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Five Metabolite Levels May Improve Risk Prediction for Diabetes

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Researchers at Massachusetts General Hospital (MGH) recently identified five amino acids whose levels indicated an increased diabetes risk in a general population. Moreover, the biomarkers could differentiate, among individuals with traditional risk factors such as obesity, those most likely to actually develop diabetes. The findings are published in the journal Nature Medicine.

According to lead author Thomas Wang, MD, of the MGH Cardiovascular Research Center (CVRC) and Division of Cardiology:

These findings could provide insight into metabolic pathways that are altered very early in the process leading to diabetes. They also raise the possibility that, in selected individuals, these measurements could identify those at highest risk of developing diabetes so that early preventive measures could be instituted.

Researchers analyzed data from the Framingham Offspring Study, which follows a group of adult children of participants in the original Framingham Heart Study. Just over 8% of 2,400 study participants who entered the study between 1991 and 1995 developed type 2 diabetes during the subsequent 12 years. Using baseline blood samples, investigators measured levels of 61 metabolites in 189 participants who later developed diabetes and compared them to metabolite measurements from 189 others matched for age, sex and diabetes risk factors (e.g. obesity and fasting glucose levels) but who remained diabetes free.

The scientists found that increased levels of five amino acids – isoleucine, leucine, valine, tyrosine and phenylalanine – were significantly associated with the later development of type 2 diabetes. Several of the biomarkers have previously been found to be elevated in smaller studies in individuals with obesity or insulin resistance; other evidence has suggested they may directly affect glucose regulation.

Measurement of a three amino acid combination – isoleucine, tyrosine and phenylalanine – significantly predicted future diabetes with a more than five-fold increased risk for those in the top quartile for the three amino acids at baseline, compared with those in the bottom quartile.

The association between levels of the five amino acids with future diabetes development was then replicated in a separate cohort of 326 participants (163 cases, 163 controls) from the Malmo Diet and Cancer Study, a study in which participants were followed up for a similar period to that of participants in the Framingham Offspring Study.

Four amino acids – leucine, valine, tyrosine, and phenylalanine – were all significantly associated with Type 2 diabetes risk in the replication cohort.

The three amino acid combination – isoleucine, tyrosine and phenylalanine – association was also replicated in the Malmo Diet and Cancer study cohort. Scientists found that those in the highest quartile for the three metabolites at baseline were at a four-fold higher risk for incident diabetes than those in the lowest quartile.

Robert Gerszten, MD, director of Clinical and Translational Research for the MGH Heart Center and the paper’s senior author said:

Several groups have suggested that these amino acids can aberrantly activate an important metabolic pathway involved in cellular growth or can somehow poison the mitochondria that provide cellular energy. From a clinical perspective, we need to see if these markers, which we found using data from only about 1,000 individuals, do identify truly high-risk individuals who should be triaged to early preventive treatment and intensive lifestyle interventions. Additional basic investigations can reveal if these metabolites play a role in the process leading to diabetes and if there are ways we can stop the damage.

Study: Metabolite profiles and the risk of developing diabetes

Source: Massachusetts General Hospital