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 autoimmune process leading to the destruction of pancreatic beta-cells is mediated by T lymphocytes. Peripheral T cells from subjects with preclinical and clinical type I diabetes respond weakly in vitro to lectin stimulation. We, therefore, investigated in a group of newly diagnosed diabetic patients the presence of a defect in the signal transduction pathway of the T cell receptor (TcR)/CD3 complex. Following stimulation with anti-CD3-coupled beads, the proliferative response in diabetic T cells was significantly decreased in comparison with that from normal T cells. Interestingly, addition of either recombinant interleukin (IL)-2 or phorbol 12-myristate 13-acetate to the cell culture was able to completely restore impaired anti-CD3-induced proliferation in diabetic T cells, suggesting the presence of a defect through the TcR/CD3 pathway, located upstream of protein kinase C (PKC) activation and resulting in low IL-2 production and proliferation. Intracellular Ca2+ measurements by Fluo-3 labeling and flow cytometry analysis on diabetic and control T cells after anti-CD3 stimulation gave comparable results, indicating that this defect does not involve events leading to intracellular Ca2+ mobilization. In contrast, anti-CD3 stimulation of diabetic T cells resulted in a marked impairment of PKC translocation and CD69 antigen expression, as assessed by peptide substrate phosphorylation and by flow cytometry analysis, respectively. Taken together, our data clearly show the presence in individuals at the onset of the disease of an in vitro defect in the signal transduction pathway of the TcR/CD3 complex, resulting in ineffective PKC activation which is not able to induce normal IL-2 production and proliferation of diabetic T cells.
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PMID:Defective T cell receptor/CD3 complex signaling in human type I diabetes. 814 68

Parental genomic imprinting is the phenomenon in which the behavior of a gene is modified, depending on the sex of the transmitting parent [Peterson and Sapienza (1993): Annu Rev Genet 27:7-31]. Recent observations have revealed that the inheritance patterns, age-of-onset, severity, and etiology of certain human diseases can be explained by aberrations in the establishment or the maintenance of the imprint. Examples include the Prader-Willi, Angelman, and Beckwith-Wiedemann syndromes [Nicholls (1994): Am J Hum Genet 54:733-740], malignancy [Sapienza (1990): Biochim Biophys Acta 1072:51-61; Feinberg (1993): Nat Genet 4:110-113], and insulin-dependent diabetes mellitus (IDDM) [Julier et al. (1994) Nature 354:155-159; Bennett et al. (1995) Nat Genet 9:284-292]. We review the evidence that implicates an imprinted gene in the INS-IGF2 region of chromosome 11p15 in the etiology of IDDM (referred to as the IDDM2 locus) and show that in human fetal pancreas, INS is not imprinted, thus providing an argument against INS as the candidate gene. We also examine imprinting effects on the expression of IGF2 in components of the human immune system believed to be important in IDDM and show imprinted expression in fetal thymus as early as 15 weeks gestation. We demonstrate further that in the circulating mononuclear cells of two individuals, lectin-stimulated IGF2 transcription was biallelic, indicating relaxation of imprinting, whereas in one individual, transcription was monoallelic. Finally, we review the current available data supporting a role for insulin-like growth factor-II (IGF-II) in the immune system and, more specifically, discuss the evidence supporting a role for the IGFs in the prevention of apoptosis. These data have led us to formulate a novel hypothesis that could mechanistically explain the involvement of the IDDM2 locus in the pathogenesis of IDDM.
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PMID:Imprinting of IGF2, insulin-dependent diabetes, immune function, and apoptosis: a hypothesis. 856 31

It is generally accepted that glycoconjugates secreted by salivary glands are important in the protection of the oral environment. Studies with diabetic rodents have shown that their salivary glands are adversely affected. Little effort has been made to determine whether altered synthesis and/or secretion of glycoconjugates occur in salivary glands of diabetic individuals, either human or non-human. The major salivary glands of male Swiss-Webster mice, rendered diabetic with alloxan, were examined and compared to controls. Sections of major salivary glands were examined using a battery of non-lectin staining methods for glycoconjugates. Granular duct diameters were measured in sections of the submandibular glands (SM) from controls and all experimental groups. Neutral glycoconjugate staining in SM acini of glands from diabetic animals was depressed, while staining of acidic glycoconjugates increased. Neutral glycoconjugate staining in granular ducts of SM glands of diabetic animals was depressed, as were granule content and granular duct diameters. Induced diabetes did not affect staining of neutral glycoconjugates in parotid glands but staining of acidic non-sulfated glycoconjugates appeared to increase. There were no apparent differences in neutral or acidic glycoconjugate staining of sublingual (SL) glands of diabetic or control mice.
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PMID:Salivary glands, glycoconjugates and diabetes mellitus. 887 94

