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)

Aminoguanidine (AG; < or =0.5 mM) is a potent inhibitor of the inducible form of nitric oxide synthase (iNOS) and, at higher concentrations, is also able to prevent advanced glycosylation of proteins. Due to these properties, AG might be an interesting therapeutic compound for prevention of the development of diabetes and for prevention of diabetes complications. In the present study, we examined the effect of AG (0.1, 0.5, 1.0, 5.0, or 10 mM) on prolonged in vitro culture of isolated rat pancreatic islets. Furthermore, the acute effect of AG on pancreatic and islet blood flow in anaesthetized rats was studied with a microsphere technique. Culture for 6 days of pancreatic islets at either 11.1 mM or 28 mM glucose, in the presence of 0.1-1.0 mM AG, was not toxic to the islet cells or impaired insulin secretion. However, when islets were cultured for 8 days with the addition of 5 mM AG at 11.1 mM or 28 mM glucose, a 50% inhibition of glucose-stimulated insulin release was observed. Rats injected intravenously with AG (1, 10, or 50 mg/kg body weight) had a decreased pancreatic blood flow 30 min later. Glucose injection (1 g/kg body weight) increased the islet blood flow, and this effect was not attenuated by AG. The present data suggest that AG, when used in concentrations that inhibit iNOS, can affect pancreatic blood flow, but appears not to be directly harmful to beta-cell function.
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PMID:Effects of aminoguanidine on rat pancreatic islets in culture and on the pancreatic islet blood flow of anaesthetized rats. 868 86

Aminoguanidine (AG) is a nucleophilic compound that inhibits nonenzymatic, glucose-derived collagen cross-linking in animal tissues. Whether AG can attenuate the accumulation of collagen cross-links in the Biceps femoris muscle of 64-wk-old broiler breeder hens as well as improve meat quality, was investigated. Eighty-four broiler breeder hens (30-wk-old) were divided into four equal groups. Each group was assigned randomly to diets supplemented with 0. 200, 400, or 800 ppm AG, respectively. Birds were fed individually, 150 g diet/d. After feeding AG for 34 wk, six birds from each group were killed and samples from the leg muscle were analyzed for changes in collagen content. Aminoguanidine decreased (P < 0.05) glucose-derived collagen cross-links in skeletal muscle as measured by fluorescence and collagen solubility. Insoluble collagen fraction decreased with increasing AG dosage, whereas acid-soluble and pepsin-soluble fractions increased with increasing AG dosage. Aminoguanidine did not affect shear force. In agreement with studies on animals with diabetes, AG is a potent inhibitor of glucose-derived cross-linking in chickens although the results from the measurements of shear force do not support its used for improving carcass quality in spent hens.
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PMID:Inhibition by aminoguanidine of glucose-derived collagen cross-linking in skeletal muscle of broiler breeder hens. 877 39

Aminoguanidine treatment prevents the development of nerve conduction velocity (NCV) deficits and some renal and retinal complications in diabetic rats. Pharmacological actions include inhibition of the formation of advanced glycosylation end products (AGEs) and nitric oxide (NO) synthase. The aims of the study were to determine the extent to which diabetic NCV and nerve blood flow deficits could be corrected by aminoguanidine in an intervention study, to assess the time course of drug action, and to examine the effects of cotreatment with the NO synthase inhibitor, NG-nitro-L-arginine (NOLA). A 19.3% +/- 0.9% reduction in sciatic motor NCV after 4 weeks of untreated diabetes was corrected 86.6% +/- 3.7% by aminoguanidine treatment for a further 4 weeks. Time-course studies showed that 50% of the maximal effect was attained within 6 days. Sciatic endoneurial capillary blood flow, reduced approximately 45% by diabetes, was corrected 85.6% +/- 12.1% by aminoguanidine treatment. The NCV and blood flow effects of aminoguanidine were completely blocked by cotreatment with NOLA. Thus, the data support a neurovascular mechanism for aminoguanidine involving improved NO action. The rapidity of aminoguanide's effect is consistent with inhibition of free radical production by autoxidative glycosylation or glycoxidation.
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PMID:Rapid reversal by aminoguanidine of the neurovascular effects of diabetes in rats: modulation by nitric oxide synthase inhibition. 878 3

