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

Using a tissue culture system based on a nearly pure population of avian precartilage mesenchymal cells, we have found that ambient glucose levels as little as 50% lower, or 100% higher, than normally present in embryonic sera are deleterious to cartilage development, as measured by the accumulation of highly sulfated proteoglycan and the corresponding cartilage-specific chondroitin sulfate core protein mRNA. Abnormal glucose concentrations in the ranges studied did not selectively influence cell replication, and the effects on chondrogenesis were not due to differences in overall protein synthesis or glucose utilization in the treatment groups. Core protein gene expression was more severely affected than accumulation of extracellular product, suggesting the existence of posttranscriptional compensatory mechanisms. The sensitivity to ambient glucose levels of both expression of the cartilage-specific chondroitin sulfate core protein gene and the accumulation of the corresponding extracellular matrix macromolecules during chondrogenesis suggest a molecular mechanism for the well-known adverse effect of maternal diabetes on embryonic skeletogenesis. The results further suggest that hypoglycemia resulting from stringent control of diabetes may also be deleterious to skeletal development.
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PMID:Abnormal ambient glucose levels inhibit proteoglycan core protein gene expression and reduce proteoglycan accumulation during chondrogenesis: possible mechanism for teratogenic effects of maternal diabetes. 260 60

The occurrence of heparan sulfate proteoglycan anionic site staining in the glomerular basement membranes of healthy and streptozotocin-induced diabetic rats was investigated. After 12 weeks diabetes, a marked loss of staining by ruthenium red was observed, compared with the age-matched controls. However, extraction and quantitation of total proteoglycan from the glomerular basement membrane revealed no significant differences between the two groups, in terms of absolute yield of glycosaminoglycan, when the latter is expressed per glomerulus. Glomerular basement membranes from both groups become thicker in an age-dependent manner, although they do so at a faster rate in the diabetic group, and a higher collagen content is found in the diabetic membrane at 12 weeks. Thus when proteoglycan content is expressed per mass protein, relative decreases are observed in diabetes. Similarly, a relative but not absolute decrease in proteoglycan content was observed in glomerular basement membranes from spontaneously diabetic BB rats with diabetes of 12 weeks duration. Glycosaminoglycans isolated from control and diabetic glomerular basement membrane have similar characteristics on ion exchange chromatography, to each other, and to newly sulfated, intact glomerular proteoglycans labelled in vitro. We conclude that loss of anionic site staining with ruthenium red in early diabetes is not a consequence of absolute loss or undersulfation of heparan sulfate proteoglycan but reflects structural or biochemical changes in the diabetic matrix.
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PMID:Retention of glomerular basement membrane-proteoglycans accompanying loss of anionic site staining in experimental diabetes. 275 78

The metabolism of glomerular proteoglycans was studied in an effort to understand the mechanisms leading to reduction of glomerular basement membrane (GBM) heparan sulfate (heparan-SO4) proteoglycan in diabetes. Glomeruli were isolated from control and streptozocin-induced diabetic rats after exposure to [35S]sulfate. A pool of rapidly metabolized 35S-glycosaminoglycans (GAG), predominantly heparan-35SO4, was present in GBMs from controls but not diabetics, whereas intact isolated glomeruli from the two groups contained similar quantities of 35S-macromolecules after 4 and 16 h in vitro. Glomeruli from diabetics contained less 35S-proteoglycan than controls after 16 h in vivo. A more rapid disappearance of [35S]sulfate from serum and an increased inorganic sulfate concentration in diabetes may account for this difference. Glomeruli from diabetics contained more heparan-35SO4 and less dermatan-35SO4 proteoglycan than control glomeruli in vitro. Diabetic glomerular heparan-35SO4 proteoglycan and its GAG chains had hydrodynamic sizes similar to controls (Mr, 13 and 1.25 X 10(4), respectively). A heparin-releasable heparan-35SO4 proteoglycan detected in isolated control glomeruli by gel electrophoresis was present in chase medium of glomeruli from diabetics in the absence of heparin. Two dermatan-35SO4 proteoglycans were synthesized in vitro. One had size and charge properties similar to glomerular heparan-35SO4 proteoglycan. A second, larger dermatan-35SO4 proteoglycan accumulated in tissue over 16 h. It was partially excluded from Sepharose CL-6B columns and eluted from Sepharose CL-4B columns at Kav = 0.32. The hydrodynamic sizes of both tissue forms of dermatan-35SO4 proteoglycans were similar in diabetics and controls. Differences in the biochemical characteristics of the major de novo synthesized glomerular proteoglycan pools could not be invoked to explain altered metabolism of GBM heparan sulfate in diabetic animals. These changes may result from diminished affinity of heparan sulfate proteoglycan for extracellular matrix or cell surfaces and may account for altered glomerular ultrafiltration properties in diabetes mellitus.
Diabetes 1986 Oct
PMID:Glomerular proteoglycans in diabetes. Partial structural characterization and metabolism of de novo synthesized heparan-35SO4 and dermatan-35SO4 proteoglycans in streptozocin-induced diabetic rats. 294 82

