Slc11a1 enhances the autoimmune diabetogenic T-cell response by altering processing and presentation of pancreatic islet antigens.


OBJECTIVE:Efforts to map non-major histocompatibility complex (MHC) genes causing type 1 diabetes in NOD mice identified Slc11a1, formerly Nramp1, as the leading candidate gene in the Idd5.2 region. Slc11a1 is a membrane transporter of bivalent cations that is expressed in late endosomes and lysosomes of macrophages and dendritic cells (DCs). Because DCs are antigen-presenting cells (APCs) known to be critically involved in the immunopathogenic events leading to type 1 diabetes, we hypothesized that Slc11a1 alters the processing or presentation of islet-derived antigens to T-cells. RESEARCH DESIGN AND METHODS:NOD mice having wild-type (WT) or mutant Slc11a1 molecules and 129 mice having WT or null Slc11a1 alleles were examined for parameters associated with antigen presentation. RESULTS:We found that Slc11a1 enhanced the presentation of a diabetes-related T-cell determinant of GAD65, and its function contributed to the activation of a pathogenic T-cell clone, BDC2.5. An enhanced generation of interferon (IFN)-gamma-producing T-cells was also associated with functional Slc11a1. The alteration of immune responsiveness by Slc11a1 genotype did not correlate with altered MHC class II expression in DCs; however, functional Slc11a1 was associated with accelerated phagocytosis and phagosomal acidification in DCs. CONCLUSIONS:The association of variants encoding Slc11a1 with type 1 diabetes may reflect its function in processing and presentation of islet self-antigens in DCs. Thus, non-MHC genes could affect the MHC-restricted T-cell response through altered antigen processing and presentation.






Dai YD,Marrero IG,Gros P,Zaghouani H,Wicker LS,Sercarz EE




Has Abstract


2009-01-01 00:00:00
















  • Segregation analysis of urinary albumin excretion in families with type 2 diabetes.

    abstract::Elevated urinary albumin excretion (UAE) is a predictor of the development of nephropathy and cardiovascular mortality. To study whether genetic factors may determine UAE, we examined familial aggregation of UAE in 96 large multigenerational pedigrees ascertained for type 2 diabetes. A total of 1,269 subjects had UAE ...


    pub_type: 杂志文章


    authors: Fogarty DG,Hanna LS,Wantman M,Warram JH,Krolewski AS,Rich SS

    更新日期:2000-06-01 00:00:00

  • Phenotypic correction of diabetic mice by adenovirus-mediated glucokinase expression.

    abstract::Hyperglycemia of diabetes is caused in part by perturbation of hepatic glucose metabolism. Hepatic glucokinase (GK) is an important regulator of glucose storage and disposal in the liver. GK levels are lowered in patients with maturity-onset diabetes of the young and in some diabetic animal models. Here, we explored t...


    pub_type: 杂志文章


    authors: Desai UJ,Slosberg ED,Boettcher BR,Caplan SL,Fanelli B,Stephan Z,Gunther VJ,Kaleko M,Connelly S

    更新日期:2001-10-01 00:00:00

  • Development of rat embryos cultured in glucose-deficient media.

    abstract::Embryo-culture techniques were used to study the effects of exposure to glucose-deficient culture media on rat embryos during organogenesis. Embryos and their extraembryonic membranes (explants) were cultured either in control media or in media with low or very low glucose concentrations. At the start of the culture t...


    pub_type: 杂志文章


    authors: Ellington SK

    更新日期:1987-12-01 00:00:00

  • The mechanism of action of insulin on phospholipid metabolism in rat adipose tissue. Requirement for protein synthesis and a carbohydrate source, and relationship to activation of pyruvate dehydrogenase.

    abstract::We studied certain metabolic requirements for insulin-induced increases in phospholipids, and the relationship of phospholipid changes to the insulin-induced activation of pyruvate dehydrogenase, in rat adipocytes and fat pads in vitro. Increases in the contents of phosphatidylinositol and phosphatidylserine mass were...


    pub_type: 杂志文章


    authors: Farese RV,Farese RV Jr,Sabir MA,Larson RE,Trudeau WL 3rd,Barnes D

    更新日期:1984-07-01 00:00:00

  • Inhibition of TGF-β Signaling Promotes Human Pancreatic β-Cell Replication.

