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.

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 < 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.

SUBMITTER: Welsh P

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

REPOSITORIES: biostudies-literature

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Publications

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.

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Project description:BackgroundPhysical activity (PA) is considered beneficial for lowering cardiovascular risks following type 2 diabetes mellitus (T2DM) and prediabetes, but existing evidence relies mainly on self-reported measurements. We aimed to describe the intensity-specific dose-response associations of PA and sedentary behavior (SB) with macrovascular and microvascular events among individuals with T2DM and prediabetes.MethodsThis study included 11,474 individuals with T2DM and prediabetes from the UK Biobank. PA, including total PA, moderate-to-vigorous intensity PA (MVPA), light-intensity PA (LPA), and SB, were measured by accelerometers over 7 days. MVPA was categorized according to the American Diabetes Association guideline-recommended level (at least 150 min/week), and total PA, LPA, and SB were grouped by tertiles. The outcomes were incidences of macrovascular events, microvascular events, heart failure (HF), and their combination (composite events). The events were ascertained using the International Classification of Diseases-10 (ICD-10) codes on the hospital or death records.ResultsDuring a median follow-up of 6.8 years, 1680 cases were documented, including 969 macrovascular events, 839 microvascular events, and 284 incidents of HF. Accelerometer-measured PA, irrespective of intensity, was inversely associated with the risk of composite events and each outcome in the dose-response patterns. Regarding categorized PA, engagement in total PA (high vs. low) was associated with decreased risk of macrovascular events (hazard ratio (HR) = 0.80; 95% confidence interval (95%CI): 0.67-0.95), microvascular events (HR = 0.76; 95%CI: 0.63-0.93), and HF (HR = 0.46; 95%CI: 0.32-0.66). Adherence to MVPA, but not LPA, above the guideline-recommended level (at least 150 min/week) was associated with reduced risk of macrovascular events (HR = 0.80; 95%CI: 0.68-0.95), microvascular events (HR = 0.76; 95%CI: 0.63-0.92), and HF (HR = 0.65; 95%CI: 0.46-0.92). The minimum dose of MVPA for lowering the risk of composite events was approximately 59.0 min/week. More time spent in SB was associated with an increased risk of composite events (high vs. low, HR = 1.17; 95%CI: 1.02-1.35) and HF (high vs. low, HR = 1.54; 95%CI: 1.09-2.20). Replacement of 30 min of SB (HR = 0.73; 95%CI: 0.65-0.81) and LPA (HR = 0.74; 95%CI: 0.66-0.83) with MVPA dramatically reduced the risk of composite events.ConclusionAdherence to a higher amount of accelerometer-measured PA, especially MVPA at least 59 min/week, is associated with reduced risks of macrovascular and microvascular events among individuals with T2DM and prediabetes. Replacement of SB and LPA with MVPA helped lower the risk of diabetic vascular events.

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.

Aims/hypotheses

Methods

Results

Conclusions/interpretation

Publications

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

Similar Datasets

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