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

Laminin, a basement membrane protein derived from the matrix of the Engelbreth-Holm-Swarm murine tumor, was nonenzymatically glycosylated in vitro in the presence of increasing glucose concentrations. The amount of glucose incorporated per laminin molecule was shown to be proportional to the molarity of glucose used. Nonenzymatic glycosylation resulted in formation of cross-links and alterations of the cruciform shape of laminin molecules; these alterations were dramatic when high concentrations of glucose were used. One of the functions of laminin, the process of self-assembly, was shown to be impaired after in vitro nonenzymatic glycosylation. Glucose incorporation resulted in a dramatic decrease of long-to-long laminin dimers, which normally form during the initial steps of assembly. Furthermore, nonenzymatic glycosylation of laminin reduced its ability to self-associate into complexes larger than dimers, as judged by turbidimetry. The observed decrease of maximal turbidity was proportional to the degree of nonenzymatic glycosylation. Aminoguanidine, which has been suggested to inhibit cross-link formation, was shown to restore to a large extent the shape of laminin, the percentage of long-to-long arm dimers, and the maximal turbidity when included in the mixtures of laminin and glucose. These data suggest that structural and functional alterations of laminin may be primarily due to formation of cross-links. Such modifications of laminin (along with our basement membrane components) may contribute to the morphological and physiological changes observed in basement membranes under diabetic conditions.
Diabetes 1990 Jul
PMID:Laminin alterations after in vitro nonenzymatic glycosylation. 211 13

The effects of islet isografting and of aminoguanidine on the accumulation of advanced glycosylation end-products (AGE) in renal basement membranes were studied in Streptozotocin (STZ)-induced diabetes mellitus in female BALB/c mice. The characteristic autofluorescence of glycosylated collagen was used to quantitate AGE. We studied the effect of islet isografting using 3 groups of mice, sacrificed at age 13 to 15 months: group A, untreated diabetes (STZ 250 mg/kg intravenously at age 6 to 8 weeks); group B, untreated diabetes for 7 months, then successfully grafted with cultured islet cells; and group C, age-matched normal control animals. At sacrifice, AGE were measured in digests of renal basement membranes as collagen-linked fluorescence/unit of hydroxyproline. Group A animals had significantly greater renal basement membrane glycosylation than did the other 2 groups, (group A median 88.0 arbitrary units/mumol hydroxyproline, range 30.2 to 127.5; group B median 19.4, range 5.1 to 56.8; group C median 2.9 range 0-13.5; p = .001 A versus B). To study the effect of aminoguanidine, 4 groups of animals were used: group 1, untreated diabetics (STZ 250 mg/kg intravenously at age 6 to 8 weeks); group 2, diabetics treated with aminoguanidine 50 mg/kg intraperitoneally daily; group 3, age-matched control animals, and group 4, age-matched controls treated with aminoguanidine. At sacrifice after 7 months, AGE were measured in digests of renal basement membranes as collagen-linked fluorescence/unit of hydroxyproline. Aminoguanidine significantly attenuated the accumulation of AGE in diabetic mice (group 1 median 47.2 arbitrary units/mumol hydroxyproline, range 16.1 to 56.0; group 2 median 24.4, range 5.0 to 37.7; group 3 median 13.6, range 0 to 30.3; group 4 median 10.8, range 2.1 to 17.2; p less than 0.01, groups 1 versus 2). These results indicate that further basement membrane glycosylation is prevented by restoration of euglycemia by islet grafting after a significant duration of diabetes, and that aminoguanidine prevents AGE accumulation despite hyperglycemia.
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PMID:Advanced glycosylation end-products in experimental murine diabetic nephropathy: effect of islet isografting and of aminoguanidine. 249 73

Age-associated increases in collagen cross-linking and accumulation of advanced glycosylation products are both accelerated by diabetes, suggesting that glucose-derived cross-link formation may contribute to the development of chronic diabetic complications as well as certain physical changes of aging. Aminoguanidine, a nucleophilic hydrazine compound, prevented both the formation of fluorescent advanced nonenzymatic glycosylation products and the formation of glucose-derived collagen cross-links in vitro. Aminoguanidine administration to rats was equally effective in preventing diabetes-induced formation of fluorescent advanced nonenzymatic glycosylation products and cross-linking of arterial wall connective tissue protein in vivo. The identification of aminoguanidine as an inhibitor of advanced nonenzymatic glycosylation product formation now makes possible precise experimental definition of the pathogenetic significance of this process and suggests a potential clinical role for aminoguanidine in the future treatment of chronic diabetic complications.
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PMID:Aminoguanidine prevents diabetes-induced arterial wall protein cross-linking. 348 17

