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Genetic differences in amino acid metabolism are linked to a higher risk of diabetes

Date:
November 29, 2016
Source:
Medical Research Council
Summary:
A new study has identified the five genetic variants associated with higher levels of the branched-chain amino acids isoleucine, leucine and valine. The researchers also found that these genetic variants were associated with an increased risk of type 2 diabetes.
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A study published today in the journal PLOS Medicine has identified the five genetic variants associated with higher levels of the branched-chain amino acids isoleucine, leucine and valine. The researchers also found that these genetic variants were associated with an increased risk of type 2 diabetes.

The researchers, led by the Medical Research Council (MRC) Epidemiology Unit at the University of Cambridge, used large-scale genetic data together with detailed measurements of the branched-chain amino acids and their metabolites in the blood of more than 16,000 volunteers*.

Branched-chain amino acids have fundamental roles in human metabolism and are building blocks of proteins. Unlike some of the other 20 amino acids, they cannot be made by the human body. This means that their levels depend entirely on external sources, from food sources or dietary supplements, and the ability of our body to metabolise them.

To date, while higher circulating levels of branched-chain amino acids have been found to be associated with type 2 diabetes, no study has been able to establish whether this link is causal. This is important, because if the relationship is found to be causal, reducing dietary intake or altering the metabolism of these amino acids could help to prevent diabetes, an increasingly common and serious disease.

The researchers studied over 10 million genetic variants in more than 16,000 men and women and discovered five regions of the human genome with genetic differences that are associated with higher levels of circulating branched-chain amino acids.

They then found that in 300,000 individuals**, including 40,000 diabetes patients, those carrying the genetic differences associated with higher levels of branched-chain amino acids were also found to be at increased risk of type 2 diabetes, providing strong evidence of a causal link.

PPM1K, the gene found to be most strongly associated with levels of all three amino acids and also with a higher risk of diabetes, encodes a known regulator of the key step in the breakdown of branched-chain amino acids. This suggests that an impaired breakdown of these amino acids may put individuals at higher risk of type 2 diabetes. Intervening on this pathway may reduce diabetes risk.

"Our results suggest that treatment strategies which target metabolism of branched-chain amino acids could help to reduce the risk of diabetes, and we already know which molecules target this metabolic pathway," says Dr Claudia Langenberg from the MRC Epidemiology Unit at the University of Cambridge.

Clinical trials will now need to be carried out to establish if drugs that target the breakdown of branched-chain amino acids can reduce the risks of type 2 diabetes.

Notes to editors:

*16,000 volunteers were from the Fenland Study & meta-analysis of KORA and TwinsUK studies.

** 300,000 individuals were from the Diabetes Genetics Replication and Meta-analysis, EPIC_InterAct, GoDART and UK Biobank


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Materials provided by Medical Research Council. Note: Content may be edited for style and length.


Journal Reference:

  1. Luca A. Lotta, Robert A. Scott, Stephen J. Sharp, Stephen Burgess, Jian’an Luan, Therese Tillin, Amand F. Schmidt, Fumiaki Imamura, Isobel D. Stewart, John R. B. Perry, Luke Marney, Albert Koulman, Edward D. Karoly, Nita G. Forouhi, Rasmus J. O. Sjögren, Erik Näslund, Juleen R. Zierath, Anna Krook, David B. Savage, Julian L. Griffin, Nishi Chaturvedi, Aroon D. Hingorani, Kay-Tee Khaw, Inês Barroso, Mark I. McCarthy, Stephen O’Rahilly, Nicholas J. Wareham, Claudia Langenberg. Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis. PLOS Medicine, 2016; 13 (11): e1002179 DOI: 10.1371/journal.pmed.1002179

Cite This Page:

Medical Research Council. "Genetic differences in amino acid metabolism are linked to a higher risk of diabetes." ScienceDaily. ScienceDaily, 29 November 2016. <www.sciencedaily.com/releases/2016/11/161121174710.htm>.
Medical Research Council. (2016, November 29). Genetic differences in amino acid metabolism are linked to a higher risk of diabetes. ScienceDaily. Retrieved May 26, 2017 from www.sciencedaily.com/releases/2016/11/161121174710.htm
Medical Research Council. "Genetic differences in amino acid metabolism are linked to a higher risk of diabetes." ScienceDaily. www.sciencedaily.com/releases/2016/11/161121174710.htm (accessed May 26, 2017).

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