Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have investigated the effect of advanced glycation end products (AGEs) on the crosslinking of collagen. The potential pathological significance of AGEs and the altered metabolism of ascorbic acid (ASA) in diabetes have prompted us to investigate the role of ASA in the crosslinking and advanced glycation of collagen. Rat tail tendons were incubated with ASA and dehydroascorbic acid (DHA) under physiological conditions of temperature and pH, and the crosslinking and the level of AGEs were analyzed. Analysis of crosslinking was conducted by pepsin solubility and cyanogen bromide digestion. Level of AGEs was estimated by enzyme-linked immunosorbent assay (ELISA) using antibodies raised against AGE-ribonuclease. It was noted that ASA and DHA induced crosslinking of collagen and stimulated the formation of AGEs. It was also noted that these pathways were dependent on oxidative conditions. Similarly incubation of collagen with AGEs, prepared by the in vitro incubation of bovine serum albumin (BSA) with glucose, also resulted in increased crosslinking. The extent of crosslinking was dependent on the duration of incubation. The novel finding of this study, which is in contrast to the earlier reports on glucose-induced crosslinking of collagen, was that AGEs-induced crosslinking of collagen was not inhibited by radical scavengers and the metal chelator. EDTA, whereas glucose-induced crosslinking of collagen was almost completely prevented by free radical scavengers. The increased fluorescence intensity observed in collagen incubated with AGEs was also not prevented by radical scavengers. Estimation of AGEs by ELISA revealed an increased accumulation of AGEs in collagen incubated with AGE-BSA. The inhibitory effect of aminoguanidine and aspirin on AGEs-induced modification of collagen, strongly suggests that the amino-carbonyl interaction between AGEs and collagen may play a key role in the crosslinking process. The results obtained in this study indicate that soluble AGEs can directly induce crosslinking of collagen and this process is independent of oxidative conditions. From these results it may be hypothesized that glucose, under oxidative conditions, reacts with proteins to form potentially reactive end products called AGEs. These AGEs, once formed, could induce crosslinking of collagen even in the absence of both glucose and oxygen.
 ...
PMID:Advanced glycation end products induce crosslinking of collagen in vitro. 974 85

The relationships between long-term intensive control of glycemia and indicators of skin collagen glycation (furosine), glycoxidation (pentosidine and N(epsilon)-[carboxymethyl]-lysine [CML]), and crosslinking (acid and pepsin solubility) were examined in 216 patients with type 1 diabetes from the primary prevention and secondary intervention cohorts of the Diabetes Control and Complications Trial. By comparison with conventional treatment, 5 years of intensive treatment was associated with 30-32% lower furosine, 9% lower pentosidine, 9-13% lower CML, 24% higher acid-soluble collagen, and 50% higher pepsin-soluble collagen. All of these differences were statistically significant in the subjects of the primary prevention cohort (P < 0.006-0.001) and also of the secondary intervention cohort (P < 0.015-0.001) with the exception of CML and acid-soluble collagen. Age- and duration-adjusted collagen variables were significantly associated with the HbA1c value nearest the biopsy and with cumulative prior HbA1c values. Multiple logistic regression analyses with six nonredundant collagen parameters as independent variables and various expressions of retinopathy, nephropathy, and neuropathy outcomes as dependent variables showed that the complications were significantly associated with the full set of collagen variables. Surprisingly, the percentage of total variance (R2) in complications explained by the collagen variables ranged from 19 to 36% with the intensive treatment and from 14 to 51% with conventional treatment. These associations generally remained significant even after adjustment for HbA1c, and, most unexpectedly, in conventionally treated subjects, glycated collagen was the parameter most consistently associated with diabetic complications. Continued monitoring of these subjects may determine whether glycation products in the skin, and especially the early Amadori product (furosine), have the potential to be predictors of the future risk of developing complications, and perhaps be even better predictors than glycated hemoglobin (HbA1c).
Diabetes 1999 Apr
PMID:Skin collagen glycation, glycoxidation, and crosslinking are lower in subjects with long-term intensive versus conventional therapy of type 1 diabetes: relevance of glycated collagen products versus HbA1c as markers of diabetic complications. DCCT Skin Collagen Ancillary Study Group. Diabetes Control and Complications Trial. 1010 6

