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

A model system using RNase A has been established for studying the nonenzymatic glucosylation and glucose-dependent cross-linking of protein (Maillard reaction) under physiological conditions in vitro. The rate of glucosylation of RNase was first order in glucose. Glucosylation was accompanied by a comparable decrease in primary amino groups in the protein and lysine recoverable by amino acid analysis. Analysis of glucosylation reaction mixtures by sodium dodecyl sulfate-polyacrylamide gel electrophoresis in the presence of mercaptoethanol revealed the time-dependent formation of RNase dimer and trimer. The polymerization reaction was mixed order with respect to glucose concentration, but was approximately first order with respect to protein concentration. When glucosylated protein was separated from glucose, the protein continued to polymerize even in the absence of glucose. Under these conditions, the primary cross-linking reaction occurred by condensation of a glucosylated amino acid on one RNase molecule with a free amino group on another. Lysine efficiently inhibited cross-linking between glucosylated and native RNase in the absence of glucose. An attempt to model the cross-linking reaction was made by studying the incorporation of [3H]lysine and N alpha-formyl-[3H]lysine into glucosylated RNase. Both were incorporated covalently into glucosylated but not native protein. However, free lysine was the major product recovered following NaBH4 reduction and amino acid analysis of the lysine derivative of glycosylated protein. The data are discussed in terms of the mechanism of protein cross-linking by glucose and the relevance of this reaction to the pathophysiology of diabetes.
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PMID:Nonenzymatic glucosylation and glucose-dependent cross-linking of protein. 640 4

Modifications of plasma lipoprotein structure and function resulting from in vivo post-translational nonenzymatic glycosylation may play a role in the premature atherosclerosis of patients with diabetes mellitus. This report describes the generation and characterization of six unique murine monoclonal antibodies that bind glucosylated human plasma lipoproteins, but do not react with normal plasma lipoproteins. This was accomplished by immunizing mice with homologous glucosylated low density lipoprotein. In competitive inhibition radioimmunoassays, the dominant epitope recognized by these antibodies on glucosylated low density lipoprotein was identified as glucitollysine, the reduced hexose alcohol form of glucose conjugated to the epsilon amino group of lysine. Each of these antibodies was capable of identifying glucitollysine epitopes on all reduced glucosylated proteins studied, including high density lipoprotein, albumin, hemoglobin, and transferrin. These antibodies were also capable of identifying and quantitating glucitollysine residues on the total plasma proteins and isolated lipoproteins of normal and diabetic individuals after reduction of the proteins with NaBH4. Preliminary data suggest that diabetic total plasma proteins and isolated lipoproteins contain at least threefold more immunochemically detectable glucitollysine residues than nondiabetic plasma proteins and lipoproteins. The technique described in this report should allow production of region-specific antibodies to any immunogenic modification of a protein.
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PMID:A novel method for generating region-specific monoclonal antibodies to modified proteins. Application to the identification of human glucosylated low density lipoproteins. 641 10

In previous studies we have shown that extensive glucosylation of low-density lipoproteins (LDL) (40% of lysines modified) completely blocks receptor-mediated degradation in animals and in man. Other studies indicated that in some diabetics up to 5% of lysine residues of LDL were glucosylated. The present study was done to determine if the extent of glucosylation of LDL which can occur in diabetics could alter LDL catabolism. We measured degradation by cultured normal human fibroblasts and turnover in guinea pigs of various LDLs with 2-17% of lysine residues glucosylated. Modification of as few as 2-5% of lysines decreased LDL catabolism by 5-25%, and the degree of inhibition of catabolism was linearly related to the extent of LDL glucosylation. These results indicate that the extent of LDL glucosylation that can occur in diabetes may slow LDL catabolism and hence increase plasma LDL levels.
Diabetes 1984 Feb
PMID:Glucosylation of low-density lipoproteins to an extent comparable to that seen in diabetes slows their catabolism. 642 Feb 16

