Abnormal metabolic fate of nitric oxide in Type I diabetes mellitus
Reduced bioavailability of endothelium-derived nitric oxide is implicated in diabetic macrovascular and microvascular disease. In patients with diabetes, we hypothesised that protein glycosylation can alter nitric oxide binding affinity of haemoglobin and plasma proteins, hence reducing nitric oxide...
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| Veröffentlicht in: | Diabetologia 2002-11, Vol.45 (11), p.1515-1522 |
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| creator | MILSOM, A. B JONES, C. J. H GOODFELLOW, J FRENNEAUX, M. P PETERS, J. R JAMES, P. E |
| description | Reduced bioavailability of endothelium-derived nitric oxide is implicated in diabetic macrovascular and microvascular disease. In patients with diabetes, we hypothesised that protein glycosylation can alter nitric oxide binding affinity of haemoglobin and plasma proteins, hence reducing nitric oxide availability and causing an alteration in nitric oxide metabolism.
Binding of nitric oxide to haemoglobin was studied across a range of glycosylation levels in vitro (HbA(1c) 5.9 to 9.8%). In clinical studies nitrate, nitrite, nitrosyl haemoglobin and plasma nitrosothiols were measured in venous blood from 23 patients with uncomplicated Type I (insulin-dependent) diabetes mellitus and 17 non-diabetic control subjects. Samples were analysed at baseline and after nitric oxide was added ex vivo.
Nitric oxide-haemoglobin binding was increased at a HbA(1c) greater than 8.5% compared with 5.9% (p |
| doi_str_mv | 10.1007/s00125-002-0956-9 |
| format | Article |
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Binding of nitric oxide to haemoglobin was studied across a range of glycosylation levels in vitro (HbA(1c) 5.9 to 9.8%). In clinical studies nitrate, nitrite, nitrosyl haemoglobin and plasma nitrosothiols were measured in venous blood from 23 patients with uncomplicated Type I (insulin-dependent) diabetes mellitus and 17 non-diabetic control subjects. Samples were analysed at baseline and after nitric oxide was added ex vivo.
Nitric oxide-haemoglobin binding was increased at a HbA(1c) greater than 8.5% compared with 5.9% (p<0.01). Basal nitrosyl haemoglobin was higher in diabetic patients compared with the control subjects (0.59+/-0.12 micro mol/l vs 0.24+/-0.12 micro mol/l, p<0.05). Plasma nitrosothiols, and nitrite and nitrate (NOx) concentrations were similar in diabetic patients compared with the control subjects (7.64+/-0.79 micro mol/l vs 5.93+/-0.75 micro mol/l, 13.98+/-2.44 micro mol/l vs 12.44+/-2.15 micro mol/l, respectively). In blood from diabetic patients, added nitric oxide was metabolised preferentially to nitrosyl haemoglobin and plasma nitrosothiols, with a twofold increase in nitrosyl haemoglobin observed across all concentrations of nitric oxide (p<0.05). These preferential increases correlated positively with HbA(1c).
Nitrosyl haemoglobin is increased in patients with Type I diabetes. Preferential metabolism to nitrosyl haemoglobin and nitrosothiols occurs after increases in nitric oxide. Our results show an accentuated association between nitric oxide and glycosylated proteins, especially deoxygenated haem. An altered metabolic fate of nitric oxide could influence microvascular regulation and tissue perfusion.</description><identifier>ISSN: 0012-186X</identifier><identifier>EISSN: 1432-0428</identifier><identifier>DOI: 10.1007/s00125-002-0956-9</identifier><identifier>PMID: 12436334</identifier><language>eng</language><publisher>Berlin: Springer</publisher><subject>Adult ; Age of Onset ; Associated diseases and complications ; Bioavailability ; Biological and medical sciences ; Biological Availability ; Blood Glucose - metabolism ; Blood Specimen Collection - methods ; Cholesterol - blood ; Diabetes ; Diabetes Mellitus, Type 1 - blood ; Diabetes. Impaired glucose tolerance ; Electron Spin Resonance Spectroscopy ; Endocrine pancreas. Apud cells (diseases) ; Endocrinopathies ; Glycated Hemoglobin A - metabolism ; Glycosylation ; Hemoglobin ; Hemoglobins - metabolism ; Humans ; Hypotheses ; Kinetics ; Medical sciences ; Metabolism ; Metabolites ; Molecular weight ; Nitrates ; Nitrates - blood ; Nitric oxide ; Nitric Oxide - blood ; Nitric Oxide - metabolism ; Nitric Oxide - pharmacokinetics ; Nitrites - blood ; Oxidation ; Plasma ; Proteins ; Triglycerides - blood</subject><ispartof>Diabetologia, 2002-11, Vol.45 (11), p.1515-1522</ispartof><rights>2003 INIST-CNRS</rights><rights>Copyright Springer-Verlag 2002</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c397t-ae9aeceaa1aeb87103c21f285c39592a9895257433e97ee5fb3239cfedcf9f2a3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=14029324$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12436334$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>MILSOM, A. B</creatorcontrib><creatorcontrib>JONES, C. J. H</creatorcontrib><creatorcontrib>GOODFELLOW, J</creatorcontrib><creatorcontrib>FRENNEAUX, M. P</creatorcontrib><creatorcontrib>PETERS, J. R</creatorcontrib><creatorcontrib>JAMES, P. E</creatorcontrib><title>Abnormal metabolic fate of nitric oxide in Type I diabetes mellitus</title><title>Diabetologia</title><addtitle>Diabetologia</addtitle><description>Reduced bioavailability of endothelium-derived nitric oxide is implicated in diabetic macrovascular and microvascular disease. In patients with diabetes, we hypothesised that protein glycosylation can alter nitric oxide binding affinity of haemoglobin and plasma proteins, hence reducing nitric oxide availability and causing an alteration in nitric oxide metabolism.
