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Circulating amino acids and the risk of macrovascular, microvascular and mortality outcomes in individuals with type 2 diabetes: results from the ADVANCE trial

Aims/hypotheses We aimed to quantify the association of individual circulating amino acids with macrovascular disease, microvascular disease and all-cause mortality in individuals with type 2 diabetes. Methods We performed a case-cohort study ( N  = 3587), including 655 macrovascular events, 342 mic... Full description

Journal Title: Diabetologia 2018, Vol.61 (7), p.1581-1591
Main Author: Welsh, Paul
Other Authors: Rankin, Naomi , Li, Qiang , Mark, Patrick B , Würtz, Peter , Ala-Korpela, Mika , Marre, Michel , Poulter, Neil , Hamet, Pavel , Chalmers, John , Woodward, Mark , Sattar, Naveed
Format: Electronic Article Electronic Article
Language: English
Subjects:
NMR
Non
Publisher: Berlin/Heidelberg: Springer Berlin Heidelberg
ID: ISSN: 0012-186X
Link: https://www.ncbi.nlm.nih.gov/pubmed/29728717
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title: Circulating amino acids and the risk of macrovascular, microvascular and mortality outcomes in individuals with type 2 diabetes: results from the ADVANCE trial
format: Article
creator:
  • Welsh, Paul
  • Rankin, Naomi
  • Li, Qiang
  • Mark, Patrick B
  • Würtz, Peter
  • Ala-Korpela, Mika
  • Marre, Michel
  • Poulter, Neil
  • Hamet, Pavel
  • Chalmers, John
  • Woodward, Mark
  • Sattar, Naveed
subjects:
  • 1103 Clinical Sciences
  • 1114 Paediatrics And Reproductive Medicine
  • 1117 Public Health And Health Services
  • 3121 Internal medicine
  • Aged
  • Alanine
  • Amino acid
  • Amino acids
  • Amino Acids - blood
  • Article
  • atira
  • Biomarkers - blood
  • Creatinine
  • Diabetes
  • Diabetes complications
  • Diabetes mellitus
  • Diabetes mellitus (non-insulin dependent)
  • Diabetes Mellitus, Type 2 - blood
  • Diabetes Mellitus, Type 2 - diagnosis
  • Diabetes Mellitus, Type 2 - mortality
  • Diabetic Nephropathies - blood
  • Diabetic Nephropathies - diagnosis
  • Diabetic Nephropathies - mortality
  • Diabetic Retinopathy - blood
  • Diabetic Retinopathy - diagnosis
  • Diabetic Retinopathy - mortality
  • Endocrinology & Metabolism
  • Epidermal growth factor receptors
  • Female
  • Glutamine
  • Gov't
  • Health risk assessment
  • Histidine
  • Human Physiology
  • Humans
  • Internal Medicine
  • Isoleucine
  • Journal Article
  • Leucine
  • Male
  • Medicine
  • Medicine & Public Health
  • Metabolic Diseases
  • Metabolomics
  • Microvasculature
  • Middle Aged
  • Mortality
  • Multicenter Study
  • Nephropathy
  • NMR
  • Non
  • Nuclear magnetic resonance
  • omized Controlled Trial
  • Phenylalanine
  • Predictive Value of Tests
  • Prognosis
  • pubmedpublicationtype
  • pure
  • Reclassification
  • Research Support
  • researchoutput
  • Retinopathy
  • Risk Assessment
  • Risk Factors
  • Time Factors
  • Type 2 diabetes
  • Tyrosine
  • Valine
  • Vascular diseases
ispartof: Diabetologia, 2018, Vol.61 (7), p.1581-1591
description: Aims/hypotheses We aimed to quantify the association of individual circulating amino acids with macrovascular disease, microvascular disease and all-cause mortality in individuals with type 2 diabetes. Methods We performed a case-cohort study ( N  = 3587), including 655 macrovascular events, 342 microvascular events (new or worsening nephropathy or retinopathy) and 632 all-cause mortality events during follow-up, in a secondary analysis of the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study. For this study, phenylalanine, isoleucine, glutamine, leucine, alanine, tyrosine, histidine and valine were measured in stored plasma samples by proton NMR metabolomics. Hazard ratios were modelled per SD increase in each amino acid. Results In models investigating associations and potential mechanisms, after adjusting for age, sex and randomised treatment, phenylalanine was positively, and histidine inversely, associated with macrovascular disease risk. These associations were attenuated to the null on further adjustment for extended classical risk factors (including eGFR and urinary albumin/creatinine ratio). After adjustment for extended classical risk factors, higher tyrosine and alanine levels were associated with decreased risk of microvascular disease (HR 0.78; 95% CI 0.67, 0.91 and HR 0.86; 95% CI 0.76, 0.98, respectively). Higher leucine (HR 0.79; 95% CI 0.69, 0.90), histidine (HR 0.89; 95% CI 0.81, 0.99) and valine (HR 0.79; 95% CI 0.70, 0.88) levels were associated with lower risk of mortality. Investigating the predictive ability of amino acids, addition of all amino acids to a risk score modestly improved classification of participants for macrovascular (continuous net reclassification index [NRI] +35.5%, p  
language: eng
source:
identifier: ISSN: 0012-186X
fulltext: no_fulltext
issn:
  • 0012-186X
  • 1432-0428
url: Link


