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)

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

Isolated pancreatic acini from streptozocin-induced diabetic rats were used to study the role of insulin on the synthesis of specific cellular proteins. When acini were incubated with 0-100 nM insulin for 2 h and then pulsed with [35S]methionine, a dose-dependent increase in [35S]methionine incorporation into total cellular proteins was observed. When acinar cell lysates were subjected to gel electrophoresis, 12 major newly synthesized protein bands were resolved. Insulin (100 nM) increased the incorporation of [35S]methionine into all bands but with significantly different rates, varying from 84 to 216% of control. Next, specific antibodies to amylase, trypsin, ribonuclease, myosin, and lactate dehydrogenase (LDH) were used to evaluate the biosynthesis of known proteins. Insulin stimulated labeled amino acid incorporation into amylase by 148% over control. Insulin stimulated the synthesis of trypsinogen to a similar degree, but ribonuclease synthesis showed a significantly smaller increase of 53% over control. Insulin stimulated myosin and LDH synthesis by 169 and 184%, respectively. A differential pattern of protein synthesis was also observed when acini were treated with two other stimulators of protein synthesis, cholecystokinin and hemin. Both of these stimulators had a reduced effect on ribonuclease synthesis compared with amylase and trypsinogen synthesis but failed to increase myosin synthesis. When the RNAs extracted from control acini and acini treated with 100 nM insulin were translated in vitro, the proteins synthesized were quantitatively similar. This study therefore indicates that insulin has translational effects on acinar protein synthesis, and these effects are nonparallel for various specific acinar cell proteins.
Diabetes 1987 Sep
PMID:Insulin and other stimulants have nonparallel translational effects on protein synthesis. 330 74

Techniques of in vitro receptor autoradiography were used to visualize binding of 125I-insulin on slices of frozen rat brain. Slide-mounted sections of frozen rat brain were incubated in 0.05 nM porcine 125I-monoiodoinsulin, alone or mixed with 1 microM unlabeled porcine insulin, ribonuclease, or glucagon, for 2 h at 22 degrees C. The labeled brain slices were apposed to LKB Ultrofilm to generate autoradiograms. The method permitted equal access of labeled insulin to both sides of the blood-brain barrier and localization of insulin binding sites in small anatomic regions. Quantitative estimates of specific iodoinsulin binding were made by computer digital image densitometry of the autoradiographic film images. High concentrations of specific binding sites for iodoinsulin were present in the choroid plexus of the lateral (26.9 +/- 2.0 X 10(-3) fmol/mm2), fourth (18.3 +/- 3.0 X 10(-3) fmol/mm2), and third (13.2 +/- 1.5 X 10(-3) fmol/mm2) ventricles (insulin binding is expressed per unit area of autoradiographic image). Binding to the third ventricular choroid plexus was similar to the concentrations observed for liver slices and the external plexiform layer of the olfactory bulb. Specific binding of iodoinsulin in the cingulate cortex and other surrounding regions was less than in choroid plexus. Ribonuclease or glucagon had no measurable effect on binding when mixed with labeled insulin. The results support the hypothesis that the choroid plexus has a high density of receptors for insulin, and suggests that the choroid plexus may be a target of CSF insulin action and/or a site of insulin transport into the CSF.
Diabetes 1986 Feb
PMID:Quantitative autoradiographic evidence for insulin receptors in the choroid plexus of the rat brain. 351 Sep 31

The nature and mechanism of the pancreatic exocrine dysfunction in diabetes mellitus were evaluated in vitro using isolated pancreatic acini prepared from streptozotocin-induced diabetic rats. The content of amylase and ribonuclease in diabetic acini was approximately 0.5 and 50% of the normal content, respectively. Further, reduced amounts of both enzymes were secreted by diabetic acini in response to both cholecystokinin (CCK) and carbamylcholine. However, when enzyme secretion was normalized relative to initial acinar contents, both normal and diabetic acini released enzymes at a comparable maximal rate. The time course of the release of these enzymes, and newly synthesized protein were similar in both acini. In normal acini, the effect of CCK was maximal at a concentration of 100 pM; higher concentrations led to submaximal enzyme release. The dose-response curve in diabetic acini was similarly shaped, but shifted three-fold towards higher concentration. The mobilization of cellular Ca(2+) in response to CCK was also shifted. In contrast to these results with CCK, the dose-response curve to carbamylcholine was unaltered by diabetes. The observed effects were confirmed to be due to insulin deficiency and not due to direct toxic effect of streptozotocin on acinar cells or malnutrition. Streptozotocin had no acute effect on acini when measured 24 h after administration, and alloxan, another beta cell toxin, induced similar changes in acinar enzyme content and secretory response. Moreover, the administration of exogenous insulin to diabetic rats returned the content of pancreatic amylase and the secretory response to CCK towards normal. Starvation for 48 h, although inducing a significant weight loss, did not mimic the effects of diabetes. The present studies demonstrate two major abnormalities in pancreatic exocrine secretion in the diabetic rat: (a) the content of certain digestive enzymes is markedly altered, leading to an altered amount of zymogen secretion, (b) the sensitivity to CCK is selectively reduced, most likely related to a defect in receptor activated transmembrane signaling.
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PMID:Effect of diabetes mellitus on the regulation of enzyme secretion by isolated rat pancreatic acini. 617 17

