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)

Solubility of tail tendon collagen from normal, streptozotocin-induced diabetic Lewis rats, and diabetic animals treated with aminoguanidine and two novel advanced glycosylation end products (AGE)-formation inhibitors was investigated by limited pepsin digestion under acidic conditions. Assays were conducted using tail tendon collagen from Lewis rats obtained from two different vendors, Harlan and Charles River Laboratories. Collagen solubility was assessed by following the kinetics of pepsin digestion. The data revealed that the rate of digestion for diabetic animals is markedly slow relative to that of normals. More strikingly, the kinetics of the diabetic animals showed the feature of a lag in digestion regardless of the animal source. Experiments designed to optimize the difference in solubility between normal and diabetic animals demonstrated that Charles River animals exhibit a greater window of solubility than the Harlan animals. More importantly, a pronounced effect of aminoguanidine, an AGE-formation inhibitor, was observed in Charles River animals, but not in the Harlan animals, presumably because of the larger window of solubility between the normal and the diabetic animals in the former. These data indicated that the Charles River Lewis rats are an animal model that demonstrates greater efficacy in this assay. Analysis of in vivo screens designed to test efficacy of aminoguanidine and two novel AGE-formation inhibitors, ALT 462 and ALT 486, demonstrated that monitoring an in vivo dose response is highly dependent on the enzyme concentration as well as the time of digestion, and that 1.5 h of digestion and 10 microg/ml pepsin (5 pg pepsin/mg collagen) appeared optimal. Under these conditions, a 29% normalization of solubility was observed with aminoguanidine at 100 mg/kg body wt, whereas a similar normalization was observed at 10 mg/kg body wt for both ALT 462 and ALT 486. Thus, on a molar basis, ALT 462 and ALT 486 are at least 20 times more potent than aminoguanidine. This is the first demonstration of dose-dependent efficacy for AGE-formation inhibitors in animal models, and as such, this assay provides a method with which to assess the in vivo efficacy of other such inhibitors.
Diabetes 1996 Dec
PMID:Chronic dosing with aminoguanidine and novel advanced glycosylation end product-formation inhibitors ameliorates cross-linking of tail tendon collagen in STZ-induced diabetic rats. 892 53

The chemical reactivity of collagen can be studied using neutron diffraction (a non-destructive technique), for certain reaction types. Collagen contains a number of lysine and hydroxylysine side chains that can react with aldehydes and ketones, or these side chains can themselves be converted to aldehydes by lysyl oxidase. The reactivity of these groups not only has an important role in the maintenance of mechanical strength in collagen fibrils, but can also manifest pathologically in the cases of aging, diabetes (reactivity with a variety of sugars) and alcoholism (reactivity with acetaldehyde). The reactivity of reducing groups with collagen can be studied by neutron diffraction, since the crosslink formed in the adduction process is initially of a Schiff base or keto-imine nature. The nature of this crosslink allows it to be deuterated, and the position of this relatively heavy scattering atom can be used in a process of phase determination by multiple isomorphous replacement. This process was used to study the following: the position of natural crosslinks in collagen; the position of adducts in tendon from diabetic rats in vivo and the in vitro position of acetaldehyde adducts in tendon.
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PMID:The chemical reactivity and structure of collagen studied by neutron diffraction. 903 21

Collagen-induced arthritis in the diabetes-resistant BB (DR BB)/Wor rat is a severe, aggressive disease initiated by immunization with heterologous native Type II collagen. Onset of clinical symptoms reproducibly occurs in 100% of animals between days 10 and 12 following collagen immunization. Hypertrophy of the synovial lining is the first histological manifestation of the early inflammatory arthritis. A mild inflammatory infiltrate in the synovium rapidly becomes a fibrovascular pannus eroding articular cartilage and subchondral bone. Beginning at the joint margins, an active synovitis is present. Light microscopy and immunohistochemical staining show the infiltrate to be comprised of mononuclear (lymphocytes, macrophages) and polymorphonuclear inflammatory cells. In addition, there is histological evidence for chronic inflammatory nodules and necrotizing vasculitis in connective tissue from diseased joints, both morphologic features associated with rheumatoid arthritis in humans. Subchondral bone erosion appears to be mediated largely by the resorptive action of activated osteoclasts. These histological parameters of disease progression in the DR BB/Wor rat are similar to human rheumatoid arthritis. The extensive degree of similarity in the pathology of DR BB/Wor rat collagen-induced arthritis and human rheumatoid arthritis supports the role of this model as an in vivo disease model for human rheumatoid arthritis.
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PMID:Clinical and histological assessment of collagen-induced arthritis progression in the diabetes-resistant BB/Wor rat. 906 45

