New research from the US suggests it may be possible to predict people at high risk of developing type 2 diabetes up to ten years before symptoms appear by measuring levels of certain molecules in their blood.
A team led by researchers from Massachusetts General Hospital (MGH) found that higher levels of five metabolites not only showed increased risk of diabetes in a general population but also determined, among people with traditional risk factors like obesity, which were most likely actually to develop diabetes.
A report of their findings appeared in an advance online issue of Nature Medicine on 20 March.
Lead author Dr Thomas Wang, of the MGH Cardiovascular Research Center (CVRC) and Division of Cardiology in Boston, Massachusetts, told the press that:
“These findings could provide insight into metabolic pathways that are altered very early in the process leading to diabetes.”
He said this could mean that individuals most likely to be at risk could be spotted early and start preventive measures.
Life in all organisms is possible because of metabolism: a series of chemical reactions that do useful things like break down food to provide energy and supply raw materials like proteins and nucleic acids for making and repairing cells.
These cellular processes produce byproducts, called metabolites, small molecules that enter the bloodstream, and which researchers, using new and emerging technologies, are getting better and better at measuring.
The metabolism of glucose is a case in point. We need steady levels of glucose for cells to function and have the right amount of energy. This regulation relies on the signalling hormone insulin. When that goes wrong, diabetes occurs. But the process does not go awry overnight, it develops over time, and what Wang and colleagues have found is that it may be possible to predict this up to a decade in advance by measuring the levels of 5 metabolites, in this case, the amino acids isoleucine, leucine, valine, tyrosine and phenylalanine.
Previous studies have found higher levels of certain amino acids in people who are obese or have insulin resistance, often a precursor to diabetes, but this is the first study to predict future development of diabetes in currently healthy people, by studying these and other metabolites.
For the first stage of the study, Wang and colleagues analyzed data from the Framingham Offspring Study, which followed a group of adult children of participants from the original Framingham Heart Study.
Of the 2,400 participants who entered the offspring study between 1991 and 1995, some 200 developed type 2 diabetes over the ensuing 12 years.
The participants gave blood samples when they entered the study (baseline).
The researchers measured the baseline levels of 61 metabolites in two groups of participants: 189 who developed diabetes and another 189 who did not develop diabetes but were matched for age, gender, and a range of diabetes risk factors such as obesity and fasting glucose levels.
They found 5 amino acids were significantly linked to development of diabetes. Some of them were the same as those found in previous studies that showed they were elevated in people with obesity or insulin resistance, and there is evidence that these may also affect the regulation of glucose.
In the next stage of the study, the researchers replicated the results of the same five amino acids with 326 participants from the Malmö Diet and Cancer Study.
They also showed that it was using a cluster of amino acids, as opposed to studying them individually, that improved the prediction of risk.
In an analysis where they ranked individuals according to their blood levels of three amino acids, the researchers found a more than fivefold higher risk among those in the top 25% of highest levels compared to those in the bottom 25%.
Wang and colleagues concluded that:
“These findings underscore the potential key role of amino acid metabolism early in the pathogenesis of diabetes and suggest that amino acid profiles could aid in diabetes risk assessment.”
Speculating on how these amino acids might be contributing to the development of diabetes, senior author Dr Robert Gerszten, director of Clinical and Translational Research for the MGH Heart Center, 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.”
He explained that from a clinical perspective, we now need to find out if these markers, which came from investigations that only involved about 1,000 people, really do identify truly high-risk individuals, who can then be screened and directed toward preventive treatment and lifestyle changes.
“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,” he added.
“Metabolite profiles and the risk of developing diabetes.”
Thomas J Wang, Martin G Larson, Ramachandran S Vasan, Susan Cheng, Eugene P Rhee, Elizabeth McCabe, Gregory D Lewis, Caroline S Fox, Paul F Jacques, Céline Fernandez, Christopher J O’Donnell, Stephen A Carr, Vamsi K Mootha, Jose C Florez, Amanda Souza, Olle Melander, Clary B Clish & Robert E Gerszten.
DOI:10.1038/nm.2307
Additional source: Massachusetts General Hospital (press release 20 Mar 2011).
Written by: Catharine Paddock, PhD