Levels of Five Metabolites Linked to Type 2 Diabetes Risk

Measuring these amino acids could identify at-risk healthy individuals 10 years before disease symptoms.

Measuring the levels of certain small molecules in the blood may help identify individuals at elevated risk of developing type 2 diabetes a decade before symptoms appear, according to a research team led by Massachusetts General Hospital (MGH). They say that levels of five amino acids not only indicated increased diabetes risk in a general population but could also differentiate, among individuals with traditional risk factors such as obesity, those most likely to actually develop diabetes.

“These findings could provide insight into metabolic pathways that are altered very early in the process leading to diabetes,” says lead author Thomas Wang, M.D., of the MGH Cardiovascular Research Center and Division of Cardiology. The paper was published in Nature Medicine.

Some earlier studies had found elevated levels of certain amino acids in individuals who are obese or have insulin resistance. But scientists had not examined whether levels of these or other metabolites predicted the future development of diabetes in currently healthy individuals.

The MGH group began with an analysis of data from the Framingham Offspring Study. It follows a group of adult children of participants in the original Framingham Heart Study. Out of 2,400 study participants who entered the study in 1991 and 1995, about 200 developed type 2 diabetes during the following 12 years.

Using baseline blood samples, the investigators measured levels of 61 metabolites in 189 participants who later developed diabetes and 189 others—matched for age, sex, and diabetes risk factors such as obesity and fasting glucose levels—who remained diabetes free.

They found that elevations in five amino acids—isoleucine, leucine, valine, tyrosine, and phenylalanine—were significantly associated with the later development of type 2 diabetes. The association of these five amino acids with future diabetes development was replicated in 326 participants from the Malmo Diet and Cancer Study.

The MGH team then found that measuring combinations of several metabolites, as opposed to a single amino acid, improved risk prediction. Overall, in individuals closely matched for traditional risk factors for type 2 diabetes, those with the highest levels of the three most predictive amino acids had a four to five times greater risk of developing diabetes than did those with the lowest levels.

Some of the amino acids pinpointed by the MGH-led team had previously been found to be elevated in smaller studies in individuals with obesity or insulin resistance. Other research has also suggested that they may directly affect glucose regulation.

“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,” says Robert Gerszten, M.D., director of clinical and translational research for the MGH Heart Center, and the paper’s senior author.

“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.”