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

Recent epidemiologic studies have suggested that cardiac disease in common in diabetics and may often have a noncoronary basis. To examine the status of the left ventricle, 17 adult-onset diabetics of familial type without hypertension or obesity underwent hemodynamic study and were compared to 9 controls of similar age. Of the 17, 12 subjects had no significant occlusive lesions by coronary angiography. From this group eight without heart failure had a modest, but significant, elevation of left ventricular end-diastolic pressure. End-diastolic and stroke volumes were reduced, but ejection fraction and mean rate of fiber shortening were within normal limits. The left ventricular end-diastolic pressure/volume ratio was significantly higher than controls. Afterload increments effected a significant increase of filling pressure compared to normals without a stroke volume response, consistent with a preclinical cardiomyopathy. Four patients with prior heart failure had similar but more extensive abnormalities. None had local dyskinesia by angiography, and lactate production was not observed during pacing-induced tachycardia. Left ventricular biopsy in two patients without ventricular decompensation showed interstitial collagen deposition with relatively normal muscle cells. These findings suggest a myopathic process without ischemia. Postmortem studies were performed in 11 uncomplicated diabetics. Nine were without significant obstructive disease of the proximal coronary arteries, and the majority succumbed with cardiac failure. On left ventricular sections, none had evident luminal narrowing of the intramural vessels. All nine exhibited periodic acid-Schiff-positive material in the interstitium. Collagen accumulation was present in perivascular loci, between myofibers, or as replacement fibrosis. Multiple samples of left ventricle and septum revealed enhanced triglyceride and cholesterol concentrations, as compared to controls. Thus, a diffuse extravascular abnormality may be a basis for cardiomyopathic features in diabetes.
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PMID:Evidence for cardiomyopathy in familial diabetes mellitus. 89 79

We studied the influence of fasting serum from nine insulin-dependent diabetic children and adolescents under insufficient metabolic control on normal human bone cells in vitro compared with serum from eight sex- and age-matched controls. Cell number 24 h after plating was significantly less under diabetic serum, indicating impaired cell attachment, spreading and initiation of cell proliferation. Cell number after five days was reduced by 1% diabetic serum, while higher serum concentrations had diverging effects on osteoblast proliferation. Collagen synthesis of human osteoblasts was significantly reduced by 8% diabetic serum compared to 8% control serum, while synthesis of non-collagenous proteins was not affected. Duration of diabetes (several weeks up to 12 years) had no influence on these parameters. The serum from one patient, which was studied a second time under excellent metabolic control three months later, however, had lost its inhibitory influence on collagen synthesis of osteoblasts. The pattern of the interstitial collagen types I, III and V was not altered by diabetic serum. These results indicate that defective regulation of proliferation and collagen synthesis of osteoblasts by components present in human diabetic serum may be an important factor in the development of diabetic osteopenia. The negative influence might be explained in part by reduced levels of IGF-I and elevated levels of IGF binding protein-1 in the diabetic sera.
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PMID:Defective stimulation of proliferation and collagen biosynthesis of human bone cells by serum from diabetic patients. 128 77

Patients with diabetes often develop complications involving collagen-containing connective tissues. Previous in vitro studies have demonstrated that glucose inhibits collagen fibril formation and subsequent cross-linking. Collagen with diminished cross-linking is more susceptible to collagenolytic degradation. This may underlie the decreased collagen levels. To test this hypothesis, D-glucose and its two analogs, L-glucose and 2-deoxy-D-glucose, were used in chick calvaria organ cultures to examine parameters of collagen metabolism. L-Glucose is not used by the cell and functions as an extracellular glucose-like molecule, while 2-deoxy-D-glucose inhibits normal D-glucose uptake by blockading the glucose transport mechanism. Each of these three sugars had the ability to inhibit collagen fibril formation. D-Glucose stimulated collagen synthesis; L-glucose had no effect; and deoxyglucose inhibited collagen synthesis. D-Glucose was able to reverse the inhibitory effect of deoxyglucose. D-Glucose did not change levels of degradation of newly synthesized collagen while both L-glucose and deoxyglucose stimulated collagen degradation. When glucose transport was inhibited by deoxyglucose, collagen degradation was further enhanced. We suggest that decreased collagen levels in the connective tissues of diabetics may result from a combination of inhibition of collagen fibril formation and subsequent cross-linking, as well as increased collagen degradation.
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PMID:Glucose and glucose analogs modulate collagen metabolism. 128 72