An increasing body of experimental data supports the important, etiologic role of advanced glycosylation end products (AGEs) in the development of the renal and vascular complications of diabetes. Advanced glycosylation end products arise from glucose-derived Amadori products and act to increase vascular permeability, enhance protein and lipoprotein deposition, inactivate nitric oxide, and promote matrix protein synthesis and glomerular sclerosis. Loss of normal renal function increases the level of circulating plasma AGEs and contributes markedly to their ultimate tissue toxicity. Aminoguanidine, a recently developed pharmacologic inhibitor of advanced glycosylation, is presently undergoing phase II/III clinical trials in diabetic nephropathy and may offer a specific therapeutic modality for diminishing the formation and toxicity of AGEs.
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PMID:Advanced glycosylation end products in diabetic renal and vascular disease. 750 61

Primary prevention with aminoguanidine-an inhibitor of advanced glycation end product (AGE) formation--has been successfully employed to prevent diabetic retinopathy in the rat. However, it is unknown whether inhibition of AGE formation is still effective in a secondary intervention strategy. The present study addresses this question by comparing secondary intervention with aminoguanidine with syngeneic islet transplantation in the rat model. After 6 months of diabetes, one group was treated with aminoguanidine (50 mg/100 ml drinking water; D-AG) while another group received syngeneic transplantation of collagenase-ficoll isolated islets by intraportal injection (Tx). After an additional 4 months, both groups were compared to a normal (NC 10) and diabetic (DC 10) control group. Retinal autofluorescence was increased 2.5-fold after 6 months and increased 3.7-fold after 10 months of diabetes (p < 0.001). Aminoguanidine and islet Tx retarded the further accumulation of autofluorescence equally (p < 0.001 vs DC 10), although the values were higher than those observed in DC at 6 months (p < 0.001). Diabetes was associated with a 2.7-fold increase in acellular capillaries after 6 months and a 4.1-fold increase after 10 months. Treatment with aminoguanidine or islet Tx reduced but did not completely attenuate the progression of vascular occlusion (p < 0.001 vs DC 10; D-AG vs DC 6, p < 0.05; Tx vs DC 6, p < 0.01). Both treatments reduced endothelial proliferation (22.4% after 10 months; p < 0.001) and completely arrested pericyte dropout (40% after 10 months; p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Secondary intervention with aminoguanidine retards the progression of diabetic retinopathy in the rat model. 767 85

Cerebral infarction (stroke) is a potentially disastrous complication of diabetes mellitus, principally because the extent of cortical loss is greater in diabetic patients than in nondiabetic patients. The etiology of this enhanced neurotoxicity is poorly understood. We hypothesized that advanced glycation endproducts (AGEs), which have previously been implicated in the development of other diabetic complications, might contribute to neurotoxicity and brain damage during ischemic stroke. Using a rat model of focal cerebral ischemia, we show that systemically administered AGE-modified bovine serum albumin (AGE-BSA) significantly increased cerebral infarct size. The neurotoxic effects of AGE-BSA administration were dose- and time-related and associated with a paradoxical increase in cerebral blood flow. Aminoguanidine, an inhibitor of AGE cross-linking, attenuated infarct volume in AGE-treated animals. We conclude that AGEs may contribute to the increased severity of stroke associated with diabetes and other conditions characterized by AGE accumulation.
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PMID:Neurotoxicity of advanced glycation endproducts during focal stroke and neuroprotective effects of aminoguanidine. 773 77

Advanced glycation is an important pathogenic mechanism in the development of diabetic complications. However, other biochemical processes, such as the polyol pathway or lipid and protein oxidation which can interact with advanced glycation can also yield tissue fluorescence and may also be implicated in the genesis of diabetic microangiopathy. Aminoguanidine is an inhibitor of advanced glycation, but it is not known if all of its effects are mediated by this mechanism. The present study explores the relative contributions of aldose reductase, oxidative stress and advanced glycation on the development of aortic and renal fluorescence and urinary albumin excretion in streptozotocin diabetic rats. The study groups included non-diabetic (control), streptozotocin diabetic rats and diabetic rats receiving aminoguanidine, the anti-oxidants butylated hydroxytoluene and probucol and the aldose reductase inhibitor, ponalrestat. Serial measurements of glycaemic control and urinary albumin excretion were performed every 8 weeks. At 32 weeks, animals were killed, tissues removed and collagen extracted for measurement of fluorescence. Diabetic rats had increased fluorescence in aorta, glomeruli and renal tubules. Aminoguanidine prevented an increase in fluorescence at all three sites suggesting that diabetes-related tissue fluorescence is predominantly due to advanced glycation. Ponalrestat retarded fluorescence in aorta only and butylated hydroxytoluene attenuated fluorescence at the renal sites but not in the aorta. Diabetic rats had increased renal cortical sorbitol levels. Ponalrestat normalized renal cortical sorbitol levels but aminoguanidine did not affect this parameter. The only agent to decrease plasma thiobarbituric acid reactive substances was butylated hydroxytoluene. Diabetic rats developed albuminuria over the 32-week period.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The relative roles of advanced glycation, oxidation and aldose reductase inhibition in the development of experimental diabetic nephropathy in the Sprague-Dawley rat. 878 32

