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

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

We evaluated the effect of platelets on prostacyclin (PGI2) production in bovine aortic endothelial cell cultures. Human platelet extract significantly stimulated PGI2 production by cultured aortic endothelial cells in a time- and dose-dependent manner, suggesting that platelets contain PGI2-stimulatory activity (PSA). Supernatant fluid separated from platelets activated by collagen also exhibited PSA. The factor(s) causing the PSA of platelets was non-dialysable and heat-stable (56 degrees C for 30 min or 100 degrees C for 3 min), was completely inhibited by trypsin pretreatment, and exhibited an affinity to heparin agarose. Furthermore, gel filtration chromatography showed that the factor(s) responsible for the platelet PSA was eluted at three different peaks with approximate molecular weights of 50,000, 25,000 and 11,000. The PSA of platelet extract from patients with non-insulin-dependent diabetes mellitus (NIDDM) (n = 10) was compared to that from age-matched control subjects (n = 10). Platelet extract from patients with NIDDM stimulated cultured aortic endothelial cells to produce greater amounts of PGI2 than did that from control subjects. These data suggest that the increased PSA of platelets isolated from diabetic patients may contribute to the abnormal interaction between platelets and the vascular wall in diabetic patients.
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PMID:Platelet stimulation for prostacyclin production in aortic endothelial cell cultures: alteration in diabetes mellitus. 181 65

The effect of alloxan induced diabetes on the dermal collagen content of albino rats was studied in relation to few lysosomal enzymes. Diabetes decreased the dermal collagen content. The specific activities of the lysosomal enzymes studied in the diabetic rat skin were elevated. It has been established that lysosomal enzymes degrade the connective tissue components. Thus, it may be suggested that the increase in the lysosomal enzymes studied should have facilitated the decrease in dermal collagen content of diabetic rats by increasing the degradation of dermal collagen.
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PMID:Increased degradation of dermal collagen in diabetic rats. 181 88

The demonstration of circulating anti-glomerular basement membrane (GBM) antibodies is almost diagnostic for anti-GBM disease and Goodpasture's syndrome. These antibodies are, however, occasionally present in SLE and diabetes, in association with IgA disease and membranous nephropathy and after transplantation in Alport's syndrome. In addition, we describe circulating anti-GBM antibodies in a research worker who handled GBM and in whom coeliec disease later developed, and in an individual with epidermolysis bullosa acquisita. Neither patient had impaired renal function nor an abnormal urinary sediment, suggesting either that these antibodies were of low affinity, or that additional factors are required for the pathogenesis of an aggressive glomerular lesion when circulating anti-GBM antibodies are present. In at least one of these individuals anti-GBM antibodies may have developed after the exposure of basement membrane collagen type IV to activated immunological mediators and cells.
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PMID:Circulating anti-glomerular basement membrane antibodies in coeliac disease and epidermolysis bullosa acquisita. 181 46

Several studies in the last decade have highlighted the importance of the hexose sugars and especially glucose, as being responsible for alterations to living protein and other molecules. The phenomenon of nonenzymatic glycation--by which the carbonyl group of glucose can directly condense with a free amino group--may be relevant for the process of aging and for the pathogenesis of late diabetic complications. Thus life-long exposure to normoglycemia in non diabetic subjects or a shorter exposure but continued association with a hyperglycemic milieu, as in diabetes mellitus, have both been shown to lead to the formation and accumulation of irreversible and highly reactive advanced glycation endproducts (AGE) over long-lived, fundamental molecules such as the constituents of arterial wall collagen, basement membranes, nerve myelin, DNA and others. For example, the introduction of foreign AGE groups into proteins might alter their tertiary structure and therefore modify their function or activity. By increasing protein-to-protein cross-links AGE could reduce protein turnover, with consequential increases in levels of modified and thus less reactive molecules. Moreover, AGE could initiate an immune response with the production of specific antibodies. Reducing the extent of nonenzymatic glycation could effectively reduce the accumulation of AGE. Many authors are experimenting with methods to achieve this aim. Amongst the products tested are aspirin and aminoguanidine which compete with glucose for the same protein amino group. D-lysine is also being investigated on the principle that by reacting with glucose in circulation, it could effectively prevent it from reaching the amino group on the protein.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes Res 1991 Jan
PMID:Advanced nonenzymatic glycation endproducts (AGE): their relevance to aging and the pathogenesis of late diabetic complications. 181 91