Rats fed a high-galactose diet develop marked thickening of their retinal capillary basement membranes. The effect is prevented if the animals also receive the aldose reductase inhibitor sorbinil. The effect does not appear to be due to aldose reductase itself, since immunoreactive aldose reductase has not been found in the retinal microvasculature of the rat but rather to a related enzyme with similar substrate specificity. The detailed biochemical mechanism for basement membrane thickening is obscure, involving an alteration of the extracellular matrix, where aldose reductase and similar enzymes have not been described; osmotic damage to the microvascular cells, such as has been described following aldose reductase-induced sugar alcohol accumulation in lens epithelial cells, is not apparent in diabetic or galactosemic animals. It is possible that concentrations of intracellular sugar alcohols that do not substantially change the osmolarity of the cell cytosol alter intracellular enzyme activities. This, in turn, could affect the biosynthesis of extracellular matrix macromolecules, as suggested, for example, by the hypothesis of Rohrbach et al, based on studies of a basement membrane-producing tumor implanted in diabetic mice, which proposes that the hyperglycemia of diabetes mellitus causes a reduced synthesis of the heparan sulfate BM-1 proteoglycan with a subsequent overproduction of type IV collagen. This and other hypotheses of basement membrane thickening can be tested in diabetic or galactosemic rats, some of which receive aldose reductase inhibitors, or in retinal microvascular pericytes and endothelial cells grown in culture.
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PMID:Aldose reductase activity and basement membrane thickening. 308 7

The effect of insulin and glucose on the synthesis of basement membrane components was studied in organ cultures of a basement membrane-producing tumor grown in diabetic and normal mice. Tumor tissue grown in diabetic mice produced more protein and basement membrane-specific proteoglycan in response to insulin than tissue grown in normal mice. Addition of high levels of glucose to the culture medium did not alter insulin-stimulated protein synthesis by diabetic or normal tissue but dampened insulin-stimulated production of proteoglycan. These data suggest that basement membrane-producing cells in diabetic hosts may be hypersensitive to insulin and that stimulation of protein production by insulin may play some role in the in situ hypertrophy of basement membranes.
Diabetes 1987 Sep
PMID:Response of diabetic basement membrane--producing cells to glucose and insulin. 330 72

The pathogenesis of clinical nephropathy in Type 1 (insulin-dependent) diabetes was investigated by measuring renal fractional clearances of albumin, total IgG, IgG4 and beta 2-microglobulin, four plasma proteins which differ in size and charge. Seventy patients and eleven control subjects were studied. In diabetic patients with normal urinary albumin excretion (less than 30 mg/24 hr), fractional IgG clearance was two to three times higher than in control subjects, whereas fractional clearance of the anionic plasma proteins IgG4 and albumin was similar to that of control subjects. These alterations indicate an increase in anionic pore charge within the glomerular basement membrane concomitant with an increase in either pore size or impairment of tubular reabsorption. Diabetic patients, whose urinary albumin excretion has started to rise (30 to 100 mg/24 hr), had unchanged fractional IgG compared to patients with normal albumin excretion, while fractional IgG4 and albumin clearances were increased three- to fourfold; indicating unchanged glomerular pore size, but a decrease in anionic pore charge. In patients demonstrating urinary albumin excretion of greater than 100 mg/24 hr fractional IgG clearance increased to the same extent as fractional albumin clearance, indicating an increase in large pore area. Fractional beta 2-microglobulin clearances were similar to that of control subjects in the different patient groups indicating unchanged tubular reabsorption of proteins. Thus, the increase in large pore area seen in patients with clinical nephropathy is preceded by loss of anionic charge in the glomerular basement membrane. It is likely that this loss of anionic charge is due to loss of heparan sulphate-proteoglycan.
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PMID:Glomerular size and charge selectivity in insulin-dependent diabetes mellitus. 335 57

