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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.

ABSTRACT: 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?

SUBMITTER: Welsh P

PROVIDER: S-EPMC6445481 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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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.

Welsh Paul P Rankin Naomi N Li Qiang Q Mark Patrick B PB Würtz Peter P Ala-Korpela Mika M Marre Michel M Poulter Neil N Hamet Pavel P Chalmers John J Woodward Mark M Sattar Naveed N

Diabetologia 20180504 7

<h4>Aims/hypotheses</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 29728717

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Project description:Aims/hypothesisThis biomarker study aimed to quantify the association of essential and other plasma fatty acid biomarkers with macrovascular disease, microvascular disease and death in individuals with type 2 diabetes.MethodsA case-cohort study (N = 3576), including 654 macrovascular events, 341 microvascular events and 631 deaths during 5 years of (median) follow-up, was undertaken as a secondary analysis of the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation (ADVANCE) study (full details of the study design and primary endpoints of the ADVANCE trial and its case-cohort have been published previously). This current study considers new data: fatty acids measured from baseline plasma samples by proton NMR analysis. The fatty acids measured were n-3, docosahexaenoic acid (DHA), n-6, linoleic acid, and polyunsaturated, monounsaturated and saturated fatty acids. HRs were modelled per SD higher (percentage) fatty acid. C statistics and continuous net reclassification improvement were used to test the added value of fatty acids compared with traditional cardiovascular risk factors.ResultsAfter adjustment for traditional cardiovascular risk factors, an inverse association was observed for n-3 fatty acids and DHA with the risk of macrovascular events (HR [95% CI]: 0.87 [0.80, 0.95] and 0.88 [0.81, 0.96], respectively, per 1 SD higher percentage), and for n-3 fatty acids with the risk of death (HR 0.91 [95% CI 0.84, 0.99] per 1 SD higher percentage). Such associations were also evident when investigating absolute levels of fatty acids. There were no statistically significant associations between any fatty acids and microvascular disease after adjustment. However, there was limited improvement in the predictive ability of models when any fatty acid was added.Conclusions/interpretationPlasma n-3 fatty acids and DHA were found to be inversely associated with macrovascular disease, while n-3 fatty acids were also inversely associated with death. These results support the cardioprotective effects of n-3 fatty acids and DHA and further merit testing the role of high-dose supplementation with n-3 fatty acids in individuals with type 2 diabetes.Trial registrationClinicalTrials.gov NCT00145925. Graphical abstract.

Project description:ObjectiveIn obesity and type 2 diabetes, hyperglucagonaemia may be caused by elevated levels of glucagonotropic amino acids due to hepatic glucagon resistance at the level of amino acid turnover. Here, we investigated the effect of exogenous glucagon on circulating amino acids in obese and non-obese individuals with and without type 2 diabetes.DesignThis was a post hoc analysis in a glucagon infusion study performed in individuals with type 2 diabetes (n = 16) and in age, sex, and body mass index-matched control individuals without diabetes (n = 16). Each group comprised two subgroups of eight individuals with and without obesity, respectively.MethodsAll participants received a 1-h glucagon infusion (4 ng/kg/min) in the overnight fasted state. Plasma amino acid concentrations were measured with frequent intervals.ResultsCompared to the control subgroup without obesity, baseline total amino acid levels were elevated in the control subgroup with obesity and in the type 2 diabetes subgroup without obesity. In all subgroups, amino acid levels decreased by up to 20% in response to glucagon infusion, which resulted in high physiological steady-state glucagon levels (mean concentration: 74 pmol/L, 95% CI [68;79] pmol/L). Following correction for multiple testing, no intergroup differences in changes in amino acid levels reached significance.ConclusionObesity and type 2 diabetes status was associated with elevated fasting levels of total amino acids. The glucagon infusion decreased circulating amino acid levels similarly in all subgroups, without significant differences in the response to exogenous glucagon between individuals with and without obesity and type 2 diabetes.Significance statementThe hormone glucagon stimulates glucose production from the liver, which may promote hyperglycaemia if glucagon levels are abnormally elevated, as is often seen in type 2 diabetes and obesity. Glucagon levels are closely linked to, and influenced by, the levels of circulating amino acids. To further investigate this link, we measured amino acid levels in individuals with and without obesity and type 2 diabetes before and during an infusion of glucagon. We found that circulating amino acid levels were higher in type 2 diabetes and obesity, and that glucagon infusion decreased amino acid levels in both individuals with and without type 2 diabetes and obesity. The study adds novel information to the link between circulating levels of glucagon and amino acids.