It has been previously demonstrated that non-enzymatic glycosylation and subsequent cross-linking of proteins can occur at high or greater than physiological concentrations of glucose. Soluble collagen was incubated in the presence of increasing glucose concentrations. The amount of cross-linked collagen was determined by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate. Our findings reveal that cross-linking due to non-enzymatic glycosylation occurs at or near physiological concentrations of glucose (3.11-4.22 mM). In addition, this glucose induced cross-linking is a time dependent reaction. When collagen was incubated with a variety of different carbohydrates it was found that ketoses are more active cross-linking agents than aldoses. The addition of a reactive group (such as an amine) alpha to the aldehyde group on the carbohydrate increases the cross-linking activity of glucose 2.8 fold. Blockage of the reactive group alpha to the aldehyde (such as N-acetyl glucosamine or 2-deoxy-D-glucose) totally abolishes glycosylation activity. Both 5-C and 7-C carbohydrates are more active than 6-C carbohydrates. Thus, although glucose may be the most abundant carbohydrate capable of non-enzymatic glycosylation and subsequent cross-linking, it is not the most chemically reactive. However, the significance of these findings to the pathogenesis of diabetes needs to be defined.
Diabetes Res 1991 Jan
PMID:Effect of carbohydrate structure and concentration on the non-enzymatic glycosylation and subsequent cross-linking of collagen. 181 96

Hypertensive diabetic rats develop a cardiomyopathy characterized by systolic and diastolic ventricular dysfunction, myocardial hypertrophy and fibrosis, pulmonary congestion and a very high mortality rate. Alterations in contractile proteins and sarcoplasmic reticular calcium (Ca2+) transport in diabetic myocardium and their partial reversal with verapamil suggest that calcium channel blockade may prevent death from congestive heart failure in hypertensive diabetic rats. A large group of rats with renovascular hypertension and streptozotocin diabetes were divided into four groups: untreated animals (Group 1) and animals treated with 100 (Group 2), 300 (Group 3) or 600 (Group 4) mg/kg per day of sustained release diltiazem mixed in their food. Treatment was begun shortly after the onset of hypertension and diabetes. Mortality rates after 4 months were 59% (19 of 32), 53% (17 of 32), 27% (7 of 26) and 35% (12 of 34) in Groups 1, 2, 3 and 4, respectively; the mortality rate in age-matched control rats was 5% (1 of 19). The reductions in mortality rates in Groups 3 and 4 were statistically significant. Diltiazem did not change systolic blood pressure, serum glucose concentration, heart rate or left ventricular mass. There was a trend to decreased left ventricular interstitial fibrosis and perivascular fibrosis in diltiazem-treated animals. Ventricular collagen concentration was similar in untreated hypertensive diabetic and control rats; levels were higher in hypertensive diabetic rats that died than in those that survived. There was a trend to decreased collagen concentration as diltiazem dose increased. Myosin isoenzyme distribution was not changed in Groups 3 and 4 (in comparison with Group 1). In all hypertensive diabetic groups, rats that died had a higher blood pressure, heart rate, relative left ventricular mass, lung weight and lung water than did survivors. The mortality rate was two to three times higher among rats with an initial blood pressure greater than or equal to 180 mm Hg. The beneficial effects of diltiazem on survival were most significant among rats with severe hypertension.
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PMID:Beneficial effects of diltiazem on the natural history of hypertensive diabetic cardiomyopathy in rats. 183 34

