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)

Semicarbazide-sensitive amine oxidases (SSAO) are widely distributed enzymes, with as yet not fully elucidated functions and roles, present in many tissues but also circulating in plasma. The enzyme also functions as an adhesion molecule, the vascular adhesion protein-1. In healthy humans, plasma SSAO activity is constant from birth until 16 years of age, when it drops to lower values, gradually increasing again at advanced ages. When measuring SSAO activity, care should be taken to ensure proper preparation and storage conditions, and it should be realized that quite a few drugs unintentionally are good inhibitors, and sometimes even substrates, of SSAO. Under normal conditions SSAO activity is constant and inter-individual variation is small. In various pathophysiological conditions plasma SSAO activities are increased, most notably in diabetes mellitus (both type I and type II), in congestive heart failure and in cirrhotic liver inflammation. In patients with other vascular and inflammatory diseases plasma SSAO is normal, while it is low in children with congenital lung diseases. Interpretation of these changes is speculative, since source and regulation of plasma SSAO are as yet unknown. However, in two situations where the disease-causing process was ended (transplantation, delivery), plasma SSAO returned to normal. Many questions remain to be answered.
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PMID:Plasma semicarbazide-sensitive amine oxidase in human (patho)physiology. 1268 7

Patients with diabetes mellitus and with vascular complications in particular, exhibit higher plasma activities of semicarbazide-sensitive amine oxidase (SSAO) compared to control subjects. It has been speculated that production of cytotoxic products of SSAO may cause endothelial damage and thus contribute to the development of diabetic vascular complications such as retino-, nephro-, and neuropathies as a result of SSAO activity.In order to explore the possibility that high SSAO activity contributes to the development of vascular complications in diabetes, we have performed two studies in patients with Type-2 diabetes quantifying plasma SSAO activity, HbA(1c), and urinary levels of the SSAO substrate, methylamine. We also examined the prevalence of retinopathy in these patients. Additionally, we have studied a model of transgenic mice expressing human SSAO in smooth muscle cells. The transgenic mice have an increased SSAO activity as well as mRNA expression. Histological studies revealed a specific aorta phenotype with a condensed and rigid vessel wall in some of the transgenic mice. No wild-type animals displayed this phenotype.In conclusion, we suggest that this transgenic mouse model may be of great value for increasing the knowledge about to what extent human SSAO contributes to vascular complications in diabetes, and also to which extent inhibition of SSAO can prevent the development of such complications.
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PMID:Studies on semicarbazide-sensitive amine oxidase in patients with diabetes mellitus and in transgenic mice. 1268 14

Aminoguanidine (AG) is a prototype therapeutic agent for the prevention of formation of advanced glycation endproducts. It reacts rapidly with alpha,beta-dicarbonyl compounds such as methylglyoxal, glyoxal, and 3-deoxyglucosone to prevent the formation of advanced glycation endproducts (AGEs). The adducts formed are substituted 3-amino-1,2,4-triazine derivatives. Inhibition of disease mechanisms, particularly vascular complications in experimental diabetes, by AG has provided evidence that accumulation of AGEs is a risk factor for disease progression. AG has other pharmacological activities, inhibition of nitric oxide synthase and semicarbazide-sensitive amine oxidase (SSAO), at pharmacological concentrations achieved in vivo for which controls are required in anti-glycation studies. AG is a highly reactive nucleophilic reagent that reacts with many biological molecules (pyridoxal phosphate, pyruvate, glucose, malondialdehyde, and others). Use of high concentrations of AG in vitro brings these reactions and related effects into play. It is unadvisable to use concentrations of AG in excess of 500 microM if selective prevention of AGE formation is desired. The peak plasma concentration of AG in clinical therapy was ca. 50 microM. Clinical trial of AG to prevent progression of diabetic nephropathy was terminated early due to safety concerns and apparent lack of efficacy. Pharmacological scavenging of alpha-oxoaldehydes or stimulation of host alpha-oxoaldehyde detoxification remains a worthy therapeutic strategy to prevent diabetic complications and other AGE-related disorders.
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PMID:Use of aminoguanidine (Pimagedine) to prevent the formation of advanced glycation endproducts. 1456 6