Binding of nitric oxide to haemoglobin was studied across a range of glycosylation levels in vitro (HbA(1c) 5.9 to 9.8%). In clinical studies nitrate, nitrite, nitrosyl haemoglobin and plasma nitrosothiols were measured in venous blood from 23 patients with uncomplicated Type I (insulin-dependent) diabetes mellitus and 17 non-diabetic control subjects. Samples were analysed at baseline and after nitric oxide was added ex vivo.
Nitric oxide-haemoglobin binding was increased at a HbA(1c) greater than 8.5% compared with 5.9% (p<0.01). Basal nitrosyl haemoglobin was higher in diabetic patients compared with the control subjects (0.59+/-0.12 micro mol/l vs 0.24+/-0.12 micro mol/l, p<0.05). Plasma nitrosothiols, and nitrite and nitrate (NOx) concentrations were similar in diabetic patients compared with the control subjects (7.64+/-0.79 micro mol/l vs 5.93+/-0.75 micro mol/l, 13.98+/-2.44 micro mol/l vs 12.44+/-2.15 micro mol/l, respectively). In blood from diabetic patients, added nitric oxide was metabolised preferentially to nitrosyl haemoglobin and plasma nitrosothiols, with a twofold increase in nitrosyl haemoglobin observed across all concentrations of nitric oxide (p<0.05). These preferential increases correlated positively with HbA(1c).
Nitrosyl haemoglobin is increased in patients with Type I diabetes. Preferential metabolism to nitrosyl haemoglobin and nitrosothiols occurs after increases in nitric oxide. Our results show an accentuated association between nitric oxide and glycosylated proteins, especially deoxygenated haem. An altered metabolic fate of nitric oxide could influence microvascular regulation and tissue perfusion.</description><subject>Adult</subject><subject>Age of Onset</subject><subject>Associated diseases and complications</subject><subject>Bioavailability</subject><subject>Biological and medical sciences</subject><subject>Biological Availability</subject><subject>Blood Glucose - metabolism</subject><subject>Blood Specimen Collection - methods</subject><subject>Cholesterol - blood</subject><subject>Diabetes</subject><subject>Diabetes Mellitus, Type 1 - blood</subject><subject>Diabetes. Impaired glucose tolerance</subject><subject>Electron Spin Resonance Spectroscopy</subject><subject>Endocrine pancreas. Apud cells (diseases)</subject><subject>Endocrinopathies</subject><subject>Glycated Hemoglobin A - metabolism</subject><subject>Glycosylation</subject><subject>Hemoglobin</subject><subject>Hemoglobins - metabolism</subject><subject>Humans</subject><subject>Hypotheses</subject><subject>Kinetics</subject><subject>Medical sciences</subject><subject>Metabolism</subject><subject>Metabolites</subject><subject>Molecular weight</subject><subject>Nitrates</subject><subject>Nitrates - blood</subject><subject>Nitric oxide</subject><subject>Nitric Oxide - blood</subject><subject>Nitric Oxide - metabolism</subject><subject>Nitric Oxide - pharmacokinetics</subject><subject>Nitrites - blood</subject><subject>Oxidation</subject><subject>Plasma</subject><subject>Proteins</subject><subject>Triglycerides - blood</subject><issn>0012-186X</issn><issn>1432-0428</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNpdkMtKA0EQRRtRTIx-gBsZBN2N9msevQzBRyDgJoK7pqanGjrMI3bPgPl7e0hAcFVc6tyiOITcMvrEKC2eA6WMZymlPKUqy1N1RuZMipgkL8_JfFqnrMy_ZuQqhB2lVGQyvyQzxqXIhZBzslpWXe9baJIWB6j6xpnEwoBJb5PODT7G_sfVmLgu2R72mKyT2kGFA4bYaBo3jOGaXFhoAt6c5oJ8vr5sV-_p5uNtvVpuUiNUMaSACtAgAAOsyoJRYTizvMziOlMcVKkynhVSCFQFYmYrwYUyFmtjleUgFuTxeHfv--8Rw6BbF0x8Ajrsx6ALnisupIzg_T9w14--i79pzkQpmRITxI6Q8X0IHq3ee9eCP2hG9aRXH_XqqFdPerWKnbvT4bFqsf5rnHxG4OEEQDDQWA-dceGPk5QrEeFfb1iBYg</recordid><startdate>20021101</startdate><enddate>20021101</enddate><creator>MILSOM, A. 