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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

As oral administration of insulin reduces the incidence of diabetes in NOD mice, and to achieve a better approximation of oral insulin trials being developed for human studies which will use human insulin, we attempted to determine the preventive efficacy of oral administration of human insulin rather than resorting to the animal insulins used in previous studies. As the strength of prevention obtained by oral insulin has not been adequately demonstrated, we determined whether the protection persisted after the oral treatment was discontinued and whether it was resistant to a diabetogenic injection of cyclophosphamide (CY). We also determined whether the effect of insulin could be increased by oral administration of lipopolysaccharide from Escherichia coli (LPS) or another immunostimulant (glycoprotein extracts from Klebsiella pneumoniae, GEKP) which may be more feasible for human application. Female NOD mice were fed once a week (from 35 to 300 days of age) with insulin, LPS, GEKP, insulin plus LPS, insulin plus GEKP, or PBS. A decreased incidence of diabetes were observed in animals fed human insulin (p < 0.01 incidence of diabetes at 300 days of age: 31% in mice fed with insulin and 65% in those fed PBS). Prevention by insulin was not enhanced by oral LPS or GEKP. Yet unexpectedly, mice fed with LPS alone or GEKP alone displayed decreases in diabetes incidence (p < 0.01). The severity of insulitis was reduced in animals fed insulin, LPS, GEKP or combinations of insulin and either immunostimulant (p < 0.02). Although the oral treatments were stopped at 300 days of age, the incidence of diabetes at 360 days remained lower in mice previously fed insulin, LPS, GEKP or combinations of insulin and either immunostimulant (p < 0.01). In mice previously fed PBS, CY injection (60 days after withdrawal of the oral treatment) led to a final incidence of diabetes of 90% (sum of the incidence during the initial 360 days and the further CY-induced incidence). Previous feedings with insulin, LPS, GEKP or combinations of insulin and either immunostimulant did not protect against CY-induced diabetes since incidences reached the final control incidence. T splenocytes from animals fed insulin, LPS, or GEKP, similarly reduced the capacity of T cells from diabetic mice to transfer the disease (p < 0.01). It is concluded that oral treatment with human insulin to be used in human trials reduces the incidence of diabetes in NOD mice. Equivalent preventive efficacy was obtained through feedings with LPS or GEKP (even though no cumulative efficiency was observed with insulin). The latter results suggest that it would be advisable to evaluate the efficiency of oral bacterial antigens for the prevention of human Type 1 diabetes. The protection afforded by oral treatments with insulin or bacterial antigens may be attributed to cellular suppression, persists for some time after treatments are stopped, but is not resistant to major immune stimulation such as injection of CY.
Diabetes Metab 1996 Oct
PMID:Prevention of diabetes in the nonobese diabetic mouse by oral immunological treatments. Comparative efficiency of human insulin and two bacterial antigens, lipopolysacharide from Escherichia coli and glycoprotein extract from Klebsiella pneumoniae. 889 96

The role of endogenous interferon-gamma (IFN gamma) in the development of insulin-dependent diabetes mellitus (IDDM) in diabetes-prone BB rats was evaluated. Several groups of these animals were treated under different, experimental conditions with a purified polyclonal antibody (Ab), antirat IFN gamma. The results show that when administered at doses of 100 or 200 micrograms/week from the 30/33th until the 105th day of age, the anti-IFN gamma Ab reversibly reduced the incidence of IDDM compared to that in control rats treated with either irrelevant rabbit IgG or PBS. Moreover, when given up to the 105th day of age, these doses of anti-IFN gamma Abs exerted comparable preventive effects regardless of whether application started as early as within 24 h after birth or at the end of the prediabetic period (e.g. 70/75 days). In contrast, under none of the above experimental conditions did larger doses of anti-IFN gamma Ab (500 micrograms or 1 mg/week) exert antidiabetogenic effects in the BB rats. Apparently, this was due to the exuberant production of neutralizing Abs elicited by the large amount of the xenogeneic Ab injected. At histoimmunological analyses, the BB rats treated with 200 micrograms/ week anti-IFN gamma Abs from 30-80 days of age exhibited a milder insulitic process along with diminished spleen frequency of activated lymphoid cells (MHC class II and interleukin-2 receptor positive). Taken together, these results provide further in vivo evidence for the central pathogenic role of IFN gamma in BB rat IDDM and anticipate the usefulness of specific IFN gamma inhibitors in the prevention of the disease in the clinical setting. Defining novel and less immunogenic forms of specific IFN gamma inhibitors than xenogeneic Abs is important for improving the efficiency of anti-IFN gamma-oriented approaches.
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PMID:Prevention of spontaneous autoimmune diabetes in diabetes-prone BB rats by prophylactic treatment with antirat interferon-gamma antibody. 897 15