The present investigation was carried out to understand the effect of metal catalyzed oxidation on glycation and crosslinking of collagen. Tail tendons obtained from rats weighing 200-225 g were incubated with glucose (250 mM) and increasing concentrations of copper ions (5, 25, 50 and 100 microM) under physiological conditions of temperature and pH. Early glycation, crosslinking and late glycation (fluorescence) of collagen samples were analyzed periodically. Early glycation was estimated by phenol sulfuric acid method, and the crosslinking was assessed by pepsin and cyanogen bromide digestion. A concentration-dependent effect of metal ions on the rate of glycation and crosslinking of collagen was observed. Tendon collagen incubated with glucose and 100 microM copper ions showed 80% reduction in pepsin digestion within seven days, indicating extensive crosslinking, whereas collagen incubated with glucose alone for the same period showed only 7% reduction. The presence of metal ions in the incubation medium accelerated the development of Maillard reaction fluorescence on collagen, and the increase was dependent on the concentration of metal ions used. The metal chelator diethylene triamine penta-acetate significantly prevented the increase in collagen crosslinking by glucose and copper ions. Free radical scavengers benzoate and mannitol effectively prevented the increased crosslinking and browning of collagen by glucose. The results indicate that the metal catalyzed oxidation reactions play a major role in the crosslinking of collagen by glucose. It is also suggested that the prevention of increased oxidative stress in diabetes may prevent the accelerated advanced glycation and crosslinking of collagen.
 ...
PMID:An in vitro study on the role of metal catalyzed oxidation in glycation and crosslinking of collagen. 1039 Nov 48

Collagenous proteins are especially prone to nonenzymatic glycation, because they contain several dibasic amino acid residues with free amino groups, have a very slow turnover rate, and are exposed to ambient levels of glucose. The aim of this study was to determine the time-dependent course of advanced glycation process in diabetic rats in relation to glycemic control and duration of diabetes, compared to age-matched controls. Immunochemical assay with antibodies to advanced glycation end products (AGE) was first developed to qualitatively detect and quantify the AGE formed in rat tendon and aortic collagen. Individual collagen samples were extracted by extensive pepsin and collagenase digestion. The amount of AGE was measured by competitive ELISA and results were expressed as AGE U/mg collagen. Diabetic rats showed a significant increase in AGE content in aortic collagen at 20 weeks (n = 6, 206.6 +/- 16.7 U/mg collagen) compared with that measured at 4 and 12 weeks (n = 6, 110 +/- 12.8 U/mg collagen, and n = 13, 184.9 +/- 12.3 U/mg collagen at 4 and 12 weeks, respectively; p < 0.001 between 20 weeks and 4 weeks; p < 0.01 between 20 weeks and 12 weeks). The amount of AGE in tendon collagen of diabetic rats increased from 1.9 +/- 0.38 U/mg at 4 weeks to 11.2 +/- 6.1 U/mg collagen at 20 weeks, p < 0.001. Considerable disparity was observed in the intensity of glycation between aortic and tendon collagen. AGE-content per mg of aortic collagen was several-fold to that found in tendon collagen (p < 0.001). To investigate the effect of glycemic control on the advanced glycation process, total aortic AGE-collagen content was compared between untreated diabetic rats (D; n = 13, 184.9 +/- 12.3 U/mg) and diabetic rats treated for 12 weeks with insulin (DI; n = 6, 133.9 +/- 10.7 U/mg), or phlorizin (DP; n = 6, 132.4 +/- 8.9 U/mg), or by a combination of insulin/phlorizin (DIP; n = 6, 124.3 +/- 6.5 U/mg). In spite of therapy used, all groups of diabetic animals had a significantly higher aortic AGE-collagen content than those in the nondiabetic control group (C: n = 8, 104.6 +/- 14.9 U/mg) of the same age (D, DI, DP, DIP vs. C, p < 0.001). Comparison between the mean levels of glycated hemoglobin (D: 5.62 +/- 0.38 % vs. C: 1.7 +/- 0.05%) and mean AGE levels in the studied group of animals yielded a very good exponential correlation (r = 0.89, p < 0.001). Glycation-derived late-stage collagen modification was detected by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), and by immunoblotting confirmed to contain (an) AGE-structure(s). Our study provides strong immunochemical evidence of AGE formation in vivo during hyperglycemia, and of their temporal association with structural alterations of extracellular matrix proteins. The advanced glycation process is retarded and reduced in intensity, but not completely abolished, by glycemia regulation with, or independently of, insulin.
 ...
PMID:Rat tissue collagen modified by advanced glycation: correlation with duration of diabetes and glycemic control. 1053 30

