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)

Advanced glycosylation endproducts (AGEs), the glucose-derived adducts that form nonenzymatically and accumulate on tissue proteins, are implicated in many chronic complications associated with diabetes and aging. We have previously described a monocyte/macrophage surface receptor system thought to coordinate AGE protein removal and tissue remodeling, and purified a corresponding 90-kD AGE-binding protein from the murine RAW 264.7 cell line. To identify AGE-binding proteins in normal animals, the tissue distribution of 125I-AGE rat serum albumin taken up from the blood was determined in rats in vivo. These uptake studies demonstrated that the liver was a major site of AGE protein sequestration. Using a solid-phase assay system involving the immobilization of solubilized membrane proteins onto nitrocellulose to monitor binding activity, and several purification steps including affinity chromatography over an AGE bovine serum albumin matrix, two rat liver membrane proteins were isolated that specifically bound AGEs, one migrating at 60 kD (p60) and the other at 90 kD (p90) on SDS-PAGE. NH2-terminal sequence analysis revealed no significant homology between these two proteins nor to any molecules available in sequence databases. Flow cytometric analyses using avian antibodies to purified rat p60 and p90 demonstrated that both proteins are present on rat monocytes and macrophages. Competition studies revealed no crossreactivity between the two antisera; anti-p60 and anti-p90 antisera prevented AGE-protein binding to rat macrophages when added alone or in combination. These results indicate that rat liver contains at least two novel and distinct proteins that recognize AGE-modified macromolecules, although p90 may be related to the previously described 90-kD AGE receptor isolated from RAW 264.7 cells. The constitutive expression of AGE-binding proteins on rat monocytes and macrophages, and the sequestration of circulating AGE-modified proteins by the liver, provides further evidence in support of a role for these molecules in the normal removal of proteins marked as senescent by accumulated glucose-derived covalent addition products, or AGEs.
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PMID:Two novel rat liver membrane proteins that bind advanced glycosylation endproducts: relationship to macrophage receptor for glucose-modified proteins. 165 76

Advanced glycosylation endproducts (AGEs) are derived from the nonenzymatic addition of glucose to proteins. AGEs have been found to accumulate on tissue proteins in patients with diabetes, and their accumulation is thought to play a role in the development of diabetic complications. The finding that macrophages and endothelial cells contain AGE-specific receptors led us to examine whether mesangial cells (MCs) also possess a mechanism for recognizing and processing AGEs. Membrane extracts isolated from rat and human MCs were found to bind AGE-bovine serum albumin (BSA) in a saturable fashion, with a binding affinity of 2.0 +/- 0.4 x 10(6) M-1 (500 nM). The binding was specific for the AGE adduct, since AGE-modified collagen I and ribonuclease both competitively inhibited 125I-AGE-BSA binding to MC membranes, while the unmodified proteins did not compete. Binding of AGE proteins was followed by slow internalization and degradation of the ligand. Ligand blotting of MC membrane extracts demonstrated three distinct AGE-binding membrane proteins of 50, 40, and 30 kD. Growth of MCs on various AGE-modified matrix proteins resulted in alterations in MC function, as demonstrated by enhanced production of fibronectin and decreased proliferation. These results point to the potential role that the interaction of AGE-modified proteins with MCs may play in vivo in promoting diabetic kidney disease.
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PMID:Human and rat mesangial cell receptors for glucose-modified proteins: potential role in kidney tissue remodelling and diabetic nephropathy. 165 49

Previous assays for nonenzymatic advanced glycosylation end products (AGEs) formed in tissues and/or circulating in blood are unsatisfactory. Based on our earlier identification of AGE-specific receptors on the macrophagelike tumor cell line RAW 264.7, a new assay system for AGEs has been devised. RAW 264.7 cells were used in competitive radioreceptor assays (RRA) after a 3-day culture in 96-well plates with 1 mu CI/ml [3H]glycine. Bovine serum albumin (BSA), modified extensively by incubation with glucose-6-phosphate in vitro to form AGE-BSA, was labeled with 125I and was used as a model ligand at a concn of 10 micrograms/ml. One unit of AGE was defined as the amount of test protein required to inhibit 50% of the specific binding of [125I]-labeled AGE-BSA to the AGE-receptors of intact RAW 264.7 cells. Nonlabeled AGE-BSA was used as a specific competitor to construct standard curves. The reproducibility of the assay was assessed at AGE levels equivalent to mean, maximum, and minimum levels of sensitivity for assays run on a single day and over an extended period, and the RRA had a reproducibility (coefficient of variation) between 5.9 and 14.7%. Protease hydrolysis of in vitro glycosylated proteins before assay increases the competitive ability of these proteins in proportion to their glycosylation. Little or no AGE cross-reactivity was detected in native BSA, Amadori-BSA, maleylated BSA, formaldehyde-treated BSA, palmitic acid-BSA, and acetylated low-density lipoproteins (acetyl-LDL). Polyanions such as heparin or fucoidan strongly interfere with this receptor binding assay.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1991 Dec
PMID:Radioreceptor assay for advanced glycosylation end products. 166 95

