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 non-obese diabetic (NOD) mouse spontaneously develops autoimmune Type 1 (insulin-dependent) diabetes mellitus. NOD mice exhibit massive infiltrates of T cells and macrophages into pancreatic islets (insulitis) prior to diabetes. The contribution of oxygen free radicals to the development of insulitis in NOD mice was examined by administration of its scavengers, such as superoxide dismutase and catalase. Bovine superoxide dismutase and catalase were each coupled to polyethylene glycol. The treatment with superoxide dismutase-polyethylene glycol reduced the number of islets with insulitis and increased the undamaged islet tissue, as compared with the control group. The treatment with catalase-polyethylene glycol showed a similar tendency which did not reach significance. Using a flow cytometric assay of the oxidation of 2', 7'-dichlorofluorescein, the content of reactive oxygen intermediates in islet cells in the culture system was measured and the effect of peritoneal exudate cells and T cells on their production examined. Peritoneal exudate cells, but not T cells, from NOD mice increased the content of reactive oxygen intermediates in islet cells of either the NOD mouse or the ILI mouse (MHC-identical to NOD); the addition of superoxide dismutase to the culture medium suppressed this increase in NOD or ILI islet cells. The present data support the concept that production of oxygen free radicals mediated by macrophages can damage islet beta cells, directly resulting in autoimmune Type 1 diabetes in NOD mice.
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PMID:Reactive oxygen intermediates in autoimmune islet cell destruction of the NOD mouse induced by peritoneal exudate cells (rich in macrophages) but not T cells. 815 Feb 25

To investigate the short-term effects of didecanoyl-L-alpha-phosphatidylcholine on the nasal mucosa and the mechanism by which didecanoyl-L-alpha-phosphatidylcholine enhances the nasal absorption of insulin, an in vitro model was developed. The mucosa from the posterior part of the rabbit nasal septum was mounted in an Ussing chamber and incubated in bicarbonate Ringer solution at 37 degrees C. Potential difference, transmucosal conductance, and unidirectional tracer fluxes were measured across an exposed tissue area of 0.44 cm2. Morphological and physiological examinations revealed a typical respiratory epithelium containing amiloride-sensitive Na+ channels and diphenylamine-2-carboxylate-sensitive Cl- channels. Spontaneous potential difference (10.8 +/- 0.4 mV [n = 50]; serosa positive) and transmucosal conductance (10.5 +/- 0.4 mS/cm2 [n = 50]) were stable for several hours. Mucosal addition of 0.1-0.5% didecanoyl-L-alpha-phosphatidylcholine increased transmucosal conductance (by 43-53%) and decreased potential difference (to 0-2 mV) to new steady-state values within 10-15 min. Control unidirectional rate constants for permeation of sucrose, polyethylene glycol 4000, and insulin were low and varied according to the molecular size. After addition of didecanoyl-L-alpha-phosphatidylcholine, unidirectional rate constants for the three compounds all increased 3- to 5.5-fold. The didecanoyl-L-alpha-phosphatidylcholine effects on potential difference and transmucosal conductance were reversible after a recovery period of at least 40 min when didecanoyl-L-alpha-phosphatidylcholine had been applied to the mucosal side for 15 min. The results suggest that didecanoyl-L-alpha-phosphatidylcholine may increase the transepithelial absorption of insulin by facilitating a paracellular passage through a reversible opening of tight junctions.
Diabetes 1993 Jul
PMID:Transport of insulin across rabbit nasal mucosa in vitro induced by didecanoyl-L-alpha-phosphatidylcholine. 851 70