The effect of an IL-1 receptor antagonist on recurrence of hyperglycaemia after syngeneic pancreatic islet transplantation to spontaneously diabetic female NOD mice was investigated. The transplanted animals were treated with either the receptor antagonist (8.0 mg/kg body weight per day for 12-14 days) or PBS, delivered by subcutaneously implanted osmotic pumps. In the control animals, a transient normoglycaemia was achieved, but hyperglycaemia was generally observed 6 days after islet transplantation. Administration of IL-1 receptor antagonist had a clear protective effect against recurrence of hyperglycaemia until day 14, but after cessation of drug delivery hyperglycaemia re-appeared. The results indicate that continuous administration of the IL-1 receptor antagonist can prevent recurrence of the diabetogenic process in NOD mice. IL-1 receptor antagonist may therefore become a useful adjuvant immunomodulating therapy after human islet transplantation in insulin-dependent diabetes mellitus.
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PMID:IL-1 receptor antagonist inhibits recurrence of disease after syngeneic pancreatic islet transplantation to spontaneously diabetic non-obese diabetic (NOD) mice. 915 4

Heat shock protein 65 (hsp65) and a derived peptide, p277, are autoantigens reported in IDDM. I.p. injection of hsp65 reduced diabetes incidence in NOD mice and administration of p277 cured already diabetic mice. Also, intrathymic (i.t.) administration of whole islets or GAD65 prevented diabetes in NOD mice. The aim of this study was to evaluate whether i.t. injection of mycobacterial hsp65 or p277 can prevent diabetes in NOD mice. Three-week-old NOD female mice were injected intrathymically with 50 microg of hsp65 (n=30), 5 microg of p277 (n=30), and PBS (n=29). Diabetes incidence was observed for the following 300 days. Pancreas was then used for histological and immunohistological evaluation. No significant differences in diabetes incidence were observed among the three groups of mice. Interestingly, hsp65-treated mice developed diabetes slightly faster at 177+/-6 days compared to 202+/-8 days (p=0.015) for the p277-treated group and 197+/-7 days (p=0.033) for controls. The insulitis score and average islet size did not differ significantly among the three groups of diabetic mice. Scattered TCR-gamma/delta positive cells were found in the pancreas of all groups of mice. In contrast, a huge infiltrate of TCR-gamma/delta positive cells was detected in four out of eight (50%) p277-diabetic NOD mice. Thus, our data show an earlier onset of diabetes in hsp65-treated mice and no improvement in the incidence with either hsp65 or p277, suggesting that hsp65 acts in a different way from what was reported with GAD65. Caution is advised in future vaccination studies as hsp65 poses a potential danger.
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PMID:Effect of intrathymic administration of mycobacterial heat shock protein 65 and peptide p277 on the development of diabetes in NOD mice: caution required in vaccination studies. 983 5

To develop a model somatic gene therapy system for diabetes, we constructed a human insulin expression vector in non B cells. As the first step, an insulin cDNA fragment of 260 bp, generated by a complet digestion of PBCA with EcoR I and BamH I, was inserted into the EcoR I/BamH I site of plasmid PBS.SK by ligation of cohevise-ended DNA to construct transition plasmid PBS.INS. Then the plasmid PBS.INS was completly digested by Hind III and Xbal I. The small DNA fragment containing insulin cDNA gene was subcloned to the expression plasmid PRC/CMV to form recombinant PRC/CMV.INS.
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PMID:[Experimental studies on somatic gene therapy for diabetes. I. Structuring of recombinant from human insulin gene and ammalian expression vector PRC/CMV]. 1045 11