Nonenzymatic glycosylation (glycation) of proteins, often referred to as the Maillard reaction, has been proposed to play a role in age and diabetes-related processes by forming protein and DNA adducts and cross-links. These cross-links may contribute to erectile dysfunction by scavenging nitric oxide, which is needed for erection. As the basis for a possible role of the advanced Maillard reaction in age-related erectile dysfunction, we investigated the presence of the specific advanced glycation endproduct (AGE) pentosidine in penile corpus cavernosum tissue and penile tunica albuginea tissue as a function of age. A total of 23 penile tissue specimens were obtained at autopsy, from which 19 samples of tunica albuginea and 21 samples of corpus cavernosum were derived. In addition, 13 penile corporal and tunical specimens were procured at the time of insertion of a penile prosthesis, from which 12 tunica albugineal specimens and 10 samples of corpus cavernosum were derived. Collagen was extracted with acetic acid and pepsin digestion, and the final insoluble collagen product was acid-hydrolyzed with 6 N HCL for 24 h at 110 degrees C. Pentosidine was quantified by high-performance liquid chromatography using a reverse-phase column. The level of pentosidine (expressed in picomoles per milligram of insoluble collagen) was found to increase with age in cadaver as well as living penile corporal and tunical albugineal tissues. Best-fit analysis revealed an exponential increase in both types of cadaver penile tissue, with regression equations of y = 15.29 x 10(9.9e-3x), R2 = 0.79, being obtained in the tunica and y = 13.2 x 10(7.63e-3x), R2 = 0.56, in the corpora. These correspond to 6- and 4-fold increases in pentosidine levels from puberty to the age of 100 years (P < 0.05), respectively. Mean pentosidine levels were higher in the tunica than in the corpora. Comparison of pentosidine levels in the tunica versus the corpora revealed a weakly linear correlation (y = 24.88 + 1.08x, R2 = 0.32). Levels in the tunical and corporal specimens from the living human specimens fell with the predicted confidence intervals of the cadaveric tissue. Tunical specimens from patients who underwent repair or revision of a previously inserted penile prosthesis had very low levels of pentosidine. The exponential age-related increase in pentosidine observed in both types of penile tissue suggests an impairment of collagen turnover, which could be related to the advanced glycation reaction in aging. It is not known whether pentosidine itself is directly associated with erectile dysfunction, but its formation is usually accompanied by extensive tissue modification. Formation of advanced Maillard reaction products, which is greatly accelerated in aging, diabetes, and uremia, could contribute to erectile dysfunction in these syndromes.
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PMID:Age-related increase in an advanced glycation end product in penile tissue. 911 57

Excessive production and deposition of extracellular matrix proteins are characteristic features of diabetic nephropathy. This study tests the hypothesis that cells from diabetic patients who develop nephropathy have a disturbance in collagen metabolism compared with cells from diabetic patients without complications. Kinetics of overall collagen metabolism and total protein synthesis were examined in serially passaged, subconfluent, quiescent skin fibroblasts cultured in either normal (5 mM) or high (25 mM) glucose concentrations from 14 insulin-dependent diabetic (IDDM) patients with nephropathy; 14 IDDM patients without nephropathy matched for age, diabetes duration, and body mass index; and 14 healthy subjects. Fibroblasts were incubated in the presence of 2 microCi/ml [3H]proline, and after labeling the incorporation of [3H]proline into total protein, collagen (collagenase-sensitive material), and noncollagen proteins (collagenase-resistant material) was determined at different time points. Collagen degradation was determined in pulse-chase experiments by following the residual collagen-bound radioactivity after incubation for 8 h with 10 microCi/ml [3H]proline. In high glucose concentrations (25 mM), overall collagen synthesis (measured as [3H]proline incorporation into extracellular and intracellular collagenase-sensitive material) was significantly greater in the patients with nephropathy (mean +/- SEM after a 24-h labeling period: 7189 +/- 671 dpm/10(6) cells) than in the patients without (4341 +/- 267 dpm/10(6) cells; P < 0.01) or healthy control subjects (3836 +/- 234 dpm/10(6) cells; P < 0.01). No significant differences were observed in noncollagen protein production or in collagen degradation rates among the three groups of subjects. In the presence of normal glucose concentrations (5 mM), collagen synthesis was lower in all groups studied, but the differences between IDDM patients with nephropathy and those without remained unaltered. These results suggest that long-term cultured fibroblasts derived from diabetic patients with nephropathy exhibit an abnormality in collagen metabolism. Cells from long-standing diabetic patients without nephropathy have normal collagen metabolism. The increased collagen synthesis is likely to be intrinsic to those diabetic patients susceptible to nephropathy and may play an important role in the sclerotic processes that occur in the kidneys, arteries, and heart.
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PMID:Enhanced collagen synthesis in cultured skin fibroblasts from insulin-dependent diabetic patients with nephropathy. 921 63

