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)

Decreased myo-inositol metabolism possibly contributes to the development of diabetic complications including micro and macrovascular disease. Previous studies have shown that hyperglycemia may be partially responsible for this defect. We have found that L-fucose, a monosaccharide present in low concentrations in normal circulation and found to be elevated in diabetes, causes defects in cultured endothelial cells, including alterations in myo-inositol metabolism and proliferation. Murine cerebral microvessel and bovine aortic endothelial cells take up L-fucose from the medium in a time and concentration-dependent manner. Both acute and chronic exposure of these cultured endothelial cells to media containing L-fucose at concentrations that may exist in diabetic sera cause a significant decrease in the accumulation of myo-inositol and its incorporation into inositol phospholipids. There is a concomitant decrease in the intracellular levels of myo-inositol. Kinetic analysis of the effect of L-fucose on myo-inositol uptake suggests that L-fucose competitively inhibits the transport of myo-inositol, exhibiting a Ki in the range of 1.6-4.1 mM for both cell types. Endothelial cells exposed to L-fucose concentrations of 0.5-20 mM exhibit depressed rates of proliferation in a concentration-dependent fashion. Furthermore, L-fucose causes a concentration-dependent decrease in synthesis of proteoglycan by cultured cerebral microvessel endothelial cells as measured by incorporation of 35S; however, this effect is not observed in the aortic endothelia. These data suggest that L-fucose at concentrations that may exist in diabetic sera may impair myo-inositol metabolism and proliferation of the vascular endothelium.
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PMID:Effect of L-fucose on proliferation and myo-inositol metabolism in cultured cerebral microvessel and aortic endothelial cells. 142 52

Costal cartilage from experimentally diabetic rats, labeled in vivo or in vitro with [35S]sulfate, was shown to incorporate less label into proteoglycans than cartilage from nondiabetic rats. Analyses of guanidine HCl cartilage extracts by gel chromatography on Sepharose CL-2B showed two major peaks at Kav approximately 0.4 and 0.8 (peaks I and II, respectively). Cartilage extracts from the diabetic rats contained predominantly peak II proteoglycans, while 60 and 55%, respectively, of the total 35S-labeled proteoglycans extracted from control cartilage labeled in vivo and in vitro with [35S]sulfate were present in peak I. After insulin treatment of the diabetic rats, the relative amount of peak I 35S-labeled proteoglycans synthesized in vivo was increased to 70%. The overall in vivo incorporation of [35S]sulfate into proteoglycans was also stimulated in diabetic rats treated with insulin to levels above those found for control rats. Thus, diabetes-induced changes in the biosynthesis of rat costal cartilage proteoglycans may be alleviated by normalization of the diabetic state by insulin treatment. However, addition of insulin (10(-5)-10(-9) M) to the culture medium did not affect the amount of 35S-labeled proteoglycans synthesized in vitro or the relative amounts of peak I proteoglycans produced by control or diabetic cartilage, suggesting that insulin does not have a direct effect on proteoglycan production. Moreover, no decrease in the amount of 35S-labeled proteoglycans produced was found when glucose at high concentrations was present in the culture medium. However, the presence of rat serum resulted in an increase in the amount of 35S-labeled proteoglycans produced by both control and diabetic cartilage, demonstrating that the cartilage explants were metabolically responsive to stimulatory factors.
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PMID:Effect of insulin on the altered production of proteoglycans in rib cartilage of experimentally diabetic rats. 189 27

Abnormalities in proteoglycan metabolism have been implicated in the pathogenesis of diabetic nephropathy. Whether hyperglycemia plays a direct role in these events is unknown. To evaluate the effects of high glucose concentrations and insulinlike growth factor I (IGF-I) on kidney proteoglycan and protein metabolism, we incubated quiescent, subconfluent human fetal mesangial cells for 24 h in serum-free media containing either physiological (5.6-mM) or elevated (25-mM) glucose concentrations with or without 1.3 x 10(-9) M IGF-I. In the presence of physiological glucose concentrations, IGF-I stimulated incorporation of [3H]leucine into protein and [35S]sulfate or [3H]glucosamine into proteoglycans. High glucose concentrations significantly amplified IGF-I-mediated stimulation of protein synthesis but totally abolished IGF-I-induced proteoglycan synthesis. The hydrodynamic size and proportions of heparan-35SO4 and chondroitin/dermatan-35SO4 proteoglycans in all experimental media were the same. However, high glucose concentrations decreased the iduronic acid content of dermatan-35SO4. In separate experiments, quiescent cells were cultured for 7 days in media supplemented with 2% fetal calf serum. IGF-I had no effect on mesangial cell proliferation, but as cells reached confluence, high glucose concentrations significantly inhibited cell proliferation. This inhibition was not mimicked by isosmolar concentrations of mannitol. After 7 days, uptake of radioactive precursors into proteoglycans and proteins over 24 h was similar under all culture conditions. However, IGF-I decreased the ratio of [35S]sulfate to [3H]glucosamine in proteoglycans and their glycosaminoglycan side chains. This difference persisted in disaccharides derived by chondroitin ABC lyase digestion of dermatan-35SO4.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1991 Oct
PMID:Effects of IGF-I and glucose on protein and proteoglycan synthesis by human fetal mesangial cells in culture. 193 96