Insulin-dependent diabetes mellitus is an autoimmune disease characterized by the selective destruction of insulin-secreting beta cells found in islets of Langerhans. The biochemical mechanisms associated with beta-cell destruction have remained elusive. Cytokines, released from T lymphocytes, macrophages, and monocytes during islet insulitis, have been implicated as effector molecules that participate in beta-cell death. Recently, cytokine-induced expression of inducible nitric oxide synthase (iNOS) and production of nitric oxide by beta cells has been suggested as one potential mechanism associated with beta-cell destruction. Treatment of rat islets with interleukin 1 (IL-1) results in a potent inhibition of insulin secretion followed by islet destruction. The inhibitory and destructive effects of this cytokine on islet function are completely prevented by the inhibition of iNOS enzymatic activity. Islets contain a heterogeneous population of both endocrine and nonendocrine cells including a low level of resident tissue macrophages ( approximately0.5% of all islet cells). The intraislet macrophage appears to one cellular source of IL-1. Activation of resident islet macrophages results in both the expression of iNOS and the release of IL-1. Intraislet macrophage production of nitric oxide (in the absence of IL-1) does not modulate beta-cell function; however, macrophage release of IL-1 and IL-1-induced iNOS expression by beta cells results in a potent inhibition of beta-cell function. These findings support a role for nitric oxide as a potential mediator of cytokine-induced inhibition of beta-cell function and implicate the intraislet macrophage as one cellular source of IL-1. Direct support for a role of nitric oxide in the development of diabetes includes the ability of inhibitors of iNOS to prevent or delay the development of this disease condition in animal models. Important to these studies has been the identification of selective inhibitors of iNOS. Many inhibitors of nitric oxide synthase have been developed; however, few selective inhibitors for the individual isoforms of NOS (inducible, endothelial, neuronal) have been described. Aminoguanidine has been identified as one of the first iNOS selective inhibitors. Aminoguanidine is over 50-fold more effective at inhibiting the enzymatic activity of iNOS than endothelial or neuronal NOS. The effects of aminoguanidine on the development of diabetes in the nonobese diabetic mouse using an adoptive transfer protocol has been evaluated. Aminoguanidine delays the onset of diabetes in this animal model by 7-10 days. These studies, which provide in vivo evidence implicating a role for nitric oxide in the development of autoimmune diabetes, also support the use of selective inhibitors of iNOS for the attenuation of disease conditions associated with the expression of iNOS and an increased production of nitric oxide.
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PMID:The Use of Aminoguanidine, a Selective iNOS Inhibitor, to Evaluate the Role of Nitric Oxide in the Development of Autoimmune Diabetes 881 41

It has been postulated that the accumulation of advanced glycation end products (AGEs) in the kidney is important in the pathogenesis of diabetic nephropathy. Previously, aminoguanidine has been shown to inhibit the accumulation of renal AGEs and to retard the development of experimental diabetic nephropathy. The present study serially assessed the accumulation of AGEs in the aorta and kidney, as well as renal functional and structural parameters over 32 weeks of experimental diabetes in the absence and presence of aminoguanidine. In addition, it was determined if aminoguanidine was more effective if administered earlier or later in the evolution of diabetic nephropathy by treating diabetic rats with aminoguanidine in the first or second half of the 32-week study period. In the serial studies, glomerular and renal tubular fluorescence increased over the 32 week period and this increase was attenuated by aminoguanidine treatment. Concomitant with the effects of aminoguanidine on fluorescence, there was a retardation in the rise in urinary albumin excretion and prevention of mesangial expansion. Early or late administration of aminoguanidine in diabetic rats reduced tissue fluorescence in glomeruli and renal tubules. At 32 weeks, renal AGEs were increased in diabetic rats as assessed by tissue fluorescence. Using a specific RIA, renal AGEs were increased in diabetic rats and decreased by aminoguanidine treatment, administered over the entire 32 weeks or in the first or latter half of the 32-week study period. Aminoguanidine therapy for the entire 32-week study period retarded the rise in albuminuria in the diabetic rats and was more effective than 16 weeks of treatment either in the first or second half of the study. Early and late aminoguanidine administration were similar in their capacity to retard the development of albuminuria in diabetic rats. Similar effects were observed on mesangial expansion. The increased glomerular basement thickness in diabetic rats was not affected by aminoguanidine, irrespective of duration or timing of therapy. This study confirms that in vivo generation of AGEs in the kidney is time dependent and closely linked to the development of experimental diabetic nephropathy. The renoprotective effects of aminoguanidine in diabetes appear to be related to the duration but not to the timing of treatment.
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PMID:Effects of aminoguanidine in preventing experimental diabetic nephropathy are related to the duration of treatment. 884 Feb 95