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titleCirculating amino acids and the risk of macrovascular, microvascular and mortality outcomes in individuals with type 2 diabetes: results from the ADVANCE trial
creatorWelsh, Paul ; Rankin, Naomi ; Li, Qiang ; Mark, Patrick B ; Würtz, Peter ; Ala-Korpela, Mika ; Marre, Michel ; Poulter, Neil ; Hamet, Pavel ; Chalmers, John ; Woodward, Mark ; Sattar, Naveed
creatorcontribWelsh, Paul ; Rankin, Naomi ; Li, Qiang ; Mark, Patrick B ; Würtz, Peter ; Ala-Korpela, Mika ; Marre, Michel ; Poulter, Neil ; Hamet, Pavel ; Chalmers, John ; Woodward, Mark ; Sattar, Naveed
descriptionAims/hypotheses We aimed to quantify the association of individual circulating amino acids with macrovascular disease, microvascular disease and all-cause mortality in individuals with type 2 diabetes. Methods We performed a case-cohort study ( N  = 3587), including 655 macrovascular events, 342 microvascular events (new or worsening nephropathy or retinopathy) and 632 all-cause mortality events during follow-up, in a secondary analysis of the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study. For this study, phenylalanine, isoleucine, glutamine, leucine, alanine, tyrosine, histidine and valine were measured in stored plasma samples by proton NMR metabolomics. Hazard ratios were modelled per SD increase in each amino acid. Results In models investigating associations and potential mechanisms, after adjusting for age, sex and randomised treatment, phenylalanine was positively, and histidine inversely, associated with macrovascular disease risk. These associations were attenuated to the null on further adjustment for extended classical risk factors (including eGFR and urinary albumin/creatinine ratio). After adjustment for extended classical risk factors, higher tyrosine and alanine levels were associated with decreased risk of microvascular disease (HR 0.78; 95% CI 0.67, 0.91 and HR 0.86; 95% CI 0.76, 0.98, respectively). Higher leucine (HR 0.79; 95% CI 0.69, 0.90), histidine (HR 0.89; 95% CI 0.81, 0.99) and valine (HR 0.79; 95% CI 0.70, 0.88) levels were associated with lower risk of mortality. Investigating the predictive ability of amino acids, addition of all amino acids to a risk score modestly improved classification of participants for macrovascular (continuous net reclassification index [NRI] +35.5%, p  < 0.001) and microvascular events (continuous NRI +14.4%, p  = 0.012). Conclusions/interpretation We report distinct associations between circulating amino acids and risk of different major complications of diabetes. Low tyrosine appears to be a marker of microvascular risk in individuals with type 2 diabetes independently of fundamental markers of kidney function.
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subject1103 Clinical Sciences ; 1114 Paediatrics And Reproductive Medicine ; 1117 Public Health And Health Services ; 3121 Internal medicine ; Aged ; Alanine ; Amino acid ; Amino acids ; Amino Acids - blood ; Article ; atira ; Biomarkers - blood ; Creatinine ; Diabetes ; Diabetes complications ; Diabetes mellitus ; Diabetes mellitus (non-insulin dependent) ; Diabetes Mellitus, Type 2 - blood ; Diabetes Mellitus, Type 2 - diagnosis ; Diabetes Mellitus, Type 2 - mortality ; Diabetic Nephropathies - blood ; Diabetic Nephropathies - diagnosis ; Diabetic Nephropathies - mortality ; Diabetic Retinopathy - blood ; Diabetic Retinopathy - diagnosis ; Diabetic Retinopathy - mortality ; Endocrinology & Metabolism ; Epidermal growth factor receptors ; Female ; Glutamine ; Gov't ; Health risk assessment ; Histidine ; Human Physiology ; Humans ; Internal Medicine ; Isoleucine ; Journal Article ; Leucine ; Male ; Medicine ; Medicine & Public Health ; Metabolic Diseases ; Metabolomics ; Microvasculature ; Middle Aged ; Mortality ; Multicenter Study ; Nephropathy ; NMR ; Non ; Nuclear magnetic resonance ; omized Controlled Trial ; Phenylalanine ; Predictive Value of Tests ; Prognosis ; pubmedpublicationtype ; pure ; Reclassification ; Research Support ; researchoutput ; Retinopathy ; Risk Assessment ; Risk Factors ; Time Factors ; Type 2 diabetes ; Tyrosine ; Valine ; Vascular diseases
ispartofDiabetologia, 2018, Vol.61 (7), p.1581-1591
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8Hamet, Pavel
9Chalmers, John
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11Sattar, Naveed
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0Circulating amino acids and the risk of macrovascular, microvascular and mortality outcomes in individuals with type 2 diabetes: results from the ADVANCE trial