Elevated semicarbazide-sensitive amine oxidase (SSAO) activity has been observed in several human conditions, eg, diabetes, and it has been speculated that SSAO contributes to the development of vasculopathies associated with this disease. To investigate in vivo consequences of elevated expression of SSAO in vascular tissues, we have developed a transgenic model for overexpression of human SSAO in mice. A smooth muscle-specific promoter, smooth muscle alpha-actin promoter 8 (SMP8) was used. Transgenic expression of human SSAO in tissues with a high content of smooth muscle cells was confirmed by Northern blot analysis. Enzymatic analysis of homogenates from transgenic tissues showed elevated levels of SSAO activity compared to non-transgenic littermates. Furthermore, when plasma SSAO activity was analyzed, much higher activity was detected compared to plasma from control mice, indicating that plasma SSAO may originate from smooth muscle cells. Histopathological evaluation of aorta and renal artery from transgenic mice revealed an abnormal structure of the elastin tissue. Instead of the regularly folded elastic laminae normally found in tunica media of sacrificed mice, the elastic laminae were straight and unfolded with irregularly arranged elastic fibers, forming tangled webs, between the intercalating elastic laminae. These alterations of the elastin structures suggest that overexpression of SSAO has led to a reduced elasticity of the arteries. Moreover, the mean femoral arterial pressure of the SMP8 SSAO transgenic mice was significantly lower in comparison to non-transgenic littermates. This suggests that the transgenic mice have a defect in their ability to regulate blood pressure.
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PMID:Overexpression of semicarbazide-sensitive amine oxidase in smooth muscle cells leads to an abnormal structure of the aortic elastic laminas. 1457 91

Semicarbazide-sensitive amine oxidases (SSAO) are enzymes that are capable of deaminating primary amines to produce aldehyde, ammonia, and hydrogen peroxide. This activity has been associated with vascular adhesion protein-1 (VAP-1) and is found in the serum, endothelium, adipose, and smooth muscle of mammals. Circulating SSAO activity is increased in congestive heart failure, diabetes, and inflammatory liver diseases. To investigate the origin of circulating SSAO activity, two transgenic mouse models were created with full-length human VAP-1 (hVAP-1) expressed on either endothelial (mTIEhVAP-1) or adipose tissues (aP2hVAP-1), with tie-1 and adipocyte P2 promoters, respectively. Under normal conditions a circulating form of hVAP-1 was found at high levels in the serum of mice with endothelium-specific expression and at low levels in the serum of mice with adipose specific expression. The level of circulating hVAP-1 in the transgenic mice varied with gender, transgene zygosity, diabetes, and fasting. Serum SSAO activity was absent from VAP-1 knockout mice and endothelial cell-specific expression of human VAP-1 restored SSAO activity to the serum of VAP-1 knockout mice. Together, these experiments show that in the mouse VAP-1 is the only source of serum SSAO, that under physiological conditions vascular endothelial cells can be a major source of circulating VAP-1 protein and SSAO, and that serum VAP-1 can originate from both endothelial cells and adipocytes during experimental diabetes. An increased endothelial cell capacity for lymphocyte binding and altered expression of redox-sensitive proteins was also associated with the mTIEhVAP-1 transgene.
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PMID:Origins of serum semicarbazide-sensitive amine oxidase. 1517 39

We previously reported that substrates of semicarbazide-sensitive amine oxidase in combination with low concentrations of vanadate exert potent insulin-like effects. Here we performed homology modeling of the catalytic domain of mouse SSAO/VAP-1 and searched through chemical databases to identify novel SSAO substrates. The modeling of the catalytic domain revealed that aromatic residues Tyr384, Phe389, and Tyr394 define a pocket of stable size that may participate in the binding of apolar substrates. We identified a number of amines as substrates of human, rat, and mouse SSAO. The compounds PD0119035, 2,3-dimethoxy-benzylamine, and C-naphthalen-1-yl-methylamine showed high affinity as substrates of rat SSAO. C-Naphthalen-1-yl-methylamine was the only substrate that showed high affinity for human SSAO. C-Naphthalen-1-yl-methylamine and 4-aminomethyl-benzenesulfonamide showed the highest capacity to stimulate glucose transport in isolated rat adipocytes. The impact of these findings on the development of new treatments for diabetes is discussed.
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PMID:Exploring the binding mode of semicarbazide-sensitive amine oxidase/VAP-1: identification of novel substrates with insulin-like activity. 1536 90

Semicarbazide-sensitive amine oxidase (SSAO) is a multi-functional enzyme widely present in nature. It converts primary amines into their corresponding aldehydes, while generating H(2)O(2) and NH(3). In mammals, SSAO circulates in plasma, while a membrane-bound form (often referred to as vascular adhesion protein-1, VAP-1) is found in many tissues and organs, especially in adipocytes and vascular endothelial and smooth muscle cells. In recent years, evidence has been accumulating that SSAO has a role in protein cross-linking, formation of advanced glycation end-products, atherogenesis, glucose regulation and leukocyte extravasation at inflammation sites. Plasma SSAO is quite stable in healthy adults, but is elevated in diabetes mellitus (both type 1 and type 2), congestive heart failure and liver cirrhosis. The origin of circulating SSAO remains unclear, but recent evidence from clinical studies and from (transgenic) animal studies suggests that adipocytes and vascular endothelial cells may be the most important source. Studies with cell cultures show evidence that the membrane-bound SSAO can be split off from the cells, thus giving rise to the (truncated) circulating form of SSAO. In some pathological conditions the diseased organ may be the main source of the elevated plasma SSAO. Little is known as yet about the regulation of plasma SSAO. Thyroid hormone appears to play a (modest) role in this respect. Further evidence from clinical, animal and cell-culture studies, helped by the new availability of selective SSAO inhibitors, is needed to shed more light on the question of the regulation of SSAO.
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PMID:Semicarbazide-sensitive amine oxidase (SSAO): from cell to circulation. 1579 8

