TY - JOUR
T1 - Circulating amino acids and the risk of macrovascular, microvascular and mortality outcomes in individuals with type 2 diabetes
T2 - results from the ADVANCE trial
AU - Welsh, Paul
AU - Rankin, Naomi
AU - Li, Qiang
AU - Mark, Patrick B.
AU - Würtz, Peter
AU - Ala-Korpela, Mika
AU - Marre, Michel
AU - Poulter, Neil
AU - Hamet, Pavel
AU - Chalmers, John
AU - Woodward, Mark
AU - Sattar, Naveed
PY - 2018/7/1
Y1 - 2018/7/1
N2 - 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 < 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.
AB - 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 < 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.
KW - Amino acid
KW - Diabetes complications
KW - Metabolomics
KW - Risk factors
KW - Type 2 diabetes
UR - http://www.scopus.com/inward/record.url?scp=85046424326&partnerID=8YFLogxK
UR - http://purl.org/au-research/grants/NHMRC/211086
UR - http://purl.org/au-research/grants/NHMRC/358395
UR - http://purl.org/au-research/grants/NHMRC/571281
U2 - 10.1007/s00125-018-4619-x
DO - 10.1007/s00125-018-4619-x
M3 - Article
C2 - 29728717
AN - SCOPUS:85046424326
SN - 0012-186X
VL - 61
SP - 1581
EP - 1591
JO - Diabetologia
JF - Diabetologia
IS - 7
ER -