Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 development of effective protocols for the low-temperature banking of pancreatic islets is an important step in islet transplantation for the treatment of type I diabetes mellitus. We have been exploring the use of islets from the newborn pig as an alternative source of tissue for transplantation. Current cryopreservation protocols are empirically derived, but may be optimized by modeling osmotic responses during the cryopreservation process. This study determined the osmotic and cryoprotectant permeability parameters of cells isolated from the pancreas of newborn pigs. Key parameters are: the osmotically inactive fraction of cell volume, hydraulic conductivity, the permeability coefficients of dimethyl sulfoxide (DMSO) and ethylene glycol (EG) at varying temperatures, and the activation energies of these transport processes. Newborn pig islets were dispersed into single cells and kinetic and equilibrium cell volumes were recorded during osmotic excursions using an electronic particle counter interfaced to a computer. Data were fitted to theoretical descriptions of the osmotic responses of cells, based on the Kedem-Katchalsky approach. The hydraulic conductivity (Lp) in the absence of cryoprotectant was calculated as 0.050 +/- 0.005, 0.071 +/- 0.006, and 0.300 +/- 0.016 microm/min/atm at 4 degrees C, 10 degrees C, and 22 degrees C, respectively (mean +/- SEM, n = 7, 6, or 9). These values give an activation energy value of 16.69 kcal/mol when put into an Arrhenius plot. The solute permeability (Ps) values for 1 M DMSO were 0.89 +/- 0.12, 1.86 +/- 0.28, and 5.33 +/- 0.26 microm/min at 4 degrees C, 10 degrees C, and 22 degrees C, respectively (n = 11, 8, or 10) giving an activation energy of 15.98 kcal/mol. The Lp values for cells exposed to 1 M DMSO were 0.071 +/- 0.006, 0.084 +/- 0.008, and 0.185 +/- 0.014 microm/min/atm at 4 degrees C, 10 degrees C, and 22 degrees C, respectively. The activation energy for these values was 8.95 kcal/mol. The Ps values for 2 M DMSO were 1.11 +/- 0.13, 1.74 +/- 0.19, and 7.68 +/- 0.12 microm/min for the same temperatures, with a calculated activation energy of 17.89 kcal/mol. The Lp values in the presence of 2 M DMSO were 0.070 +/- 0.006, 0.085 +/- 0.008, and 0.192 +/- 0.009 microm/min/atm at 4 degrees C, 10 degrees C, and 22 degrees C, respectively, with an activation energy of 9.40 kcal/mol. Solutions of 1 M EG gave Ps values of 1.01 +/- 0.13, 1.45 +/- 0.25, and 4.90 +/- 0.48 microm/min at the three test temperatures. The resulting activation energy was 14.60 kcal/mol. The corresponding Lp values were 0.071 +/- 0.007, 0.068 +/- 0.006, and 0.219 +/- 0.012 microm/min/atm with an activation energy of 10.96 kcal/mol. The solute permeabilities in the presence of 2 M EG for newborn pig islet cells were 1.03 +/- 0.15, 1.42 +/- 0.23, and 5.56 +/- 0.22 microm/min; the activation energy was 15.70. The Lp values for cells in the presence of 2 M EG were 0.068 +/- 0.008, 0.071 +/- 0.006, and 0.225 +/- 0.010 microm/min/atm; the activation energy for these values was 11.49 kcal/mol. These key cryobiological parameters permit the mathematical modeling of osmotic responses of intact islets during the cryopreservation process, which may lead to further improvements in the low temperature storage of islets from newborn pigs.
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PMID:Osmotic and cryoprotectant permeation characteristics of islet cells isolated from the newborn pig pancreas. 1171 1