Increasing evidence suggests that not only ammonia, but also its alkyl-derivatives, including methylamine, may modulate neuron firing. Methylamine occurs endogenously from amine catabolism and its tissue levels increase in some pathological conditions, including diabetes. Interestingly, methylamine and ammonia levels are reciprocally controlled by a semicarbazide-sensitive amine oxidase activity that deaminates methylamine to formaldehyde with the production of ammonia and hydrogen peroxide. As already described for ammonia, methylamine also targets the voltage-operated neuronal potassium channels, probably inducing release of neurotransmitter(s). From this interaction it has been observed that methylamine is 1) hypophagic in mice without producing amphetamine-like effects and 2) a stimulator of nitric oxide release from rat hypothalamus. Methylamine hypophagia is also maintained in genetically obese and diabetic mice and is increased when these animals are pre-treated with -amino guanidine, an inhibitor of methylamine oxidative deamination. The effect of -amino guanidine suggests a potential beneficial effect of this drug, and other such inhibitors, in controlling food intake in animals with disturbed eating behavior. Moreover, the activity of methylamine as an inducer of NO release suggests a role for the amine and for the enzymatic activity that degrades it in neurodegenerative diseases.
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PMID:Methylamine: a new endogenous modulator of neuron firing? 1604 93

A soluble form of semicarbazide-sensitive amine oxidase (SSAO) circulating in plasma is known to increase in type 1 and 2 diabetes. This cuproenzyme generates hydrogen peroxide, ammonia, and aldehydes when oxidizing circulating biogenic or exogenous amines. Based on the angiotoxicity of these products, inhibition of SSAO has been proposed to prevent vascular complications of diabetes. However, substrates of SSAO and monoamine oxidase (MAO) have been recently evidenced to activate glucose utilisation in insulin-sensitive tissues and to exhibit antihyperglycemic actions. To determine whether amine oxidase blockade or activation could be beneficial for diabetes, we aimed at comparing the influence of prolonged treatments with semicarbazide (SSAO-inhibitor), pargyline (MAO-inhibitor), or tyramine (amine oxidase substrate) on amine oxidase activities and glycemic control in streptozotocin-induced diabetic rats. The increase in plasma SSAO was confirmed in diabetic rats, while MAO and SSAO were decreased in subcutaneous adipose tissue when compared with normoglycemic controls. Among the diabetic rats, only those receiving tyramine exhibited slightly decreased hyperglycemia and improved glucose tolerance. Adipocytes from untreated or treated diabetic rats shared similar sensitivity to insulin. However glucose uptake activation and lipolysis inhibition in response to amine oxidase substrates combined with vanadate were impaired in rats treated with amine oxidase inhibitors. Thus, amine oxidase inhibition does not improve metabolic control while prolonged administration of tyramine slightly improves glucose disposal. It is therefore concluded that amine oxidase activation by increased substrate supply elicits insulin-like actions that may be more beneficial in diabetes than SSAO inhibition formerly proposed to prevent vascular complications.
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PMID:Glucose handling in streptozotocin-induced diabetic rats is improved by tyramine but not by the amine oxidase inhibitor semicarbazide. 1620 94

To clarify whether transition metals are involved in carbonyl stress in diabetic tissues, we observed the effects of a metal chelating agent, trientine (TE) hydrochloride on the levels of methylglyoxal (MG), 3-deoxyglucosone (3-DG), advanced glycation end products, 8-hydroxy-2'-deoxyguanosine (8-OHdG), and polyol pathway metabolites along with semicarbazide-sensitive amine oxidase (SSAO) enzyme activity in lenses from streptozotocin-induced diabetic rats. Lens MG and 3-DG levels were significantly higher in diabetic rats than nondiabetic controls, and TE significantly restored the increase of these compounds. Lens argpyrimidine was also increased in diabetic rats as compared with controls and was significantly reduced by TE. Lens SSAO activity and 8-OHdG were also significantly elevated in diabetic rats, and TE suppressed both of them, whereas TE showed no effect on the polyol pathway metabolites. The results indicate that transition metals play a significant role in the formation of MG and 3-DG via oxidative stress and SSAO activity.
J Diabetes Complications
PMID:A copper chelating agent suppresses carbonyl stress in diabetic rat lenses. 1626 Mar 49


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