The accelerated formation of advanced glycation end-products (AGEs) due to elevated glycemia has repeatedly been reported as a central pathogenic factor in the development of diabetic microvascular complications. The effects of a novel inhibitor of AGE formation, NNC39-0028 (2,3-diaminophenazine), and a breaker of already formed AGE cross-links, N-phenacylthiazolium bromide (PTB), were investigated in streptozotocin-diabetic female Wistar rats. Diabetes for 24 weeks resulted in decreased tail collagen pepsin solubility, reflecting the formation of AGE cross-linking. Collagen solubility was significantly ameliorated by treatment with NNC39-0028, whereas PTB had no effect. Increased urinary albumin excretion (UAE) in diabetic rats was observed in serial measurements throughout the study period, and was not reduced by any treatment. Vascular dysfunction in the eye, measured as increased clearance of 125I-albumin, was induced by diabetes. NNC39-0028 did not affect this abnormality. This study demonstrated a pharmacological inhibition of collagen solubility alterations in diabetic rats without affecting diabetes-induced pathophysiology such as the increase in UAE or albumin clearance. Treatment with PTB, a specific breaker of AGE cross-links, had no effects in this study.
 ...
PMID:Effects of advanced glycation end-product inhibition and cross-link breakage in diabetic rats. 1095 16

In this study, we examined the hypothesis that laser photostimulation can facilitate healing of impaired wounds in experimental diabetes using a rat model. Diabetes was induced in male rats by streptozotocin injection and two 6 mm diameter circular wounds were created on either side of the spine. The left wound of each animal was treated with a 632.8 nm He:Ne laser at a dose of 1.0 J/cm2 for five days a week until the wounds closed (three weeks). Measurements of the biomechanical properties of the laser-treated wounds indicated there was a marginal increase in maximum load (16%), stress (16%), strain (27%), energy absorption (47%) and toughness (84%) compared to control wounds of diabetic rats. Biochemical assays revealed that the amount of total collagen was significantly increased in laser treated wounds (274 +/- 8.7 microg) over the control wounds (230 +/- 8.4 microg). Sequential extractions of collagen from healing wounds showed that laser treated wounds had significantly greater concentrations of neutral salt soluble (15%) and insoluble collagen (16%) than control wounds, suggesting accelerated collagen production in laser treated wounds. There was an appreciable decrease in pepsin soluble collagen (19%) in laser treated wounds over control wounds, indicating higher resistance to proteolytic digestion. In conclusion, the biomechanical and biochemical results collectively suggest that laser photostimulation promotes the tissue repair process by accelerating collagen production and promoting overall connective tissue stability in healing wounds of diabetic rats.
 ...
PMID:Laser photostimulation accelerates wound healing in diabetic rats. 1147 21

Connective tissue susceptibility to nonenzymatic glycation was examined following 0, 2, 4, 6, 8, and 10 weeks of incubating the rabbit Achilles tendon in phosphate-buffered saline containing ribose (glycated). The biomechanical integrity of the glycated tendons was then compared to control tendons incubated in phosphate-buffered saline (non-glycated) at each time interval, while the biochemical stability of both groups of tendons was determined by examining collagen extractability and the formation of pentosidine at 8 weeks. Whereas there were no significant biomechanical differences between control and glycated tendons at 0- and 2-week intervals (P > 0.05), moderately significant increases in maximum load, energy to yield, and toughness of glycated tendons were observed at 4 weeks. Beyond 4 weeks of incubation, the differences between glycated and non-glycated tendons became highly significant, as glycated tendons withstood more load and tensile stress (P < 0.01 for each variable), attained significantly higher modulus of elasticity (P < 0.01), absorbed more energy (P < 0.01), and became tougher (P < 0.01) than controls. These differences in the biomechanical indices of the effects of glycation were stable between the 6th and 10th week of glycation. The maximum increases in the biomechanical measurements as a result of glycation were 29% for maximum load, 125% for stress, 19% for strain, 106% for Young's modulus of elasticity, 14% for energy to yield, and 57% for toughness. Biochemical analysis showed a 61% reduction in the extractability of neutral salt-soluble collagen, a 48% decrease in acid-soluble collagen, and a 29% decline in pepsin-soluble collagen in glycated tendons (P < 0.01). In contrast, there was a 28% increase in the amount of insoluble collagen and significantly higher amounts of pentosidine (P < 0.01) in glycated tendons. Collectively, these biomechanical and biochemical results suggest that nonenzymatic glycation may explain the altered stability of connective tissue matrix induced by the processes of diabetes and aging.
 ...
PMID:Glycation-induced matrix stability in the rabbit achilles tendon. 1188 3