An international symposium on diet as an environmental factor in development of insulin-dependent diabetes mellitus (IDDM) was held in Ottawa, Ont., Canada, September 1989. Several environmental factors such as viruses and chemicals, as well as diet modifications per se, were reviewed in both human and animal diabetes. Although the pathophysiology in the BB rat and nonobese diabetic (NOD) mouse may have different immunological mechanisms, both these animal syndromes of spontaneous IDDM are markedly affected by diet. In them, cereal-based rodent diets are the most diabetogenic and hydrolyzed casein-based purified diets are least diabetogenic. In two different NOD mouse colonies, diabetogenicity of cereal-based diets can be markedly decreased by extracting the diet with chloroform-methanol or water, reflecting either the different composition of the diets used in each colony or the chemical extraction and (or) alteration of certain diabetogenic agents. Thus, dietary lipids can be potent immune system modulators in several systems and the role of chloroform-methanol soluble agents in initiation and (or) promotion of the disease process is being studied. Attention was focused on protein sources previously identified by some groups as diabetogenic such as skim milk powder and wheat products, both of which can be found in natural ingredient rodent feeds. Circulating antibodies to dietary antigens such as bovine serum albumin and (crude) wheat gliadin may be elevated in diabetes-prone rodents and newly diagnosed patients, but their relationship to the pathogenesis of IDDM remains to be established. Because diet components can clearly influence the expression of the diabetic syndromes in the BB rat and NOD mouse, it will be crucial to identify the chemical nature of such components as a first step in understanding their mode of action.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Conference summary: diet as an environmental factor in development of insulin-dependent diabetes mellitus. 167 36

The etiology of insulin-dependent diabetes mellitus (IDDM) is multifactorial. The final cause of the disease, the specific destruction of the islet beta-cells, is the result of a cellular/humoral autoimmune process that operates in individuals with a particular genetic background in response to an external triggering factor(s). The most likely environmental triggers are virus infections and dietary factors. Among the latter group dietary proteins, mainly cow milk proteins, have been found to be important. Elimination of intact cow milk proteins from the diet significantly reduced the incidence of IDDM in the spontaneously diabetic BB rat, the elimination being most effective when it occurs during the pre-weaning period. Conversely, in newly discovered diabetics (both rats and children) increased levels of antibodies to cow milk proteins as compared with non-diabetic controls were found. These higher titres of antibodies were against beta-lactoglobulin and anti-bovine serum albumin. In further studies we found that antibodies to bovine serum albumin cross-react with a beta-cell membrane protein of Mr 69,000 and that this protein is likely induced by interferon. At the molecular level, a region of the bovine serum albumin has distinct homology to the beta-subunits of the MHC class II proteins Ia, DQ and DR, and antibodies raised against this bovine serum albumin region identified the same 69K beta cell membrane protein, in the same manner as antibodies to the third hypervariable region of DR-beta did. Our hypothesis is that bovine milk proteins (mainly bovine serum albumin) might be an important environmental factor providing specific peptides that share antigenic epitopes with host cell proteins.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Milk proteins in the etiology of insulin-dependent diabetes mellitus (IDDM). 171 25

This study used 10-nm gold particles with 5-7 insulin molecules attached (Au10-Ins) to investigate the site of interaction of insulin with the nuclear envelope during insulin uptake into intact isolated nuclei. Despite its size, and in the absence of ATP, Au10-Ins entered nuclei through the nuclear pore and associated with the heterochromatin. Because Au10-Ins is essentially gold-bovine serum albumin (Au-BSA) with a few insulin molecules attached, the effect of insulin and other growth factors on the nuclear accumulation of BSA coupled to 10-, 15-, and 24-nm-diam colloidal gold particles (Au10-BSA, Au15-BSA, and Au24-BSA) was determined. The Au-BSA complexes were excluded from nuclei in the absence of insulin. Insulin (0.5-100 ng/ml) caused a dose-dependent accumulation of Au10-BSA in the nucleus. The nuclear membrane was shown to be intact by several criteria, therefore, accumulation of Au-BSA occurred via the nuclear pore and was not due to leakage across or through the membrane. Uptake of 15- and 24-nm Au-BSA molecules was not affected by insulin, suggesting the hormone had a limited effect in increasing the functional diameter of the nuclear pores. Glucagon, epidermal growth factor, platelet-derived growth factor, insulinlike growth factor I, and insulin A or B chains did not stimulate the accumulation of Au10-BSA. The insulin-stimulated accumulation of Au10-BSA was blocked by concanavalin A, mimicked by wheat-germ agglutinin, and did not require ATP. The Au10-BSA in the nucleus was associated with heterochromatin, suggesting it bound to a nuclear element.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1992 Feb
PMID:Insulin stimulates accumulation and efflux of macromolecules in isolated nuclei from H35 hepatoma cells. 173 9