The measurement of urine albumin now has a well-established role in the monitoring of patients with diabetes mellitus. We have developed a particle-enhanced immunoturbidimetric inhibition assay for urine albumin on the Dade aca analyzer. The inhibition approach removes any of the potential antigen excess difficulties that could be expected from the wide clinical range of urine albumin, but retains the sensitivity advantages of latex-enhanced immunoturbidimetry. Human serum albumin (HSA) is covalently attached to 40-nm poly(chloromethyl)styrene-modified latex particles. This reagent, along with monoclonal antibody to HSA, is aliquoted into the aca reagent pack along with polyethylene glycol 8000 in a tablet form (giving a final reaction concentration of 15 g/L). A 150 mmol/L phosphate buffer, pH 7.8, is used to fill the reagent pack in the instrument and the agglutination reaction is monitored at 340 nm. The sample volume is 100 microL and the calibration curve covers the range 2-250 mg/L. Evaluation of commercial scale reagents against the Beckman Array nephelometric immunoassay system gave a Deming regression correlation of aca = 0.87 x Beckman + 8.5, r = 0.995, n = 145. Mean analytical recovery was 104+/-4.5%, n = 20, and there was no evidence of a lack of parallelism. Interassay precision was 8.8% at 10.0 mg/L and <2.5% at >65 mg/L. Calibrator stability was in excess of 60 days. A small reference range study (24-h urine collections, n = 27) gave a mean of 5.6 mg/L with a range of 0.5-16.2 mg/L. Analytical sensitivity (2.5 SD from zero) was 0.40 mg/L.
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PMID:Development and validation of a particle-enhanced turbidimetric inhibition assay for urine albumin on the Dade aca analyzer. 899 Feb 31

Glucagon-like insulinotropic peptide (GLP-1) and its analogs are of interest because of their therapeutic potential in type II diabetes. LY315902 is a GLP-1-(7-37)-OH analog with a modified N-terminus (IP7), an octanoic acid (C8) acylated on the lysine residue at position 34, and a substitution with arginine at position 26. We developed a sensitive and specific radioimmunoassay (RIA) for the determination of immunoreactive LY315902 in the plasma of animals. A homobifunctional cross-linker was used to couple the nonacylated form of LY315902 [IP7-R26-GLP-1-(7-37)-OH] to carrier proteins to enhance its immunogenicity. Following immunization, animal antisera were screened by RIA for the presence of LY315902 antibodies. One rabbit produced a high-affinity antiserum that display insignificant cross-reactivity against two forms of native GLP-1 and possible major metabolites of LY315902. In this RIA method, plasma samples were combined with radioiodinated LY315902 and rabbit anti-IP7-R26-GLP-1-(7-37)-OH serum, and then incubated overnight at room temperature. The bound forms of LY315902 were separated by polyethylene glycol assisted second antibody precipitation. The sensitivity of the assay was estimated to be 19 pM. Inter-assay precision (%CV) and accuracy (recovery) for quality control samples in dog plasma ranged from 8.0% to 14.7% and 92.8% to 107.3%, respectively. By applying this assay to measure plasma concentrations of immunoreactive LY315902 in dogs following twice daily subcutaneous injections of LY315902, we determined that the plasma half-life of LY315902 is significantly longer than that of native GLP-1-(7-37)-OH. We concluded that the structural modifications which were made to produce LY315902 prolonged its plasma half-life. The extended plasma half-life of LY315902 correlated well with its prolonged pharmacology in dogs.
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PMID:A radioimmunoassay for LY315902, an analog of glucagon-like insulinotropic peptide, and its application in the study of canine pharmacokinetics. 923 14

