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)

The pathogenesis of diabetic nephropathy relative to the changes in the glomerular extracellular matrices was investigated. Renal tissues from 10 diabetic patients were immunostained with antibodies directed against heparan sulfate proteoglycans (HS-PGs), laminin, type IV collagen and fibronectin. Seven patients were nephrotic and had advanced glomerulosclerosis with nodular lesion, while the other 3 had no renal manifestations or minor glomerular tissue alterations. Controls included kidneys removed from patients with renal tumors and specimens obtained by renal biopsy from patients with IgA nephropathy. Relationships among proteinuria, intensity of fluorescence and glomerular changes were studied. In diabetes 3 patients with minor glomerular lesions were found to have no changes in various components of extracellular matrices. A marked reduction in the intensity of staining with anti-HS-PG antibodies was observed in renal specimens from patients with nodular glomerulosclerosis and proteinuria, while a mild decrease in the intensity of fluorescence was observed in tissues stained with antilaminin antibodies. An increase compared to normal control sample findings in type IV collagen and fibronectin was observed in the mesangium of sclerosing glomeruli. No loss of HS-PG was observed in patients with IgA nephropathy. These results indicate that glomerular extracellular matrix HS-PG is lost in association with diabetic nephropathy; this loss results in alteration of the charge-selective properties of glomerular capillaries. This alteration may, in part, be the cause of the proteinuria associated with diabetic nephropathy.
 ...
PMID:Heparan sulfate proteoglycans are lost in patients with diabetic nephropathy. 150 38

Advanced glycosylation endproducts (AGEs) accumulate on long-lived tissue proteins such as basement membrane collagen and have been implicated in many of the long-term complications of diabetes mellitus. These products originate from glucose-derived Schiff base and Amadori products but undergo a series of complex rearrangement reactions to form ultimately protein-bound, fluorescent heterocycles. AGEs can react with and chemically inactivate nitric oxide (NO), a potent endothelial cell-derived vasodilator and antiproliferative factor. Since mesenchymal cell proliferation is an early and characteristic lesion of diabetic vasculopathy and glomerulopathy, we investigated the possibility that collagen-bound AGEs functionally inactivate the antiproliferative effect of NO. In model cell culture systems, AGEs were found to block the cytostatic effect of NO on aortic smooth muscle and renal mesangial cells. The inactivation of endothelial cell-derived NO by basement membrane AGEs may represent a common pathway in the development of the accelerated vascular and renal disease that accompany long-term diabetes mellitus.
 ...
PMID:Advanced glycosylation endproducts block the antiproliferative effect of nitric oxide. Role in the vascular and renal complications of diabetes mellitus. 152 20

The role of oxygen in chemical modification and cross-linking of rat tail collagen by glucose was studied at physiological pH and temperature in vitro. Cross-linking of collagen under air depended on glucose concentration, but was inhibited under antioxidative conditions (nitrogen atmosphere with transition metal chelators). The cross-linking reaction under air depended on phosphate buffer concentration, but this effect was eliminated by addition of chelators, identifying trace metal ions in the buffer as catalysts of oxidative cross-linking reaction. Antioxidative conditions had no effect on glycation, that is, formation of fructose lysine, but inhibited formation of the glycoxidation products N epsilon-(carboxymethyl)lysine and pentosidine as well as the development of fluorescence in glycated collagen. Glycation itself decreased during continued incubation of the collagen without glucose; however, cross-linking and concentrations of glycoxidation products and fluorescence in collagen were not reversible under either oxidative or antioxidative conditions. These observations are consistent with recent studies in vivo on the reversibility of collagen glycation, the irreversibility of formation of glycoxidation products and fluorescence, and the strong correlations between glycoxidation products and fluorescence in collagen (1). These results indicate that oxidation reactions play a critical role in the extended chemical modification and cross-linking of collagen by glucose and suggest that measurement of glycoxidation products should be useful for assessing cumulative chemical modification of collagen by glucose in vivo.
Diabetes 1992 Oct
PMID:Role of oxygen in cross-linking and chemical modification of collagen by glucose. 152 35

Laminin and type IV collagen are two major basement membrane glycoproteins; they are large multidomain macromolecules that are involved in two types of functions. First, they provide the structural framework of all basement membranes, and second, they interact with cell-surface molecules and are key to adhesion, spreading, and proliferation of cells. We summarize experimental evidence that nonenzymatic glucosylation of these two macromolecules in vitro alters their structure, their ability to polymerize, and their ability to promote cell adhesion. Additional studies are needed to document these changes in situ and therefore extend these conclusions to intact basement membranes.
Diabetes 1992 Oct
PMID:Structural and functional changes of laminin and type IV collagen after nonenzymatic glycation. 152 36

