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)

Islet transplants for large numbers of patients with diabetes will require xenografts. Microencapsulation is an appealing method for islet xenografting. However, graft function has been limited by a cellular reaction, particularly intense in spontaneously diabetic, NOD mice. The purpose of this study was to elucidate the mechanism of this reaction. Poly-1-lysine-alginate microcapsules containing 4000-12,000 dog or 1800-2000 rat islets were xenografted intraperitoneally into streptozotocin (SZN)-diabetic C57BL/6J and NOD mice, with or without recipient treatment with GK 1.5 (anti-CD4 monoclonal antibody) (20-30 microliters i.p. every 5 days, begun on day -7. Grafts were considered technically successful if random blood glucose (BG) was normalized (less than 150 mg/dl) within 36 hr. Graft failure was defined as BG greater than 250 mg/dl. Dog and rat islets in microcapsules normalized BG in both SZN and NOD mice within 24 hr routinely. Empty microcapsules and GK 1.5 treatments alone did not affect BG. NODs destroyed both microencapsulated dog and rat islets more rapidly than did SZN-diabetic mice (P less than .01). Graft biopsies showed an intense cellular reaction, composed of lymphocytes, macrophages and giant cells, and no viable islets. GK 1.5 treatment significantly prolonged both dog-to-NOD and rat-to-NOD grafts (P less than 0.01). Biopsies of long-term functioning grafts (on days 65-85) demonstrated viable islets and no cellular reaction around microcapsules; 1/4 rat and 1/8 dog islet xenografts continued to function indefinitely in NOD recipients, even after cessation of GK 1.5 therapy. Prediabetic NODs receiving encapsulated dog or rat islets mounted a moderate cellular reaction to grafts. Empty microcapsules excited no cellular reaction in diabetic or prediabetic NODs. We conclude that the NOD reaction to microencapsulated xenogeneic islets is helper T cell-dependent, and that the target of this reaction is not the microcapsule itself, but the donor cells within.
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PMID:The role of CD4+ helper T cells in the destruction of microencapsulated islet xenografts in nod mice. 196 98

Defects in insulin-receptor function have been associated with insulin-resistant states such as obesity and non-insulin-dependent diabetes mellitus (NIDDM). Several types of mutations in the insulin-receptor gene have been identified in patients with genetic syndromes of extreme insulin resistance. In some patients, insulin resistance results from a decrease in the number of insulin receptors on the cell surface. In one patient with leprechaunism (leprechaun/Minn-1), there is greater than 90% decrease in the levels of insulin-receptor mRNA. This patient is a compound heterozygote for two mutations in the insulin-receptor gene, both of which act in a cis-dominant fashion to decrease levels of mRNA transcribed from that allele. In one allele, there is a nonsense mutation at codon 897. All 22 exons of the other allele have a normal sequence, so that the mutation in this allele appears to map outside the coding sequence of the gene. Impaired insertion in the plasma membrane also causes insulin resistance. In two sisters (patients A-5 and A-8) with type A extreme insulin resistance, there is an 80-90% decrease in the number of insulin receptors expressed on the surface of their cells. Both sisters, whose parents are first cousins, are homozygous for a point mutation in which valine is substituted for phenylalanine at position 382 in the alpha-subunit of the insulin receptor. This mutation retards the posttranslational processing of the receptor and impairs the transport of receptors to the cell surface. Another patient with leprechaunism (leprechaun/Ark-1) is a compound heterozygote with two different mutant alleles of the insulin-receptor gene. In the allele derived from the father, there is a nonsense mutation at codon 672 that truncates the insulin receptor by deleting the COOH-terminal of the alpha-subunit and the entire beta-subunit. This truncated receptor, lacking a transmembrane domain, appears not to be expressed at the plasma membrane. In leprechaun/Ark-1, there is a missense mutation in the allele of the insulin-receptor gene derived from the mother. This point mutation results in substitution of glutamic acid for lysine at position 460 in the COOH-terminal half of the alpha-subunit. This mutation increases receptor affinity and impairs the ability of acid pH to dissociate insulin from the receptor within the endosome. There is a defect in recycling the receptor back to the plasma membrane associated with this defect. This results in an accelerated rate of receptor degradation and a consequent decrease in the number of receptors on the cell surface in vivo.(ABSTRACT TRUNCATED AT 400 WORDS)
Diabetes Care 1990 Mar
PMID:Mutations in insulin-receptor gene in insulin-resistant patients. 196 73