Collagen IV matrix of glomerular basement membrane may be involved in the development of various renal diseases, e.g. diabetic nephropathy. An immunoblotting method for the detection of the carboxy-terminal non-collagenous (NC1) domain of type IV collagen in plasma was developed. The high sensitivity down to the picogram range enabled characterization of NC1(IV) fragments in human blood for the first time. Both Western blotting and gel filtration chromatography coupled with an enzyme-linked immunoassay surprisingly revealed that the NC1(IV)-related components are bound to the fibrin clot forming during blood coagulation. About 40% of the NC1(IV) fragments in plasma had an apparent molecular mass higher than 340,000. Abnormal NC1(IV) immunoblot patterns were observed in about 50% of patients with insulin-dependent (n = 20) and non-insulin-dependent (n = 20) diabetes mellitus compared with less than 7% in healthy control subjects (n = 30). There were no obvious associations between abnormal immunoblots and stage of nephropathy or glycaemic control in diabetic subjects.
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PMID:Western blotting of NC1 type IV collagen fragments in human plasma. 926 46

A reasonable interpretation of the present evidence indicates that diabetes, when a complication of periodontitis, acts as a modifying and aggravating factor in the severity of periodontal infection. Diabetics with periodontitis who were young and poorly controlled, those who were long-duration diabetics, especially those over 30 years old, demonstrated more attachment loss, bone loss, and deeper probing pocket depths than their nondiabetic controls. It seems that the earlier the onset of diabetes and the longer the duration, especially without consistent control, the more susceptible the individual will be to periodontal disease. Consequently, once a diabetic contracts periodontal disease, it is usually more destructive. Although plaque scores of diabetics may be comparable to or even less than those of nondiabetics, diabetics often exhibit higher gingival index scores. The elevation of this particular clinical parameter is indicative of the microangiopathy associated with diabetes. Diabetic microangiopathy contributes to compromised delivery of nutrients to surrounding tissues and poor elimination of metabolic waste products. The complications associated with diabetes such as macroangiopathy, microangiopathy (i.e., retinopathy), ketoacidosis, and hyperglycemia result in impaired wound healing, immunosuppression, and susceptibility to bacterial infection. Individuals ages 30 to 40 suffering from diabetic retinopathy had significantly more gingival inflammation than controls or diabetics without complications. Collagen metabolism is defective in diabetics and is one component underlying delayed wound healing. Animal studies have been instrumental in elucidating the details of delayed wound healing. Hyperglycemia was associated with increased collagenase and protease activity in the gingiva of rats. Vascular wound healing in rats, particularly new re-endothelialization across vascular anastomoses, was significantly impaired. Diabetic abnormalities in immune response include impaired neutrophil chemotaxis, phagocytosis, and adhesion. Decreased neutrophilic chemotactic response seems to be attributable to protein factors in diabetic serum that competitively bind neutrophil receptors, thereby preventing complement-mediated phagocytosis. Because diabetics are not able to eliminate circulating immune complexes (CIC) effectively, serum CIC levels are elevated. There are microbiological differences in the characteristic flora of NIDDM patients and IDDM patients with periodontitis. These differences are not associated with diabetic impaired immune response. Ultimately, bacterial plaque is the primary etiology of periodontal diseases. Evidently, the host's response to bacterial plaque and ability to heal following surgery is altered by diabetic disease. Therefore, a thorough history regarding onset of diabetes, duration, and diabetic control would prove useful in the clinical management of diabetics presenting for treatment of periodontal disease.
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PMID:Periodontal disease, diabetes, and immune response: a review of current concepts. 947 64