Syrian hamsters of the APA strain (APA hamsters) develop spontaneous mesangial thickening in the renal glomeruli from an early age. They also develop focal and segmental glomerulosclerosis (FSG) at and after 6 months of age. In this study, histopathological, immunohistochemical and lectin histochemical examinations were conducted to clarify the modification of the spontaneous renal lesions of APA hamsters by streptozotocin(SZ)-induced diabetes. Histopathological analysis revealed that the expansion of the mesangial region was more prominent and the thickening of the glomerular basement membrane (GBM) was weaker in SZ-treated animals than in non-treated ones. Immunohistochemical analysis suggested that type IV collagen and laminin were involved in the expansion of the mesangial region and thickening of the GBM. In lectin histochemical analysis, podocytes, capillary endothelial cells, GBM and a part of mesangial region of SZ-treated animals were positive for RCA120 and GSL-I with neuraminidase-pretreatment although they were negative for these lectins in non-treated animals. These results suggest that the spontaneous glomerular lesion of APA hamsters is modified qualitatively and quantitatively by SZ-induced diabetes.
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PMID:Modification of spontaneous renal lesion of APA hamsters by streptozotocin-induced diabetes. 930 24

Agaricus campestris (mushroom) has been documented as a traditional treatment for diabetes. Here the administration of mushroom in the diet (62.5 g/kg) and drinking water (2.5 g/l) countered the hyperglycaemia of streptozotocin-diabetic mice. An aqueous extract of mushroom (1 mg/ml) stimulated 2-deoxyglucose transport (2.0-fold), glucose oxidation (1.5-fold) and incorporation of glucose into glycogen (1.8-fold) in mouse abdominal muscle. In acute 20 min tests, 0.25-1 mg/ml aqueous extract of mushroom evoked a stepwise 3.5- to 4.6-fold stimulation of insulin secretion from the BRIN-BD11 pancreatic B-cell line. This effect was abolished by 0.5 mM diazoxide and prior exposure to extract did not affect subsequent stimulation of insulin secretion by 10 mM L-alanine, thereby negating a detrimental effect on cell viability. The effect of extract was potentiated by 16.7 mM glucose, L-alanine (10 mM) and IBMX (1 mM), and a depolarising concentration of KCl (25 mM) did not augment the insulin-releasing activity of mushroom. Activity of the extract was found to be heat stable, acetone soluble and unaltered by exposure to alkali, but decreased with exposure to acid. Dialysis to remove components with molecular mass < 2000 Da caused a 40% reduction in activity. Sequential extraction with solvents revealed insulin-releasing activity to be greatest in polar fractions. Lack of haemagglutinin activity with extract activity indicated that activity was unlikely to be due to a lectin-mediated event. These results demonstrate the presence of antihyperglycaemic, insulin-releasing and insulin-like activity in A. campestris.
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PMID:Insulin-releasing and insulin-like activity of Agaricus campestris (mushroom). 965 89

The usefulness of a galactose specific lectin from P. tithymaloides was examined to study the hemagglutination pattern in 193 patients with diabetes mellitus out of which 34 cases were of insulin dependent. A control of 72 normal subjects was also included. The hemagglutination titre against a partially purified lectin from P. tithymaloides of control group ranged from 9.1 to 170 units per mg protein with a mean value of 54 units per mg protein. Significantly low titre was observed in the cases with insulin dependent diabetes mellitus, while non-insulin dependent diabetes mellitus cases did not show any significant change. Further significant reduction in the titre in insulin dependent diabetes mellitus group was shown to occur along with the increased duration of the diabetic condition, reflecting measurable erythrocyte surface alterations.
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PMID:Hemagglutination pattern of galactose specific lectin from Pedilanthus tithymaloides in diabetes mellitus. 971 58

Neonatal porcine pancreases may be a potential source of islets for transplantation into patients with type 1 diabetes; however, whether these cellular grafts will be susceptible to damage by human natural antibody-mediated rejection remains controversial. Although we and others have demonstrated that porcine islets bind human IgG and IgM, it remains unknown if they express the xenoreactive antigen Gal alpha(1,3)Gal beta(1,4)GlcNAc-R (Gal epitope). In this study, by using the Gal-specific lectin IB4 for immunohistochemistry and fluorescence-activated cell sorter (FACS) analysis, we determined which cell types present in porcine neonatal islet cell (NIC) aggregates express the Gal epitope and which ones are susceptible to lysis by activation of the human complement. After FACS analysis, 30.0 +/- 3.0% of porcine NICs were shown to express Gal, whereas 70.0 +/- 2.0% did not. Histological assessment of Gal-expressing cells revealed that 54.9 +/- 8.8% stained positive for either insulin or glucagon. In contrast, 68.8 +/- 8.4% of the Gal-negative population stained positive for the pancreatic hormones insulin and glucagon. Incubation of either the Gal-positive or -negative cells with human AB serum plus complement for 1.5 h resulted in the lysis of >90% of the cells. These results demonstrate that porcine NIC aggregates are composed of Gal-expressing cells and that expression of Gal is not restricted to nonendocrine cells. Furthermore, both Gal-positive and Gal-negative cells are susceptible to human antibody/complement-mediated cytolysis, suggesting that this form of immunological destruction is an obstacle that will need to be overcome before porcine NIC aggregates can be used clinically.
Diabetes 1998 Sep
PMID:Expression of Gal alpha(1,3)gal on neonatal porcine islet beta-cells and susceptibility to human antibody/complement lysis. 972 28