Pancreatic islets and insulinoma cells are particularly vulnerable to serious damage by cytotoxic nitric oxide (NO) and/or oxidative stress, most probably due to their low expression levels of antioxidant enzymes. This cellular damage has been regarded as one of major obstacles to success of encapsulated islet transplantation for the treatment of type 1 diabetes. As an approach to preventing NO induced damage, crosslinked hemoglobin (Hb-C) with poly(ethylene glycol) was co-encapsulated with rat islets or insulinoma cells (RINm5F) in alginate/poly(L-lysine)/alginate microcapsules. Hb-C effectively protected the cells from NO damage, generated by treating the cell microcapsules with S-nitroso-N-acetylpenicillamine (SNAP, a nitric oxide donor) at concentrations up to 400 microM, preserving higher viability and insulin secretion than a control group (no SNAP and no Hb-C). When the cells were incubated with SNAP without Hb, there was SNAP concentration dependent cellular damage, and a colorimetric TUNEL assay revealed a typical cell apoptosis sign, indicating DNA damages.
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PMID:Protection of insulin secreting cells from nitric oxide induced cellular damage by crosslinked hemoglobin. 1460 73

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: Abetimus sodium, adalimumab, alefacept, alemtuzumab, almotriptan, AMGN-0007, anakinra, anti-CTLA-4 Mab, L-arginine hydrochloride, arzoxifene hydrochloride, astemizole, atazanavir sulfate, atlizumab; Belimumab, BG-9928, binodenoson, bosentan, botulinum toxin type B, bovine lactoferrin, BufferGel; Caspofungin acetate, ciclesonide,cilomilast, ciluprevir, clofarabine, CVT-3146; Darbepoetin alfa, desloratadine, diflomotecan, doripenem, dronedarone hydrochloride, drotrecogin alfa (activated), DT388-GM-CSF, duloxetine hydrochloride, E-5564, efalizumab, enfuvirtide, esomeprazole magnesium, estradiol acetate, ETC-642, exenatide, exisulind, ezetimib; Febuxostat; Gallium maltolate, ganirelix acetate, garenoxacin mesilate, gefitinib; H11, HuMax; IL-15, IDD-1, IGIV-C, imatinib mesylate, ISIS-14803, ITF-1697, ivabradine hydrochloride; KRN-5500; L-365260, levetiracetam, levosimendan, licofelone, linezolid, LJP-1082, lopinavir lumiracoxib; MCC-478, melatonin, morphine hydrochloride, morphine-6-glucuronide, moxidectin; N-Acetylcarnosine, natalizumab, NM-702, NNC-05-1869, NSC-703940; Ocinaplon OM-89, omalizumab, omeprazole/ sodium bicarbonate, OPC-28326, ospemifene; PEG-filgrastim peginterferon alfa-2a, pegsunercept, pirfenidone, pralmorelin, pregabalin; Recombinant glucagon-like peptide-1 (7-36) amide, repifermin, RSD-1235; S-8184, selodenoson, sodium dichloroacetate, suberanilohydroxamic acid; TAS-102, terfenadine, teriparatide, tipranavir troxacitabine; Ximelagatran; YM-337.
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PMID:Gateways to clinical trials. 1473 33

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: Abetimus sodium, Ad5-FGF4, adeno-Interferon gamma, AE-941, AERx, alemtuzumab, alicaforsen sodium, almotriptan, alpharadin, anakinra, anatumomab mafenatox, ANG-453, anti-CTLA-4 Mab, AP-12009, aprepitant, aripiprazole, arsenic trioxide, astemizole, atlizumab, atomoxetine hydrochloride; Bevacizumab, BG-9928, BMS-188667, botulinum toxin type B, BufferGel; Caffeine, CDP-870, cetuximab, cilomilast, ciluprevir, clofarabine, continuous erythropoiesis receptor activator, CP-461; Darbepoetin alfa, deferasirox, desloratadine, desoxyepothilone B, diflomotecan, dolasetron, drotrecogin alfa (activated), duloxetine hydrochloride; ED-71, efalizumab, efaproxiral sodium, EKB-569, eletriptan, EMD-72000, enfuvirtide, erlotinib hydrochloride, escitalopram oxalate, etoricoxib; Fampridine, ferumoxytol, fondaparinux sodium; Gadofosveset sodium, gastrazole, gefitinib, gemtuzumab ozogamicin, gepirone hydrochloride glutamine; hLM609, HSPPC-96, human insulin; IDD-1, imatinib mesylate, indisulam, inhaled insulin, ixabepilone; Keratinocyte growth factor; Lapatinib, laquinimod, LDP-02, LE-SN38, levetiracetam, levosimendan, licofelone, liposomal doxorubicin, liposomal NDDP, lopinavir, lumiracoxib, LY-156735; Morphine hydrochloride, morphine-6-glucuronide, motexafin gadolinium, MS-27-275, MVA-5T4, MVA-Muc1-IL-2; Nemifitide ditriflutate, neridronic acid nitronaproxen, NSC-683864, NSC-703940, NVP-LAF-237; Oblimersen sodium, ocinaplon, oncomyc-NG, OPC-28326, ortataxel, ospemifene; Palonosetron hydrochloride, PEG-filgrastim peginterferon alfa-2(a), peginterferon alfa-2b, pegsunercept, pemetrexed disodium, pregabalin, prilocaine, pyridoxamine; RDP-58, recombinant glucagon-like peptide-1 (7-36) amide, recombinant human ApoA-I milano/phospholipid complex; SB-715992, soblidotin, sodium dichloroacetate, St. John's Wort extract; TAS-102, terfenadine, TG-1024, TG-5001, 4'-Thio-ara-C, tipranavir, topixantrone hydrochloride, trabectedin, transdermal selegiline, trimethoprim, troxacitabine, TT-232; Vatalanib succinate, vinflunine; Ximelagatran; Ziprasidone hydrochloride, Zoledronic acid monohydrate.
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PMID:Gateways to clinical trials. 1498 42