Antibodies to oxidized LDL (ox-LDL) and LDL-containing immune complexes (LDL-IC) have been reported to be associated with the presence or progression of arteriosclerosis. We screened for anti-modified LDL antibodies and isolated soluble IC by precipitation with 3.5% (w/v) polyethylene glycol (PEG) 6000 in two groups. The patient group was constituted by 16 insulin-dependent diabetes mellitus subjects free of macrovascular complications. The control group was constituted by 16 healthy, age-, gender-, race-, and body mass index-matched nondiabetic subjects. We detected anti-ox-LDL antibodies and anti-malondialdehyde-modified LDL antibodies with similar levels in patients and controls, while the levels of anti-glycated LDL antibodies were very low, but slightly higher in diabetics than in healthy controls. Isolated LDL-IC were adsorbed to red blood cells (RBC) and incubated with human macrophages for 18 hr at 37 degrees C. Under those experimental conditions, RBC-adsorbed IC are taken up by macrophages but the RBC remain intact and are not ingested. Slightly higher levels of cholesteryl ester (CE) accumulation were measured in macrophages incubated with RBC to which we adsorbed IC isolated from diabetics (15.4 +/- 2.5 micrograms/mg of protein, mean +/- SEM) than in macrophages incubated with IC isolated from controls (12.5 +/- 1.6 micrograms/mg of protein, mean +/- SEM), but the difference did not reach statistical significance. PEG-precipitable IC isolated from both normal and diabetic subjects led, in some instances, to the transformation of macrophages into foam cells. Significant correlations were observed between CE accumulation and the content of apo B (P < 0.0001), total cholesterol (P = 0.0004), IgG (P = 0.015), and IgA (P = 0.015) in the isolated IC. The correlation between CE accumulation and the content of apo B in isolated IC was stronger in diabetics than in the control group (r = 0.759 vs r = 0.500). Fractionation of isolated IC in immobilized protein A/G yielded immunoglobulin-rich fractions which contained cholesterol and IgG anti-ox-LDL antibodies. The cholesterol content of these fractions was significantly correlated (P = 0.001) with CE accumulation. In conclusion, both diabetics and normal individuals have circulating IC whose atherogenic potential appears to be related to the presence of LDL and antibodies of the IgG and IgA isotypes.
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PMID:Anti-modified LDL antibodies and LDL-containing immune complexes in IDDM patients and healthy controls. 932 72

Treatment of diabetes mellitus by insulin injections provides long-term control of the disease but lacks any feedback response to glucose concentration changes, which finally leads to a number of life-threatening conditions. The purpose of this study was to improve and optimize an implantable, concanavalin A (Con A) based, glucose-responsive insulin delivery system studied earlier [Jeong, S. Y., Kim, S. W., Holmberg, D. L., and McRea, J. C. (1985) J. Controlled Release 2, 143-152], which can be used for long-term diabetes treatment. To optimize the "insulin component" of the delivery system, we prepared PheB1 insulin amino group monosubstituted monoglucosylpoly(ethylene glycol) (G-PEG) insulin conjugates (PEG M(r) 600 or 2000), which showed preserved bioactivity, significantly improved solubility and solution stability at neutral pH, and substantially suppressed hexamerization/dimerization. To improve the delivery system further, we synthesized and characterized a conjugate of Con A and monomethoxypoly(ethylene glycol) (mPEG, M(r) 5000) grafted hydrophilic poly(vinylpyrrolidone-co-acrylic acid) (PVPAA) with M(r) of 250,000. The optimal conjugate contained around eight PEG chains and two to three Con A tetramers attached through the amide bonds to the PVPAA chain. The Con A sugar binding characteristics were preserved, and, more importantly, Con A solubility at pH 7.4 substantially increased. This also holds true for a complex formed by the Con A conjugate and G-PEG insulin, which is soluble and does not precipitate under the physiologically relevant conditions under which the complex formed by the Con A conjugate and glycosyl insulin immediately precipitates. Finally, no leakage of the Con A conjugate from a membrane device was detected. Preliminary in vitro release experiments with Con A conjugate and G-PEG insulin complex enclosed in the membrane device showed a pulsative, reversible release pattern for G-PEG insulin in response to glucose challenges of 50-500 mg/dL, demonstrating the feasibility of the release system for use in planned, chronic in vivo studies with diabetic (pancreatectomized) dogs.
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PMID:Glucose-induced release of glycosylpoly(ethylene glycol) insulin bound to a soluble conjugate of concanavalin A. 932 29

We present a girl with severe combined immunodeficiency (SCID) from adenosine deaminase (ADA) deficiency who developed insulin dependent diabetes mellitus (IDDM). This combination of features has not been previously reported. Because HLA typing (DQbeta-57 Asp/Asp and DQalpha-52 Ser/Ser) showed no alleles usually associated with IDDM, and ICA were repeatedly negative even after treatment with PEG-ADA and gene transplant, hypotheses on the pathogenesis of diabetes mellitus in this patient are discussed.
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PMID:A girl with diabetes and severe combined immunodeficiency from adenosine deaminase deficiency. 936 70

