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 products of the class II-like H2-M genes of the major histocompatibility complex are required for class II antigen processing. We sequenced H2-Ma and Mb from several mouse strains to determine whether these genes are polymorphic like the classical H2-A and E genes, or are oligomorphic, like H2-O. Both Mb loci appear to be transcribed and are distinct from each other. Mb1 and Mb2 differ by about 11% at the nucleotide level and are most dissimilar in their second exons (corresponding to the beta 1 domain). Relative to the published Mb1d haplotype sequence, the products of the b, g7, f, and k2 alleles of Mb1 from Mus musculus domesticus and the separate mouse species Mus spretus differ by only one to four amino acids. The majority of the changes occurred in the second exon of Mb1, in contrast to HLA-DMB, the human orthologue. Little polymorphism was seen for Mb2, and Ma was invariant in all strains tested. The similarity of the g7 allele to those from other haplotypes makes it unlikely that the M class II genes play a role in the autoimmune diabetes of NOD strain mice. The M genes are regulated in a manner similar to classical class II genes, in that they are upregulated by IFN-gamma in macrophages, and to a lesser extent by IL4 in B cells. When modeled on the crystal structure of the HLA-DR1 class II molecule, nearly all of the differences between M beta 1 and M beta 2 affect residues facing away from the putative peptide binding groove.
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PMID:Characterization of polymorphism within the H2-M MHC class II loci. 760 4

The alpha 4 beta 1-integrin (CD49d, CD29) constitutively expressed on leukocytes regulates cell migration to inflammatory sites, cell activation, and development through its interactions with two alternate ligands, vascular cell adhesion molecule-1 (VCAM-1; CD106) expressed on cytokine-activated endothelium, dendritic and stromal cells, and the extracellular matrix protein fibronectin. Another alpha 4-integrin receptor, alpha 4 beta 7, expressed on leukocytes also binds VCAM-1 and fibronectin (FN), and controls homing to mucosal tissues through its interactions with mucosal vascular addressin MAdCAM-1. In vitro studies have shown that alpha 4-dependent cell adhesion is regulated by the activation state of the cell and by divalent cations. However, the existence and role of cells with different alpha 4 activation states in vivo have not been defined. Herein we show that a soluble ligand with the two N-terminal domains of human VCAM-1 fused to a human IgG1 constant region, VCAM-Ig, binds selectively to activated alpha 4-receptors on murine cells, such as those induced by Mn2+ in vitro. To determine whether the cells identified by VCAM-Ig were required under physiologic conditions, we assessed its anti-inflammatory effect. We show that VCAM-Ig is not bound to the majority of murine alpha 4+ cells after in vivo administration, yet it significantly delays the onset of adoptively transferred autoimmune diabetes. Thus, soluble VCAM-Ig can modify alpha 4-dependent disease progression, apparently by its selective action on cells with activated alpha 4-integrin receptors, thereby providing evidence for distinct alpha 4 activation states in vivo.
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PMID:Vascular cell adhesion molecule-Ig fusion protein selectively targets activated alpha 4-integrin receptors in vivo. Inhibition of autoimmune diabetes in an adoptive transfer model in nonobese diabetic mice. 760 69