Platelets could contribute to vascular disease in diabetes through enhanced adherence to collagen exposed in injured vessels. Increased platelet adherence to collagen in diabetes could result from an alteration in platelets and/or platelet hypersensitivity to collagen that has been glycated to a greater extent. In this study, the adherence of platelets from diabetic or control subjects to glycated or nonglycated collagen coated onto glass surfaces was examined. Membrane fluidity of platelets was also determined, since decreased membrane fluidity associated with increased glycation of membrane proteins of platelets from diabetic subjects was shown in a previous study, and decreases in membrane fluidity have been shown by others to increase platelet adhesion. Thirteen diabetic subjects were compared with 13 age-and sex-matched control subjects. Collagen was glycated (9.7 nmol glucose/mg protein) by preincubation for 12 days in glucose-rich medium (500 mmol/L). A control solution of collagen incubated without glucose for the same time had 3.3 nmol glucose/mg protein. There were no differences in the adherence of platelets from diabetic and control subjects to nonglycated and glycated collagen-coated glass. The mean steady-state fluorescence polarization value (0.187 +/- 0.002) in 1.6-diphenyl-1,3,5-hexatriene-labeled platelets from diabetic subjects was significantly greater than in platelets from control subjects (0.174 +/- 0.002, p < 0.002); thus membrane fluidity in platelets from the group of diabetic subjects was decreased. The extent of glycation of membrane proteins from diabetic subjects (25.4 +/- 0.5 nmol glucose/mg protein) was significantly greater than from control subjects (20.2 +/- 0.4 nmol glucose/mg protein, p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Reduced membrane fluidity and increased glycation of membrane proteins of platelets from diabetic subjects are not associated with increased platelet adherence to glycated collagen. 145 13

Collagen production has been shown to be decreased in costal cartilage from nondiabetic animals after incubation with diabetic rat serum. Since collagen was decreased to a similar degree in tissues from diabetic animals, we questioned whether altered collagen production in vivo could be related to altered production induced in vitro. Collagen and noncollagen protein production in articular cartilage from diabetic animals (production in vivo) was compared to protein production in dermal fibroblasts from non-diabetic rats exposed to serum from the same diabetic rats (production in vitro). Diabetes was induced by intravenous administration of 90 mg/kg of streptozotocin into male Sprague-Dawley rats. Cartilage was removed and incubated with [3H]-proline for 2 hours at 37 degrees C (in vivo), while fibroblasts were exposed to experimental serum from individual animals for 24 hours with addition of 5 microCi of [5-3H]-proline for the final 6 hours (in vitro). Collagen and noncollagen protein production were quantitated using purified bacterial collagenase. Collagen production in cartilage decreased to 46% (p less than .01) and noncollagen to 68% (p less than .05) of levels in control animals. Fibroblasts exposed to 2.5% diabetic serum decreased collagen and noncollagen protein production to levels of 30% (p less than .01) and 54% (p less than .05) of production in cells incubated in 2.5% normal rat serum. Correlation between defective collagen production in cartilage from individual rats and the effects of their own serum on collagen production in fibroblasts was significant (r = 0.84, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Correlation between decreased collagen production in diabetic animals and in cells exposed to diabetic serum: response to insulin. 160 33

Enzymatically mediated crosslinks and nonenzymatic glycation were quantified in granulation tissue collagen in two models of hyperglycemia, diabetes and galactosemia, that have opposite effects on collagen solubility. The effects of castration, which alters collagen solubility, was also investigated. Collagen from both diabetic and galactosemic rats had significantly increased levels of dihydroxylysinonorleucine (DHLNL), a difunctional reducible crosslink. Galactosemic rats had significantly decreased levels of hydroxypyridinium, a trifunctional product of DHLNL and hydroxylysine, relative to control values, while diabetic rats had normal levels. Values for all other detectable crosslinks in collagen from hyperglycemic rats were indistinguishable from control values. Nonenzymatic glycation was increased in both groups of hyperglycemic rats. In diabetic rats, but not in galactosemic rats, nonenzymatic glycation was strongly correlated with DHLNL content. Castration had no effect on crosslink content of collagen from diabetic or galactosemic rats. This study demonstrates that (1) collagen crosslinking is abnormal in granulation tissue collagen in both experimental diabetes and galactosemia, (2) these changes are similar to those observed in skin collagen from insulin-dependent diabetic subjects and (3) the crosslinking abnormalities are not correlated with alterations in collagen solubility. We conclude that hyperglycemia-associated increases in immature crosslinks cannot account for altered collagen solubility, although impaired maturation of such crosslinks may be partially responsible for the lathyrogenic effect of galactosemia.
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PMID:Lysyl oxidase-mediated crosslinking in granulation tissue collagen in two models of hyperglycemia. 167 90

