Welsh et al. Circulating amino acids and the risk of macrovascular, microvascular and mortality outcomes in individuals with type 2 diabetes: results from the ADVANCE trial. Diabetologia. 2018. DOI: https://doi.org/10.1007/s00125-018-4619-x
The global burden of type 2 diabetes affects over 420 million people worldwide, resulting in a range of health complications and increased risk of premature death.(1) Type 2 diabetes complications include macrovascular (e.g. myocardial infarction, stroke and cardiovascular death) and microvascular diseases (e.g. kidney and eye diseases). These health complications have a severe impact on patient quality of life, along with reducing employee productivity and causing a substantial economic burden. Metabolic profiling techniques are now helping researchers to unravel the molecular mechanisms underpinning these complications of type 2 diabetes. Many epidemiological studies have reported associations between circulating levels of amino acids with insulin resistance and risk for onset of type 2 diabetes. However, only few large studies have examined the link between amino acids with micro- and macro-vascular complications among diabetes patients.
In order to address this, Welsh and colleagues set out to establish if altered amino acid profiles differentially associate with type 2 diabetes complications. The team conducted a case-cohort study (N=3587), including 655 macrovascular events, 342 microvascular events and 632 all-cause mortality events during follow-up. Measurements of eight circulating amino acids were analyzed for individual associations with macrovascular disease, microvascular disease and all-cause mortality. In addition, joint effects of these amino acids were evaluated with a risk score.
Main results included phenylalanine positively associating with macrovascular disease risk and all-cause mortality. Whilst these association were not strong enough to still be significant after adjustment for classical risk factors (including eGFR and urinary albumin/creatinine ratio), the findings are in line with previously reported links between phenylalanine, all-cause mortality (Fischer, PLoS Med 2014) and cardiovascular disease risk (Würtz, Circ 2015).(2, 3) Notably, increased concentrations of a number of amino acids were found to associate with a decreased risk for diabetes complications. For example, elevated histidine levels were associated with lower risk for macrovascular disease and elevated levels of leucine and valine were associated with reduced risk of all-cause mortality. A particularly strong association was reported between increased tyrosine and alanine levels, and a decreased risk of microvascular disease events. These associations remained significant even after adjusting for classical risk factors.
The role of tyrosine and other amino acids in type 2 diabetes development and complications is not well understood. However, this is the first time that its potential as a marker for microvascular disease risk has been reported and shown to be independent of fundamental markers of kidney function. Prior studies have found that metformin (first line treatment of type 2 diabetes) lowers tyrosine levels, highlighting a need for further studies to clarify its involvement.(4)
Although this study did not identify significant associations between branched-chain amino acids and macrovascular events, it showed distinctly different association patterns between amino acid levels and risk of different major complications of type 2 diabetes, further suggesting their specific involvement in a number of diabetes-related disease mechanisms. In addition, it was found that combining these amino acids to a risk score improved the classification of participants for macrovascular and microvascular disease events.(5)
In this study, Nightingale’s blood biomarker analysis service was used to quantify a range of metabolic measures (including amino acids) for 3587 individuals in the ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation). Nightingale's assay has been successfully used in a wide range of research applications and has featured in over 100 peer-reviewed studies.
1. World Health Organization. Global Report on Diabetes. 2016. http://www.who.int/diabetes/global-report/en/
2. Fischer et al. Biomarker profiling by nuclear magnetic resonance spectroscopy for the prediction of all- cause mortality: an observational study of 17,345 persons. PLoS Medicine. 2014;11:e1001606
3. Würtz et al. Metabolite Profiling and Cardiovascular Event Risk: A Prospective Study of Three Population-Based Cohorts. Circulation. 2015;131(9):774
4. Preiss et al. Effect of metformin therapy on circulating amino acids in a randomized trial: the CAMERA study. Diabetic Medicine. 2016;33:1569
5. Welsh et al. Circulating amino acids and the risk of macrovascular, microvascular and mortality outcomes in individuals with type 2 diabetes: results from the ADVANCE trial. Diabetologia. 2018. Doi: 10.1007/s00125-018-4619-x