The endothelium-specific antigen PAL-E, associated with transport vesicles in non-barrier endothelium, is almost absent from barrier capillaries in the normal brain and retina. We have recently demonstrated that only leaking retinal capillaries in diabetic retinopathy (DR) in humans characteristically express PAL-E. Here we investigated the relation between the expression of the PAL-E antigen and vascular endothelial growth factor-A (VEGF) in human post-mortem eyes of individuals with diabetes mellitus (DM) and in experimental VEGF-induced retinopathy in cynomolgus monkeys. Cryosections were cut of eyes of 41 individuals with and 30 individuals without DM and eyes of 2 cynomolgus monkeys who received 4 injections of 0.5 microg VEGF in the vitreous of one eye and PBS in the other. The sections were stained with antibodies against VEGF, PAL-E and endogenous markers for microvascular leakage. Specific retinal vascular staining for VEGF was only observed in 10 out of the 41 cases with DM. These 10 cases also had marked uniform PAL-E staining and widespread vascular leakage. In contrast, diabetic patients without microvascular leakage and controls were negative for VEGF and PAL-E. Likewise, PAL-E was found only in the leaky retinal vessels of monkey eyes injected with VEGF. These results indicate that increased expression of the PAL-E antigen in retinal endothelium in conditions with microvascular leakage is related to VEGF and suggest that VEGF directly or indirectly induces PAL-E. PAL-E expression may reflect important endothelial changes involved in the disturbance of the blood-retina barrier in DR.
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PMID:Role of VEGF-A in endothelial phenotypic shift in human diabetic retinopathy and VEGF-A-induced retinopathy in monkeys. 1134 Apr 7

Cytokines produced by immune system cells infiltrating pancreatic islets are candidate mediators of islet beta-cell destruction in autoimmune insulin-dependent diabetes mellitus. After 72 h exposure of human pancreatic islets to a cytotoxic cytokine combination of interleukin 1 beta (50 U/ml), tumor necrosis factor alpha (1,000 U/ml), and interferon gamma (1,000 U/ml), an increase of cell death vs. control islets was demonstrated by TUNEL and cell death detection ELISA method. Islet death was associated with apoptosis and mitochondrial swelling as evidenced by electron microscopy. This effect was correlated with a marked decrease of Bcl-2 mRNA expression (without any major change of Bax mRNA) and a marked increase of inducible nitric oxide synthase mRNA. Since peripheral benzodiazepine receptors constitute the aspecific mitochondrial permeability transition pore, and that it has been suggested to be involved in cytokine-induced cell death, we evaluated the effects of the cytotoxic cytokines on PBR density and mRNA expression. We demonstrated that cytokine treatment of human islets induced an increase of maximum density of (3)H1-(2-chlorophenyl-N-methyl-1-methylpropyl)-3- isoquinolinecarboxamide binding sites, (5,110+/-193 vs. 3,421+/-336 fmol/mg proteins, P<0.05) with no significant change in the affinity constant value (9.45+/-0.869 vs. 8.7+/-1.159 nM). Moreover, an increase of the expression of peripheral benzodiazepine receptor mRNA was observed, suggesting an increased transcription from the coding gene. These results suggest a possible role of peripheral benzodiazepine receptors in the organism response to tissue damage associated with inflammatory mediator production.
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PMID:Upregulation of mitochondrial peripheral benzodiazepine receptor expression by cytokine-induced damage of human pancreatic islets. 1181 68

IL-18 is a cytokine structurally and functionally related to IL-1 that, in synergy with IL-12, stimulates the synthesis of IFN-gamma from T lymphocytes and natural killer cells. Because IFN-gamma plays a key pathogenic role in the development of murine immunoinflammatory diabetes induced by multiple low doses of streptozotocin (STZ) we investigated the effect of negating the actions of endogenous IL-18 in this model by administering recombinant IL-18-binding protein:Fc (IL-18 bp:Fc). C57BL/6 mice were injected once daily with 40 mg/kg STZ for 5 consecutive days, day 0 being the first day of STZ challenge. Relative to control animals treated in parallel with either PBS or human IgG, mice treated from day -3 to day 7 with daily doses of 150 microg of IL-18 bp:Fc exhibited lower incidence of diabetes and milder insulitis. In contrast, mice that were treated with IL-18 bp:Fc from day 7 to day 14 exhibited clinical and histological signs of STZ-induced diabetes similar to those of control mice treated with IgG. The protective effect of IL-18 bp:Fc was accompanied by modified ex vivo immune responses, in that spleen cells and peritoneal macrophages contained fewer IFN-gamma secreting cells and released lower amounts of nitrite (an index of nitric oxide production) and IL-1beta. We conclude that intact IL-18 function is essential for the full diabetogenic effect of low dose STZ in C57BL/6 mice.
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PMID:Essential pathogenic role of endogenous IL-18 in murine diabetes induced by multiple low doses of streptozotocin. Prevention of hyperglycemia and insulitis by a recombinant IL-18-binding protein: Fc construct. 1288 3