Recent reports show a pro-oxidant activity of aminoguanidine. Aminoguanidine is able to generate hydrogen peroxide in the presence of Cu (II). These observations have been confirmed by the present studies in that aminoguanidine is, indeed, able to generate oxidants similar in reactivity to the hydroxyl radical and is also able to fragment BSA in a Cu (II)-dependent manner. Studies on glycated bovine serum albumin show that aminoguanidine can affect a number of parameters associated with the nonenzymatic glycation of protein. This includes an ability to decrease glucose attachment and levels of protein fluorescence termed glycophore, resulting from protein glycation. Aminoguanidine also increases the generation of dicarbonyl compounds by glycated protein. All of these effects on parameters of glycation appear to be Cu (II) dependent. Further studies show that one effect of protein glycation is to decrease its susceptibility to proteolysis. The reverse is true of protein oxidation, which has previously been shown to increase the susceptibility of proteins to proteolytic digestion. Evidence is presented suggesting that aminoguanidine is able to enhance the proteolytic digestion of glycated BSA, a protein shown to be protease resistant. Our observations are discussed within the context of current concepts of protein glycation in the development of diabetic complications and aminoguanidine's potential use as a prophylactic agent in diabetes mellitus.
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PMID:Aminoguanidine and its pro-oxidant effects on an experimental model of protein glycation. 890 26

We examined the effects of aminoguanidine and methylguanidine on vascular dysfunction, glomerular structural changes, and indexes of early and late nonenzymatic glycation in 7-month streptozotocin-induced diabetic rats. Kidney weight, glomerular volume, fractional mesangial volume, glomerular capillary basement membrane width, and urinary albumin excretion were increased in diabetic rats. Diabetes also 1) increased vascular albumin permeation twofold in retina, sciatic nerve, aorta, skin, and kidney; 2) decreased renal collagenase-soluble collagen; 3) increased collagen-associated fluorescence in kidney and skin but not in aorta; and 4) increased glycated hemoglobin levels and aortic pentosidine levels. Aminoguanidine reduced albuminuria by 70% after 4 months, and both guanidines 1) normalized aortic pentosidine levels and renal collagenase-soluble collagen, 2) had no effect on glycated hemoglobin levels or collagen-associated fluorescence (in aorta, kidney, or skin), and 3) had little or no effect on regional albumin permeation. These discordant effects of aminoguanidine on diabetes-induced vascular changes versus parameters of nonenzymatic glycation are consistent with a multifactorial pathogenesis of diabetic complications, including roles for metabolic imbalances independent of nonenzymatic glycation. To the extent that glomerular matrix accumulation and increased regional albumin permeation in chronically diabetic rats are sequelae of nonenzymatic glycation, these findings point to an important role for early glycation reactions and products.
Diabetes 1997 Jan
PMID:Discordant effects of guanidines on renal structure and function and on regional vascular dysfunction and collagen changes in diabetic rats. 897 Oct 88

