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

We investigated the relationship of serum protein glycosylation to peripheral tissue membrane glycosylation. We studied 27 Sprague-Dawley rats and induced diabetes in 20 of them. Blood glucose levels were treated in 10 of the diabetic animals with daily subcutaneous insulin. After 8 wk, liver and kidney tissue was removed, purified membranes were prepared, and the percentage of glycosylated membrane protein was determined for the liver and kidney membranes by boronate-affinity methods. The percentage of glycosylated membrane protein for both liver and kidney tissue was found to correlate significantly with the glycemic state of the animal as assessed with glycosylated serum albumin, total glycosylated serum proteins, and glycosylated hemoglobin determinations (P less than 0.001 for each glycosylated protein parameter). In addition, the percentage of glycosylated membrane protein in the liver tissue correlated significantly with the measured level in the corresponding kidney tissue (r = 0.78, P less than 0.001). To identify the nature of the glycosylated membrane proteins, boronate-affinity methods were used to separate the glycosylated and nonglycosylated membrane proteins. It was determined that two major glycosylated protein bands exist for the liver membrane (78,000 and 58,700 Mr) and four for the kidney membranes (ranging from 48,700 to 74,000 Mr). The ultrastructural location and identification of these glycosylated membrane proteins are not known. This study demonstrates that measurement of clinical glycemic state, as reflected in glycosylated blood protein parameters such as glycosylated serum albumin and glycosylated hemoglobin, correlates significantly with ongoing tissue membrane accumulation of glucose.
Diabetes 1991 Jul
PMID:Liver and kidney tissue membranes as tissue markers for nonenzymatic glycosylation. 206 Jul 26

Laminin, a basement membrane protein derived from the matrix of the Engelbreth-Holm-Swarm murine tumor, was nonenzymatically glycosylated in vitro in the presence of increasing glucose concentrations. The amount of glucose incorporated per laminin molecule was shown to be proportional to the molarity of glucose used. Nonenzymatic glycosylation resulted in formation of cross-links and alterations of the cruciform shape of laminin molecules; these alterations were dramatic when high concentrations of glucose were used. One of the functions of laminin, the process of self-assembly, was shown to be impaired after in vitro nonenzymatic glycosylation. Glucose incorporation resulted in a dramatic decrease of long-to-long laminin dimers, which normally form during the initial steps of assembly. Furthermore, nonenzymatic glycosylation of laminin reduced its ability to self-associate into complexes larger than dimers, as judged by turbidimetry. The observed decrease of maximal turbidity was proportional to the degree of nonenzymatic glycosylation. Aminoguanidine, which has been suggested to inhibit cross-link formation, was shown to restore to a large extent the shape of laminin, the percentage of long-to-long arm dimers, and the maximal turbidity when included in the mixtures of laminin and glucose. These data suggest that structural and functional alterations of laminin may be primarily due to formation of cross-links. Such modifications of laminin (along with our basement membrane components) may contribute to the morphological and physiological changes observed in basement membranes under diabetic conditions.
Diabetes 1990 Jul
PMID:Laminin alterations after in vitro nonenzymatic glycosylation. 211 13

Despite significant advances in past years on the chemistry and biology of insulin and its receptor, the molecular events that couple the insulin-receptor interaction to the regulation of cellular metabolism remain uncertain. Progress in this area has been complicated by the pleiotropic nature of the actions of insulin. These most likely involve a complex network of pathways resulting in the coordination of mechanistically distinct cellular effects. Because the well-recognized mechanisms of signal transduction (i.e., cyclic nucleotides, ion channels) appear not to be central to insulin action, investigators have searched for a novel second-messenger system. A low-molecular-weight substance has been identified that mimics certain actions of insulin on metabolic enzymes. This substance has an inositol glycan structure, and is produced by the insulin-sensitive hydrolysis of a glycosylphosphatidylinositol in the plasma membrane. This hydrolysis reaction, which is catalyzed by a specific phospholipase C, also results in the production of a structurally distinct diacylglycerol that may selectively regulate one or more of the protein kinases C. The glycosyl-phosphatidylinositol precursor for the inositol glycan enzyme modulator is structurally analogous to the recently described glycosyl-phosphatidylinositol membrane protein anchor. Preliminary studies suggest that a subset of proteins anchored in this fashion may be released from cells by a similar insulin-sensitive phospholipase-catalyzed reaction. Future efforts will focus on the precise role of the metabolism of glycosyl phosphatidylinositols in insulin action.
Diabetes Care 1990 Mar
PMID:Second messengers of insulin action. 213 71