HLA-DR2 is negatively associated with insulin-dependent diabetes mellitus (IDDM). The aim of the present study was to analyze DR2-positive patients among 425 consecutively diagnosed unrelated Swedish children with IDDM and in 367 matched controls. HLA-DRB, -DQA and -DQB were determined by Taq I restriction fragment length polymorphism analysis. Amplification by polymerase chain reaction (PCR) and hybridization with sequence-specific oligonucleotide probes was done for DQA1, DQB1 and DRB1 and DRB5. DR2 was positive in 11/425 patients (3%) and 101/367 (28%) controls (OR 0.07, p < 0.0001). Of the 11 DR2-positive patients, PCR was done in 10, of whom 8 were positive for DRB1*1601-DRB5*0201 compared to 4/96 (4%) controls (OR 92.0: p < 0.001) while the remaining 2 were positive for DRB1*1501-DRB5*0101 compared to 92/96 (96%, OR 0.01; p < 0.001). In 2 patients, a recombination between the haplotypes DQB1*0502-DQA1*0102 (DQ5)-DRB1*1601-DRB5*0201 (DR16 Dw21) and DQB1*0301-DQA1*0501 (DQ7)-DRB1*1602-DRB5*0202 (DR16 Dw22) was observed resulting in the DQB1*0301-DQA1*0501 (DQ7) DRB1*1601-DRB5*0201 (DR16 Dw22) haplotypes. The second haplotype was DR3 DQ2 in 6/11 and DR4 DQ8 in 2/11 DR2-positive patients. In all 3 DQB1*0602-DQA1*0102-DR15-positive patients the second haplotype was DR4-positive. In order to test whether physicochemical properties of the DR2 molecules were associated with IDDM, we constructed three-dimensional models of the peptide binding and T-cell recognition sites (alpha 1 and beta 1 domains) of five subtypes of DR2-DRB1, based on the published DR1 crystal structure. No correlations were observed for DR molecule physicochemical properties and diabetes susceptibility. Islet cell antibodies, insulin autoantibodies and GAD65 antibodies, were measured in DR2-positive patients (n = 11) and controls (n = 101). Despite the presence of the DR2 haplotype the antibody markers were significantly elevated in the patients compared to the controls (GAD65 3/10 patients and 2/101 controls; ICA 7/11 patients and 1/101 controls and IAA 3/11 patients and 0/101 controls). In conclusion, of the five subtypes of DR2, only one, the DRB1*1501, DRB5*0101, DQB1*0602-DQA1*0102 haplotype, was negatively associated with IDDM. DQ may therefore confer more protection from the disease than DR.
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PMID:Analysis of antibody markers, DRB1, DRB5, DQA1 and DQB1 genes and modeling of DR2 molecules in DR2-positive patients with insulin-dependent diabetes mellitus. 781 75

The contribution of metabolic control to in vivo myocardial contractile function in response to beta 1-adrenergic stimulation was determined in the spontaneously diabetic BB Wor rat. The study involved a group of insulin-dependent BB Wor rats showing marked variations in metabolic control, assessed by the level of glycosylated hemoglobin (gHb). These diabetic BB rats were divided into moderate and severe (%gHb > 14), diabetic groups. A group of Wistar rats and diabetes-resistant BB Wor rats served as controls. In vivo myocardial contractile function was measured under basal conditions and after i.v. dobutamine infusions in anesthetized rats, using a catheter-tip pressure transducer inserted into the left ventricle. No dramatic differences in heart rate with dobutamine stimulation were observed between the moderate, severe diabetic, and diabetes-resistant groups. However, heart rate was lower in Wistar control rats compared with these groups. Systolic left ventricular pressure was depressed in severe diabetic rats compared with Wistar controls. In addition, positive dP/dt was significantly less in the severe diabetic group at the highest doses of stimulation, whereas negative dP/dt was depressed under basal conditions and remained so with increasing doses of dobutamine. In the diabetic group maximal systolic left ventricular pressure, rate-pressure product, and negative dP/dt responses to dobutamine were all inversely correlated with gHb. These results indicate that changes in metabolic control of the insulin-dependent BB diabetic rat can contribute to a depressed myocardial contractile function.
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PMID:Relation of glycosylated hemoglobin to in vivo cardiac function in response to dobutamine in spontaneously diabetic BB Wor rats. 782 80

Polymorphisms in HLA class II genes have been shown to contribute to susceptibility or protection against insulin-dependent diabetes mellitus (IDDM). In the present study the role of HLA class II haplotypes and the role of DQ alpha Arg52, DQ beta Asp57 and of polymorphic amino acids, located in the antigen-binding groove and the CD4-binding domain of the DR beta 1 chain, were studied in 210 unrelated Caucasian IDDM patients and 205 controls. The results showed that the genotype homozygous for DR beta 1Lys71+, which is in linkage disequilibrium with DQ alpha 1Arg52+ provided a major risk (relative risk, RR = 15.46) for IDDM and that combination of DR beta 1Lys71+/+ with homozygosity for DQ beta qAsp57-/- of the DQ beta 1 chain significantly increased the RR for developing IDDM (RR = 20.41). The DQ alpha 1Arg52(-)-DQ beta 1Asp57+ haplotype in cis or trans position conferred the highest protection against IDDM (RR = 0.08). Our findings confirm that protection against IDDM is provided by HLA-DQ loci but that susceptibility for IDDM is provided by both HLA-DRB1 and DQB1 loci. Our results also provide a new and more specific approach to determine the risk of any random Caucasian individual to develop IDDM. Indeed, increased susceptibility or protection against IDDM can be determined by the rapid and simple typing of DR beta 1Lys71, DQ alpha 1Arg52 and DQ beta 1Asp57 in a random person.
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PMID:Improved risk assessment for insulin-dependent diabetes mellitus by analysis of amino acids in HLA-DQ and DRB1 loci. 783 77