Collagen undergoes progressive browning with age and diabetes characterized by yellowing, fluorescence, and cross-linking. The present research was undertaken in order to investigate the nature of the collagen-linked fluorescence. Human collagen was exhaustively cleaved into peptides by enzymatic digestion. Upon purification, a highly fluorescent chromophore was identified and purified from old human collagen. Structure elucidation revealed the presence of an imidazo [4,5-b] pyridinium-type structure acting as a cross-link between arginine, lysine, and a pentose. This advanced glycosylation end-product and protein cross-link results from the reaction of pentoses with proteins and was named pentosidine. Further work indicated that long-term glycosylation of proteins with hexoses also leads to pentosidine formation through sugar fragmentation. The proposed mechanism of pentosidine formation involves the dehydration of the pentose-derived Amadori compound to form an intermediate which is attacked under base catalysis by the guanido group of arginine. The strict requirement for the Amadori rearrangement is uncertain. However, oxidation is definitely involved since pentosidine is not formed in the absence of oxygen. Five-carbon sugars contributing to pentosidine formation could be formed from larger sugars by oxidative fragmentation or from trioses, tetroses, and ketoses by condensation and/or reverse aldol reactions. Pentosidine increases exponentially in human skin at autopsy. Mean age-adjusted skin levels were significantly increased in subjects with uremia and especially in type 1 diabetics with uremia vs. controls. In skin biopsy, levels were significantly elevated in all diabetic (type 1) vs. control subjects. The highest degree of association was with the cumulative grade of diabetic complication (retinopathy, nephropathy, arterial stiffness, and joint stiffness). Pentosidine also forms in various proteins other than collagen, although to a much lesser extent. In blood, pentosidine is mainly associated with plasma proteins and is highly elevated during uremia. In the lens, it is associated with both water-soluble and -insoluble protein fractions and is especially elevated during brunescent cataract formation. The origin of pentosidine in vivo is uncertain. Evidence suggests that the pentoses are the most reactive sugars in pentosidine formation in vitro; however, the origin and importance of free pentoses in vivo, especially during the diabetic state, are not certain. Possible origins include hemolysis and/or a defect in the primary pentose metabolism.(ABSTRACT TRUNCATED AT 400 WORDS)
Diabetes Metab Rev 1991 Dec
PMID:Pentosidine: a molecular marker for the cumulative damage to proteins in diabetes, aging, and uremia. 181 79

Chronic experimental hyperglycemia mediated by galactose has been shown to induce browning and cross-linking of rat tail tendon collagen that could be duplicated in vitro by nonenzymatic galactosylation. To investigate the nature of these changes, Sprague-Dawley rats were placed on a 33% galactose diet without and with sorbinil for 6 and 12 mo. Collagen-linked fluorescence and pentosidine cross-links increased with age and galactosemia in tail tendons (P less than 0.001) and skin but were essentially unresponsive to aldose reductase inhibition (ARI). In contrast, tendon breaking time in urea, a likely parameter of cross-linking, was markedly improved (P less than 0.001) by ARI. Fluorescence that was inhibited by sorbinil treatment was increased in pepsin and proteinase K digest of aortic tissue from galactosemic rats (P less than 0.001), but impaired enzymatic digestibility was not observed. Systolic blood pressure as potential consequence of aortic stiffening was not increased in galactosemia. These data suggest that fluorescence in skin and tendon might be in part due to advanced glycosylation and pentosidine formation because these were not decreased by ARI. However, they also suggest that nonfluorescent cross-links may also be forming because, in contrast to fluorescence, tail tendon breaking time was partly corrected by ARI. Thus, it appears that extracellular matrix changes in chronic galactosemia are complex, being partly attributable to advanced glycosylation and partly to polyol-pathway activation.
Diabetes 1991 Aug
PMID:Tissue-specific effects of aldose reductase inhibition on fluorescence and cross-linking of extracellular matrix in chronic galactosemia. Relationship to pentosidine cross-links. 190 47

