM, not only the [Ca2+]i but also the membrane-bound PKC activity was found to be significantly increased. In addition, PKC translocation into the cell membrane of diabetic PMNLs could be further triggered with FMLP as judged by the measurement of 32P incorporation into histone. Based on these results, it appears that the signaling of FMLP receptors in PMNLs of some NIDDM patients may have an alternative pathway through Ca2+ influx from extracellular medium, arachidonic acid cascade, and PKC activation.
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PMID:Altered postreceptor signal transduction of formyl-Met-Leu-Phe receptors in polymorphonuclear leukocytes of patients with non-insulin-dependent diabetes mellitus. 943 1

The glycation of liver histones was studied in rats with streptozotocin-induced diabetes, in ethanol (EtOH)-treated rats, and in EtOH-treated diabetic rats. In diabetes, the conditions of glucose-protein addition are more favourable extracellularly in serum and in erythrocytes than in the nucleus. This is indicated by the increased level of serum fructosamine and by the high level of glycated haemoglobin, while the glycation of intracellular histone is decreased. In the serum of diabetic rats, we found a relatively high acetaldehyde level, which resulted in elevated histone fluorescence. Fluorescence is an accepted marker of advanced glycation end-product (AGE), the intensity of which, according to our experiments is related not to the level of serum glucose, but to the level of acetaldehyde. The data obtained with histone proteins in diabetic rats treated with EtOH are in good agreement with the results of our earlier in vitro experimental results obtained with H1 histone: the reaction of the two aldehydes (glucose and acetaldehyde) in combination gives a lower glycohistone value than they do separately.
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PMID:The effect of ethanol on histone glycation in diabetic rats. 1078 89

Mutations in the gene encoding hepatic nuclear factor 1-alpha (HNF1-alpha) cause a subtype of human diabetes resulting from selective pancreatic beta-cell dysfunction. We have analyzed mice lacking HNF1-alpha to study how this protein controls beta-cell-specific transcription in vivo. We show that HNF1-alpha is essential for the expression of glut2 glucose transporter and L-type pyruvate kinase (pklr) genes in pancreatic insulin-producing cells, whereas in liver, kidney, or duodenum tissue, glut2 and pklr expression is maintained in the absence of HNF1-alpha. HNF1-alpha nevertheless occupies the endogenous glut2 and pklr promoters in both pancreatic islet and liver cells. However, it is indispensable for hyperacetylation of histones in glut2 and pklr promoter nucleosomes in pancreatic islets but not in liver cells, where glut2 and pklr chromatin remains hyperacetylated in the absence of HNF1-alpha. In contrast, the phenylalanine hydroxylase promoter requires HNF1-alpha for transcriptional activity and localized histone hyperacetylation only in liver tissue. Thus, different HNF1-alpha target genes have distinct requirements for HNF1-alpha in either pancreatic beta-cells or liver cells. The results indicate that HNF1-alpha occupies target gene promoters in diverse tissues but plays an obligate role in transcriptional activation only in cellular- and promoter-specific contexts in which it is required to recruit histone acetylase activity. These findings provide genetic evidence based on a live mammalian system to establish that a single activator can be essential to direct nucleosomal hyperacetylation to transcriptional targets.
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PMID:Hepatic nuclear factor 1-alpha directs nucleosomal hyperacetylation to its tissue-specific transcriptional targets. 1128 26

LOT1 is a zinc-finger nuclear transcription factor, which possesses anti-proliferative effects and is frequently silenced in ovarian and breast cancer cells. The LOT1 gene is localized at chromosome 6q24-25, a chromosomal region maternally imprinted and linked to growth retardation in several organs and progression of disease states such as transient neonatal diabetes mellitus. Toward understanding the molecular mechanism underlying the loss of LOT1 expression in cancer, we have characterized the genomic structure and analyzed its epigenetic regulation. Genome mapping of LOT1 in comparison with the other splice variants, namely ZAC1 and PLAGL1, revealed that its mRNA ( approximately 4.7 kb; GenBank accession number U76261) is potentially spliced using six exons spanning at least 70 kb of the human genome. 5'-RACE (rapid amplification of cDNA ends) data indicate the presence of at least two transcription start sites. We found that in vitro methylation of the LOT1 promoter causes a significant loss in its ability to drive luciferase transcription. To determine the nature of in vivo methylation of LOT1, we used bisulfite-sequencing strategies on genomic DNA. We show that in the ovarian and breast cancer cell lines and/or tumors the 5'-CpG island of LOT1 is a differentially methylated region. In these cell lines the ratio of methylated to unmethylated CpG dinucleotides in this region ranged from 31 to 99% and the ovarian tumors have relatively higher cytosine methylation than normal tissues. Furthermore, we show that trichostatin A, a specific inhibitor of histone deacetylase, relieves transcriptional silencing of LOT1 mRNA in malignantly transformed cells. It appears that, unlike DNA methylation, histone deacetylation does not target the promoter, and rather it is indirect and may be elicited by a mechanism upstream of the LOT1 regulatory pathway. Taken together, the data suggest that expression of LOT1 is under the control of two epigenetic modifications and that, in the absence of loss of heterozygosity, the biallelic (two-hit) or maximal silencing of LOT1 requires both processes.
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PMID:LOT1 (PLAGL1/ZAC1), the candidate tumor suppressor gene at chromosome 6q24-25, is epigenetically regulated in cancer. 1247 47