Advanced glycation end products (AGE), formed by nonenzymatic Maillard reactions between carbohydrate and protein, contribute to the increase in chemical modification and crosslinking of tissue proteins with age. Acceleration of AGE formation in collagen during hyperglycemia, with resultant effects on vascular elasticity and basement membrane permeability, is implicated in the pathogenesis of diabetic complications. AGE-breakers, such as N-phenacylthiazolium (PTB) and N-phenacyl-4,5-dimethylthiazolium (PMT) halides, have been proposed as therapeutic agents for reversing the increase in protein crosslinking in aging and diabetes. We have confirmed that these compounds, as well as the AGE-inhibitor pyridoxamine (PM), cleave the model AGE crosslink, phenylpropanedione, and have studied the effects of these compounds in reversing the increased crosslinking of skin and tail collagen isolated from diabetic rats. Crosslinking of skin collagen, measured as the half-time for solubilization of collagen by pepsin in 0.5M acetic acid, was increased approximately 5-fold in diabetic, compared to nondiabetic rats. Crosslinking of tail tendon collagen, measured as insolubility in 0.05 N acetic acid, was increased approximately 10-fold. Collagen preparations were incubated in the presence or absence of AGE-breakers or PM in phosphate buffer, pH 7.4, for 24h at 37 degrees C. These treatments did not decrease the half-time for solubilization of diabetic skin collagen by pepsin or increase the acid solubility of diabetic tail tendon collagen. We conclude that, although AGE-breakers and PM cleave model crosslinks, they do not significantly cleave AGE crosslinks formed in vivo in skin collagen of diabetic rats.
 ...
PMID:AGE-breakers cleave model compounds, but do not break Maillard crosslinks in skin and tail collagen from diabetic rats. 1264 66

Changes in the structural and functional properties of collagen caused by advanced glycation might be of importance for the etiology of late complications in diabetes. The present study was undertaken to investigate the influence of oral administration of aqueous pod extract (200 mg/kg body weight) of Phaseolus vulgaris, an indigenous plant used in Ayurvedic Medicine in India, on collagen content and characteristics in the tail tendon of streptozotocin-diabetic rats. In diabetic rats, collagen content (117.01 6.84 mg/100 mg tissue) as well as its degree of cross-linking was increased, as shown by increased extent of glycation (21.70 0.90 g glucose/mg collagen), collagen-linked fluorescence (52.8 3.0 AU/ mol hydroxyproline), shrinkage temperature (71.50 2.50 C) and decreased acid (1.878 0.062 mg hydroxyproline/100 mg tissue) and pepsin solubility (1.77 0.080 mg hydroxyproline/100 mg tissue). The alpha/ ratio of acid- (1.69) and pepsin-soluble (2.00) collagen was significantly decreased in streptozotocin-diabetic rats. Administration of P. vulgaris for 45 days to streptozotocin-diabetic rats significantly reduced the accumulation and cross-linking of collagen. The effect of P. vulgaris was compared with that of glibenclamide, a reference drug administered to streptozotocin-diabetic rats at the dose of 600 g/kg body weight for 45 days by gavage. The effects of P. vulgaris (collagen content, 64.18 1.97; extent of glycation, 12.00 0.53; collagen-linked fluorescence, 33.6 1.9; shrinkage temperature, 57.0 1.0; extent of cross-linking - acid-soluble collagen, 2.572 0.080, and pepsin-soluble collagen, 2.28 0.112) were comparable with those of glibenclamide (collagen content, 71.5 2.04; extent of glycation, 13.00 0.60; collagen-linked fluorescence, 38.9 2.0; shrinkage temperature, 59.0 1.5; extent of cross-linking - acid-soluble collagen, 2.463 0.078, and pepsin-soluble collagen, 2.17 0.104). In conclusion, administration of P. vulgaris pods had a positive influence on the content of collagen and its properties in streptozotocin-diabetic rats.
 ...
PMID:Effect of an aqueous extract of Phaseolus vulgaris on the properties of tail tendon collagen of rats with streptozotocin-induced diabetes. 1284 72

The function of the stomach includes initiation of digestion by exocrine secretions such as acid and pepsin, which are under the control of the endocrine secretion of hormones that also coordinate intestinal motility. The stomach also stores and mechanically disrupts ingested food. Various techniques have been developed to assess gastric physiology, the most important of which is assessment of acid secretion, as well as gastric motility and gastric emptying. The influence of drugs on gastric function and the effect of gastric secretion and mechanical actions on the bioavailability of novel compounds are of critical importance in drug development and hence to clinical pharmacologists. The control of acid secretion is essential in the treatment of peptic ulcer disease as well as gastrooesophageal reflux disease (GORD); pH-metry can be used to determine the necessary dose of an acid suppressant to heal mucosal damage. Disturbed gastric myoelectric activity leading to gastroparesis can cause delayed gastric emptying, often found in patients with diabetes mellitus. Electrogastrography (EGG) may be used to evaluate the influence of prokinetics and other drugs on this condition and aid in determining effective therapy.
 ...
PMID:Gastric function measurements in drug development. 1289 88


<< Previous 1 2 3 4 5 6 Next >>