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)

Serum Deoxyribonuclease (DNase) of normal persons and of patients with chronic pancreatitis, pancreatic cancer, Diabetes Mellitus, or other malignant diseases was determined with (32P) DNA as substrate. Serum DNase activity was much lower in patients with chronic pancreatitis, pancreatic cancer, or other malignant diseases than in control subjects, and serum DNase activity was almost normal in patients with Diabetes Mellitus. There was no correlation between serum DNase and serum amylase, but there was a good correlation between serum DNase and DNase I output in duodenal juice. There was an inverse correlation between serum DNase and serum RNase. These results imply that in the diagnosis of possible pancreatic disorders serum DNase may be a good indicator and thus may be useful for the detection of malignant diseases.
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PMID:Clinical investigation of serum deoxyribonuclease: II. Clinical studies of serum deoxyribonuclease activity in pancreatic disease. 52 Jul 66

Aminoguanidine-HCl inhibits the formation of advanced glycosylation end products (AGEs) in vitro and in vivo, but the mechanism by which this occurs has not been determined. Aminoguanidine inhibited glucose-derived AGE formation on RNase A by 67-85% at aminoguanidine-glucose molar ratios of 1:5 to 1:50 without affecting the concentration of Amadori products. Fast-atom-bombardment mass spectrometry of RNase peptides incubated with glucose alone or with glucose plus aminoguanidine showed that aminoguanidine inhibited the formation of AGEs without forming an adduct with glycosylated peptide. These data suggest that the primary mechanism of aminoguanidine action is reaction with Amadori-derived fragmentation products in solution. These findings are relevant to the potential clinical use of aminoguanidine in the prevention of diabetic complications.
Diabetes 1992 Jan
PMID:Mechanistic studies of advanced glycosylation end product inhibition by aminoguanidine. 172 35

Because basic fibroblast growth factor (bFGF) is recognized as an angiogenic factor and diabetes is characterized by multiple vascular complications, including diabetic microangiopathy, we examined the regulation of tissue bFGF mRNA levels by diabetes. Diabetes was induced in male Sprague-Dawley rats by injection of 125 mg/kg body wt i.v. streptozocin (STZ), with intensive insulin therapy initiated in half of the diabetic rats. Rats were killed 96 h postinjection of STZ. Tissue bFGF and insulinlike growth factor I (IGF-I) mRNA levels were measured simultaneously with a solution hybridization-RNase protection assay. bFGF mRNA levels increased from 1.7- to 2.7-fold in eye, heart, lung, and brain from diabetic compared with buffer-injected control rats. In skeletal muscle, bFGF mRNA levels decreased to 23% of control levels, whereas bFGF mRNA levels were unchanged in kidneys from diabetic versus control rats. Changes in tissue bFGF mRNA levels were partially reversed by insulin treatment in all tissues. In contrast, IGF-I mRNA levels were significantly decreased from 15 to 50% of control levels in all tissues studied except those in brain, which decreased to only 85% of control levels. These data demonstrate that bFGF mRNA levels are altered by diabetes in a tissue-specific fashion and are consistent with the hypothesis that increased production of bFGF may contribute to the development of diabetic microangiopathy in some tissues.
Diabetes 1992 Feb
PMID:Tissue-specific regulation of basic fibroblast growth factor mRNA levels by diabetes. 173 13

Rat insulin-like growth factor-I (IGF-I) mRNAs with different 5'-untranslated region/prepeptide coding sequences result from transcription initiation in one of two leader exons. While not altering the mature IGF-I coding sequence, these different leaders potentially encode two distinct IGF-I prepeptides, one of 48 amino acids (exon 1) and one of 32 amino acids (exon 2). Within exon 1, transcription initiation is dispersed (i.e. occurs over a approximately 350-basepair region), while within exon 2, it is highly localized. A fourth exon 1 start site, residing only approximately 30 basepairs from its 3' end, is suggested on the basis of RNase protection assays; its use would produce an mRNA encoding a third distinct IGF-I leader peptide of 22 amino acids. We have determined that during postnatal development, and as a result of insulinopenic diabetes and fasting, choice of transcription start sites within exon 1 in the liver is coordinately regulated, i.e. use of all start sites increased during development and decreased in the two catabolic states. Transcription initiation at the single major site within exon 2 was also reduced in diabetes and fasting. Insulin replacement therapy and refeeding restored the levels of all transcripts coordinately. During postnatal development, however, transcripts initiating within exon 2 exhibited a different developmental profile than did exon 1 transcripts, increasing especially at the onset of GH-dependent linear growth. In liver, therefore, negative regulation of exon 1 and exon 2 transcription start site usage occurs in catabolic states, while in development, differential regulation of exon 1 and exon 2 transcription start sites occurs.
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PMID:Regulation of start site usage in the leader exons of the rat insulin-like growth factor-I gene by development, fasting, and diabetes. 177 70