Thrombomodulin (TM) is a membrane protein in the vascular endothelium, and it plays an important role as a cofactor in the thrombin-catalyzed activation of protein C. It has also been found in human plasma; however, its clinical significance is not known. In this study, fasting plasma TM concentrations in 67 diabetic patients with different degrees of albuminuria (39 men aged 57 +/- 8 yr, 28 women aged 57 +/- 11 yr; means +/- SD) and 34 age- and sex-matched healthy subjects were investigated by use of a one-step sandwich enzyme immunoassay, a new method developed by H.I. and others. As a screening, the patients were divided into three groups according to the first morning urinary concentrations of albumin: group 1, less than 30 micrograms/ml (normoalbuminuria); group 2, 30-140 micrograms/ml (microalbuminuria); group 3, greater than 140 micrograms/ml (clinical nephropathy). There was no significant difference in plasma TM level between the control group (17.7 +/- 3.7 ng/ml, n = 34) and group 1 (16.9 +/- 3.4 ng/ml, n = 30); however, plasma TM concentrations in group 2 (22.8 +/- 3.4 ng/ml, n = 22) and group 3 (29.6 +/- 6.1 ng/ml, n = 15) increased significantly compared with those in the control group and group 1, respectively. As a further investigation, three timed overnight urine collections were made. The patients were allocated to three groups according to their rates of albumin excretion: group I, less than 20 micrograms/min (normoalbuminuria); group II, 20-200 micrograms/min (microalbuminuria); group III greater than 200 micrograms/min (clinical nephropathy).(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1990 Aug
PMID:Elevation of plasma thrombomodulin level in diabetic patients with early diabetic nephropathy. 216 5

Macrophages internalize and degrade proteins modified by advanced glycosylation end products (AGEs) via a specific receptor (AGE-R). Chemical cross-linking studies with AGE-bovine serum albumin have demonstrated that the molecular weight of this receptor is approximately 90,000. We previously established that the binding constant (Ka) of this receptor site for the chemically synthesized model AGE, 2-(2-furoyl)-4(5)-(2-furanyl)-1H- imidazole-butyric acid (FFI-BA), on cells of the mouse macrophagelike cell line RAW 264.7 is identical to that for AGE proteins. Therefore, FFI was used as an affinity matrix in the first purification step of the AGE-R. The membranes of RAW 264.7 cells were solubilized in octyl-beta-glucoside and subjected to affinity chromatography on FFI-sepharose and gel permeation on Superose 6 fast protein liquid chromatography. Sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis analysis of this material revealed a high enrichment of a 90,000-Mr protein that had AGE binding activity. Approximately 25% of the protein at this step was the 90,000-Mr protein. The 90,000-Mr membrane protein was purified to homogeneity by rechromatographing the material on Superose 12 in the presence of SDS before and after reduction with 2-mercaptoethanol. After these harsh conditions, the 90,000-Mr protein lost AGE binding activity. Additional cross-linking studies on human peripheral monocytes revealed an AGE-R protein of identical size to that on RAW 264.7 cells, suggesting the relatively highly conserved nature of this molecule.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1990 Dec
PMID:Isolation of surface binding protein specific for advanced glycosylation end products from mouse macrophage-derived cell line RAW 264.7. 217 9