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Apud cells (diseases)</topic><topic>Endocrinopathies</topic><topic>Glycated Hemoglobin A - metabolism</topic><topic>Glycosylation</topic><topic>Hemoglobin</topic><topic>Hemoglobins - metabolism</topic><topic>Humans</topic><topic>Hypotheses</topic><topic>Kinetics</topic><topic>Medical sciences</topic><topic>Metabolism</topic><topic>Metabolites</topic><topic>Molecular weight</topic><topic>Nitrates</topic><topic>Nitrates - blood</topic><topic>Nitric oxide</topic><topic>Nitric Oxide - blood</topic><topic>Nitric Oxide - metabolism</topic><topic>Nitric Oxide - pharmacokinetics</topic><topic>Nitrites - blood</topic><topic>Oxidation</topic><topic>Plasma</topic><topic>Proteins</topic><topic>Triglycerides - blood</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>MILSOM, A. B</creatorcontrib><creatorcontrib>JONES, C. J. H</creatorcontrib><creatorcontrib>GOODFELLOW, J</creatorcontrib><creatorcontrib>FRENNEAUX, M. 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B</au><au>JONES, C. J. H</au><au>GOODFELLOW, J</au><au>FRENNEAUX, M. P</au><au>PETERS, J. R</au><au>JAMES, P. E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Abnormal metabolic fate of nitric oxide in Type I diabetes mellitus</atitle><jtitle>Diabetologia</jtitle><addtitle>Diabetologia</addtitle><date>2002-11-01</date><risdate>2002</risdate><volume>45</volume><issue>11</issue><spage>1515</spage><epage>1522</epage><pages>1515-1522</pages><issn>0012-186X</issn><eissn>1432-0428</eissn><abstract>Reduced bioavailability of endothelium-derived nitric oxide is implicated in diabetic macrovascular and microvascular disease. In patients with diabetes, we hypothesised that protein glycosylation can alter nitric oxide binding affinity of haemoglobin and plasma proteins, hence reducing nitric oxide availability and causing an alteration in nitric oxide metabolism.
Binding of nitric oxide to haemoglobin was studied across a range of glycosylation levels in vitro (HbA(1c) 5.9 to 9.8%). In clinical studies nitrate, nitrite, nitrosyl haemoglobin and plasma nitrosothiols were measured in venous blood from 23 patients with uncomplicated Type I (insulin-dependent) diabetes mellitus and 17 non-diabetic control subjects. Samples were analysed at baseline and after nitric oxide was added ex vivo.
Nitric oxide-haemoglobin binding was increased at a HbA(1c) greater than 8.5% compared with 5.9% (p<0.01). Basal nitrosyl haemoglobin was higher in diabetic patients compared with the control subjects (0.59+/-0.12 micro mol/l vs 0.24+/-0.12 micro mol/l, p<0.05). Plasma nitrosothiols, and nitrite and nitrate (NOx) concentrations were similar in diabetic patients compared with the control subjects (7.64+/-0.79 micro mol/l vs 5.93+/-0.75 micro mol/l, 13.98+/-2.44 micro mol/l vs 12.44+/-2.15 micro mol/l, respectively). In blood from diabetic patients, added nitric oxide was metabolised preferentially to nitrosyl haemoglobin and plasma nitrosothiols, with a twofold increase in nitrosyl haemoglobin observed across all concentrations of nitric oxide (p<0.05). These preferential increases correlated positively with HbA(1c).
Nitrosyl haemoglobin is increased in patients with Type I diabetes. Preferential metabolism to nitrosyl haemoglobin and nitrosothiols occurs after increases in nitric oxide. Our results show an accentuated association between nitric oxide and glycosylated proteins, especially deoxygenated haem. An altered metabolic fate of nitric oxide could influence microvascular regulation and tissue perfusion.</abstract><cop>Berlin</cop><pub>Springer</pub><pmid>12436334</pmid><doi>10.1007/s00125-002-0956-9</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adult Age of Onset Associated diseases and complications Bioavailability Biological and medical sciences Biological Availability Blood Glucose - metabolism Blood Specimen Collection - methods Cholesterol - blood Diabetes Diabetes Mellitus, Type 1 - blood Diabetes. Impaired glucose tolerance Electron Spin Resonance Spectroscopy Endocrine pancreas. Apud cells (diseases) Endocrinopathies Glycated Hemoglobin A - metabolism Glycosylation Hemoglobin Hemoglobins - metabolism Humans Hypotheses Kinetics Medical sciences Metabolism Metabolites Molecular weight Nitrates Nitrates - blood Nitric oxide Nitric Oxide - blood Nitric Oxide - metabolism Nitric Oxide - pharmacokinetics Nitrites - blood Oxidation Plasma Proteins Triglycerides - blood |
| title | Abnormal metabolic fate of nitric oxide in Type I diabetes mellitus |
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