To examine the peripheral and central roles of adiponectin in energy intake and expenditure, we investigated the effects of adiponectin on food intake, adiposity, sympathetic nerve activity (SNA), and mRNA expressions of uncoupling protein (UCP) in the brown adipose tissue (BAT), white adipose tissue (WAT) and skeletal muscle in agouti yellow (A(y)/a) obese mice. Intraperitoneal administration of adiponectin (1.5 mg/kg for 7 days) attenuated body weight gain and reduced visceral adiposity in A(y)/a obese mice compared with PBS-treated controls. In addition, adiponectin treatment increased the expression of UCP1 mRNA in BAT, UCP2 mRNA in WAT, and UCP3 mRNA in skeletal muscle compared with PBS-treated A(y)/a controls. Acute peripheral administration of adiponectin (1.5 mg/kg, one injection) also increased SNA in the BAT accompanied by an increase in rectal temperature. Finally, these above responses as well as expression of c-Fos-like immunohistochemistry in the hypothalamus were not induced by central application of adiponectin (0-15 micro g/kg). Taken together, adiponectin effectively regulated visceral adiposity, SNA, and UCP mRNA expression peripherally, suggesting that this substance can be used as a therapeutic tool, administered peripherally, in the treatment of visceral obesity and related metabolic disorders.
Diabetes 2003 Sep
PMID:Peripheral, but not central, administration of adiponectin reduces visceral adiposity and upregulates the expression of uncoupling protein in agouti yellow (Ay/a) obese mice. 1294 65

Mechanisms that hinder ischemia-induced neovascularization in diabetes remain poorly understood. We hypothesized that endogenous bone marrow mononuclear cell (BM-MNC) dysfunction may contribute to the abrogated postischemic revascularization reaction associated with diabetes. We first analyzed the effect of diabetes (streptozotocin, 40 mg/kg) on BM-MNC pro-angiogenic potential in a model of surgically induced hindlimb ischemia. In nondiabetic animals, transplantation of BM-MNCs isolated from nondiabetic animals raised the ischemic/nonischemic angiographic score, capillary number, and blood flow recovery by 1.8-, 2.7-, and 2.2-fold, respectively, over that of PBS-injected nondiabetic animals (P < 0.05). Administration of diabetic BM-MNCs also improved the neovascularization reaction in ischemic hindlimbs of nondiabetic mice but to a lesser extent from that observed with nondiabetic BM-MNC transplantation. In diabetic mice, injection of nondiabetic BM-MNCs was still more efficient than that of diabetic BM-MNCs. Such BM-MNC dysfunction was associated with the impairment of diabetic BM-MNC capacity to differentiate into endothelial progenitor cells (EPCs) in vitro and to participate in vascular-like structure formation in a subcutaneous Matrigel plug. Placenta growth factor (PlGF) administration improved by sixfold the number of EPCs differentiated from diabetic BM-MNCs in vitro and enhanced ischemic/nonischemic angiographic score, capillary number and blood flow recovery by 1.9-, 1.5- and 1.6-fold, respectively, over that of untreated diabetic animals (P < 0.01). Endogenous BM-MNC pro-angiogenic potential was affected in diabetes. Therapeutic strategy based on PlGF administration restored such defects and improved postischemic neovascularization in diabetic mice.
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PMID:Impairment in ischemia-induced neovascularization in diabetes: bone marrow mononuclear cell dysfunction and therapeutic potential of placenta growth factor treatment. 1474 52


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