Serum albumin, transferrin, transthyretin (prealbumin), and retinol binding protein concentrations were determined in 74 children with insulin-dependent diabetes mellitus before and after a 10-day camp session during which blood glucose concentrations were controlled. Initial concentrations of albumin and transferrin in the subjects were not different from those in 21 children and adults without diabetes, and did not change during the study period. Transthyretin and retinol binding protein concentrations were lower in subjects with diabetes than in the control population, and increased from 182 +/- 49 mg/l and 42.5 +/- 13.4 mg/l to 232 +/- 71 mg/l and 47.2 +/- 13.5 mg/l, respectively. We observed correlations between the changes in transferrin, transthyretin, and retinol binding protein. Although reductions in glycated albumin and transferrin indicated improvement in blood glucose control, there was no correlation between changes in the glycated markers and the concentrations of serum transport proteins. Thus, serum protein concentrations were influenced by the metabolic control of diabetes, but did not directly reflect blood glucose.
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PMID:Effect of metabolic control on serum protein concentrations in diabetes. 175

Patients with cirrhosis of liver are more prone to have accompanying diabetes mellitus. The present study was conducted to investigate various biochemical parameters in patients with hepatic cirrhosis without diabetes. In these patients blood pyruvate, total bilirubin and globulin levels were elevated as compared to normal individuals. In contrast serum albumin level declined significantly whereas no significant change was observed in the concentrations of blood glucose, total proteins, total lipids, urea and serum cholesterol. These studies confirm the previous reports that carbohydrate metabolism is deranged in hepatic cirrhosis which may lead to diabetes mellitus.
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PMID:Carbohydrate metabolism in liver cirrhosis. 177 May 58

Using the data of 131 patients with non-insulin dependent diabetes mellitus (NIDDM), the correction formulas of fructosamine value ([FRA]) were devised to standardize the uncorrected [FRA] to serum albumin concentrations ([ALB]) of 4 g/dl, globulin concentrations ([GLB]) of 3 g/dl, and total protein concentrations ([TP]) of 7 g/dl. The following formula was derived for its maximum correlation coefficient (r) between corrected [FRA] ([FRAc]) and fasting blood glucose concentration ([G]); [FRAc] = [FRA]x33.3/(7.6 [ALB]+[GLB]). In these 131 diabetic patients, r between uncorrected [FRA] and [G] at 2 weeks ago was 0.562. When corrected by [FRA]x33.3/(7.6 [ALB]+[GLB]), [FRA]x4/[ALB], [FRA]+30 (4-[ALB]), [FRA]+23 (4-[ALB]), [FRA]+30 (7-[TP]), [FRA]x7/[TP], and [FRA]x3/[GLB], r was, respectively, 0.616, 0.612, 0.595, 0.589, 0.582, 0.581 and 0.478. In 24 patients with NIDDM whose [ALB] is either above 4.5 g/dl or below 3.5 g/dl, r between uncorrected [FRA] and [G] was as low as 0.389 without positive correlation. By using our correction formulas of [FRA]x33.3/(7.6 [ALB]+[GLB]) or [FRA] x 4/[ALB], r was statistically increased, respectively, to 0.769 or 0.788 (P less than 0.05 in both cases) in contrast to no significant increase of r by other formulas being at 0.598, 0.556, 0.540, 0.562 and 0.121. Based on these analyses, it is concluded that our correction formula of [FRA] by [FRAc]=[FRA]x33.3/(7.6 [ALB]+[GLB]) accurately reflects [G] in NIDDM even with hypo- or hyper-albuminemia, and [FRAc]=[FRA]x4/[ALB] is useful for practical application for its simplicity.
Diabetes Res Clin Pract 1991 Aug
PMID:Correction of fructosamine value for serum albumin and globulin concentrations. 177 12

Since the recently reported relationship between serum fructosamine and IgA concentrations appears to throw doubt on the clinical utility of fructosamine as a measure of hyperglycemic status if IgA concentration is not taken into account, we studied serum immunoglobulin concentrations in 169 diabetics and their relationship with various clinical and analytical parameters. Over 41% of the patients studied had abnormal serum IgA concentrations. Serum IgA concentration was negatively correlated with serum albumin, and among IDDM patients was positively correlated with age (so that the prevalence of abnormal IgA was 57.7% among IDDM patients aged over 30 years). Among NIDDM patients, abnormal IgA concentrations were especially prevalent among those being treated with oral hypoglycemics. Abnormal IgA was also more frequently found in both IDDM and NIDDM patients, who had been under treatment for 10 years or more. Abnormal IgG concentrations were found in 11.8% of the diabetics, and the mean IgM concentration found in the patients was 41.6% lower than in the normoglycemic group. We conclude that abnormal serum IgA concentrations are very common in diabetic patients and that further research should be carried out to verify whether the determination of serum immunoglobulins, IgA in particular, is of clinical use for monitoring diabetes or evaluating its secondary effects.
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PMID:Abnormal serum immunoglobulin concentrations in patients with diabetes mellitus. 177 77


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