Thrombomodulin is an endothelial cell membrane protein acting as a cofactor for the activation of plasma protein C. Recently, it was found that soluble forms of thrombomodulin exist in plasma. Although the physiological significance of circulating thrombomodulin is presently obscure, it may reflect injury of the endothelial cell. In the present study, we examined plasma thrombomodulin concentrations in 106 Type 2 (non-insulin-dependent) diabetic patients. Plasma thrombomodulin was determined by a sandwich ELISA employing monoclonal anti-thrombomodulin antibodies. The patients with proteinuria had higher plasma thrombomodulin concentrations (61.0 +/- 36.0 ng/ml) compared to the patients without proteinuria (33.6 +/- 9.5 ng/ml, P less than 0.001) and control subjects (32.8 +/- 6.5 ng/ml, P less than 0.001). Plasma thrombomodulin concentrations were positively correlated with the level of serum creatine, blood urea nitrogen, urinary albumin and urinary beta 2-microglobulin (P less than 0.001 for each), but not with fasting plasma glucose, hemoglobin A1c or fructosamine. Elevated plasma thrombomodulin was also observed in the patients with pre-proliferative (63.4 +/- 28.9 ng/ml) or proliferative retinopathy (57.4 +/- 34.7 ng/ml), but not in the patients with non-proliferative retinopathy (33.5 +/- 12.9 ng/ml) or those without retinopathy (32.4 +/- 8.9 ng/ml). Even in the 81 diabetic subjects without proteinuria as determined by a dip and read method, and whose serum creatinine was lower than 1.0 mg/dl, the plasma thrombomodulin concentration was significantly higher in the patients with pre-proliferative (41.5 +/- 4.4 ng/ml) and proliferative retinopathy (41.0 +/- 12.8 ng/ml) compared to the patients without retinopathy (32.2 +/- 8.8 ng/ml) and those with non-proliferative retinopathy (31.9 +/- 7.8 ng/ml).(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes Res Clin Pract 1990 Oct
PMID:Plasma thrombomodulin concentration in diabetes mellitus. 217 97

Previous studies showed that islet cell autoantibodies are present at the onset of insulin-dependent diabetes mellitus (IDDM) in humans and in rodent models of this disease. The targets of these antibodies are not well characterized. Using an immunoblot assay on protein extracts from rat insulinoma (RIN) cells (RINm5F), we showed that serums from nonobese diabetic (NOD) mice bind to a 52,000-Mr islet cell antigen. Nondiabetic NON mice do not have antibodies to this antigen. The NOD and NON serums also contained antibodies to salivary gland proteins. Analysis of the tissue distribution of the 52,000-Mr antigen revealed that it is present in purified RINm5F membranes but is not found in other endocrine or nonendocrine tissues. Autoantibodies to an antigen of similar molecular weight are detected in 29% of human IDDM serums. To determine whether the autoantibodies from mouse and human serums bind the same antigen, two-dimensional immunoblots were carried out. The 52,000-Mr protein isoforms appeared identical when probed with NOD and human IDDM serums. We conclude that serums from NOD mice and some humans with IDDM contain similar autoantibodies to a 52,000-Mr RINm5F cell-specific membrane protein. The presence of autoantibodies to this 52,000-Mr islet cell protein at the onset of the disease suggests that it may be an important antigen in IDDM.
Diabetes 1990 Sep
PMID:Recognition of common islet antigen by autoantibodies from NOD mice and humans with IDDM. 220 Jul 29