The effect of insulin on pancreatic enzyme secretion was studied in vitro by using isolated pancreatic acini prepared from rats rendered diabetic with streptozotocin. Preincubation of acini with insulin increased the maximal release of amylase and ribonuclease in response to CCK8 but not to carbamylcholine, a secretagogue acting via a different receptor. Insulin by itself had no effect on enzyme release. The effect of insulin was time dependent and increased up to 2 h, the longest time studied. An effect was observed at 1 nM insulin and the maximal effect was observed at 100 nM. The properties of CCK receptors on the acini were studied using biologically active 125I-BH-CCK33. Insulin pretreatment decreased both the affinity of the high-affinity CCK receptors and the capacity of the low-affinity CCK receptors. Within the framework of the current model, in which occupancy of high-affinity CCK receptors stimulates and low-affinity receptors inhibits amylase release, the change in receptors induced by insulin could account for the altered enzyme secretion. Thus, insulin appears to have a direct effect to regulate CCK receptors and CCK-induced secretion in isolated pancreatic acini.
Diabetes 1983 Mar
PMID:Direct modulation of pancreatic CCK receptors and enzyme secretion by insulin in isolated pancreatic acini from diabetic rats. 618 56

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

Nitric oxide (NO) is an important intercellular signaling molecule synthesized in diverse human tissues by proteins encoded by a family of NO synthase (NOS) genes. The similarity of sequence and cofactor binding sites has suggested that the NOS genes may also be related to cytochrome P450 reductase, as well as to plant and bacterial oxidoreductases. Endothelial NOS activity is a major determinant of vascular tone and blood pressure, and in several important (and sometimes hereditary) disease states, such as hypertension, diabetes, and atherosclerosis, the endothelial NO signaling system appears to be abnormal. To explore the relationship of the endothelial NOS gene to other similar genes, and to delineate the genetic factors involved in regulating endothelial NOS activity, we isolated the human gene encoding the endothelial NOS. Genomic clones containing the 5' end of this gene were identified in a human genomic library by applying a polymerase chain reaction (PCR)-based approach. Identification of the human gene for endothelial NOS (NOS3) was confirmed by nucleotide sequence analysis of the first coding exon, which was found to be identical to its cognate cDNA. The NOS3 gene spans at least 20 kb and appears to contain multiple introns. The transcription start site and promoter region of the NOS3 gene were identified by primer extension and ribonuclease protection assays. Sequencing of the putative promoter revealed consensus sequences for the shear stress-response element, as well as cytokine-responsive cis regulatory sequences, both possibly important to the roles played by NOS3 in the normal and the diseased cardiovascular system.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Isolation and chromosomal localization of the human endothelial nitric oxide synthase (NOS3) gene. 751 68

Glutamic acid decarboxylase (GAD), a target of both autoantibodies and autoreactive T-cells in insulin-dependent diabetes (IDD), exists as two homologous forms, GAD65 and GAD67. GAD65 is preferentially expressed in human islets and recognized by autoantibodies in IDD, but which form primarily elicits GAD autoimmunity is unknown. GAD67 gene expression in human islets has been demonstrated only by the polymerase chain reaction. We, therefore, quantitatively compared the expression of each GAD gene in human islets and mapped the binding of autoantibodies to recombinant human GAD67 by enzyme-linked immunosorbent assay. In ribonuclease protection assays, both forms of GAD messenger RNA (mRNA) were detected in human islets, although GAD65 mRNA was 200 times more abundant than GAD67 mRNA. Immunoblotting of islets with GAD form-specific antisera revealed GAD65, but not GAD67. By in situ hybridization and immunohistochemistry, GAD65 mRNA and protein were localized to islets, predominantly, but not entirely, to beta-cells; GAD67 mRNA and protein were undetectable. Thus, although GAD67 protein expression was undetectable in human islets, the GAD67 gene is transcribed, albeit weakly. Antibodies that recognized multiple epitopes in recombinant GAD67 were found in 20% of sera from ICA positive "at risk" first degree relatives of IDD subjects and recent-onset IDD subjects. The majority of GAD67 epitopes were mapped within the mid- and C-terminal thirds of the protein, a region that is highly conserved in GAD65. Although GAD67 may share cross-reactive epitopes with GAD65, these findings do not exclude the possibility that autoimmunity to GAD arises as a consequence of the aberrant up-regulation of GAD67 in human islets.
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PMID:Glutamic acid decarboxylase-67 (GAD67): expression relative to GAD65 in human islets and mapping of autoantibody epitopes. 753 77


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