Aminoguanidine is an investigational agent that may slow or prevent many diabetes-related complications. Since the elimination of aminoguanidine is dependent on renal function, its pharmacokinetics was investigated in eight chronic renal failure patients maintained on hemodialysis. Each patient received 300 mg of aminoguanidine hydrochloride during both an interdialytic and an intradialytic period. During the interdialytic period, the maximum aminoguanidine concentration (Cmax) and time to reach Cmax was 4.5 micrograms/mL and 1.5 hours, respectively. The terminal elimination half-life in these patients was prolonged (37.9 hours). The renal clearance was 2.1 mL/min. Only 8.7% of the administered dose was recovered unchanged in the urine, which is markedly reduced from what is recovered in urine in subjects with normal renal function. There was a positive correlation between the renal clearance of aminoguanidine and the patients' residual renal function (P < 0.05). During hemodialysis, the half-life of aminoguanidine was shortened to 3.9 hours. The hemodialysis clearance of aminoguanidine was 203.6 mL/min. After cessation of hemodialysis, a significant rebound in plasma aminoguanidine concentrations (mean, 39%) was observed. Thus, the dose of aminoguanidine hydrochloride will need to be significantly reduced in patients with end-stage renal disease. Given the interdialytic and intradialytic pharmacokinetics of aminoguanidine, three times weekly dosing after each hemodialysis session is suggested.
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PMID:The pharmacokinetics of aminoguanidine in end-stage renal disease patients on hemodialysis. 787 19

Cytokines may be important mediators of beta-cell damage in early insulin-dependent diabetes mellitus. In order to further characterize the mechanism(s) of action of cytokines on insulin-producing cells, mouse pancreatic islets were exposed for 48 h to IL-1 beta, IFN-gamma or TNF-alpha, alone or in combinations. The three cytokines induced islet nitric oxide (NO) production, an effect most marked when islets were exposed to the three cytokines together. In parallel with NO production, IL-1 beta+IFN-gamma+TNF-alpha impaired islet function, as judged by decreased islet DNA and insulin content, decreased glucose metabolism and decreased glucose-induced insulin release. Aminoguanidine, an inhibitor of NO production, prevented all the above described suppressive effects of the cytokines, with exception of depletion in islet insulin content. In parallel experiments, insulin-producing RIN cells were exposed for 6 h to the same cytokines. Both IL-1 beta and TNF-alpha, but not IFN-gamma, induced NO production and expression of the mRNA encoding for the inducible form of the enzyme NO synthase (iNOS). These effects were most pronounced when combinations of IL-1 beta+IFN-gamma or IL-1 beta+IFN-gamma+TNF-alpha were used. As a whole, the data suggest that combinations of cytokines induce higher amounts of NO generation by mouse pancreatic islets than each of the cytokines isolated. An important source of islet NO production are probably the beta-cells, as pointed by data obtained with an insulinoma cell line. Most of the deleterious effects of the cytokines of mouse islets are prevented by blocking NO production, suggesting that NO is the main mediator of cytokine-induced beta-cell damage.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:TNF-alpha and IFN-gamma potentiate the deleterious effects of IL-1 beta on mouse pancreatic islets mainly via generation of nitric oxide. 794 48

Aminoguanidine (AG) is a potential therapeutic agent for preventing the generation of advanced glycation end products in diabetes mellitus. In this study, the effect of AG on insulin secretion was investigated in in vitro rat pancreatic islets. The islets were aseptically isolated and cultured in tissue culture medium 199 for 48 h with or without AG. After the culture, batches of 10 islets were incubated in Krebs-Ringer bicarbonate buffer containing 3.3 mM or 16.7 mM glucose. Islets previously exposed to 0.18 mM AG or 0.45 mM AG showed similar insulin release to control islets at a 16.7 mM glucose concentration, but high glucose-stimulated insulin release was inhibited in the islets exposed to 1.8 mM. In the perifusion experiment, insulin release caused by 16.7 mM glucose from the islets previously exposed to 1.8 mM AG was not significantly different from that of the control islets. However, culture of the islets with higher AG concentrations, 4.55 mM and 9.1 mM, significantly inhibited glucose-stimulated insulin release (< 0.02 and 0.002, respectively). These results suggest that AG at high concentrations impairs pancreatic B-cell response to a high concentration of glucose.
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PMID:Effects of aminoguanidine on insulin release from pancreatic islets. 795 84


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