Many abnormalities in collagen have been reported in insulin-dependent diabetes mellitus, some or all of which have been attributed to increased cross-linking. Although recent work has focused on the role of glucose-derived collagen cross-links in the pathogenesis of diabetic complications, relatively few studies have investigated the role of lysyl oxidase-dependent (LOX) cross-links. In the present study, LOX cross-links and nonenzymatic glycosylation were quantified in skin collagen from diabetic subjects. There was an increase in the difunctional cross-link dihydroxylysinonorleucine (DHLNL) as well as in one of its trifunctional maturation products, hydroxypyridinium. All other LOX crosslinks were normal. Nonenzymatic glycosylation was increased in diabetic skin collagen, and this increase was correlated with increases in DHLNL (P less than 0.001). The biochemical results were examined for correlations with clinical data from the same subjects. Increases in DHLNL content were associated with duration of diabetes (P less than 0.003), glycohemoglobin levels (P less than 0.001), hand contractures (P less than 0.05), skin changes (P less than 0.005), and microalbuminuria (P less than 0.01). In nondiabetic subjects age was not correlated with collagen cross-link content with the exception that his-HLNL increased with age (r = 0.79, P less than 0.02). In diabetic subjects, PA levels decreased with age (r = 0.51, P less than 0.02). With increased duration of diabetes, DHLNL content was increased (r = 0.55, P less than 0.003) and OHP was increased (r = 0.59, P less than 0.01), whereas PA levels were decreased (r = -0.48, P less than 0.04). Nonenzymatic glycosylation of collagen was also increased with increased duration of diabetes (hex-lys, r = 0.47, P less than 0.02; hex-hyl, r = 0.39, P less than 0.05). We conclude that: (a) lysyl oxidase-dependent cross-linking is increased in skin collagen in diabetes and (b) that these changes in skin collagen are correlated with duration of diabetes, glycemic control, and long-term complications.
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PMID:Relationship between the content of lysyl oxidase-dependent cross-links in skin collagen, nonenzymatic glycosylation, and long-term complications in type I diabetes mellitus. 197 53

To elucidate the putative role of proteases in the action of interleukin 1 beta (IL-1 beta) on pancreatic beta-cells, we studied the effects on islet function of different protease inhibitors when added together with recombinant IL-1 beta to isolated rat pancreatic islets. It was found that the trypsin inhibitor N alpha-p-tosyl-L-lysine chloromethyl ketone (TLCK) counteracted the acute stimulatory effects of IL-1 beta on islet glucose oxidation, insulin release, and biosynthesis. TLCK also partially or completely counteracted the long-term inhibitory effects of IL-1 beta on islet glucose oxidation, insulin biosynthesis, content, and release. This protease inhibitor also counteracted IL-1 beta-induced beta-cell cytotoxicity as assessed by DNA content measurements. Of the other group-specific protease inhibitors investigated, only N-tosyl-L-phenylalanine chloromethyl ketone, N alpha-p-tosyl-L-arginine methyl ester, and chloromercuriphenylsulfonic acid were found to partially protect against IL-1 beta action. We concluded that protease activation, putatively a serine protease, may be an early and perhaps primary event in the action of IL-1 beta on beta-cells.
Diabetes 1991 Feb
PMID:Influence of protease on inhibitory and stimulatory effects of interleukin 1 beta on beta-cell function. 199 76

Accumulating amino acid sequence data have made it increasingly evident that many essential complement proteins have potentially modifiable lysine residues in putative critical functional regions. Evidence is now presented that glucose is covalently attached to lysine-266 of purified human complement Factor B as a result of glycation. Purified B was treated with NaB3H4, which reduces such bound glucose to a mixture of radiolabelled hexitols. Amino acid analysis revealed the expected radiolabelled hexitol-lysine epimers. In addition, fluorography of dried gels resolving the major high-molecular-mass h.p.l.c.-fractionated CNBr-cleavage peptides of NaB3H4-reduced B indicated that this radioactivity was specifically associated with the 15 kDa fragment derived from the N-terminal region of fragment Bb. Amino acid sequence analysis suggested that the C-terminal lysine (residue 266 of B) of the N-terminal Lys-Lys doublet of this peptide is preferentially modified. If such glycation can subsequently be shown to occur in vivo, then perhaps this modification might also be found to affect the functional activity of B and offer a potential explanation for some of the immunopathological complications of diseases exposing key plasma proteins, such as this active-site-containing proteinase of the multimeric alternative-complement-pathway C3/C5 convertases, to long-term high concentrations of glucose, such as the decreased resistance to infection and impaired chemotaxis and phagocytosis characteristic of diabetes.
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PMID:The principal site of glycation of human complement factor B. 200 11

N epsilon-(carboxymethyl)lysine, N epsilon-(carboxymethyl)hydroxylysine, and the fluorescent cross-link pentosidine are formed by sequential glycation and oxidation reactions between reducing sugars and proteins. These compounds, termed glycoxidation products, accumulate in tissue collagen with age and at an accelerated rate in diabetes. Although glycoxidation products are present in only trace concentrations, even in diabetic collagen, studies on glycation and oxidation of model proteins in vitro suggest that these products are biomarkers of more extensive underlying glycative and oxidative damage to the protein. Possible sources of oxidative stress and damage to proteins in diabetes include free radicals generated by autoxidation reactions of sugars and sugar adducts to protein and by autoxidation of unsaturated lipids in plasma and membrane proteins. The oxidative stress may be amplified by a continuing cycle of metabolic stress, tissue damage, and cell death, leading to increased free radical production and compromised free radical inhibitory and scavenger systems, which further exacerbate the oxidative stress. Structural characterization of the cross-links and other products accumulating in collagen in diabetes is needed to gain a better understanding of the relationship between oxidative stress and the development of complications in diabetes. Such studies may lead to therapeutic approaches for limiting the damage from glycation and oxidation reactions and for complementing existing therapy for treatment of the complications of diabetes.
Diabetes 1991 Apr
PMID:Role of oxidative stress in development of complications in diabetes. 201 41