Age and diabetes-related changes in the extent of non-enzymatic glycosylation of two anatomically distinct human basement membranes were examined. The amount of glucose in ketoamine linkage to glomerular basement membrane, measured by the thiobarbituric acid reaction, correlated positively and significantly with age. For analysis of lens capsule basement membrane, adsorption to agarose-linked phenylboronate was used. The ability of this resin to completely discriminate non-glycosylated from glycosylated residues was first documented by separating synthetic preparations of radioactive glucitol-lysine and glucitol-hydroxylysine, the glucosylamines formed with non-enzymatic glycosylation of collagen, from the respective free amino acids by affinity chromatography on and batch adsorption to phenylboronate. The extent of non-enzymatic glycosylation of lens capsule basement membranes correlated with age in both non-diabetic and diabetic samples, and the slopes of the lines for age versus glycosylation were similar in both groups. The calculated line for diabetic specimens, however, was displaced about 15 years to the left, compatible with premature aging. The results indicate that non-enzymatic glycosylation can be accurately assessed in minute amounts of tissue by phenylboronate adsorption, and provide evidence that human basement membrane is subject to increased glycosylation with aging and diabetes.
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PMID:Age-related changes in non-enzymatic glycosylation of human basement membranes. 642 73

1-month-old Sprague-Dawley rats were fed synthetic diets containing 55% sucrose (SU) or starch (ST) as the sole source of carbohydrate for 2, 3 or 8 months. Both the ST and SU fed rats gained weight normally, but SU fed rats had enlarged kidneys. A higher yield of glomerular basement membrane (GBM) was recovered from 9-month-old SU rats. An increase in the hydroxylated amino acid content was found in GBM prepared from SU fed rats and the glycine content was also higher. The increase in the hydroxylation of lysine was accompanied by increased glycosylation and there was 30% more Glc-Gal-Hyl present in GBM from 9-month-old SU rats. GBM was solubilised with sodium dodecyl sulphate (SDS) and 2-mercaptoethanol and subjected to electrophoresis on 5% polyacrylamide gels. There was an apparent fall in the intensity of the bands with molecular weights greater than 200,000 and a concomitant rise in low molecular weight components (50,000-100,000) in GBM from 4-month-old SU rats. These differences between ST and SU membrane were accentuated when the membranes from 9-month-old rats were compared. No significant differences were found in the glucosyl transferase activities of renal cortical homogenates prepared from 3-month-old SU and ST rats, but the activities in SU rats were significantly higher at 4 and 9 months. The feeding of SU-rich diets to rats induces a number of biochemical changes in the kidney which are similar to those found in diabetes. The feeding of SU diets provides a useful animal model with which to study the effect of dietary carbohydrate on renal GBM. SU should not be included in diets fed to diabetic rats because of the similarity of some of its effects and those seen in chemically induced diabetes.
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PMID:Composition and biosynthesis of glomerular basement membrane in rats fed diets rich in sucrose. 645 28

For a better understanding of the processes leading to diabetic microangiopathy, type IV collagen from kidneys of patients with long-term diabetes was compared with the collagen from kidneys of sex- and age-matched controls. Type IV collagen from diabetic kidneys revealed no abnormalities in amino acid composition, hydroxylation of proline and lysine, enzymatic glycosylation of hydroxylysine, and immunological reactivity with several monoclonal and polyclonal, anti-type IV collagen antibodies. However, ketoamine-linked hexose, resulting from the nonenzymatic condensation of glucose with lysyl or hydroxylysyl residues, was 1.7-fold higher in diabetic type IV collagen. The stoichiometry of this modification was estimated to be 1-2 residues of hexose per triple helical molecule (Mr 380,000). This small amount of ketoamine-linked hexose might hardly have an effect on the function and turnover of type IV collagen, unless it is bound to a crucial site along the collagen molecule. The nonenzymatic glycosylation of collagen might therefore be a mere consequence of the metabolic disturbances, rather than the primary cause for the late complications of diabetes mellitus.
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PMID:Nonenzymatic glycosylation of basement membrane collagen in diabetes mellitus. 647 68