The aim of this work was to determine whether polyethylene glycol 20000 Da (PEG) could be used as protective agent in porcine islet cryopreservation. Cryopreservation was performed on 1-wk cultured pig islets and consisted in an overnight storage in liquid nitrogen. In a first set of experiments, we compared the in vitro function of PEG-cryopreserved islets to that of porcine islets cryopreserved under the standard procedure using dimethylsulfoxide (DMSO), by incubating the islets over 45 min in Krebs buffer containing either 2.8 or 10 mmol/L glucose. Insulin secretion of both types of islets reached a maximum at day 10 postthawing and had stimulation indices above 2 up to 3 wk after thawing. PEG-cryopreserved islets secreted more insulin than DMSO-treated islets and showed glucose-dependency insulin secretion in a 0-16.6 mmol/L glucose range. We also established that PEG-cryopreserved islets were as functional in vitro as nonfrozen tissue and that they could reverse experimental diabetes of the mouse for longer periods of time than noncryopreserved islets (p < 0.005 3 wk after transplantation) when implanted in the peritoneal cavity, being immunoprotected in a semipermeable hollow fiber. PEG can, therefore, be considered as a suitable cryoprotective compound for porcine islet storage.
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PMID:Use of polyethyleneglycol for porcine islet cryopreservation. 944 Aug 71

Although an anion gap at less than 20 mEq/L rarely has a defined etiology, significant elevations in the anion gap almost always signify presence of an acidosis that can be easily identified. Anion gap acidoses can be divided into those caused by lactate accumulation, ketoacid production, toxin/drugs, and uremia. Lactic acidoses caused by decreased oxygen delivery or defective oxygen utilization are associated with high mortality. The treatment of lactic acidosis is controversial. The use of bicarbonate to increase pH is rarely successful and, by generating PCO2, may worsen outcome. Ketoacidosis is usually secondary to diabetes or alcohol. Treatment is aimed at turning off ketogenesis and repairing fluid and electrolyte abnormalities. Methanol, ethylene glycol, and salicylates are responsible for the majority of toxin-induced anion gap acidoses. Both methanol and ethylene glycol are associated with severe acidoses and elevated osmolar gaps. Treatment of both is alcohol infusion to decrease formation of toxic metabolites and dialyses to remove toxins. Salicylate toxicity usually is associated with a mild metabolic acidosis and a respiratory alkalosis. Uremia is associated with a mild acidosis secondary to decreased ammonia secretion and an anion gap caused by the retention of unmeasured anions. A decrease in anion gap is caused by numerous mechanisms and thus has little clinical utility.
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PMID:Anion gap acidosis. 945 91

Selected esters of succinic acid are currently under investigation as insulinotropic tools for the treatment of non-insulin-dependent diabetes mellitus. The aim of the present study was to investigate, in isolated rat pancreatic islets, the insulin secretory response to ten novel esters of succinic acid. According to six different methods of comparison, the following hierarchy in insulinotropic potential was established: 4-tert-butyl-succinate < or = glycerol-1,2-dimethylsuccinate-3-hydrogenosuccinate < or = threitol-3-succinoyl-1,2,4-trimethylsuccinate < or = ethanediol-1,2-diethylsuccinate < or = glycerol-1,2-dimethylsuccinate < or = glycerol-3-hydroxy-1,2-dimethylsuccinate < or = arabitol-5-hydroxy-1,2,3,4-tetramethylsuccinate < or = threitol-1,2,4-trimethylsuccinate < or = ethanediol-1,2-dimethylsuccinate < propanediol-1,2-dimethylsuccinate. There was a close correlation (r = 0.823) between the insulinotropic potential and the minimal effective concentration, which ranged between the extreme values of 10 microM and 2.5 mM. In the presence of the esters, the concentration-response relationship for glucose-stimulated insulin release was changed from its typically sigmoidal shape to a hyperbolic pattern, with most agents enhancing insulin output at a low hexose concentration (2.8 mM) but failing to do so at a high glucose level (16.7 mM). Highly potent insulinotropic esters have several advantages over other antidiabetic agents in clinical use.
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PMID:Comparison between the insulinotropic potential of ten new esters of succinic acid. 957 Apr 52


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