    abstract::Diabetes is associated with loss of functional pancreatic β-cells, and restoration of β-cells is a major goal for regenerative therapies. Endogenous regeneration of β-cells via β-cell replication has the potential to restore cellular mass; however, pharmacological agents that promote regeneration or expansion of endog...


    pub_type: 杂志文章


    authors: Dhawan S,Dirice E,Kulkarni RN,Bhushan A

    更新日期:2016-05-01 00:00:00

  • Effect of combined antisense oligonucleotides against high-glucose- and diabetes-induced overexpression of extracellular matrix components and increased vascular permeability.

    abstract::The effect of combined antisense oligonucleotides (AS-oligos) against overexpression of extracellular matrix (ECM) components, fibronectin, laminin, and collagen IV and on cell monolayer permeability was examined in rat microvascular endothelial cells (RMECs) grown in high glucose medium and on retinal vascular permea...


    pub_type: 杂志文章


    authors: Oshitari T,Polewski P,Chadda M,Li AF,Sato T,Roy S

    更新日期:2006-01-01 00:00:00

  • Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study: associations with neonatal anthropometrics.

    abstract:OBJECTIVE:To examine associations of neonatal adiposity with maternal glucose levels and cord serum C-peptide in a multicenter multinational study, the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study, thereby assessing the Pederson hypothesis linking maternal glycemia and fetal hyperinsulinemia to neonatal adi...


    pub_type: 杂志文章


    authors: HAPO Study Cooperative Research Group.

    更新日期:2009-02-01 00:00:00

  • PPARδ activation protects endothelial function in diabetic mice.

    abstract::Recent evidence highlights the therapeutic potential of peroxisome proliferator-activated receptor-δ (PPARδ) agonists to increase insulin sensitivity in diabetes. However, the role of PPARδ in regulating vascular function is incompletely characterized. We investigate whether PPARδ activation improves endothelial funct...


    pub_type: 杂志文章


    authors: Tian XY,Wong WT,Wang N,Lu Y,Cheang WS,Liu J,Liu L,Liu Y,Lee SS,Chen ZY,Cooke JP,Yao X,Huang Y

    更新日期:2012-12-01 00:00:00

  • The frequency and immunodominance of islet-specific CD8+ T-cell responses change after type 1 diabetes diagnosis and treatment.

    abstract:OBJECTIVE:Islet-reactive CD8(+) T-cells play a key role in the pathogenesis of type 1 diabetes in the NOD mouse. The predominant T-cell specificities change over time, but whether similar shifts also occur after clinical diagnosis and insulin treatment in type 1 diabetic patients is unknown. RESEARCH DESIGN AND METHOD...


    pub_type: 杂志文章


    authors: Martinuzzi E,Novelli G,Scotto M,Blancou P,Bach JM,Chaillous L,Bruno G,Chatenoud L,van Endert P,Mallone R

    更新日期:2008-05-01 00:00:00

  • Metabolic factors contributing to increased resting metabolic rate and decreased insulin-induced thermogenesis during the development of type 2 diabetes.

    abstract::Previous studies have indicated that individuals with type 2 diabetes have an increased resting metabolic rate (RMR) but decreased insulin-induced thermogenesis (IIT) compared with those with normal glucose tolerance (NGT). When and by which mechanisms these abnormalities occur during the development of diabetes remai...


    pub_type: 杂志文章


    authors: Weyer C,Bogardus C,Pratley RE

    更新日期:1999-08-01 00:00:00

  • Community screening for diabetes by blood glucose measurement. Results of a five-year experience.

    abstract::The Diabetes Association of greater Cleveland screened 307,000 individuals in the metropolitan area for diabetes with a 75-gm. oral load of carbohydrate. Of these subjects 12,600 (4.1 per cent) had a two-capillary blood glucose level of greater than 139 mg. per cent and were defined as positive. Seventy per cent of th...


    pub_type: 杂志文章


    authors: Genuth SM,Houser HB,Carter JR Jr,Merkatz I,Price JW,Schumacher OP,Wieland RG