This study evaluated the relationship between the development of fluorescence related to advanced glycosylation end products (AGEs) in the kidney and experimental diabetic nephropathy over a 32-wk period. Control, untreated diabetic, and aminoguanidine-treated diabetic rats were followed for 32 wk with eight weekly measurements of urinary albumin excretion. After 32 wk, collagen-related fluorescence in aorta and kidney (whole kidney, isolated glomeruli, and renal tubules) and glomerular ultrastructure were evaluated. Diabetes was associated with a significant increase in collagen-related fluorescence in the aorta and kidney. Aminoguanidine prevented the increases in collagen-related fluorescence in aorta, isolated glomeruli, and renal tubules but not in whole kidney. Diabetes was associated with increased albuminuria, fractional mesangial volume, and glomerular basement membrane (GBM) thickness. Aminoguanidine attenuated the rise in albuminuria and prevented mesangial expansion without influencing GBM thickness in diabetic rats. The concomitant changes in collagen-related fluorescence, albuminuria, and mesangial expansion with aminoguanidine therapy are consistent with the hypothesis that AGEs may play a role in the development of diabetic nephropathy.
Diabetes 1991 Oct
PMID:Retardation by aminoguanidine of development of albuminuria, mesangial expansion, and tissue fluorescence in streptozocin-induced diabetic rat. 183 97

Increased free radical activity may contribute to thrombosis via effects on platelet aggregation and the prostanoid balance. To investigate this further we studied 15 Type 1 diabetic patients with retinopathy, matched with uncomplicated Type 1 patients for age, duration of diabetes and HbA1, together with matched healthy non-diabetic control subjects. The oxidative effects of free radicals as total diene conjugates and lipid peroxides were measured, together with redox status extracellularly as plasma albumin-thiols and intracellularly as erythrocyte superoxide dismutase activity. Platelet count, aggregation of platelets in whole blood to collagen, thromboxane B2, and prostacyclin stimulating factor (PGI2SF) were also assessed. Free radicals measured as lipid peroxides were significantly higher (9.6 (8.1-11.6) mumol l-1 (median and interquartile range) in diabetic patients with retinopathy than in control subjects (8.1 (7.4-9.2) mumol l-1; p less than 0.05). There were also significant reductions in redox status both extracellularly as plasma albumin thiols (408 (383-473) vs 490 (456-517) mumol l-1, p less than 0.001) and intracellularly as erythrocyte superoxide dismutase activity (34 (27-41) vs 44 (36-51) g l-1, p less than 0.05) between patients with retinopathy and control subjects. Platelet counts were increased in diabetic patients with retinopathy (p less than 0.05), as was collagen-induced platelet aggregation (p less than 0.01). Prostacyclin stimulating factor was reduced in patients with retinopathy (p less than 0.05) and correlated within the plasma with lipid peroxides (r = -0.53, p less than 0.04) and albumin thiols (r = 0.64, p less than 0.01). The results suggest that diabetic patients, particularly with retinopathy, are under oxidative stress and have an increased thrombotic tendency with increased platelet reactivity and a reduction in prostacyclin stimulating factor.
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PMID:The relationship of oxidative stress to thrombotic tendency in type 1 diabetic patients with retinopathy. 183 13

Most ischemic heart disease in associated with severe coronary atherosclerosis. A small subset of patients, however, had angina pectoris despite angiographically normal coronary arteries and absence of inducible coronary spasm. Coronary microcirculation (i.e. arteries too small to be visualized by current angiographic techniques) has been identified as the weak point of these patients. Small coronary vessel involvement may be due to organic conditions (such as diabetes, vasculitis, systemic collagen-vascular diseases, infectious processes) that act through coronary thrombosis or embolism and related alteration in coronary vasomotion; alternatively, the vascular abnormality appears to be entirely functional (no ultrastructural myocardial changes) such as the case of hypertension, hypertrophic cardiomyopathy and syndrome X. Whatever the cause(s) and mechanism(s) of the small coronary artery involvement, this leads to myocardial ischemia and to the related complications as in classic atherosclerotic heart disease. Syndrome X is characterized by effort-induced angina pectoris, ST-segment changes during exercise testing, negative ergonovine test and reduced coronary reserve. A pre-arteriolar hypersensitivity to vasoconstrictor influences (elicited by cold pressor test or ergonovine) and a reduced vasodilator capacity (unmasked by metabolic and pharmacological studies) have been proposed as potential pathogenetic substrate. This dynamic alteration in vasomotion would answer for both symptoms and signs of myocardial ischemia, that, however, appear to be contemporarily elicitable in a minority of patients. Treatment with beta-blockers and calcium-antagonists has been found to be effective. The long-term follow-up shows favorable outcome with a high survival rate and a low incidence of cardiovascular events.
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PMID:[Angina due to microvascular pathology]. 184 63


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