The biohybrid artificial pancreas (BAP), a promising therapy for type 1 diabetes, faces several obstacles such as the need for a large implantation volume of encapsulated islets because of low functionality. To address such problems, in this study we examined long-term insulinotropic activity of glucagon-like peptide-1 (GLP-1)/polymer conjugate [VAPG: poly(N-vinylpyrrolidone-co-acrylic acid-g-PEG) (VAP)-GLP-1] as well as GLP-1/Zn(2+) crystal by coencapsulation with islets. Microcapsules with VAPG or crystal produced round-shaped beads whereas free GLP-1 showed poor capsule morphology. A perfusion experiment suggested that VAPG showed higher bioactivity than did microcapsules with GLP-1/Zn(2+). In long-term culture (200 mg of glucose/dL [G]), VAPG also enhanced insulinotropic activity over 5 weeks compared with the crystal form of GLP-1. However, maintenance of the high bioactivity of VAPG suddenly declined after week 5, possibly because of degradation, metabolism, and overstimulation. Basal (50 G) and glucose-stimulated (300 G) levels of insulin secretion confirmed a see-saw pattern in which the VAPG gradually decreased insulin secretion from encapsulated islets and then fell below the insulin level secreted from microcapsules containing GLP-1/Zn(2+) crystal. Viability of the microcapsulated islets of each group was not significantly different. Consequently, the coencapsulation of VAPG or GLP-1/Zn(2+) crystal can be a potential approach to reducing BAP volume with further optimization of activity duration.
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PMID:Long-term insulinotropic activity of glucagon-like peptide-1/polymer conjugate on islet microcapsules. 1568 69

Pancreatic islet encapsulation into synthetic, passive material matrixes can provide protection for transplanted islets from destruction via cell-contacted mediated interactions with autoreactive immune cells for treatment of Type I diabetes mellitus. However, one of the fundamental deficiencies with current encapsulation technology is that passive material barriers cannot protect islets from exposure to cytokines and other small, diffusible cytotoxic molecules produced by activated immune cells, subsequently leading to beta-cell destruction. Preparation of material matrixes that can actively provide localized immunosuppression of autoreactive immune cells may prolong the viability, and hence function, of encapsulated islet grafts. We have demonstrated the ability to conjugate apoptosis-inducing anti-Fas monoclonal antibodies (MAbs) to the surfaces of poly(ethylene glycol)-modified hydrogels, providing a surface that actively attempts to locally down-regulate the autoimmune response by destroying autoreactive T cells against pancreatic islet cells. We have conjugated anti-Fas MAbs to a high degree to the surface of these hydrogels, with retention of anti-Fas recognition of the Fas antigen as shown by ELISA testing. Apoptosis induction of Fas-sensitive Jurkat T cells was enhanced in the presence of anti-Fas conjugated hydrogels. In addition, this apoptosis induction was specific to anti-Fas MAbs, with no apoptosis induction with control antibodies or with Fas-insensitive T cells. These experiments promote the concept that surface-conjugated hydrogel constructs can provide localized immunosuppression for encapsulated grafted tissue.
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PMID:Synthesis of immunoisolation barriers that provide localized immunosuppression for encapsulated pancreatic islets. 1684 13