    更新日期:1976-12-01 00:00:00

  • Leptin receptor mRNA identifies a subpopulation of neuropeptide Y neurons activated by fasting in rat hypothalamus.

    abstract::The decline of leptin (Ob protein) concentrations during fasting is implicated as a signal for increasing the expression of the orexigenic peptide neuropeptide Y (NPY) in the hypothalamus. To test the hypothesis that the effects of food intake on arcuate nucleus NPY activation are mediated by leptin, we performed simu...


    pub_type: 杂志文章


    authors: Baskin DG,Breininger JF,Schwartz MW

    更新日期:1999-04-01 00:00:00

  • The human glucokinase gene beta-cell-type promoter: an essential role of insulin promoter factor 1/PDX-1 in its activation in HIT-T15 cells.

    abstract::The glycolytic enzyme glucokinase plays a primary role in the glucose-responsive secretion of insulin, and defects of this enzyme can cause NIDDM. As a step toward understanding the molecular basis of glucokinase (GK) gene regulation, we assessed the structure and regulation of the human GK gene beta-cell-type promote...


    pub_type: 杂志文章


    authors: Watada H,Kajimoto Y,Umayahara Y,Matsuoka T,Kaneto H,Fujitani Y,Kamada T,Kawamori R,Yamasaki Y

    更新日期:1996-11-01 00:00:00

  • Insulin release. Demonstration of a priming effect of 3-isobutyl-1-methyl-xanthine (IBMX) on islets of Langerhans.

    abstract::Exposure of isolated rat pancreatic islets to 1 mM 3-isobutyl-1-methyl-xanthine (IBMX) resulted in a 5.7-fold increase in the rate of insulin release. After a 30-min rest period under basal conditions, reexposure of the islets to 1 mM IBMX resulted in an enhanced rate of release when compared with either a timed contr...


    pub_type: 杂志文章


    authors: Wiedenkeller DE,Sharp GW

    更新日期:1981-09-01 00:00:00

  • Experimental hyperosmolar diabetic syndrome. Ketogenic response to medium-chain triglycerides.

    abstract::The clinical features of the experimental hyperosmolar diabetic (EHD) rat model resemble those seen in the human syndrome--extreme hyperglycemia without ketoacidosis is common to both. The absence of ketoacidosis in the syndrome has been ascribed to both substrate (free fatty acid) deficiency and to interference with ...


    pub_type: 杂志文章


    authors: Gordon EE,Duga J

    更新日期:1975-03-01 00:00:00

  • Protein engineering strategies for sustained glucagon-like peptide-1 receptor-dependent control of glucose homeostasis.

    abstract:OBJECTIVE:We have developed a novel platform for display and delivery of bioactive peptides that links the biological properties of the peptide to the pharmacokinetic properties of an antibody. Peptides engineered in the MIMETIBODY platform have improved biochemical and biophysical properties that are quite distinct fr...


    pub_type: 杂志文章


    authors: Picha KM,Cunningham MR,Drucker DJ,Mathur A,Ort T,Scully M,Soderman A,Spinka-Doms T,Stojanovic-Susulic V,Thomas BA,O'Neil KT

    更新日期:2008-07-01 00:00:00

  • Effects of ponalrestat, an aldose reductase inhibitor, on neutrophil killing of Escherichia coli and autonomic function in patients with diabetes mellitus.

    abstract::In diabetic subjects, polyol pathway activity might inhibit neutrophil function and cause nerve damage. The effects of ponalrestat, an aldose reductase inhibitor, were assessed on neutrophil intracellular killing of Escherichia coli and on autonomic function in diabetic subjects in a randomized double-blind, placebo-c...


    pub_type: 临床试验,杂志文章,随机对照试验


    authors: Boland OM,Blackwell CC,Clarke BF,Ewing DJ

    更新日期:1993-02-01 00:00:00

  • Dynamics of glucose-induced insulin release during the spontaneous remission of streptozocin diabetes induced in the newborn rat.