Nonenzymatic protein glycation (Maillard reaction) leads to heterogeneous, toxic, and antigenic advanced glycation end products ("AGEs") and reactive precursors that have been implicated in the pathogenesis of diabetes, Alzheimer's disease, and normal aging. In vitro inhibition studies of AGE formation in the presence of high sugar concentrations are difficult to interpret, since AGE-forming intermediates may oxidatively arise from free sugar or from Schiff base condensation products with protein amino groups, rather than from just their classical Amadori rearrangement products. We recently succeeded in isolating an Amadori intermediate in the reaction of ribonuclease A (RNase) with ribose (Khalifah, R. G., Todd, P., Booth, A. A., Yang, S. X., Mott, J. D., and Hudson, B. G. (1996) Biochemistry 35, 4645-4654) for rapid studies of post-Amadori AGE formation in absence of free sugar or reversibly formed Schiff base precursors to Amadori products. This provides a new strategy for a better understanding of the mechanism of AGE inhibition by established inhibitors, such as aminoguanidine, and for searching for novel inhibitors specifically acting on post-Amadori pathways of AGE formation. Aminoguanidine shows little inhibition of post-Amadori AGE formation in RNase and bovine serum albumin, in contrast to its apparently effective inhibition of initial (although not late) stages of glycation in the presence of high concentrations of sugar. Of several derivatives of vitamins B1 and B6 recently studied for possible AGE inhibition in the presence of glucose (Booth, A. A., Khalifah, R. G., and Hudson, B. G. (1996) Biochem. Biophys. Res. Commun. 220, 113-119), pyridoxamine and, to a lesser extent, thiamine pyrophosphate proved to be novel and effective post-Amadori inhibitors that decrease the final levels of AGEs formed. Our mechanism-based approach to the study of AGE inhibition appears promising for the design and discovery of novel post-Amadori AGE inhibitors of therapeutic potential that may complement others, such as aminoguanidine, known to either prevent initial sugar attachment or to scavenge highly reactive dicarbonyl intermediates.
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PMID:In vitro kinetic studies of formation of antigenic advanced glycation end products (AGEs). Novel inhibition of post-Amadori glycation pathways. 903 43

Aminoguanidine (AG) is a potential therapeutic agent for preventing the generation of advanced glycation end products in diabetes mellitus. In this study, the effects of AG on glucagon and insulin secretion in in vitro rat pancreatic islets were investigated. The islets were aseptically isolated and cultured in tissue culture medium 199 for 48 h with or without 9.1 mM AG (1 mg/ml). After the culture, 50 islets were perifused in Krebs-Ringer bicarbonate buffer containing 20 mM arginine or 1 U/ml pancreozymin in the presence of 3.3 mM glucose. Islets previous exposed to AG showed similar glucagon response to control islets at a 20 mM arginine concentration, and insulin response, too. Glucagon release caused by 1 U/ml pancreozymin from the islets previously exposed to AG was also not different from that of the control islets, but the release of insulin was much lower than that of control. These results suggest that AG would not be toxic to alpha-cells but toxic to beta-cells at high concentrations, although there is slightly different sensitivity to beta-cell secretagogues.
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PMID:Effects of aminoguanidine on glucagon and insulin release from rat pancreatic islet. 907 14

Aminoguanidine (AG) treatment can prevent the development of some functional anomalies in experimentally diabetic rats, possibly via the prevention of a diabetes-induced vascular dysfunction. The acute effects of AG on endothelium-dependent relaxation of aortae in the presence of indomethacin and on pressor responses and prostacyclin release in isolated perfused lungs, were therefore investigated using tissues from control and streptozotocin-diabetic rats. Endothelium-dependent relaxations of aortae were reduced by aminoguanidine (control 20%, and diabetic 25%). For lungs, angiotensin II-induced pressor responses were unaffected by AG, whereas the nitric oxide synthase inhibitor L-NAME caused integrated pressor responses to be increased in lungs from control and diabetic rats (2.0 and 1.8 fold respectively). Individually, AG (1 mM) and L-NAME (10 microM) did not affect total cumulative prostacyclin release by control lungs, whereas significant increases for both were observed for diabetic lungs. In summary, these studies firstly provide evidence that AG can increase prostacyclin release from tissues in vitro, with little effect upon endothelium-dependent vasodilatation, and secondly, that the regulation of vasodilator prostanoid release by the pulmonary circulation of the rat may be altered in experimental diabetes.
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PMID:Effects of aminoguanidine and N(G)-nitro-L-arginine methyl ester on vascular responses of aortae and lungs from streptozotocin-diabetic rats. 915 Mar 78


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