In these studies, we examined the effect of excess levels of growth hormone (GH) on rat insulinlike growth factor I (IGF-I) gene expression in streptozocin-induced diabetes mellitus. A solution hybridization/RNase protection assay was used to simultaneously quantitate the relative tissue content of the variant IGF-I mRNA species arising from alternative splicing in the region encoding the COOH-terminal extension E-peptide (IGF-Ia and IGF-Ib). IGF-Ia and IGF-Ib mRNAs were markedly decreased in liver, kidney, and lung tissues of diabetic rats. Although GF stimulates IGF-I gene expression, chronic GH excess from implanted somatomammotropic tumors did not appropriately induce tissue IGF-I mRNA content in diabetic animals. Treatment of diabetic rats with insulin for 1 wk restored basal and GH-stimulated IGF-Ia and IGF-Ib mRNA content toward that present in tissues of nondiabetic rats. The ratio of IGF-Ia to IGF-Ib mRNA remained relatively constant for each tissue and was not affected by the diabetic state, chronic GH hyperstimulation, or insulin therapy, suggesting that posttranscriptional splicing is not a regulated event in these conditions. Thus, both circulating IGF-I levels and tissue IGF-I gene expression are profoundly decreased in this model of experimental diabetes. Diminished tissue availability of IGF-I from endocrine and/or paracrine sources may be responsible for the growth retardation seen in uncontrolled diabetes mellitus.
Diabetes 1989 Apr
PMID:Coordinate decrease of tissue insulinlike growth factor I posttranscriptional alternative mRNA transcripts in diabetes mellitus. 292 6

The major histocompatibility complex of the rat (RT1 complex) encodes two sets of class II molecules referred to as RT1.B and RT1.D. The complete structure of the RT1.D alpha u chain of the diabetes prone BB rat was determined by the isolation and characterization of a full size cDNA. Comparisons of the nucleotide and protein sequences of RT1.D alpha with the analogous molecules, H-2 I-E alpha and HLA DR alpha, revealed that these alpha chains have been highly conserved during evolution. Southern blot analysis indicated an association of the RT1 haplotypes, 'u' and 'l', with Bam H1 DNA bands of 9.8 kb and 11.7 kb, respectively. The BB rat develops insulin dependent diabetes as an autoimmune abnormality. Accumulating evidence suggests a cellular mediated etiology and the involvement of class II molecules. The steady state levels of RT1.D alpha mRNA were measured in splenic lymphocytes of diabetes prone BB rats and age matched histocompatible normal nondiabetic WF rats by a RNase protection assay. Compared to WF rats, elevated transcripts of RT1.D alpha were found in lymphocytes of young BB rats (approximately 4x and approximately 2.5x greater at 20-40 and 40-75 d, respectively). In lymphocytes of older diabetic and nondiabetic BB rats (greater than 75 d) the levels of RT1.D alpha mRNA were lower than in the young BB rats and were found at the WF control levels. The increased steady state RT1.D alpha mRNA levels in the young BB rats may reflect differences in the proportion of splenic lymphocytes expressing this gene (activated lymphocytes), and thus differences in splenic lymphocyte populations. The steady state RT1.D alpha mRNA levels in lymphocytes of the normal rats were found to be relatively similar at all ages examined. The increased class II gene transcripts found in lymphocytes of young BB rats indicates that they possess a highly activated immune system.
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PMID:The complete sequence of the MHC class II chain RT.1D alpha u of the diabetic BB rat: mRNA levels of RT1.D alpha in lymphocytes. 312 83

A model system using RNase A has been established for studying the nonenzymatic glucosylation and glucose-dependent cross-linking of protein (Maillard reaction) under physiological conditions in vitro. The rate of glucosylation of RNase was first order in glucose. Glucosylation was accompanied by a comparable decrease in primary amino groups in the protein and lysine recoverable by amino acid analysis. Analysis of glucosylation reaction mixtures by sodium dodecyl sulfate-polyacrylamide gel electrophoresis in the presence of mercaptoethanol revealed the time-dependent formation of RNase dimer and trimer. The polymerization reaction was mixed order with respect to glucose concentration, but was approximately first order with respect to protein concentration. When glucosylated protein was separated from glucose, the protein continued to polymerize even in the absence of glucose. Under these conditions, the primary cross-linking reaction occurred by condensation of a glucosylated amino acid on one RNase molecule with a free amino group on another. Lysine efficiently inhibited cross-linking between glucosylated and native RNase in the absence of glucose. An attempt to model the cross-linking reaction was made by studying the incorporation of [3H]lysine and N alpha-formyl-[3H]lysine into glucosylated RNase. Both were incorporated covalently into glucosylated but not native protein. However, free lysine was the major product recovered following NaBH4 reduction and amino acid analysis of the lysine derivative of glycosylated protein. The data are discussed in terms of the mechanism of protein cross-linking by glucose and the relevance of this reaction to the pathophysiology of diabetes.
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PMID:Nonenzymatic glucosylation and glucose-dependent cross-linking of protein. 640 4