The Maillard reaction, a non-enzymatic reaction of ketones and aldehydes with amino groups of proteins, contributes to the aging of proteins and to complications associated with diabetes. Methylglyoxal (MG) is a 2-oxoaldehyde derived from glycolytic intermediates and produced during the Maillard reaction. We reported previously the formation of a lysine-lysine protein cross-linking structure (imidazolysine) and a fluorescent arginine modification (argpyrimidine) from the Maillard reaction of MG. Here we show that rabbit antibodies to MG-modified ribonuclease A identify proteins modified by the Maillard reaction of glucose, fructose, ribose, glyceraldehyde, glyoxal, ascorbate, and ascorbate oxidation products (dehydroascorbate, 2,3-diketogulonate, L-xylosone, and L-threose) in addition to those modified by MG. The antibody recognized imidazolysine and argpyrimidine and a glyoxal-derived lysine-lysine cross-link. It did not react with Nepsilon-carboxymethyllysine. Incubations with amino acids revealed strongest reactivity with Nalpha-t-butoxycarbonylarginine and MG, and we identified argpyrimidine as one of the epitopes from this incubation mixture. Serum proteins from human diabetics reacted more strongly with the antibody than those from normal individuals, and the levels correlated with glycemic control. Collagen from human corneas contained MG-derived modifications, with those from older subjects containing higher levels of modified proteins than those from younger ones. An immunoaffinity-purified antibody showed higher reactivity with old corneas than with younger ones and localized the antigens primarily within the stromal region of the cornea. These results confirm reported MG-derived modifications in tissue proteins and show that dicarbonyl-mediated protein modification occurs during Maillard reactions in vivo.
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PMID:Immunological evidence for methylglyoxal-derived modifications in vivo. Determination of antigenic epitopes. 950 98

We investigated the relationship between left ventricular diastolic function and interstitial collagen content in the endocardium, mesocardium and epicardium of transverse sections of the heart, using an image analysis system in normotensive and hypertensive long-term streptozotocin (STZ) diabetic rats. STZ-induced diabetes was characterised by elevated blood glucose, polyuria, polydypsia and loss of body weight. In vivo systolic blood pressure was 165 +/- 4, 136 +/- 3 and 129 +/- 7 mmHg in hypertensive and normotensive diabetic rats and age-matched controls, respectively. Heart rate was significantly lower (P < 0.01) in diabetic rats (283 +/- 8 and 280 +/- 10 beats min-1 in normotensive and hypertensive rats, respectively) than controls (393 +/- 18 beats min-1). Pressure-volume (P-V) curves were studied in isolated Langendorff perfused hearts at rest and after 20 min global ischaemia and 30 min reperfusion 6 months after induction of diabetes. Left ventricular volumes were significantly smaller in diabetic rats than age-matched controls, but volumes normalised for heart weight were higher in normotensive (by 28%) and hypertensive (by 10%) diabetic rats. Slopes of end-diastolic P-V curves were similar between groups in basal conditions, but left ventricular systolic P-V curves were steeper in normotensive and flatter in hypertensive diabetic hearts. Post-ischaemic left ventricular end-diastolic pressure was significantly higher than the pre-ischaemic value at comparable increments of volume in each group. Collagen content significantly increased in the heart of rats with STZ-diabetes both in the free left ventricular wall and septum, and suggested this may play a role in the cardiac defects in contractility and relaxation in our experimental conditions. These results indicate that diabetes, irrespective of associated hypertension, can cause major changes in cardiac performance and susceptibility to ischaemia and reperfusion.
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PMID:Changes in diastolic function and collagen content in normotensive and hypertensive rats with long-term streptozotocin-induced diabetes. 960 73

Mesenteric vascular hypertrophy occurs in experimental diabetes. The present study examines whether this medial hypertrophy originates via cellular hyperplasia or hypertrophy of smooth muscle cells or an increase in collagen content. Male Sprague-Dawley diabetic (streptozotocin, 50 mg/kg, i.v.) rats were compared with control rats after 3 weeks in order to study mesenteric and aortic smooth muscle cell size and degree of cellular polyploidy. Collagen content in the mesenteric vessels was examined via staining with Sirius red. Further groups of control and diabetic animals were studied after 7 and 14 days of diabetes to assess proliferation in the various layers of the vessel wall using incorporation of [3H]thymidine (0.5 mCi/kg, i.p.). Smooth muscle cell size was measured by a Coulter counter and polyploidy assessed using flow cytometry measurement of cellular DNA content. Diabetic smooth muscle cell size was reduced in both the aorta and the mesenteric vessels and polyploidy was increased in these cells. The collagen content of diabetic mesenteric media was proportionally increased. At day 7, diabetic mesenteric endothelial and adventitial layers showed increased [3H]thymidine labeling of cells and this was not observed in the media of these vessels. These findings indicate that increased endothelial and adventitial cell proliferation are early events in diabetes associated vascular hypertrophy. Furthermore, an increase in extracellular matrix within the media is an important feature of diabetes associated vascular hypertrophy.
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PMID:Cellular mechanisms of diabetic vascular hypertrophy. 988 58


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