Biosynthetic regulation of renal glomerular heparan sulfate-proteoglycans by various aldohexoses (mannose, glucose, and galactose) was investigated. Isolated kidneys were perfused for 5 hr with medium containing [35S]sulfate, to label sulfated proteoglycans, or [35S]methionine, to label total glomerular proteins. All the hexoses, above 10 mM concentration, caused a significant decrease in the de novo synthesis of [35S]sulfate-labeled proteoglycans. The relative effectiveness of the hexoses was as follows: mannose much greater than glucose greater than galactose. The proteoglycans were of relatively lower molecular weights and exhibited reduced charge-density characteristics. Autoradiographic studies revealed a 2- to 3-fold decrease of grain density over the glomerular basement membrane and mesangial compartments, and immunoprecipitable heparan sulfate-proteoglycans were similarly decreased 2- to 3-fold. There was no significant decrease in the total [35S]methionine-labeled glomerular proteins or immunoprecipitable type IV collagen and laminin. Cellular ATP levels were dramatically reduced in all groups, and the maximal depletion was caused by mannose. Addition of ATP (0.1-1.0 mM) to the perfusion medium resulted in the normalization of the de novo synthesis and of the biochemical characteristics of heparan sulfate-proteoglycans. The relevance of decreased de novo synthesis of proteoglycans due to the depletion of ATP in hyperglycemic states is discussed in terms of increased glomerular permeability to plasma proteins, as seen in diabetes mellitus.
 ...
PMID:Biosynthetic regulation of proteoglycans by aldohexoses and ATP. 152 71

To see whether or not blood-retinal barrier breakdown during diabetes was associated with breakdown of the endothelial cell tight junctions or with other membrane alterations in the cells comprising the wall of the retinal microvasculature, streptozotocin-induced diabetic rat retinas were studied using lanthanum tracer and freeze-fracture electron microscopic morphometry. This study showed that endothelial cell tight junction permeability to lanthanum and luminal surface area were normal in these diabetic rats. However, freeze-fracture morphometry showed several alterations in the diabetic retinal microvessels. First, the endothelial cell membranes had abnormally large (80-120 nm) plasmalemmal vesicles not evident in the control retinas, suggesting that membrane turnover was abnormal. Second, endothelial cell P-face membranes at the blood front contained more larger particles than those in the control rats (P less than 0.05), implying an alteration in endothelial cell luminal membrane composition. Third, endothelial cell P-face membranes in areas of close apposition with pericyte membranes showed abnormal areas of particle clearing not seen in the control animals, suggesting a change in pericyte-endothelial cell interactions. Finally, pericyte membranes facing the neural retina contained increased numbers of plasmalemmal vesicles compared with control membranes (P less than 0.05). Moreover, the association of these vesicles with collagen fibrils in the extracellular space suggested an alteration in extracellular matrix turnover.
 ...
PMID:Freeze-fracture and lanthanum studies of the retinal microvasculature in diabetic rats. 153 91

Streptozotocin-induced, insulin-deficient diabetic rats were administrated either minocycline (MC) or a chemically modified non-antimicrobial tetracycline (CMT) by oral gavage for a 3-week period; untreated diabetic and nondiabetic rats served as controls. On day 21, all rats received an intravenous injection of 3H-proline followed by perfusion fixation with an aldehyde mixture at 20 minutes and 4 hours after isotope injection. The parietal bones of these rats were dissected and processed for quantitative electron microscopic autoradiography to study 3H-proline utilization by osteoblasts. At 20 minutes after 3H-proline injection, radioprecursor was incorporated by the Golgi-RER system of the osteoblasts in the periosteal surface of the control rats. At the 4-hour time period, most of the label was present over the collagen fibers of the osteoid. In contrast, the flattened bone-lining cells in the untreated diabetic rats showed minimal uptake (20 minutes) and secretion (4 hours) of labeled proline. In both MC and CMT-treated diabetic rats, the radioprecursor was localized in the osteoblasts and osteoid matrix in a pattern similar to that seen in the control rats at both 20 minutes and 4 hours after isotope injection. Labeling of the osteoid by the radioprecursor was greater as a result of CMT treatment than during minocycline treatment. These results suggest that the diabetes-induced suppression of synthesis and secretion of protein (presumably collagen and its precursor) by osteoblasts can be restored to near-normal levels by administration of tetracycline(s) and that this effect is mediated by a non-antimicrobial property of these antibiotics.
 ...
PMID:Tetracycline administration increases collagen synthesis in osteoblasts of streptozotocin-induced diabetic rats: a quantitative autoradiographic study. 153 8