    abstract::Neonatal rats injected with streptozocin (STZ, 100 mg/kg) at birth exhibited an acute diabetes followed by a spontaneous remission. We have previously shown that this recovery from neonatal diabetes is due to B-cell regeneration and reaccumulation of pancreatic insulin stores starting from 3 to 5 days after birth. The...


    pub_type: 杂志文章


    authors: Portha B,Kergoat M

    更新日期:1985-06-01 00:00:00

  • Human prohormone convertase 3 gene: exon-intron organization and molecular scanning for mutations in Japanese subjects with NIDDM.

    abstract::Proinsulin is converted to insulin by the concerted action of two sequence-specific subtilisin-like proteases termed prohormone convertase 2 (PC2) and prohormone convertase 3 (PC3). PC3 is a type I proinsulin-processing enzyme that initiates the sequential processing of proinsulin to insulin by cleaving the proinsulin...


    pub_type: 杂志文章


    authors: Ohagi S,Sakaguchi H,Sanke T,Tatsuta H,Hanabusa T,Nanjo K

    更新日期:1996-07-01 00:00:00

  • Control of adipose tissue inflammation through TRB1.

    abstract:OBJECTIVE:Based on its role as an energy storage compartment and endocrine organ, white adipose tissue (WAT) fulfills a critical function in the maintenance of whole-body energy homeostasis. Indeed, WAT dysfunction is connected to obesity-related type 2 diabetes triggered at least partly by an inflammatory response in ...


    pub_type: 杂志文章


    authors: Ostertag A,Jones A,Rose AJ,Liebert M,Kleinsorg S,Reimann A,Vegiopoulos A,Berriel Diaz M,Strzoda D,Yamamoto M,Satoh T,Akira S,Herzig S

    更新日期:2010-08-01 00:00:00

  • Metformin inhibits monocyte-to-macrophage differentiation via AMPK-mediated inhibition of STAT3 activation: potential role in atherosclerosis.

    abstract::Monocyte-to-macrophage differentiation is a critical event that accentuates atherosclerosis by promoting an inflammatory environment within the vessel wall. In this study, we investigated the molecular mechanisms responsible for monocyte-to-macrophage differentiation and, subsequently, the effect of metformin in regre...


    pub_type: 杂志文章


    authors: Vasamsetti SB,Karnewar S,Kanugula AK,Thatipalli AR,Kumar JM,Kotamraju S

    更新日期:2015-06-01 00:00:00

  • Tacrolimus-Induced BMP/SMAD Signaling Associates With Metabolic Stress-Activated FOXO1 to Trigger β-Cell Failure.

    abstract::Active maintenance of β-cell identity through fine-tuned regulation of key transcription factors ensures β-cell function. Tacrolimus, a widely used immunosuppressant, accelerates onset of diabetes after organ transplantation, but underlying molecular mechanisms are unclear. Here we show that tacrolimus induces loss of...


    pub_type: 杂志文章


    authors: Triñanes J,Ten Dijke P,Groen N,Hanegraaf M,Porrini E,Rodriguez-Rodriguez AE,Drachenberg C,Rabelink TJ,de Koning E,Carlotti F,de Vries APJ

    更新日期:2020-02-01 00:00:00

  • WISP1 is a novel adipokine linked to inflammation in obesity.

    abstract::WISP1 (Wnt1-inducible signaling pathway protein-1, also known as CCN4) is a member of the secreted extracellular matrix-associated proteins of the CCN family and a target gene of the Wingless-type (WNT) signaling pathway. Growing evidence links the WNT signaling pathway to the regulation of adipogenesis and low-grade ...


    pub_type: 临床试验,杂志文章


    authors: Murahovschi V,Pivovarova O,Ilkavets I,Dmitrieva RM,Döcke S,Keyhani-Nejad F,Gögebakan Ö,Osterhoff M,Kemper M,Hornemann S,Markova M,Klöting N,Stockmann M,Weickert MO,Lamounier-Zepter V,Neuhaus P,Konradi A,Dooley S,von L

    更新日期:2015-03-01 00:00:00

  • Transplantation without immunosuppression.

    abstract::Exciting new findings have been reported in the past few years that indicate that islets can be transplanted successfully across major histocompatibility barriers without the continuous use of immunosuppressive agents by techniques designed to eliminate passenger leukocytes. In vitro culture of donor islets either at ...