Dietary protein restriction has been shown to slow the rate of loss of kidney function in humans with progressive glomerulosclerosis due to glomerulonephritis or diabetes mellitus. A central feature of glomerulosclerosis is the pathological accumulation of extracellular matrix within the diseased glomeruli. Transforming growth factor beta 1 (TGF-beta 1) is known to have widespread regulatory effects on extracellular matrix and has been implicated as a major cause of increased extracellular matrix synthesis and buildup of pathological matrix within glomeruli in experimental glomerulonephritis. In the present study, it is shown that administration of a low protein diet to rats rapidly reduces the elevated expression of TGF-beta 1 mRNA and TGF-beta 1 protein that is known to occur within glomeruli after induction of glomerulonephritis. Compared to a normal protein diet, glomerulonephritic rats receiving the low protein diet did not develop an increase in glomerular extracellular matrix and showed significantly less proteinuria. Glomeruli isolated from glomerulonephritic rats fed the normal protein diet showed a marked increase in proteoglycan synthesis on day 7 of disease and were demonstrated to be secreting increased amounts of TGF-beta 1 into the medium, whereas glomeruli at the same point in time isolated from rats on a low protein diet showed no increase in proteoglycan production or TGF-beta 1 secretion. These results suggest that a mechanism of the rapid therapeutic effect of a low protein diet on experimental glomerulonephritis is through suppression of TGF-beta 1 expression and prevention of the induction of extracellular matrix synthesis within the injured glomeruli.
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PMID:Dietary protein restriction rapidly reduces transforming growth factor beta 1 expression in experimental glomerulonephritis. 194 1

Collagen and proteoglycans are two major constituents of the extracellular matrix, and their abnormalities have been incriminated in the pathogenesis of diabetic complications. A decrease of plasma ascorbic acid has been reported in diabetes and thus may play a role in the collagen and proteoglycan abnormalities in diabetes. Ascorbic acid and glucose share structural similarity, and their metabolism may interact at the level of membrane transport and cellular action. In this study, we used a fibroblast culture system to explore this possibility. Ascorbic acid increased collagen and proteoglycan both in the culture medium and the cell layer. This stimulatory action of ascorbic acid was inhibited by the presence of glucose at a concentration of 25 mM. The effect of high glucose concentration was not mediated by inhibition of ascorbic acid uptake by fibroblasts. Insulin is able to abolish this inhibitory action of glucose on collagen production, but the precise mechanism is unclear. These results show that the high glucose concentration in diabetes can impair the action of ascorbic acid at the cellular level. This may further accentuate the problem of decreased availability of this vitamin as a result of its low plasma concentration.
Diabetes 1991 Mar
PMID:Interaction of ascorbic acid and glucose on production of collagen and proteoglycan by fibroblasts. 199 79

Diabetes in the mother may cause disturbances in the chondrocyte development in the embryo. A rat model was used to investigate whether this was reflected in the production of proteoglycans by cells from two embryonic regions. One of these regions is resistant (limb bud) and the other susceptible (mandibular arch) to malformation in diabetic pregnancy. Chondroitin sulphate proteoglycans from cultures of day-12 rat embryo limb bud and mandibular arch chondrocytes were extracted with guanidine-HCl and analyzed by gel chromatography after in vitro 35S-sulphate-labeling. Two sizes of proteoglycans (Kav 0.26 and 0.66 on CL-2B Sepharose) were found in both types of chondrocytes and in all media. The polysaccharide chain length was the same (Kav 0.36 on CL-6B Sepharose) for both proteoglycans. Elevated levels of D-glucose or beta-hydroxybutyric acid had no effect on either proteoglycan size or proportion, nor on polysaccharide chain length. However, there were differences (in all culture conditions) between limb bud and mandibular arch cultures in that the larger proteoglycan accounted for 80% of total radioactivity in the limb bud cultures, 53% in the mandibular arch cultures, and only 25-29% in the media from both types of cultures. Furthermore, different ratios between radioactive proteoglycans in medium and matrix suggested markedly different efficiencies for matrix formation in the two cell types. These findings indicate differences in the metabolism of the proteoglycans in these two cell types which may be related to the induction of mandibular malformation in diabetic pregnancy.
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PMID:Metabolism in vitro of cartilage proteoglycans in rat (pre)chondrocytes from different embryonic regions. 221 60