Type 1 diabetes is associated with antibodies that immunoprecipitate a 64-kD islet cell membrane protein from detergent extracts of pancreatic islets. In this study we have determined whether mild trypsin treatment of islet membranes can release fragments of the antigen that bind antibodies in the serum of Type 1 diabetic patients. Partial tryptic proteolysis of [35S]methionine-labeled 64-kD antigen immunoprecipitated from detergent extracts of rat islets resulted in the formation of 50-, 40-, and 37-kD fragments. Similar sized fragments were recovered when sera from diabetic patients were employed to immunoprecipitate polypeptides solubilized by mild trypsin treatment of a particulate fraction of radiolabeled rat islets. Of 27 diabetic patients, 22 possessed antibodies to the 50-kD polypeptide and 21 to the 40- and 37-kD polypeptides. A positive association was found between 64k antibodies and antibodies to the 50-kD fragment but not between 64k antibodies and antibodies to the 40- or 37-kD fragments. Some 64k antibody negative patients possessed antibodies that efficiently immunoprecipitated the latter fragments. Serum from 25 of 27 (93%) diabetic patients immunoprecipitated at least one of the three tryptic polypeptides. One of 20 nondiabetic controls immunoprecipitated a 50-kD polypeptide and all controls were negative for antibodies to 40- and 37-kD fragments. Thus, Type 1 diabetes is associated with the presence of at least two antibody reactivities to distinct determinants of the 64-kD antigen, and some patients may possess antibodies to a cryptic epitope on the detergent-solubilized molecule. These data suggest that the detection of antibodies (present in 93% of patients) to epitopes on tryptic polypeptides of the 64-kD antigen may be of even greater diagnostic value for the onset of Type 1 diabetes than analyses of antibodies reactive with the intact 64-kD antigen.
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PMID:Distinct antibody specificities to a 64-kD islet cell antigen in type 1 diabetes as revealed by trypsin treatment. 220 48

This study describes and characterizes a putative sulfonylurea receptor. The radioligand used was [3H]glipizide (9 Ci/mmol). The beta-cell plasma membranes were derived from a transplantable rat insulinoma generated by subcutaneous injection of RINm5F cells and purified by ultracentrifugation on a 15-55% sucrose gradient. Specific binding of [3H]glipizide to purified beta-cell plasma membranes was determined to be maximal at temperatures of 4-23 degrees C, pH 7.3, and an incubation of 2 h. Scatchard analysis indicated a single binding site with Kd = 7 nM and sulfonylurea binding of 0.93 pmol/mg membrane protein. Displacement of [3H]glipizide from the purified beta-cell plasma membranes by various sulfonylureas and their analogues correlated well with their known hypoglycemic and insulin-releasing activities. Various agents, including nutrients, agents affecting Ca2+ flux, gastrointestinal hormones, and pancreatic hormones, had no effect on [3H]glipizide binding to the beta-cell plasma membranes. Putative sulfonylurea receptors on beta-cell and brain cell plasma membranes have been reported by several groups of investigators. Sulfonylurea binding to the beta-cell is hypothesized to close an ATP-sensitive K+ channel, which leads to depolarization of the membrane and activation of a voltage-dependent Ca2+ channel.
Diabetes Care 1990 Aug
PMID:Characterization and significance of sulfonylurea receptors. 220 40

The highest risk for the development of type I diabetes resides with first-degree relatives of the diabetic proband, this risk being in the order of 2.9%, 6.6% and 4.9% for parents, siblings and children of the proband, respectively. The major genetic markers associated with the development of insulin-dependent diabetes mellitus (IDDM) is the possession of the HLA alleles DR3/DR4 and more recently the absence of aspartate in the 57th position on the beta-chain of the HLA DQ gene (HLA DQ beta Asp 57 negative). The most important auto-immune marker for predicting preclinical IDDM is the presence of high titres (greater than 40 Juvenile Diabetes Foundation units) of islet cell antibodies (ICA), while the finding of insulin auto-antibodies (IAA) is a good predictive marker in children less than 5 years of age. The presence in a susceptible individual of ICA plus IAA is a better predictor of impending IDDM than the presence of either of these two markers alone. Antibodies which precipitate an islet membrane protein (MW 64K) are highly sensitive and specific markers of preclinical IDDM. The presence of 64K antibodies may well be the most important predictive marker of impending IDDM in the future. The progressive decline of the first phase of insulin secretion in response to an intravenous glucose challenge is associated with the onset of IDDM within 18 months. Of the immunotherapeutic agents at present used in clinically manifest IDDM, azathioprine has been shown to be ineffective in increasing the remission phase, while the value of nicotinamide is controversial.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Can we predict and/or prevent type I diabetes? 221 82


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