    pub_type: 杂志文章,评审


    authors: Faustman D,Lacy PE,Davie JM

    更新日期:1982-08-01 00:00:00

  • New approach for oral administration of insulin with polyalkylcyanoacrylate nanocapsules as drug carrier.

    abstract::Polyalkylcyanoacrylate nanocapsules (mean size 220 nm), composed of spheric polymeric structures, have been used as a drug carrier for insulin. The rate of encapsulation of insulin is 54.9%, and we studied the therapeutic efficiency of the nanocapsules in diabetic and normal rats. When administered subcutaneously, ins...


    pub_type: 杂志文章


    authors: Damgé C,Michel C,Aprahamian M,Couvreur P

    更新日期:1988-02-01 00:00:00

  • Biosynthesis of proinsulin and other islet cell proteins in pancreatic beta cells of the rat: a radioautographic evaluation of glucose effects in vitro.

    abstract::Rat pancreatic islets were incubated in vitro with L-[4,5-3H]leucine or with L-[2,3-3H]tryptophan in Krebs-Ringer bicarbonate buffer, containing 0, 5, or 20 mM glucose. Incorporation of labeled amino acids in islet cells was evaluated quantitatively by a validated radioautographic procedure. Incorporation of labeled l...


    pub_type: 杂志文章


    authors: Logothetopoulos J,Jain K

    更新日期:1980-10-01 00:00:00

  • The hemodynamic abnormalities in short-term insulin deficiency: the role of prostaglandin inhibition.

    abstract::It has been suggested that the hemodynamic derangements present in diabetic ketoacidosis are the results not only of profound volume depletion but also of the effects of increased production of vasodilating prostaglandins (PGs), principally PGI2, released by adipose tissue. In animal and in vitro models, prostaglandin...


    pub_type: 临床试验,杂志文章,随机对照试验


    authors: Avogaro A,Crepaldi C,Piarulli F,Milan D,Valerio A,Pavan P,Sacerdoti D,Calabrò A,Macdonald I,Crepaldi G,Scognamiglio R,Tiengo A

    更新日期:1996-05-01 00:00:00

  • Insulin sensitivity and body weight changes in young white carriers of the codon 64 amino acid polymorphism of the beta 3-adrenergic receptor gene.

    abstract::Recently, a missense mutation replacing tryptophan with arginine at codon 64 of the beta 3-adrenergic receptor gene was shown to be associated with insulin resistance in nondiabetic subjects and to an earlier onset of NIDDM in Pima Indians. We studied whether the codon 64 amino acid polymorphism of the beta 3-adrenerg...


    pub_type: 杂志文章


    authors: Urhammer SA,Clausen JO,Hansen T,Pedersen O

    更新日期:1996-08-01 00:00:00

  • Coordinate phosphorylation of insulin-receptor kinase and its 175,000-Mr endogenous substrate in rat hepatocytes.

    abstract::To investigate the early events in insulin signal transmission in liver, isolated rat hepatocytes were labeled with 32P, and proteins phosphorylated in response to insulin were detected by immunoprecipitation with anti-phosphotyrosine and anti-receptor antibodies and analyzed by sodium dodecyl sulfate (SDS)-polyacryla...


    pub_type: 杂志文章


    authors: Okamoto M,Karasik A,White MF,Kahn CR

    更新日期:1991-01-01 00:00:00

  • The common polymorphisms (single nucleotide polymorphism [SNP] +45 and SNP +276) of the adiponectin gene predict the conversion from impaired glucose tolerance to type 2 diabetes: the STOP-NIDDM trial.

    abstract::Adiponectin is an adipose tissue-specific protein with insulin-sensitizing and antiatherogenic properties. Therefore, the adiponectin gene is a promising candidate gene for type 2 diabetes. We investigated the single nucleotide polymorphisms (SNPs) +45T/G and +276G/T of the adiponectin gene as predictors for the conve...


    pub_type: 杂志文章


    authors: Zacharova J,Chiasson JL,Laakso M,STOP-NIDDM Study Group.

    更新日期:2005-03-01 00:00:00