Project description:BackgroundType 2 diabetes mellitus (T2DM) is a chronic, metabolic disorder in which concomitant insulin resistance and β-cell impairment lead to hyperglycemia, influenced by genetic and environmental factors. T2DM is associated with long-term complications that have contributed to the burden of morbidity and mortality worldwide. The objective of this manuscript is to conduct an Exome-Wide Association Study (EWAS) on T2DM Emirati individuals to improve our understanding on diabetes-related complications to improve early diagnostic methods and treatment strategies.MethodsThis cross-sectional study recruited 310 Emirati participants that were stratified according to their medically diagnosed diabetes-related complications: diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, and cardiovascular complications. The Illumina's Infinium Exome-24 array was used and 39,840 SNPs remained for analysis after quality control.FindingsThe analysis revealed the associations of various genes with each complication category: 1) diabetic retinopathy was associated to SHANK3 gene in locus 22q13.33 (SNP rs9616915; p=5.18 x10-4), ZSCAN5A gene in locus 19q13.43 (SNP rs7252603; p=7.55 x10-4), and DCP1B gene in locus 12p13.33 (SNPs rs715146, rs1044950, rs113147414, rs34730825; p=7.62 x10-4); 2) diabetic neuropathy was associated to ADH4 gene in locus 4q23 (SNP rs4148883; p=1.23 x10-4), SLC11A1 gene in locus 2q35 (SNP rs17235409; p=1.85 x10-4), and MATN4 gene in locus 20q13.12 (SNP rs2072788; p=2.68 x10-4); 3) diabetic nephropathy was associated to PPP1R3A gene in locus 7q31.1 (SNP rs1799999; p=1.91 x10-4), ZNF136 gene in locus 19p13.2 (SNP rs140861589; p=2.80 x10-4), and HSPA12B gene in locus 20p13 (SNP rs6076550; p=2.86 x10-4); and 4) cardiovascular complications was associated to PCNT gene in locus 21q22.3 (SNPs rs7279204, rs6518289, rs2839227, rs2839223; p=2.18 x10-4,3.04 x10-4,4.51 x10-4,5.22 x10-4 respectively), SEPT14 gene in locus 7p11.2 (SNP rs146350220; p=2.77 x10-4), and WDR73 gene in locus 15q25.2 (SNP rs72750868; p=4.47 x10-4).InterpretationWe have identified susceptibility loci associated with each category of T2DM-related complications in the Emirati population. Given that only 16% of the markers from the Illumina's Infinium Exome chip passed quality control assessment, this demonstrates that multiple variants were, either, monomorphic in the Arab population or were not genotyped due to the use of a Euro-centric EWAS array that limits the possibility of including targeted ethnic-specific SNPs. Our results suggest the alarming possibility that lack of representation in reference panels could inhibit discovery of functionally important loci associated to T2DM complications. Further effort must be conducted to improve the representation of diverse populations in genotyping and sequencing studies.

Project description:ImportanceSerum uric acid (SUA) level is associated with vascular dysfunction in Eurasian populations, but little is known about this association in individuals from sub-Saharan Africa, who have a high prevalence of both relatively high SUA levels and vascular dysfunction.ObjectivesTo assess the associations of SUA levels with macrovascular and kidney microvascular dysfunction in individuals of sub-Saharan African ancestry and evaluate potential factors that could mediate these associations.Design, setting, and participantsCross-sectional analyses of baseline data from the multicenter Research on Obesity and Diabetes Among African Migrants study, conducted from 2012 to 2015, were performed from January to March 2021. The population included Ghanaian individuals living in Ghana and Europe.ExposureAbnormal SUA levels.Main outcomes and measuresLogistic regression was used to examine the associations of SUA level quartiles with microvascular (albuminuria) and macrovascular (peripheral artery disease and coronary artery disease) dysfunction, with adjustments for age, sex, estimated glomerular filtration rate, site of residence, socioeconomic status, alcohol, smoking, diabetes, hypertension, waist-hip ratio, and total cholesterol level. Mediation analysis was performed to assess whether the association was via elevated blood pressure, hemoglobin A1c, and high-sensitivity C-reactive protein levels or via weight-hip ratio. The research questions were formulated after data collection.ResultsA total of 4919 Ghanaian individuals (3047 [61.9%] women) aged 25-75 years (mean [SD], 46.26 [11.08] years) were included. There was a significant positive association between SUA quartiles and albuminuria, but not coronary artery disease or peripheral artery disease, after adjustment for covariates. After full adjustment, individuals in the fourth SUA quartile had higher odds of albuminuria (adjusted odds ratio [aOR], 1.54; 95% CI, 1.07-2.21), but not peripheral artery disease (aOR, 1.35; 95% CI, 0.87-2.08) or coronary artery disease (aOR, 1.09; 95% CI, 0.77-1.55), compared with individuals in the first quartile. After full adjustment, systolic and diastolic blood pressure significantly mediated the association between SUA concentrations and albuminuria, accounting for 19.4% of the total association for systolic and 17.2% for diastolic blood pressure; hemoglobin A1c, high-sensitivity C-reactive protein, and waist-hip ratio did not mediate this association.Conclusions and relevanceIn this cross-sectional study among a sub-Saharan African population, elevated SUA levels were significantly associated with kidney microvascular dysfunction and mediated partly through elevated blood pressure. These findings suggest that individuals from sub-Saharan Africa with elevated SUA levels may benefit from periodic screening for kidney microvascular dysfunction to aid early detection or treatment.

Dataset Information

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

Publications

Circulating 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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