Diabetes mellitus is associated with a generalized defect in connective tissue metabolism. Since collagen is the major protein of connective tissues, we used collagen as a probe to examine the role of factors in diabetic rat serum (DRS) in the etiology of these defects. Serum and skin fibroblasts were isolated from nondiabetic rats, and serum was taken from rats 48 h after injection of 200 mg/kg streptozotocin. Within 24 h of confluency, the fibroblast medium was changed to experimental serum for 24 h, with 5 microCi [3H]proline added for the final 6 h. Collagen and noncollagen proteins were quantitated using purified collagenase. Compared to cells incubated in medium without serum, collagen fell to 58% with 0.5% DRS (P less than 0.05) and continued to decrease with increasing concentrations of DRS. Noncollagen protein decreased below levels in cells incubated in medium without serum only when concentrations of diabetic serum were 1% or greater and did not decrease further with higher concentrations of diabetic serum. Collagen was decreased to a greater degree than noncollagen protein at each concentration of DRS, such that collagen relative to total protein production was significantly reduced at 0.5% or more DRS. Addition of 10(-7)-10(-9) M insulin or insulin-like growth factor-I (0.1-1000 ng/ml) to DRS did not return collagen production to the level seen in cells incubated in medium with no added serum (basal production). After separation of serum components based on size, incubation of cells with the low mol wt fraction (less than 5000 daltons) of normal and diabetic rat serum resulted in equivalent collagen production, while incubation with the high mol wt fraction of DRS resulted in 200-fold less collagen compared to the similar fraction of normal serum. This decrease in collagen production appeared due to the presence of a high mol wt factor(s) in diabetic serum which had a direct inhibitory effect on collagen and was not due to deficiency of growth peptides. The degree and specificity of these changes in collagen production probably contribute to long term complications in diabetes through altered connective tissue metabolism.
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PMID:Inhibition of collagen production by diabetic rat serum: response to insulin and insulin-like growth factor-I added in vitro. 195 85

Considerable progress has been made in our understanding of nonenzymatic glycation of collagen, and the relationship between glycation of collagen and changes in connective tissue associated with aging and diabetes. Recent studies surveyed in this review suggest the following conclusions: 1. Collagen content of early glycation products does not appear to increase throughout the life span in normal human subjects, although small increases may occur that are linked to glycemic changes. These products are increased, relative to age-matched controls, in experimental diabetes and in diabetes mellitus in collagen from virtually all tissues analyzed. 2. Collagen content of browning products increases with aging and appears to be higher in diabetic subjects than in age-matched controls. Rates of accumulation may be accelerated in subpopulations of diabetic subjects at high risk for developing complications. 3. Increases in early glycation products do not appear to be associated with alterations in collagen solubility, thermal rupture time, or mechanical strength, nor is there an association with most diabetic complications. Alterations in these products may, however, affect conformation, ligand binding, lysyl oxidase-mediated cross-linking, and interactions between collagen and other macromolecules in the extracellular matrix. 4. Increased content of browning products is associated with many physicochemical changes in collagen as well as with long-term complications in diabetes mellitus. 5. Regulatory mechanisms have been identified in vivo that may serve to control or limit the formation of glycation products. 7. Pharmacologic agents have been identified that may be able to reduce collagen content of late glycation products. Despite the progress that has been made in this field, many areas of uncertainty and controversy exist. For example, there is not yet a consensus that the browning products associated with collagen exclusively comprise advanced Maillard products derived from nonenzymatically glycated residues. There is evidence that oxidative reactions involving lipids also play a role in generating fluorophores and chromophores that may alter properties of collagen. Thus, in the extracellular matrix collagen may be continuously modified by at least three very different processes: Maillard reactions, interactions with oxidizing lipids, and enzymatically mediated cross-linking. The interrelationships between these and possibly other posttranslational modifications remain a poorly understood area of great complexity.
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PMID:Nonenzymatic glycation of collagen in aging and diabetes. 198 39


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