The aim of this study was to test the hypothesis that the antiadrenergic action of adenosine is reduced in diabetes. This was determined by evaluating the effect of experimental diabetes mellitus on the in vivo myocardial antiadrenergic action of cyclopentyladenosine, and adenosine A1-receptor agonist. Changes in heart rate and ventricular performance in response to infusion of dobutamine, a beta 1-adrenergic agonist, were determined in the absence and presence of cyclopentyladenosine, in anesthetized, 10- to 12-week male diabetic (60 mg/kg streptozotocin), insulin-treated diabetic and control rats. Intravenous dobutamine (16 micrograms/kg) increased +dP/dtmax and -dP/dtmax in control rats from 7,706 +/- 553 and 5,449 +/- 403 mmHg/s (1 mmHg = 133.3 Pa) to 19,170 +/- 465 and 8,855 +/- 317 mmHg/s, respectively. In diabetic rats dobutamine increased +dP/dtmax and -dP/dtmax from 5,733 +/- 541 and 4,016 +/- 426 to 15,015 +/- 1,521 and 7,039 +/- 809 mmHg/s, respectively. Cyclopentyladenosine significantly attenuated dobutamine-stimulated increases in +dP/dtmax and -dP/dtmax in both control and diabetic rats in a dose-dependent (0.1-3.0 micrograms/kg) manner. Cyclopentyladenosine potency to attenuate dobutamine-enhanced +dP/dtmax was reduced significantly (p < 0.05) in diabetic rats compared with controls (ID50, 1.07 vs. 0.59 micrograms/kg, respectively) with no change in efficacy. The magnitude of cyclopentyladenosine inhibition of dobutamine-enhanced -dP/dtmax was greater in control than diabetic rats (81 vs. 54%, respectively), but ID50 values were not different. Insulin treatment of diabetic rats prevented the observed changes. These data suggest that the antiadrenergic action of adenosine is compromised in diabetes and that this may contribute to the development of diabetic cardiomyopathy.
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PMID:The antiadrenergic effect of cyclopentyladenosine on myocardial contractility is reduced in vivo in diabetic rats. 788 91

Offspring of women with poorly controlled diabetes exhibit hypoxemia, elevated catecholamine concentration at birth, and an increased incidence of fetal death. Experimental fetal hyperinsulinemia results in increased catecholamine concentration and hemodynamic changes including increased combined ventricular output and vasodilation of select fetal organs. We hypothesized that insulin-induced catecholamine-mediated beta-adrenergic stimulation supports some of these hemodynamic changes in the hyperinsulinemic ovine fetus. To study this, 24 chronically instrumented fetal sheep receiving insulin for 24 h were exposed to beta-(propranolol),beta 1-(metoprolol), and beta 2-(ICI 118,551) adrenergic blockade. Insulin infusion resulted in hyperinsulinemic-hypoglycemia, a surge in epinephrine and norepinephrine concentration, and increases in the combined ventricular output and regional blood flow to the heart, adrenal glands, kidney, gastrointestinal tract, liver, fat, muscle, carcass, and placenta. In the hyperinsulinemic state, beta-adrenergic blockade was associated with significant reductions in the combined ventricular output and blood flow to fat, carcass, lungs, and the placenta; beta 1-blockade was associated with reductions in the combined ventricular output and blood flow to the lungs; and beta 2-adrenergic blockade was associated with reductions in blood flow to muscle and lungs. Because beta-adrenergic blockade was associated with reductions in placental blood flow during hyperinsulinemia, oxygen and glucose metabolism were also compromised. We conclude that in the hyperinsulinemic-hypoglycemic normoxemic ovine fetus, insulin-induced catecholamine-mediated hemodynamic changes are modulated in part by beta-adrenergic receptor stimulation.
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PMID:Circulatory and metabolic effects of beta-adrenergic blockade in the hyperinsulinemic ovine fetus. 790 2