Pancreatic islet transplantation is one of the most promising strategies for patients suffering from type 1 diabetes mellitus, but several therapeutic immunosuppressive medications must be administered simultaneously to protect transplanted islets in the long-term, and these expose patients to the risk of serious complications. Thus, we developed chemically modified islets with a protective poly(ethylene glycol) (PEG) layer, which reduces immunogenicity by preventing cellular immune reactions. We report here that PEG-based chemical immunomodulation can provide a semi-permanent effective therapy that protects transplanted islets at least for 1 year when accompanied by cyclosporine. Moreover, this combinatorial approach appears to avoid the toxicities associated with immunosuppressive medications because of the reduced amounts of medication required. Also, the conjugated PEG molecules were found to be continuously present at the transplanted islets. However, unmodified islets (control) were completely eliminated within 2 weeks even when CsA was administered. These results strongly suggest that this new combinatorial therapy provides a semi-permanent, effective clinical means of attenuating transplanted islet immunogenicity for a long time, whilst avoiding the toxicities associated with therapeutic levels of immunosuppressants owing to the minimized immunosuppressant.
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PMID:Functional and histological evaluation of transplanted pancreatic islets immunoprotected by PEGylation and cyclosporine for 1 year. 1718 50

We report the case of a 42-year-old woman with chronic hepatitis C (genotype 1), who in June 2004 started therapy with pegylated interferon alpha (PEG-IFNalpha) plus ribavirin. Two months later, she discontinued treatment because of polydipsia, polyuria and vomiting leading to a marked dehydration. Biochemical data showed type 1 diabetes mellitus with ketoacidosis, and insulin therapy was started. The patient, who before starting PEG-IFN alpha plus ribavirin therapy tested negative for glutamic acid decarboxylase antibodies (GADAb) and islet cell (ICAb) antibodies, became strongly positive for both autoimmune markers. This case confirms that patients with chronic hepatitis C who do not have baseline markers of pancreatic autoimmunity may develop severe ketoacidosis during treatment with PEG-IFNalpha, as well as with standard IFNalpha. In order to avoid this complication, as no guidelines are available and the pancreatic autoimmunity markers are not routinely analysed, we suggest frequent monitoring (e.g., every one to two weeks) of glycaemic values: e.g., every one to two weeks during the first 3 months (when this complication occurs most frequently) and monthly thereafter so as to identify diabetes at an early stage and before the onset of the appearance of severe ketoacidosis, which is life-threatening.
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PMID:A case of pegylated interferon alpha-related diabetic ketoacidosis: can this complication be avoided? 1772 57

Encapsulating pancreatic islets in a semipermeable poly(ethylene glycol) (PEG) hydrogel membrane holds potential as an immuno-isolation barrier for the treatment of type 1 diabetes mellitus. The semipermeable PEG hydrogel not only permits free diffusion of nutrients, metabolic waste, and insulin produced from the encapsulated beta-cells, but also provides a size-exclusion effect to prevent direct contact of entrapped islets to host immune cells and antibodies. However, the use of unmodified PEG hydrogels for islet encapsulation is not ideal, as there is no bioactive cue to promote the long-term survival and function of the encapsulated cells. Herein, we report the synthesis and characterization of a bioactive glucagon-like peptide 1 (GLP-1) analog, namely, GLP-1-cysteine or GLP-1C, and the fabrication of functional GLP-1 immobilized PEG hydrogels via a facile thiol-acrylate photopolymerization. The immobilization of bioactive GLP-1C within PEG hydrogels is efficient and does not alter the bulk hydrogel properties. Further, the GLP-1 immobilized PEG hydrogels enhance the survival and insulin secretion of encapsulated islets. Overall, this study demonstrates a strategy to modify PEG hydrogels with bioactive peptide moieties that can significantly enhance the efficacy of islet encapsulation.
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PMID:Glucagon-like peptide-1 functionalized PEG hydrogels promote survival and function of encapsulated pancreatic beta-cells. 1958 41


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