The effects of insulin (5 U/day subcutaneously for 60 days) and aminoguanidine (25 mg./kg./day via gavage for 60 days) on collagen concentration, resistance to enzymatic digestion with Pronase E, and the accumulation of advanced glycosylation end products in bladder tissue were studied in male streptozotocin-diabetic rats. The characteristic autofluorescence of glycosylated connective tissue was used to quantitate advanced glycosylation end products. Fluorescence was measured in digests of bladder tissue and expressed as fluorescence/micrograms. of hydroxyproline. Correlation to alterations in bladder function was made by studying in-vivo bladder micturition and in-vitro length-tension relations of bladder strips. Five groups of age-matched rats were studied: 1) controls, 2) controls treated with aminoguanidine, 3) diabetics, 4) diabetics treated with aminoguanidine, and 5) diabetics treated with insulin. The collagen concentration and the amount of collagen released by enzymatic digestion decreased while the connective tissue autofluorescence increased in bladders from diabetic rats. Insulin was able to prevent all of the observed changes while aminoguanidine protected against changes in accumulation of advanced glycosylation end products and resistance to enzymatic digestion but not against changes in collagen concentration. Stretchability of the bladder as measured by length-tension relations of bladder strips was inversely proportional to the amount of collagen, and therefore increased in diabetic rats. Diabetes of two months duration resulted in altered micturition pattern (increased fluid consumption, diuresis, micturition frequency, and average volume per micturition). Alterations in in-vivo and in-vitro bladder function were prevented by insulin treatment but not by aminoguanidine treatment. We have shown that the collagen component of the bladder wall changes in amount as well as in quality in the diabetic rat. Our data suggest that the amount, rather than the properties of collagen, is important for bladder function.
 ...
PMID:Collagen and bladder function in streptozotocin-diabetic rats: effects of insulin and aminoguanidine. 153 82

The angiotensin converting enzyme (ACE) inhibitors are a group of effective drugs with a unique mechanism of action. These drugs have proven to be useful for hypertension and congestive heart failure. Early clinical trials of captopril used doses that are now known to be inappropriately high, and dose-related adverse effects were observed frequently. The recognition that lower doses are effective has reduced the incidence of adverse reactions and resulted in improved patient tolerance. When patients are properly selected and correctable risk factors are removed, serious side effects are uncommon. Unfortunately, the early reputation of nephrotoxicity persists, as does the belief that significant blood dyscrasias, endocrine effects and rash are serious risks for the average patient. After wide use of captopril, enalapril and lisinopril, and investigational trials of nearly a dozen newer agents, a sufficiency of clinical observation, experimental evidence and accurate postmarketing recording of events is accumulating to allow insight into the major toxicities with regard to more intelligent patient selection, more rational dosing and proper identification of risk factors. The most common adverse reactions are cough and skin rash. It appears that the agents are generally not cross-reactive with regard to skin rash, although it is not clear whether this effect is drug-specific or class-specific with regard to cough. Statistically but not clinically significant lowering of haemoglobin and hematocrit is common; these effects are inconsequential in most patients. Neutropenia, once thought to be prevalent, now appears to be so only in patients with autoimmune or collagen-vascular disease; the majority of patients outside these groups are at low risk. Hyperkalaemia is a frequent occurrence. This should not be surprising in view of the effect of the ACE inhibitors on plasma aldosterone. When dietary potassium intake is regulated and sources of altered potassium excretion are identified, hyperkalaemia is seldom a serious problem. Identification of sodium and water deficits allows correction before the drugs are started, and the frequency of hypotension and hyperkalaemia caused by the drugs is quite low if these factors are properly managed. An unexpected finding emerging in recent years is the dry cough associated with ACE inhibitor therapy. Its mechanism is not definitely known. Nonsteroidal anti-inflammatory drugs may control this symptom in some patients. The frequent observation of proteinuria in patients taking ACE inhibitors has gained notice and sometimes caused undue alarm. It is difficult to separate disease effects in diabetes and hypertension from true drug effects.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Adverse effects of angiotensin converting enzyme (ACE) inhibitors. An update. 153 95

Alterations in the biophysical properties of connective tissues in diabetes mellitus have been attributed to the nonenzymatic glycation of the collagens and the subsequent formation of browning products, cross-linking the proteins. Aminoguanidine may bind to carbonyl groups of these nonenzymatic glycation products and thereby block the process. Rats with streptozotocin-induced diabetes were treated with aminoguanidine, 25 mg.kg-1.day-1, for 120 days. The aminoguanidine treatment did not counteract the increase in blood glucose concentrations, nor did it prevent the arrest in weight gain of diabetic rats. The increased stability in 7 mol/l urea and increased tensile strength of tail tendons from the diabetic rats, however, were prevented by the aminoguanidine treatment. Aminoguanidine did not reduce the formation of early nonenzymatic glycation products (aldimine and Amadori rearrangement products), whereas the amount of browning products (fluorescent compounds) was reduced in the tail tendon collagen of the diabetic rats. Aminoguanidine treatment of intact rats did not influence these parameters. These findings indicate that the biophysical alterations of collagens induced by experimental diabetes are caused by cross-links derived from the nonenzymatic glycation, and furthermore, that aminoguanidine treatment may prevent the concomitant changes in biophysical properties of connective tissues.
 ...
PMID:Aminoguanidine treatment reduces the increase in collagen stability of rats with experimental diabetes mellitus. 154 76


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>