Xenotransplantation of porcine tissue to human recipients promises to alleviate the organ shortage. Human antibody-mediated and cell-mediated immune responses against porcine grafts, however, represent barriers to successful xenotransplantation. We compared neonatal porcine islet cells (NPICs) and neonatal porcine splenocytes for the ability to stimulate proliferation of human peripheral blood lymphocytes (PBLs), and for their susceptibility to human natural killer (NK) and cytotoxic T-lymphocyte (CTL)-mediated lysis. Human peripheral blood CD4+ lymphocytes showed strong proliferation in response to NPICs, likely because of occasional swine leukocyte antigen (SLA) class II+ cells in the NPIC preparations. In contrast, human peripheral blood CD8+ lymphocytes did not proliferate in response to NPICs, although they showed clear responses to both porcine splenocytes and endothelial cells. Both human CTL-raised-against-porcine splenocytes and endogenous NK cells lysed porcine splenocytes, but the same cells showed little or no lytic activity against NPICs. Lysis of porcine splenocyte targets was completely abrogated by pretreatment of the human NK or CTL populations with concana-mycin A, suggesting a perforin-dependent effector mechanism. Pretreatment of the NPIC targets with proinflammatory porcine cytokines to upregulate SLA class I expression failed to enhance human CTL-mediated lysis. However, lysis of NPICs by human CTLs could be elicited when a lectin was added to form stable effector:target cell conjugates. It appears that NPICs do not express sufficiently high levels of co-stimulatory and/or adhesion molecules to either activate human CD8+ T-cells or to be effective targets for activated human CTLs. These data suggest that NPICs may not be destroyed by NK- or CTL-mediated lytic mechanisms after transplantation into humans.
Diabetes 1999 Sep
PMID:Neonatal porcine islet cells induce human CD4+, but not CD8+, lymphocyte proliferation and resist cell-mediated cytolytic injury in vitro. 1048 May 99

The effects of substituting a plant-based control diabetogenic diet (NIH diet) by a protective hydrolyzed casein diet (HC diet) upon selected metabolic and functional variables were recently investigated in Peyer's patch cells, splenocytes, mesenteric lymph node cells, and pancreatic islets from either control (BBc) or diabetes-prone (BBdp) BB rats. In the present work, the plasma d-glucose and insulin concentrations, the protein and insulin content of pancreatic islets, the metabolism of d-glucose, and its insulinotropic action in islets first cultured for 24 h in the absence or presence of IL-1beta, the production of IFN-gamma and IL-10 by mesenteric lymph node cells cultured for 48 h in the absence or presence of concanavalin A, the mitogenic activity of Peyer's patch cells and pancreatic lymph node cells in the absence or presence of the same lectin, and the biosynthetic activity of Peyer's patch cells were measured in the BBc and BBdp rats fed either the NIH or the HC diet. Two major novel findings emerged from this study. First, in immune cells, diet HC increased to a greater extent the responsiveness to concanavalin A of certain metabolic and functional variables in BBdp rats than in BBc rats. Second, pancreatic islet cells of BBdp rats were less sensitive to IL-1beta than those of BBc rats and this difference was further accentuated when the animals were fed the HC rather than the NIH diet. These findings afford further support to the view that, in BB rats, changes in the biological behavior of Peyer's patch cells, mesenteric and pancreatic lymph node cells, and pancreatic islet cells participate in the pathogenesis of insulin-dependent diabetes mellitus and its prevention by a suitable dietary manipulation.
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PMID:Effects of a protective hydrolyzed casein diet upon the metabolic and secretory responses of pancreatic islets to IL-1beta, cytokine production by mesenteric lymph node cells, mitogenic and biosynthetic activities in Peyer's patch cells, and mitogenic activity in pancreatic lymph node cells from control and diabetes-prone BB rats. 1056 66

A glucose-sensitive gel formulation containing concanavalin A and glycogen has been reported previously. Precipitation resulting from the addition of concanavalin A to glycogen has been documented, but the formation of glucose-sensitive gels based on lectin-glycogen interactions is novel and used here in our studies. An improved in-vitro self-regulating drug-delivery system, using covalently modified glucose-sensitive gels based on concanavalin A and a polysaccharide displacement mechanism, is described. The successful use of the covalently modified gels addresses a problem identified previously where significant leaching of the mitogenic lectin from the gel membranes of non-coupled gels was encountered. Concanavalin A was covalently coupled to glycogen by use of derivatives of Schiff's bases. The resulting gels, like the non-coupled gels, were shown to undergo a gel-sol transformation in response to glucose. Insulin delivery was demonstrated using this covalently modified system in conditions of repeated glucose triggering at 20 degrees C and 37 degrees C. The magnitude of the response was less variable than for the dextran-based gels studied previously. The performance of this system has been improved in terms of concanavalin A leaching. This could, therefore, be used as the basis of the design of a self-regulating drug-delivery device for therapeutic agents used to treat diabetes mellitus.
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PMID:Insulin delivery governed by covalently modified lectin-glycogen gels sensitive to glucose. 1057 79


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