Phosphoenolpyruvate carboxykinase (PEPCK) is the rate-limiting enzyme of gluconeogenesis. This metabolically important enzyme is unique in that it has no known allosteric modifiers, and all of the regulation of its activity is exerted at the level of gene expression. The expression of the PEPCK gene in liver is elevated in most forms of diabetes, and plays a major contributory role in the hyperglycemia characteristic of this disease. In this study, we initiated studies to determine the molecular basis for the increased PEPCK gene expression in diabetes. RNase protection assays of RNA isolated from control, streptozotocin-induced diabetic, and insulin-treated diabetic rat liver indicated that PEPCK mRNA levels are elevated two- to threefold in diabetic rat liver compared to controls. Nuclear run-on assays indicated that the increased PEPCK mRNA levels can be fully accounted for by changes in the transcription rate of the gene. We next initiated characterization of the cAMP response element binding protein (CREB) in diabetic rat liver, since it is known to play a major role in mediating the it is known to play a major role in mediating the basal transcriptional activity of the PEPCK gene as well as the cAMP-dependent stimulation of PEPCK gene transcription, the latter through the phosphorylation of serine 133 of CREB. Western blot analysis of nuclear lysates prepared from rat livers indicated that CREB protein levels in diabetic rat liver nuclei were similar to those of controls. However, using an antibody which specifically recognizes the serine 133-phosphorylated form of CREB, we found that the levels of phospho-CREB were significantly decreased in diabetic rat liver, an effect which insulin treatment reversed. This observation suggests that overexpression of the PEPCK gene in diabetes is not linked to the cAMP signaling system in liver.
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PMID:The phosphorylation state of the cAMP response element binding protein is decreased in diabetic rat liver. 748 14

Fatty-acid-binding protein (FABP) expressed in rat aorta has been shown to be homologous to heart FABP (H-FABP) but its precise primary structure, cellular localization and function are not known. To establish the nucleotide identity between heart and aorta FABP, we performed an RNase protection assay with antisense RNA of rat H-FABP. The results demonstrate that the primary nucleotide sequence of aortic FABP is identical to that of rat H-FABP. In situ hybridization analysis revealed that aortic H-FABP mRNA is present in both smooth muscle cells and endothelial cells. In order to explore the function of aortic H-FABP, we examined whether a quantitative change in aortic H-FABP occurred in diabetes mellitus, since this pathological state has been shown to cause abnormalities in fatty acid metabolism. Northern blot analysis revealed that the level of aortic H-FABP mRNA was markedly decreased in rats made diabetic by streptozotocin treatment. The suppression of the mRNA level paralleled that of the protein level, as assessed by Western blot analysis. In distinct contrast, no major changes in the H-FABP mRNA level were observed in any other tissues examined, including heart, kidney and skeletal muscle, suggesting that this decrease is highly tissue-specific. The suppression of the aortic H-FABP in streptozotocin-diabetic rats was abolished by insulin supplementation. Taken together, these results suggest that the expression of the H-FABP gene in aorta may be specifically and dramatically suppressed in streptozotocin-diabetic rats, and that this suppression appears to be regulated by insulin.
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PMID:Tissue-specific suppression of aortic fatty-acid-binding protein in streptozotocin-induced diabetic rats. 774 30

Glycation and oxidation reactions contribute to protein modification in aging and diabetes. Formation of dicarbonyl sugars during autoxidation of glucose is the hypothetical first step in the autoxidative glycosylation and subsequent browning of proteins by glucose [Wolff, S. P., & Dean, R. T. (1987) Biochem. J. 245, 243-250]. In order to identify the dicarbonyl sugar(s) formed during autoxidation of glucose under physiological conditions, glucose was incubated in phosphate buffer (pH 7.4) at 37 degrees C under air (oxidative conditions) or nitrogen with transition metal chelators (antioxidative conditions). Dicarbonyl compounds were analyzed spectrophotometrically and by HPLC after reaction with Girard-T reagent. Carbohydrates were analyzed by gas chromatography-mass spectrometry. Both dicarbonyl sugar and arabinose concentrations increased with time and glucose concentration in incubations conducted under oxidative conditions; only trace amounts of these products were detected in glucose incubated under antioxidative conditions. HPLC analysis of adducts formed with Girard-T reagent indicated that glyoxal was the only alpha-dicarbonyl sugar formed on autoxidation of glucose. Glyoxal and arabinose accounted for > or = 50% of the glucose lost during a 21 day incubation. Neither glucosone nor its degradation product, ribulose, was detectable. Reaction of glyoxal with RNase yielded the glycoxidation product, N epsilon-(carboxymethyl)lysine, while arabinose is a source of pentosidine. Our results implicate glyoxal and arabinose as intermediates in the browning and crosslinking of proteins by glucose under oxidative conditions. They also provide a mechanism by which antioxidants and dicarbonyl trapping reagents, such as aminoguanidine, limit glycoxidation reactions and support further evaluation of these types of compounds for inhibition of chemical modification and crosslinking of proteins during aging and diabetes.
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PMID:Mechanism of autoxidative glycosylation: identification of glyoxal and arabinose as intermediates in the autoxidative modification of proteins by glucose. 789 66


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