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descriptionAims/hypotheses We aimed to quantify the association of individual circulating amino acids with macrovascular disease, microvascular disease and all-cause mortality in individuals with type 2 diabetes. Methods We performed a case-cohort study ( N  = 3587), including 655 macrovascular events, 342 microvascular events (new or worsening nephropathy or retinopathy) and 632 all-cause mortality events during follow-up, in a secondary analysis of the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study. For this study, phenylalanine, isoleucine, glutamine, leucine, alanine, tyrosine, histidine and valine were measured in stored plasma samples by proton NMR metabolomics. Hazard ratios were modelled per SD increase in each amino acid. Results In models investigating associations and potential mechanisms, after adjusting for age, sex and randomised treatment, phenylalanine was positively, and histidine inversely, associated with macrovascular disease risk. These associations were attenuated to the null on further adjustment for extended classical risk factors (including eGFR and urinary albumin/creatinine ratio). After adjustment for extended classical risk factors, higher tyrosine and alanine levels were associated with decreased risk of microvascular disease (HR 0.78; 95% CI 0.67, 0.91 and HR 0.86; 95% CI 0.76, 0.98, respectively). Higher leucine (HR 0.79; 95% CI 0.69, 0.90), histidine (HR 0.89; 95% CI 0.81, 0.99) and valine (HR 0.79; 95% CI 0.70, 0.88) levels were associated with lower risk of mortality. Investigating the predictive ability of amino acids, addition of all amino acids to a risk score modestly improved classification of participants for macrovascular (continuous net reclassification index [NRI] +35.5%, p  < 0.001) and microvascular events (continuous NRI +14.4%, p  = 0.012). Conclusions/interpretation We report distinct associations between circulating amino acids and risk of different major complications of diabetes. Low tyrosine appears to be a marker of microvascular risk in individuals with type 2 diabetes independently of fundamental markers of kidney function.
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21Diabetic Nephropathies - diagnosis
22Diabetic Nephropathies - mortality
23Diabetic Retinopathy - blood
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25Diabetic Retinopathy - mortality
26Endocrinology & Metabolism
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32Histidine
33Human Physiology
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46Mortality
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titleCirculating amino acids and the risk of macrovascular, microvascular and mortality outcomes in individuals with type 2 diabetes: results from the ADVANCE trial
authorWelsh, Paul ; Rankin, Naomi ; Li, Qiang ; Mark, Patrick B ; Würtz, Peter ; Ala-Korpela, Mika ; Marre, Michel ; Poulter, Neil ; Hamet, Pavel ; Chalmers, John ; Woodward, Mark ; Sattar, Naveed
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20Diabetic Nephropathies - blood
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62Risk Assessment
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abstractAims/hypotheses We aimed to quantify the association of individual circulating amino acids with macrovascular disease, microvascular disease and all-cause mortality in individuals with type 2 diabetes. Methods We performed a case-cohort study ( N  = 3587), including 655 macrovascular events, 342 microvascular events (new or worsening nephropathy or retinopathy) and 632 all-cause mortality events during follow-up, in a secondary analysis of the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study. For this study, phenylalanine, isoleucine, glutamine, leucine, alanine, tyrosine, histidine and valine were measured in stored plasma samples by proton NMR metabolomics. Hazard ratios were modelled per SD increase in each amino acid. Results In models investigating associations and potential mechanisms, after adjusting for age, sex and randomised treatment, phenylalanine was positively, and histidine inversely, associated with macrovascular disease risk. These associations were attenuated to the null on further adjustment for extended classical risk factors (including eGFR and urinary albumin/creatinine ratio). After adjustment for extended classical risk factors, higher tyrosine and alanine levels were associated with decreased risk of microvascular disease (HR 0.78; 95% CI 0.67, 0.91 and HR 0.86; 95% CI 0.76, 0.98, respectively). Higher leucine (HR 0.79; 95% CI 0.69, 0.90), histidine (HR 0.89; 95% CI 0.81, 0.99) and valine (HR 0.79; 95% CI 0.70, 0.88) levels were associated with lower risk of mortality. Investigating the predictive ability of amino acids, addition of all amino acids to a risk score modestly improved classification of participants for macrovascular (continuous net reclassification index [NRI] +35.5%, p  < 0.001) and microvascular events (continuous NRI +14.4%, p  = 0.012). Conclusions/interpretation We report distinct associations between circulating amino acids and risk of different major complications of diabetes. Low tyrosine appears to be a marker of microvascular risk in individuals with type 2 diabetes independently of fundamental markers of kidney function.
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pmid29728717
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