Allogeneic islets obtained from Lewis rats were transplanted into diabetic BB/W rats with or without cyclosporine. In addition, these islets were encapsulated in alginate-poly L-lysine membranes and then transplanted into diabetic BB/W rats with or without immunosuppressive and/or antiinflammatory agents. The agents used were cyclosporine, dexamethasone, indomethacin (Ind), or a combination of these. Our results show that islets alone survived for 7 days, with or without CsA therapy. Encapsulated islets survived for 14.2 days, and this was extended by CsA, Dex, or CsA + Ind. Loss of encapsulated graft functions was associated with formation of a dense pericapsular infiltrate, which was inhibited by CsA, Dex, CsA + Ind, or CsA + Dex. In addition, the infiltrate was reduced in animals that had diabetes for long periods of time (greater than 5 months versus less than 1 month). Empty capsules also provoked this cellular response. Thus, encapsulation of islets resulted in slightly prolonged islet survival, which was further enhanced by immunosuppression.
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PMID:Transplantation of encapsulated allogeneic islets into diabetic BB/W rats. Effects of immunosuppression. 201 25

An enzyme-linked immunosorbent assay (ELISA) has been developed to detect antibodies against surface components of rat islet and spleen lymphocytes. Live islet tumor RIN5 AH cells expressing characteristic ganglioside target antigens or rat spleen cells were immobilized onto wells of microtiter polystyrene plates precoated with poly-l-lysine and then incubated with test or normal rat sera. Cell surface-bound antibodies were quantitated after reaction with horseradish peroxidase-conjugated rabbit anti-rat Ig. With this assay, 46% (6/13) of sera from diabetes-prone BB rats and 100% (8/8) of sera from rats treated with complete Freund's adjuvant/streptozotocin (CFA/STZ) prior to immunization with RIN cells had islet cell surface antibodies: 54% (7/13) and 75% (6/8), respectively, were positive for lymphocyte antibodies (defined as the HRP anti-rat Ig binding exceeding the mean + 2SD of control group values). SDS polyacrylamide gel electrophoresis followed by immunoblotting analysis suggested that the islet cell antibodies in sera from the BB and CFA/STZ rats recognized RIN-cell components that were different in their molecular weights. These antigens were not detectable on spleen cells indicating that the ELISA described can be used to quantitate levels of islet cell specific antibodies which possibly reflect beta cell damage with progression to islet degeneration in the rat.
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PMID:Detection of antibodies to islet cell and splenic lymphocytes in diabetes-prone BB and adjuvant-streptozotocin treated Lewis rats by ELISA and immunoblot analysis. 209

The anticancer activity of melphalan and N-(2-chloroethyl)-N-nitrosocarbamoyl-omega-lysine (CNC-omega-Lys), was compared in the autochthonous, methylnitrosourea-induced mammary carcinoma of the Sprague-Dawley rat. In addition, the influence on the therapeutic efficacy of the combination with diazoxide, causing a mild, reversible diabetes, and with insulin was investigated. The comparison of melphalan and CNC-omega-Lys clearly showed the superiority of melphalan. Both compounds displayed a significant tumour inhibition in their medium and the highest dosages in comparison to the untreated control. The combination with diazoxide resulted for almost all groups in an increased tumour inhibition. Only the lowest dose of CNC-omega-Lys + diazoxide did not reduce the tumour volume significantly versus the control group. The combination with insulin, however, resulted in a loss of tumour inhibition compared to the effect of the cytotoxic drug alone, although in these groups, too, a significant decrease of tumour volumes versus controls could be observed. Mortality was within tolerable limits (less than 20%) through the treatment period for all experimental groups. Median lifespans were increased in all therapy groups, but no additional benefit could be observed in the combination treatment groups.
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PMID:Antineoplastic efficacy of melphalan and N-(2-chloroethyl)-N-nitrosocarbamoyl-omega-lysine, in combination with diazoxide or insulin in autochthonous mammary carcinoma of the Sprague-Dawley rat. 210 82

The localization of glycated protein in the kidney of diabetic rats was examined immunohistochemically with antiserum against glucitol-lysine. In diabetic rats the brush border and basement membrane of the proximal convoluted tubules were strongly immunoreactive with the antiserum but in control rats, only the brush border was weakly reactive. The immunoreactive tubules were more abundant in diabetic rats. No immunoreaction was found in any other structures in the kidney. Glycation of the proximal convoluted tubules may be an alteration in diabetic nephropathy.
Diabetes Res Clin Pract 1990 Mar
PMID:Immunohistochemical localization of glycated protein in diabetic rat kidney. 211 Dec 38


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