Because of its general effects on connective tissue metabolism diabetes mellitus is becoming more and more important in the orthopaedic field. For investigation of morphologic changes in the cartilage a model of streptozotocin-induced diabetes was used in 80 rats. Studies were performed by light-, scanning- and transmission-electron microscopy and by biochemical analysis of proteoglycan and collagen metabolism. Three months after onset of diabetes the chondrocytes show increased metabolic activity and at the same time first stage regressive changes. The morphologic changes correlate with a significant decrease of hexosamine content in the cartilage. There is no evidence for any disturbance of collagen metabolism at that time. After seven months the cartilage is widely necrotic, the collagen fibers are swollen and show almost total loss of their microstructure. There is no sign for reparation of the necrotic zones at this time. It is most remarkable that in many specimen crystal deposits are found just below the cartilage surface which from the TEM-findings look very much like calciumpyrophosphate crystals. The morphologic and biochemical results show that in the rat diabetes leads to a special type of cartilage changes with crystallic arthropathy which seems to be a valuable model for the study of metabolic osteoarthrosis.
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PMID:[Morphological and biochemical studies of the cartilage in the diabetic rat--a model for metabolism-induced arthritis]. 371 47

Diabetes mellitus induces alterations in the metabolism of the macromolecules present in the intercellular matrices and particularly in the basement membranes. These contribute to the morphological changes characteristic of the disease : basement membrane thickening, skin thickening and induration. Accumulation of overglycosylated collagens and diminution of sulfated proteoglycan concentrations are the most generally reported biochemical modifications in human or animal diabetic states. More limited data are available concerning elastin, fibronectin and laminin in diabetes.
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PMID:Connective tissue in diabetes mellitus: biochemical alterations of the intercellular matrix with special reference to proteoglycans, collagens and basement membranes. 388 3

There is abundant evidence that changes in diet and various types of vessel wall injury can independently induce the growth of arterial lesions in experimental animals. These lesions closely resemble those found in humans with atherosclerosis. Whether endothelial injury or accumulation of lipoprotein in the arterial intima is the initial event, the progression of the disease is characterized by changes in the neointima that favor the deposition of lipid. The metabolism of proteoglycans may be especially important in this process; this is relevant to diabetes because changes in proteoglycan metabolism are associated with this disease. Insulin and growth hormone may favor the proliferation of smooth muscle cells in the arteries of diabetic patients. Many agents, which are potentially injurious to the endothelium, accentuate the response of the vessel wall to injury. Modifications of the thrombotic process, such as increased production of thromboxane by platelets, decreased production of prostacyclin by the endothelium, and increased production of von Willebrand factor further enhance the thrombotic process and may be important in the initiation and subsequent progression of atherosclerosis in diabetics. Alterations in lipoprotein metabolism may also facilitate the development of endothelial injury.
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PMID:Pathogenesis of atherosclerosis. 390 56

In diabetes, certain basement membranes become thicker yet more porous than normal. To identify possible changes in the basement membrane, we have grown the Engelbreth-Holm-Swarm tumor, a tissue that produces quantities of basement membrane in normal mice and in streptozotocin-treated, insulin-deficient, diabetic mice. The level of laminin, a basement membrane-specific glycoprotein, and the level of total protein were slightly elevated in the diabetic tissue. In contrast, the level of the basement membrane specific heparan sulfate proteoglycan was only 20% of control. The synthesis of this proteoglycan was also reduced in the diabetic animals, while the synthesis of other proteoglycans by tissues such as cartilage was normal. The synthesis of the heparan sulfate proteoglycan in diabetic animals was inversely related to plasma glucose levels showing an abrupt decrease above the normal range of plasma glucose. Insulin restored synthesis to normal but this required doses of insulin that maintained plasma glucose at normal levels for several hours. Since the heparan sulfate proteoglycan in the basement membrane restricts passage of proteins, its absence could account for the increased porosity of basement membrane in diabetes. A compensatory synthesis of other components could lead to their increased deposition and the accumulation of basement membrane in diabetes.
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PMID:Reduced synthesis of basement membrane heparan sulfate proteoglycan in streptozotocin-induced diabetic mice. 622 78


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