We examined steady-state levels of mRNA encoding type IV collagen, B1 chain of laminin, and the basement membrane heparan sulfate proteoglycan in the kidney cortex of a mouse model (KKAy) of non-insulin-dependent diabetes. mRNAs encoding laminin B1 and the proteoglycan were unchanged in kidneys taken from diabetic mice with demonstrable basement membrane thickening. mRNA levels for type IV collagen, in contrast, were significantly elevated (2-fold) in diabetic mice concurrent with but not preceding morphologically thickened basement membranes. There was a negative correlation between a ratio of proteoglycan/type IV collagen and levels of albuminuria in the diabetic mice. No correlation was noted with laminin. We also examined the effects of inhibiting the synthesis of thromboxane, a potent vasoconstrictor, on the steady-state levels of type IV collagen in the diabetic mice. Inhibition of thromboxane stopped the progression of albuminuria and prevented an increase in type IV collagen mRNA levels. We conclude that basement membrane thickening in diabetes, a hallmark of diabetic nephropathy, is partly a consequence of an unbalanced increase in the production of type IV collagen. The relative decrease in proteoglycan production may contribute to chronic albuminuria.
Diabetes 1990 Feb
PMID:Altered steady-state mRNA levels of basement membrane proteins in diabetic mouse kidneys and thromboxane synthase inhibition. 222 27

Insulin seems to regulate the biosynthesis of proteoglycans in some tissues such as growth plate and glomeruli. The present investigation was undertaken to assess the ex vivo influence of insulin on proteoglycan metabolism in bones. Mandible and femur bones were used. Xiphoid cartilage was used as a control tissue of high glycosaminoglycan content. Diabetes was induced by 0.12 mg/g b.w. streptozotocin in male Sprague-Dawley rats, a number of which was treated with insulin (1 I.U./100 g b.w.) for 6 days. As compared with control animals, diabetic rats exhibited a decreased [35S]sulfate uptake as well as a shift to the right in Sephacryl S-500 chromatography. In addition, they showed lower density of proteoglycans in sucrose gradient and shorter glycosaminoglycan side chains in Sephadex G-200 chromatography. These changes were partly reversed by insulin.
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PMID:Proteoglycans in bones of streptozotocin-induced diabetic rats. 224 27

Abnormalities in the incorporation of heparan sulfate proteoglycan into the glomerular basement membrane have been implicated in the pathogenesis of various proteinuric states, including diabetes mellitus. To understand further the interactions between proteoglycans and glomerular extracellular matrices, glomeruli were isolated from normal and streptozocin-induced diabetic rats after in vivo exposure to 35S-labeled sulfate and were treated with heparin in vitro. Heparin treatment released a unique heparan sulfate proteoglycan from glomerular cell surface or extracellular matrix proteoglycan receptors. Another, smaller heparan sulfate proteoglycan was the most abundant proteoglycan released into medium and was released constitutively in medium with or without added heparin. While the two heparin-extracted proteoglycans copurified on anion-exchange and gel-filtration chromatographic columns, they were resolved by composite 0.6% agarose--1.8% polyacrylamide gel electrophoresis. Glomeruli from diabetic rats contained decreased proportions of the heparin-releasable heparan sulfate proteoglycan and more constitutively released heparan sulfate proteoglycan. The apparent molecular weight and intrinsic charge of the heparin-released proteoglycan mixture and the apparent molecular weight and sulfation pattern of their 35S-labeled glycosaminoglycan chains after nitrous acid deaminative cleavage were similar in the two groups. A brief trypsin digestion of heparin-treated glomeruli released proportionately less integral membrane and extracellular matrix 35S-labeled proteoglycans and 35S-labeled glycopeptides from diabetic glomeruli than form control glomeruli. Elution of these 35S-labeled macromolecules from anion-exchange columns and migration in agarose-polyacrylamide gels were similar in the two groups. Abnormalities in proteoglycan-matrix interactions or proteoglycan processing may account for changes in the proportions of heparin- and trypsin-extracted proteoglycan compartments in diabetes.
Diabetes 1989 Jan
PMID:Release of glomerular heparan-35SO4 proteoglycan by heparin from glomeruli of streptozocin-induced diabetic rats. 252 Dec 10

A variant form of Ehlers-Danlos syndrome with single adrenocorticotrophic hormone (ACTH) deficiency and mild diabetes mellitus was studied by immunohistochemical and biochemical analyses of the connective tissue. The patient exhibited features characteristic of the Ehlers-Danlos syndrome, such as fragility, hyperextensibility, and bruisability of the skin and large veins were readily seen, but no hypermobility of any joint was detectable. Biochemical studies of the connective tissue confirmed that the apparent synthesis of collagens was within normal limits, but the deposition of the major proteoglycan in the skin of this patient was markedly reduced, mainly because the synthesis of core protein of dermatan sulphate proteoglycan was defective.
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PMID:Deficiency of the core proteins of dermatan sulphate proteoglycans in a variant form of Ehlers-Danlos syndrome. 256 51


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