Reactive carbonyl species (RCS) are potent mediators of cellular carbonyl stress originating from endogenous chemical processes such as lipid peroxidation and glycation. Skin deterioration as observed in photoaging and diabetes has been linked to accumulative protein damage from glycation, but the effects of carbonyl stress on skin cell genomic integrity are ill defined. In this study, the genotoxic effects of acute carbonyl stress on HaCaT keratinocytes and CF3 fibroblasts were assessed. Administration of the alpha-dicarbonyl compounds glyoxal and methylglyoxal as physiologically relevant RCS inhibited skin cell proliferation, led to intra-cellular protein glycation as evidenced by the accumulation of N(epsilon)-(carboxymethyl)-L-lysine (CML) in histones, and caused extensive DNA strand cleavage as assessed by the comet assay. These effects were prevented by treatment with the carbonyl scavenger D-penicillamine. Both glyoxal and methylglyoxal damaged DNA in intact cells. Glyoxal caused DNA strand breaks while methylglyoxal produced extensive DNA-protein cross-linking as evidenced by pronounced nuclear condensation and total suppression of comet formation. Glycation by glyoxal and methylglyoxal resulted in histone cross-linking in vitro and induced oxygen-dependent cleavage of plasmid DNA, which was partly suppressed by the hydroxyl scavenger mannitol. We suggest that a chemical mechanism of cellular DNA damage by carbonyl stress occurs in which histone glycoxidation is followed by reactive oxygen induced DNA stand breaks. The genotoxic potential of RCS in cultured skin cells and its suppression by a carbonyl scavenger as described in this study have implications for skin damage and carcinogenesis and its prevention by agents selective for carbonyl stress.
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PMID:DNA damage by carbonyl stress in human skin cells. 1251 11

The growth hormone (GH)-GH receptor (GHR) axis modulates growth and metabolism and contributes to complications of diabetes mellitus. We analyzed the promoter region of the dominant transcript (L2) of the murine GHR to determine that a cis element, L2C1, interacts with transcription factors NF-Y, BTEB1, and HMG-Y/I. These proteins individually repress GHR expression and together form a repressosome complex in conjunction with mSin3b. The histone deacetylase inhibitor trichostatin A increases expression of the murine GHR gene, enhances association of acetyl-H3 at L2C1, inhibits formation of the repressosome complex, and decreases NF-Y's association with L2C1. Our studies reveal that murine models of experimental diabetes mellitus are characterized by reduced hepatic GHR expression, decreased acetyl-H3 associated with L2C1, and increased formation of the repressosome complex. In contrast, in the kidney diabetes mellitus is associated with enhanced GHR expression and lack of alteration in the assembly of the repressosome complex, thus permitting exposure of kidneys to the effects of elevated levels of GH in diabetes mellitus. Our findings define a higher-order repressosome complex whose formation correlates with the acetylation status of chromatin histone proteins. The delineation of the role of this repressosome complex in regulating tissue-specific expression of GHR in diabetes mellitus provides a molecular model for the role of GH in the genesis of certain microvascular complications of diabetes mellitus.
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PMID:Recruitment of a repressosome complex at the growth hormone receptor promoter and its potential role in diabetic nephropathy. 1252 87

We recently described novel regulatory roles for protein histidine phosphorylation of key islet proteins (e.g., nucleoside diphosphate kinase and succinyl thiokinase) in insulin secretion from the islet beta-cell (Kowluru A. Diabetologia 44: 89-94, 2001; Kowluru A, Tannous M, and Chen HQ. Arch Biochem Biophys 398: 160-169, 2002). In this context, we also characterized a novel, ATP- and GTP-sensitive protein histidine kinase in isolated beta-cells that catalyzed the histidine phosphorylation of islet (endogenous) proteins as well as exogenously added histone 4, and we implicated this kinase in the activation of islet endogenous G proteins (Kowluru A. Biochem Pharmacol 63: 2091-2100, 2002). In the present study, we describe abnormalities in ATP- or GTP-mediated histidine phosphorylation of nucleoside diphosphate kinase in islets derived from the Goto-Kakizaki (GK) rat, a model for non-insulin-dependent diabetes. Furthermore, we provide evidence for a marked reduction in the activities of ATP- or GTP-sensitive histidine kinases in GK rat islets. On the basis of these observations, we propose that alterations in protein histidine phosphorylation could contribute toward insulin-secretory abnormalities demonstrable in the diabetic islet.
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PMID:Defective protein histidine phosphorylation in islets from the Goto-Kakizaki diabetic rat. 1279 14


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