This study compares the utility of nonenzymatically glycosylated serum proteins (lys-GSP) to glycosylated hemoglobins (HbA1a-c) as control indices of glucose homeostasis in patients with IDDM. The diagnostic value of lys-GSP was also examined in patients with non-insulin-dependent diabetes mellitus, in subjects with impaired glucose tolerance, and in two patients with insulinoma. The intraindividual fluctuation of lys-GSP in normoglycemic subjects is very small, resulting in an interindividual range of 3.0 +/- 0.3 lysine-bound glucose/mg protein (means +/- SD, N = 52). HbA1a-c with a normal range of 6.4 +/- 0.9% (N = 52) shows greater variability. In IDDM there is no overlap of lys-GSP levels between the normal and the diabetic range at the 95% confidence level. In patients treated with an open-loop insulin delivery system failure of normalization of the glucose balance was clearly discernible by an elevation of GSP. In contrast, in about 40% of the patients with incomplete glycemic control the HbA1a-c levels fell within the normal range. The utility of lys-GSP for diagnosis of diabetes is compared with the results of 60 oral glucose tolerance tests. Two patients suffering from insulinoma displayed decreased lys-GSP values. From these results it appears that determination of lys-GSP represents a more sensitive parameter for long-term control than HbA1a-c and is suitable for monitoring even small fluctuations of blood glucose.
Diabetes Care
PMID:Clinical utility of nonenzymatically glycosylated blood proteins as an index of glucose control. 651 Jan 80

Post-translational modifications of hemoglobin can provide special insights into metabolic disorders. A variety of small molecules in health and disease can form covalent adducts with hemoglobin. The most abundant and best understood of these nonenzymatic modifications is the glycosylation of hemoglobin at the N-terminus of the beta chain (Hb AIc) as well as at the N-terminus of the alpha chain and at certain lysine residues. Glycosylated hemoglobins are elevated in diabetics and offer a useful way of monitoring diabetic control. Moreover, non-enzymatic glycosylation of other tissues may contribute significantly to the long term complications of diabetes. Additional minor hemoglobin components can be formed from other small reactive compounds. For example, cyanate, a breakdown product of urea, reacts with hemoglobin to form distinct minor components in red cells of uremic patients. Acetaldehyde can form hemoglobin adducts in red cells of alcoholics. Thus, hemoglobin can be viewed as a "reporter molecule", revealing metabolic perturbations in a variety of diseases.
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PMID:Post-translational modifications of hemoglobin. 653 26

Proteins exposed to glucose over long periods are known to undergo physicochemical changes including crosslinking and formation of brown fluorescent pigments of poorly characterized structure. Acid hydrolysis of both browned poly(L-lysine) and browned bovine serum albumin is found to release a major fluorescent chromophore, which after alkalinization is extractable into organic solvents and which can be purified by silica gel chromatography. The fluorescence properties of this compound very closely resemble those of the bulk browned polypeptides. By NMR, mass spectroscopy, and chemical derivatization, this compound is assigned the structure 2-(2-furoyl)-4(5)-(2-furanyl)-1H-imidazole (FFI). Confirmation was obtained by independent chemical synthesis from furylglyoxal and ammonia. The incorporation of two peptide-derived amine nitrogens and two glucose residues in FFI strongly suggests that peptide-bound FFI precursors are implicated in the crosslinking of proteins by glucose in vivo. This reaction has potential implications in the understanding of glucose-mediated protein modifications and their role in the complications of diabetes and aging.
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PMID:Aging of proteins: isolation and identification of a fluorescent chromophore from the reaction of polypeptides with glucose. 658 21

Nonenzymatic glucosylation interferes with recognition of low density lipoprotein (LDL) by its receptor and markedly decreases the rate of plasma clearance of glucosylated LDL, both in experimental animals and in normal human subjects. However, in selected diabetic subjects we have observed a paradoxical increase in the clearance of glucosylated LDL, suggesting the possibility of immune-mediated clearance. Immunoassay demonstrated antibodies specific for glucosylated LDL in the preinjection plasma of each of four such diabetic subjects studied. These antibodies cross-react with other glucosylated proteins and recognize specifically the glucosylated lysine epitope--i.e., glucitollysine . These data suggest that nonenzymatic glucosylation of plasma or structural proteins may render them immunogenic and result in production of autoantibodies that recognize not only the particular immunogen but also many other glucosylated proteins, including glucosylated tissue proteins. These findings may be relevant to the increased prevalence of immune complexes in plasma of diabetic subjects and the late complications of diabetes mellitus.
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PMID:Autoantibodies to glucosylated proteins in the plasma of patients with diabetes mellitus. 658 46


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