Na,K-ATPase activity and isoform expression were measured in rat small intestinal mucosa taken from both normal and streptozocin-treated diabetic rats. Enzyme activity and abundance was 1.7-2.3-fold higher in rats diabetic for 2 wk than in controls. This was associated with 1.4-1.7-fold increases in small intestinal protein and DNA content. Ouabain inhibition curves of Na,K-ATPase were monophasic with Kis of 2.6 +/- 1.4 x 10(-4) and 2.0 +/- 1.2 x 10(-4) M for control and diabetic rats, respectively (NS). Northern blot analysis revealed a 2.5-fold increase in mRNA alpha 1 and a 3.4-fold increase in mRNA beta 1 in diabetic rats relative to controls. Two thirds of this increase occurred within 24h after injection of streptozocin. Immunoblots of intestinal enzyme preparations from diabetic and control rats indicated the presence of alpha 1 and beta 1 subunits but not of alpha 2 or alpha 3. Administration of glucagon (80 micrograms/kg) to normal rats daily for 14-16 d increased mRNA alpha 1 3.1-fold but did not increase mRNA beta 1 or enzyme activity. In experimental diabetes, alpha 1 and beta 1 isoforms of Na,K-ATPase are coordinately upregulated at both protein and mRNA levels, an effect which appears to be partially mediated by the associated hyperglucagonemia.
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PMID:Na,K-ATPase in diabetic rat small intestine. Changes at protein and mRNA levels and role of glucagon. 820 Oct 10

The effects of norepinephrine and insulin on glucose transport were investigated in brown adipocytes isolated from obese nondiabetic Lister and Albany (LA/N-cp strain) rats (O-LA), obese diabetic spontaneously hypertensive (SHR/N-cp strain) rats (O-SHR), and from their lean (L) controls to test whether the decreased calorigenic response to norepinephrine of O-SHR adipocytes was specifically associated with alterations in glucose metabolism. Norepinephrine and insulin independently stimulated glucose transport in L-LA, O-LA, and L-SHR brown adipocytes, but their stimulatory effects were markedly reduced in O-SHR cells. Both insulin responsiveness and the total number of insulin receptors were significantly decreased in O-SHR adipocytes but not in O-LA cells. The number of high-affinity beta 1/beta 2-adrenoceptors was significantly increased (+70%) in O-LA adipocytes but was similar in L-SHR and O-SHR cells. These results indicate that 1) major metabolic defects are present in brown adipose tissue (BAT) of O-SHR but not of O-LA, although these two strains are homozygous for the cp allele, 2) postreceptor defects are predominantly involved in O-SHR adipocyte refractoriness to norepinephrine, and 3) a reduced mitochondrial content may represent the principal metabolic alteration explaining the decreased effects of norepinephrine on both thermogenesis and glucose transport. It is postulated that the marked insulin resistance of O-SHR leads to a decreased mitochondriogenesis in BAT, resulting in a diminished tissue thermogenic capacity and reduced glucose metabolism, thereby contributing to obesity and diabetes.
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PMID:Norepinephrine- and insulin-resistant glucose transport in brown adipocytes from diabetic SHR/N-cp rats. 821 49

The repertoire of V beta 5 and V beta 8 T-cell receptors in pancreatic lesions of autoimmune diabetic NOD mice was analysed by sequencing the CDR3 and adjacent regions. T-cell receptor mRNA isolated from four different cell populations (i.e. spleen, lymph node, infiltrated islets from male and female NOD mice) was amplified by PCR and cloned; out of these, 339 clones were sequenced. Of 170 beta chains sequenced from intra-islet T cells, nearly 90% were unique and six other sequences were found 2 to 4 times. These data argue against any oligoclonality of the islet infiltrate. Despite the lack of clonal restriction, we observed a bias in TcR usage which indicates the existence of some selective pressure with regard to TcR structure. Of the V beta 5 positive cells, 30% to 40% showed a rearrangement of V beta 5 to J beta 2.6 and a complete lack of V beta 5-J beta 1.6 combination. The selective J beta usage was not restricted to islets but was found in all tissues analysed. V beta 8 positive cells did not show such an overrepresentation of V beta-J beta combinations with the exception of clones of infiltrated islets of partially diabetes-resistant male NOD mice. There the rearrangement of V beta 8-J beta 1.1 was markedly over-expressed. Analysis of the CDR3 region did not show selection of specific TcR with regard to region length. However, we found a restricted use of amino acids in the second position of the CDR3 region. V beta 8 chains had conserved an aspartic acid from the germline configuration in about half of the cases in all tissues analysed. V beta 5 chains also showed diversity of position 2 but not islet specificity of rearrangements. Mutated chains had a clear bias towards proline indicating selective pressure in favour of this amino acid. In conclusion, sequence analysis of V beta 5 and V beta 8 TcRs excludes oligoclonality of T-cell receptors in pancreatic lesions. The bias found for J beta usage and CDR3 structure was seen also in extra-pancreatic tissues and thus probably is due to selective pressure during T-cell maturation in thymus or periphery.
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PMID:Molecular analysis of the T-cell receptor V beta 5 and V beta 8 repertoire in pancreatic lesions of autoimmune diabetic NOD mice. 821 86


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